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  • 1995-1999  (2,348)
  • 1980-1984
  • 1995  (2,348)
  • Life and Medical Sciences  (2,263)
  • pharmacokinetics
  • Nuclear reactions
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Years
  • 1995-1999  (2,348)
  • 1980-1984
Year
Keywords
  • 1
    Electronic Resource
    Electronic Resource
    Pharmacokinetic, insulinotropic, and glucagonostatic properties of GLP-1 [7–36 amide] after subcutaneous injection in healthy volunteers. Dose-response-relationships (1995)
    Springer
    Diabetologia 38 (1995), S. 720-725 
    Details
    ISSN: 1432-0428
    Keywords: Key words GLP-1 [7 ; 36 amide] ; incretin ; insulin ; glucagon ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Intravenous infusions of glucagon-like peptide 1 (GLP-1) [7–36 amide] are glucose-dependently insulinotropic and glucagonostatic and normalize plasma glucose concentrations in non-insulin-dependent diabetic patients. It was the aim of this study to investigate whether subcutaneous GLP-1 [7–36 amide] also has an influence on insulin and glucagon secretion, and which doses are required for significant effects. Therefore, eight healthy volunteers (24 ± 2 years, body mass index [BMI] 21.9 ± 2.3 kg/m2) were studied in the fasting state on five occasions in randomized order. Placebo (0.9 % NaCl with 1 % human serum albumin) or GLP-1 [7–36 amide] in doses of 0.15, 0.5, 1.5 or 4.5 nmol/kg body weight (volume 1 ml or, at the highest dose, 2 ml) was administered subcutaneously. An intravenous glucose bolus (0.33 g/kg body weight) was injected 30 min later. Blood was drawn for the measurement of glucose, insulin, C-peptide, GLP-1 [7–36 amide], and glucagon using specific radioimmunoassays. There were dose-related increments in GLP-1 [7–36 amide] concentrations (p 〈 0.0001). However, basal values were reached again after 90–120 min. Before glucose administration, insulin (p 〈 0.0001) and C-peptide (p 〈 0.0004) increased, whereas glucagon (p = 0.0018) and glucose (p 〈 0.0001) decreased in a dose-dependent manner. After glucose stimulation, integrated increments in insulin (p = 0.0007) and C-peptide (p = 0.02) were augmented and kG-values increased (p 〈 0.0001) in a dose-related fashion. The extent of reactive hypoglycaemia was related to the GLP-1 [7–36 amide] dose. With the highest GLP-1 [7–36 amide] dose, at the time of peak plasma concentrations, most volunteers felt unwell, and nausea and vomiting were observed in four subjects. In conclusion, subcutaneous GLP-1 [7–36 amide] is also able to stimulate insulin and inhibit glucagon secretion, thereby altering glucose assimilation. However, with unmodified GLP-1 [7–36 amide], the duration of action is short, and with high doses side effects are common. [Diabetologia (1995) 38: 720–725]
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00401846
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  • 2
    Electronic Resource
    Electronic Resource
    Dosing of thioTEPA for myeloablative therapy (1995)
    Springer
    Cancer chemotherapy and pharmacology 37 (1995), S. 155-160 
    Details
    ISSN: 1432-0843
    Keywords: ThioTEPA ; bone marrow transplantation ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract High-dose thioTEPA is used frequently in myeloablative regimens for marrow transplantation, but the need for dose adjustments in obese patients has not been explored. We determined the pharmacokinetics of thioTEPA and its metabolite TEPA during first-dose infusion of thioTEPA 150–250 mg/m2 given daily for 3 days in combination with busulfan and cyclophosphamide, and evaluated the results for correlations with toxicity and dosing strategies. The study included 15 adults undergoing marrow transplantation for hematologic malignancies. Plasma samples were obtained at various times over a 24-h period, and concentrations of thio TEPA and TEPA were measured by gas chromatography. At 22–24 h after initiation of a 4-h infusion, the mean ±SE plasma concentration of thioTEPA was 124±63 ng/ml, while that of TEPA was 235±69 ng/ml. For CFU-GM and BFU-E growth in vitro, the IC50s of thioTEPA were 83 ng/ml and 16 ng/ml, respectively, and the IC50s of TEPA were 141 ng/ml and 47 ng/ml, respectively. Using a twocompartment model, the mean thioTEPA Vc was 47.4±4.7 l/m2, t1/2α 19±5 min,t 1/2β 3.7±0.5 h, and plasma clearance 302±21 ml/min per m2. The mean AUCs were 6.9–16.2 mg h/l for thioTEPA and 8.9–21.2 mg h/l for TEPA, while the mean peak concentrations were 0.95–2.08 μg/ml for thioTEPA and 0.88–1.90 μg/ml for TEPA. There was a significant association of grades 2–4 maximum regimen-related toxicity (RRT) with TEPA peak 〉1.75 μg/ml and with combined thioTEPA and TEPA AUC 〉30 mgh/l (5/6 vs 0/9,P=0.01 for both comparisons), suggesting that drug exposure was an important determinant of toxicity and, potentially, efficacy. ThioTEPA Vc correlated best with adjusted body weight (r=0.74,P=0.0015). In an evaluation of 74 adults receiving thioTEPA 750 mg/m2 in combination with busulfan and cyclophosphamide, the maximum RRT for patients at ideal weight was significantly greater than that for obese patients dosed on ideal weight (mean RRT grade 1.7 vs 1.0,P=0.004) but did not differ from the maximum RRT for obese adults dosed on actual or adjusted weights. We recommend that for obese patients thioTEPA be dosed on adjusted body weight. Measurements at time-points after 24 h are needed to determine when thioTEPA and TEPA concentrations are below myelosuppressive levels and safe for marrow infusion.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00685643
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  • 3
    Electronic Resource
    Electronic Resource
    Methotrexate in juvenile rheumatoid arthritis (1995)
    Springer
    European journal of clinical pharmacology 47 (1995), S. 507-511 
    Details
    ISSN: 1432-1041
    Keywords: Methotrexate ; Juvenile rheumatoid arthritis ; pharmacokinetics ; age dependence
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Children with juvenile rheumatoid arthritis (JRA) have been reported to require higher doses (per kg body weight) of methotrexate (MTX) than adults with rheumatoid arthritis to control their disease. The purpose of the present study was to characterise the plasma pharmacokinetics of MTX and its major metabolite, 7-hydroxymethotrexate (7-OHMTX) in children, and to compare the results with those previously obtained in adults. Thirteen patients (age 5–16 y) with JRA (median disease duration 5.5 y) were studied after once weekly oral administration of MTX (median 0.21 mg·kg−1). The analytical method was sufficiently sensitive to permit determination of plasma and urinary concentrations of MTX and 7-OHMTX during the entire dose interval in most of the patients. The dose normalized area under the plasma concentration versus time-curve (AUC) of MTX increased with the age of the children and was lower than previously found in adults. The dose normalized AUC of 7-OHMTX was not dependent on age. No correlation was found between the AUCs of MTX and 7-OHMTX. The results suggest that the age-dependence of the pharmacokinetics of MTX might explain the observation that at least some children require higher doses of MTX than adults to obtain a sufficient therapeutic effect.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00193703
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  • 4
    Electronic Resource
    Electronic Resource
    Antipyrine disposition in obesity: evidence for negligible effect of obesity on hepatic oxidative metabolism (1995)
    Springer
    European journal of clinical pharmacology 47 (1995), S. 525-530 
    Details
    ISSN: 1432-1041
    Keywords: Antipyrine disposition ; Obesity ; pharmacokinetics ; oxidative metabolism ; weight reduction
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Following an overnight fast and 2 days of abstention from caffeine, a single 1.0-g oral dose of antipyrine was administered to 20 obese but otherwise healthy subjects (group A) and 11 healthy volunteers (group B). Weight, Body Mass Index (BMI) and % of Ideal Body Weight (IBW) were significantly greater in the obese than in the lean group. (Mean 110.4 vs 62.7 kg; 38.5 vs 22.3 kg · m−2 and 181vs 106 % respectively). In a subgroup of 6 obese subjects (group C) antipyrine was given again 11.3 months later after a 29.8 kg mean weight loss. Antipyrine apparent volume of distribution (V) and elimination half-life (t 1/2) were significantly greater in the obese than in the lean group (V 49.9 vs 34.3 l respectively; t 1/2 15.5 vs 12.0 h respectively), but its clearance rate (CLo) values were similar. V corrected for total body weight was significantly reduced in group A than in group B (0.45 vs 0.55 l · kg−1 respectively). Stratified comparison of antipyrine pharmacokinetics between obese and lean subjects according to age, gender and smoking habits did not alter the overall results. In group C, weight reduction was associated with a significant decrease in antipyrine V (from 51.8 to 47.5 l) and t 1/2 (from 15.1 to 12.7 h), and a non-significant increase in antipyrine CLo. We conclude that in severely obese subjects, antipyrine total V is mildly increased but V corrected for total body weight is significantly decreased. In addition, obesity is associated with a slight prolongation of antipyrine t 1/2 whereas its CLo is unaltered. These findings may indicate that obesity, even in its extreme form, has a negligible effect on the oxidative metabolic capacity of the liver.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00193706
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  • 5
    Electronic Resource
    Electronic Resource
    Oral bioavailability of CHF1194, an inclusion complex of piroxicam and β-cyclodextrin, in healthy subjects under single dose and steady-state conditions (1995)
    Springer
    European journal of clinical pharmacology 47 (1995), S. 531-536 
    Details
    ISSN: 1432-1041
    Keywords: Piroxicam ; β-Cyclodextrin ; pharmacokinetics ; healthy volunteers ; multiple dose ; adverse event
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract CHF1194 is an inclusion complex of β-cyclodextrin with the nonsteroidal anti-inflammatory drug piroxicam. In man, β-cyclodextrin acts as a carrier of piroxicam. As the inclusion complex of piroxicam-β-cyclodextrin is wettable and more water soluble, the absorption rate of the drug is increased whilst its other pharmacokinetic characteristics remain unchanged. The aim of the present study in 12 healthy subjects was to compare the oral bioavailability of 20 mg piroxicam in a CHF1194 tablet and a plain piroxicam capsule after a single dose and after two weeks of once daily administration, and also to assess the plasma levels and urinary excretion of β-cyclodextrin after CHF1194 administration. The two treatments were administered in cross-over fashion, separated by a wash-out period of three weeks. Piroxicam, 5′-hydroxypiroxicam and β-cyclodextrin were monitored in plasma and urine for 120 h after the first and last doses. Clinical tolerance was excellent and no adverse event occurred during either phase of the study. The extent of absorption of piroxicam from the CHF1194 tablet after the single dose was equivalent to that after the plain piroxicam capsule, within confidence limits of less than 80–125%. After repeated dosing, CHF1194 yielded the same steady-state systemic concentrations of piroxicam and 5′-hydroxypiroxicam as the reference capsule, and similar excretion pattern of the metabolite. After both single and multiple dosing, piroxicam was absorbed more rapidly after CHF1194, an expected consequence of the complexation of piroxicam with β-cyclodextrin. This may be of therapeutic interest as it might accelerate the onset of pain relief. The pharmacokinetics of piroxicam was linear after the doses used here, suggesting that long term treatment with CHF1194 should not require any change in dosing regimen. Even after 14 days of repeated administration of CHF1194, β-cyclodextrin could not be detected in plasma or urine, suggesting that in man the unchanged oligosaccharide was absorbed to a very small extent.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00193707
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  • 6
    Electronic Resource
    Electronic Resource
    Furosemide disposition in patients on CAPD (1995)
    Springer
    European journal of clinical pharmacology 48 (1995), S. 385-390 
    Details
    ISSN: 1432-1041
    Keywords: Furosemide ; Dialysis ; continuous ambulatory peritoneal ; drug disposition ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Single doses of oral and intravenous furosemide were given to 8 healthy male volunteers (40 mg) and 11 patients with renal failure maintained on continuous ambulatory peritoneal dialysis (CAPD) (80 mg). In the volunteers, absorption was variable. Only one half of the intravenous dose and one third of the oral dose was available for renal pharmacological action as judged by the urinary recovery. In the patients, absorption was also variable and was markedly delayed (t max 128 vs 90 min) but more complete (bioavailability 70.1 vs 53.6%). The differences between the two groups were not significant, however (95% C.I.: -90 to 30 and -40.4 to 7.5 respectively). The mean elimination half-life was significantly longer in the patients following both the oral (228 vs 65.1 min) and intravenous dose (195 vs 60.3 min). The total body clearance of furosemide in the volunteers was 138 ml·min−1 and this was much lower in the CAPD patients (61.9 ml·min−1) in whom the renal clearance was minimal. The peritoneal clearance of furosemide was negligible. Although there were trends indicating differences in absorption between the two groups, the significant differences in furosemide disposition observed in CAPD patients were due to renal failure.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00194955
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  • 7
    Electronic Resource
    Electronic Resource
    Effects of altitude (4300 M) on the pharmacokinetics of caffeine and cardio-green in humans (1995)
    Springer
    European journal of clinical pharmacology 48 (1995), S. 167-170 
    Details
    ISSN: 1432-1041
    Keywords: Caffeine ; Cardio-green ; Indocyanine Green ; altitude ; metabolism ; pharmacokinetics ; hypoxia
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract The effects of chronic exposure to high altitude on the pharmacokinetics of caffeine and cardiogreen (ICG) were examined in eight healthy males (23–35 y) at sea level (SEA) and following 16 days residence at 4300 m (ALT). ICG (0.5 mg · kg−1) was administered as an intravenous bolus and caffeine (4 mg · kg−1) in an orally ingested solution. The concentration of ICG, caffeine, and the primary metabolites of caffeine (MET) were determined in serial blood samples and their pharmacokinetics computed. In comparison to SEA, ALT resulted in a significant decrease in the caffeine half-life (t1/2, 4.7 vs 6.7 h) and area under the curve (2.5 vs 3.7 g · 1−1 · min−1), and increased clearance (117 vs 86 ml · min−1 · 70 kg−1). In ALT the area under the curve of ICG significantly decreased (85 vs 207 mg · 1−1 · min−1) and the volume of distribution and clearance increased (5.2 vs 2.41 and 532 vs 234 ml · min−1 respectively) compared to SEA. There was a significant increase in the AUC ratio of MET to caffeine indicating that either metabolite formation or elimination was increased in ALT. These results demonstrate that in humans, chronic exposure to 4300 m results in the modification of the pharmacokinetics of caffeine and ICG.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00192744
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  • 8
    Electronic Resource
    Electronic Resource
    Pharmacokinetics and bioavailability of a sustained-release diltiazem formulation (Mono-Tildiem LP 300 mg) after repeated administration in healthy volunteers (1995)
    Springer
    European journal of clinical pharmacology 48 (1995), S. 259-264 
    Details
    ISSN: 1432-1041
    Keywords: Diltiazem ; sustained-release formulation ; pharmacokinetics ; bioavailability ; bioequivalence
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract The usual dosage regimen of diltiazem (Tildiem) is 60 mg 3–4 times a day. A sustained-release formulation has been developed (Mono-Tildiem LP 300 mg) in order to allow a single daily administration. Two repeated dosing studies were performed in healthy volunteers. The absolute bioavailability of sustained-release diltiazem LP 300 mg was investigated using concomitant i.v. administration of 13C-labelled drug: absolute bioavailability of the “once a day” formulation was 35%. The second study compared sustained-release diltiazem LP 300 mg with the standard formulation of diltiazem. The results showed that the diltiazem plasma concentrations obtained after the LP formulation remained stable between 2 and 14 h after administration and were compatible with a once a day administration. Relative bioavailability of sustained-release diltiazem LP 300 mg was 79.3% compared with diltiazem. Therefore, a unitary dose of sustained-release diltiazem LP 300 mg was chosen as the dose equivalent to the daily dose administered with the standard diltiazem formulation.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00198308
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  • 9
    Electronic Resource
    Electronic Resource
    Disposition of lorazepam in diabetes: differences between patients treated with beef/pork and human insulins (1995)
    Springer
    European journal of clinical pharmacology 48 (1995), S. 253-258 
    Details
    ISSN: 1432-1041
    Keywords: Diabetes ; Human insulin ; Lorazepam ; pharmacokinetics ; glucuronidation ; enterohepatic circulation ; animal insulin
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract The pharmacokinetics of lorazepam was examined in 10 male patients with insulin-dependent diabetes mellitus before and following treatment with neomycin and cholestyramine. Neomycin and cholestyramine were given in an attempt to block the enterohepatic circulation of lorazepam and so to permit an in vivo estimate of hepatic glucuronidation. The volume of distribution and clearance of free lorazepam in diabetic patients were not significantly different from the corresponding estimates in 14 normal controls. Neomycin and cholestyramine increased the clearance of lorazepam by 63% consistent with their effect in non-diabetic controls. However, patients on beef/pork insulin exhibited a greater than normal increase on this interupting regimen (125%), and had a significantly greater neomycin/cholestyramine cycling-interrupted clearance of lorazepam than either normal controls or patients on human insulin (15.4 vs. 6.96 and 7.87 ml·min−1·kg−1). The clearance was correlated positively and significantly with HbA1c and glycated proteins (fructosamine), but only in patients on human insulin. Thus, the pharmacokinetics of lorazepam was not altered in patients with insulin-dependent diabetes mellitus. However, it is possible that there are differences in the rate and extent of hepatic glucuronidation and enterohepatic circulation of lorazepam between patients treated with beef/pork and human insulins and between diabetics treated with beef/pork insulin and non-diabetic controls.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00198307
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  • 10
    Electronic Resource
    Electronic Resource
    Pharmacokinetics of 5-aminosalicylic acid from controlled-release capsules in man (1995)
    Springer
    European journal of clinical pharmacology 48 (1995), S. 273-277 
    Details
    ISSN: 1432-1041
    Keywords: Mesalamine ; 5-aminosalicylic acid ; controlled release capsules ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract One gram single dose of Pentasa controlled-release capsules was administered to 24 healthy volunteers under fasting condition. Mean plasma 5-aminosalicylic acid (5-ASA) and acetyl 5-ASA concentrations peaked at 0.53 μg · ml−1 and 1.33 μg · ml−1 from 3 to 4 hours following dosing, respectively. The half-lives of both compounds could not be determined as absorption of 5-ASA was continuous throughout the gastrointestinal tract. An average of 29.4% (CV: 27%) of the dose was excreted in the urine primarily as acetyl 5-ASA. Up to 91.1% of the dose was released from the capsules. Forty percent of the dose (CV: 40%) was eliminated in the feces, with 8.9% of the dose remained as formulation bounded 5-ASA, indicating that controlled-release capsules continue to release drug throughout the GI tract. 5-ASA contributed 46.7% of the salicylates eliminated in the feces and acetyl 5-ASA accounted for the balance. Controlled-release capsules produced three times more total salicylates and 10 times more total and free 5-ASA in the feces than did 5-ASA suspension. Thus, while lower systemic levels of salicylates were absorbed, greater therapeutic quantities of 5-ASA were available in the bowel.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00198311
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  • 11
    Electronic Resource
    Electronic Resource
    Pharmacokinetics of thiopental after single and multiple intravenous doses in critical care patients (1995)
    Springer
    European journal of clinical pharmacology 49 (1995), S. 127-137 
    Details
    ISSN: 1432-1041
    Keywords: Thiopental ; Pharmacokinetic modelling ; pharmacokinetics ; single dose ; multiple dosing ; neurosurgical patients ; variability
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Thiopental was administered to neurosurgical patients for cerebral protection and its pharmacokinetic parameters were determined after a single bolus of 540, 1000 or 1500 mg (3 subjects) or after multiple doses of 250 mg (5 subjects) and 500 mg (2 subjects) every two hours for up to 7 days. The data were analysed by a two- or three- compartment model and linear kinetics. After a single IV bolus, the mean initial volume of distribution (V1) was 0.4811·kg−1, and the steady-state volume of distribution (Vss) was 2.16 1·kg−1. The distribution (t1/2α) and elimination (t1/2β) half-lives were 0.590 and 5.89 h, respectively, and the mean residence time (MRT) was 7.44 h. The clearance was 5.41 ml·min−1·kg−1. With repeated injections, the pharmacokinetic parameters for each patient were estimated taking into account all administered doses and blood samples, which were taken whenever possible daily at steady state and after the last dose. The variability observed in the pharmacokinetic parameters of thiopental reflected by the coefficient of variation (CV%) was wide but was of similar magnitude within patients (CVintra) as it was between patients (CVinter). The steady-state trough plasma concentration (Cmin obs) ranged from 4.8 to 30 mg·1−1 (mean 16.0 mg·1−1 and median 14.3 mg·1−1). Peak concentrations (Cmax obs) ranged from 8.35 to 45 mg·1−1 (25.4 mg·1−1, and median 23.3 mg·1−1). The values of V1 and Vss were similar to those obtained after a single dose. For V1, the mean was 0.333 1·kg−1. The mean Vss was 2.68 1·kg−1, with a CVintra of 12.6 to 56% and a CVinter of 13.2%. A shorter distribution half-life t1/2α was noted on multiple dosing; the mean value was 0.122 h. The elimination half-life t1/2β and the mean residence time became longer due to a decrease in clearance. For t1/2β the mean value was 16.3 h. The mean MRT was 21.9 h, CVintra 9.19 to 48.5%, and the CVinter 35.3%. The mean clearance was 2.16 ml·min−1·kg−1, CVintra 7.28 to 25.5%, and the CVinter 20.4%. This value is 50% lower than after a single dose. Identification of the kinetic parameters of thiopental allows simulation of the effects of doses on subsequent plasma levels and will permit a priori prediction of day to day adjustment of drug dosage.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00192371
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  • 12
    Electronic Resource
    Electronic Resource
    Limitations of the maximum entropy principle in devising drug input rate (1995)
    Springer
    European journal of clinical pharmacology 49 (1995), S. 139-143 
    Details
    ISSN: 1432-1041
    Keywords: Intestinal absorption ; Amoxicillin ; pharmacokinetics ; maximum entropy ; input rate
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract A computer program applying the principle of maximum entropy to the analysis of drug absorption rate has been developed. Plasma concentrations of amoxicillin obtained after oral and intravenous dosing have been analysed, together with simulated data corresponding to a complex input. Amoxicillin absorption rates devised by the program were similar to those obtained by a standard deconvolution method, although they were displayed as an almost continuous profile. However, improbable fluctuations were obtained with some data sets and the fraction absorbed was underestimated by 13%. With the simulated data, the maximum entropy program did not provide a better solution than the standard deconvolution procedure, and it was sensitive to the addition of random error and to the number of samples. The maximum entropy principle, as implemented in our computer program, may not have a better performance than standard deconvolution procedures, especially in human experiments where the number of blood samples is usually limited.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00192372
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  • 13
    Electronic Resource
    Electronic Resource
    Single dose pharmacokinetics of sumatriptan in healthy volunteers (1995)
    Springer
    European journal of clinical pharmacology 47 (1995), S. 543-548 
    Details
    ISSN: 1432-1041
    Keywords: Sumatriptan ; pharmacokinetics ; single dose ; bioavailability ; dose proportionality ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Sumatriptan is classified as a vascular 5HT1 receptor agonist and is effective in the acute treatment of migraine and cluster headache. Sumatriptan is available as an injection for subcutaneous administration and as a tablet for oral administration. The pharmacokinetics of sumatriptan differ depending on the route of administration. The mean subcutaneous bioavilability is 96% compared to 14% for the oral tablet. The lower bioavailability following oral administration is due mainly to presystemic metabolism. The inter-subject variability in plasma sumatriptan concentrations is greater following oral administration and a faster rate of absorption of drug into the systemic circulation is achieved following subcutaneous dosing. The pharmacokinetics of sumatriptan are linear up to a subcutaneous dose of 16 mg. Following oral dosing up to 400 mg, the pharmacokinetics are also linear, with the exception of rate of absorption, as indicated by a dose dependent increase in time to peak concentration. Sumatriptan is a highly cleared compound that is eliminated from the body primarily by metabolism to the pharmacologically inactive indoleacetic acid analogue. Both sumatriptan and its metabolite are excreted in the urine. Although the renal clearance of sumatriptan is only 20% of the total clearance, it exceeds the glomerular filtration rate, indicating that sumatriptan undergoes active renal tubular secretion. Sumatriptan has a large apparent volume of distribution (170 1) and an elimination half-life of 2 h. Oral doses of sumatriptan were administered as a solution of dispersible tablets and subcutaneous dosing was by injection into the arm. In clinical practice, sumatriptan is administered as a film coated tablet or by subcutaneous injection into the thigh.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00193709
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  • 14
    Electronic Resource
    Electronic Resource
    The pharmacokinetics of granisetron, a 5-HT3 antagonist in healthy young and elderly volunteers (1995)
    Springer
    European journal of clinical pharmacology 48 (1995), S. 519-520 
    Details
    ISSN: 1432-1041
    Keywords: Granisetron ; pharmacokinetics ; elderly ; tolerance
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00194344
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  • 15
    Electronic Resource
    Electronic Resource
    Pharmacokinetics and pharmacodynamics of a single dose of recombinant human growth hormone after subcutaneous administration by jet-injection: comparison with conventional needle-injection (1995)
    Springer
    European journal of clinical pharmacology 49 (1995), S. 69-72 
    Details
    ISSN: 1432-1041
    Keywords: Growth hormone ; Jet-injection ; pharmacokinetics ; pharmacodynamics ; Somatomedin C ; free fatty acids
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract The pharmacokinetics and pharmacodynamics of recombinant human growth hormone (rhGH) were studied after a single subcutaneous dose given by jet-injection, and have been compared with the results obtained after conventional needle-injection. Twelve healthy male volunteers completed an open label, randomised, two-way crossover study, with a 7-day washout period between the two single sc doses. Pharmacokinetic parameters were derived from rhGH concentrations in blood samples collected regularly over 24 h after dosing on Day 1 of each period. To investigate the pharmacodynamics, additional samples were taken for the analysis of somatomedin C (IGF-I) and free fatty acids (FFA). A higher and earlier Cmax was found after jet-injection (ratio (%) jet-injected/needle-injected 124; 90%-confidence interval 108 – 142). The AUC0−∞ for rhGH were similar (ratio (%) jet-injected/needle-injected 98; 90%-confidence interval 93 – 103). Both treatments were associated with a significant and similar rise in IGF-I. Both administrations of rhGH were associated with identical rhythmical changes in FFA. The study indicates that jet-injected and needle-injected rhGH are bioequivalent with respect to the amount absorbed. The criterion for bioequivalence is not met for the rate of absorption. It is unlikely that the latter finding will influence the pharmacodynamics of rhGH, since bioequipotency was established for the effect on IGF-I generation. Jet-injection was safe in use and was generally well tolerated.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00192361
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  • 16
    Electronic Resource
    Electronic Resource
    Effects of cimetidine on pharmacokinetics and pharmacodynamics of losartan, an AT1-selective non-peptide angiotensin II receptor antagonist (1995)
    Springer
    European journal of clinical pharmacology 49 (1995), S. 115-119 
    Details
    ISSN: 1432-1041
    Keywords: Losartan ; Cimetidine ; pharmacokinetics ; plasma renin activity
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract This was a 2-period randomized, crossover study in 8 healthy males to determine the effects of cimetidine (400 mg q.i.d. for 6 days) on the pharmacokinetics and pharmacodynamic effects of the angiotensin II receptor antagonist, losartan (100 mg). Cimetidine increased the AUC for losartan 18% without affecting the AUC for E-3174, the active metabolite of losartan. The increase in plasma renin activity following losartan was not affected by cimetidine (maximum mean increases 12.6 and 12.1 ng Ang I·ml−1·h−1 without and with cimetidine, respectively). These results indicate that cimetidine does not appear to alter the pharmacokinetics or pharmacodynamics of losartan to a clinically significant extent.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00192369
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  • 17
    Electronic Resource
    Electronic Resource
    Lack of relationship between quinidine pharmacokinetics and the sparteine oxidation polymorphism (1995)
    Springer
    European journal of clinical pharmacology 48 (1995), S. 501-504 
    Details
    ISSN: 1432-1041
    Keywords: Quinidine ; CYP2D6 ; Sparteine oxidation polymorphism ; (3S)-3OH-quinidine ; quinidine-N-oxide ; dihydroquinidine ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Quinidine is a very potent inhibitor of CYP2D6, but the role of the enzyme in the biotransformation of quinidine has only been investigated in a single in vitro study and in two small in vivo experiments, with contradictory results. The present investigation was designed to present definite evaluation of whether quinidine is metabolised by CYP2D6. Eight poor metabolizers (PM) and 8 extensive metabolizers (EM) of sparteine each took one oral dose of 200 mg quinidine. In the EM, the total clearance, the clearance via 3-hydroxylation and the clearance via N-oxidation, were 33, 3.7 and 0.23 l·h−1, respectively. In the PM, the corresponding values were 29, 3.1 and 0.18 l·h−1, respectively. There were no statistically significant differences between EM and PM in any of these pharmacokinetic parameters. It is concluded that CYP2D6 is not an important enzyme for the oxidation of quinidine.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00194341
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  • 18
    Electronic Resource
    Electronic Resource
    Single-dose pharmacokinetics of nefazodone in healthy young and elderly subjects and in subjects with renal or hepatic impairment (1995)
    Springer
    European journal of clinical pharmacology 49 (1995), S. 221-228 
    Details
    ISSN: 1432-1041
    Keywords: Nefazodone ; Geriatric assessment ; Hepatic cirrhosis ; Renal impairment ; pharmacokinetics ; antidepressive agents
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract The single-dose pharmacokinetics of nefazodone (NEF) and its metabolites hydroxynefazodone (HO-NEF) and m-chlorophenylpiperazine (mCPP) were examined in 12 healthy younger subjects ≤55 years of age (YNG), 12 elderly subjects ≥65 years of age (ELD), 12 patients with biopsy proven hepatic cirrhosis (HEP) and 12 patients with moderate renal impairment (REN), ClCR 20–60 ml·min−1. The study was of parallel group design, with each of the four subject groups receiving escalating single oral doses of 50, 100 and 200 mg of nefazodone at 1 week intervals. Serial blood samples for pharmacokinetic analysis were collected for 48 h following each dose and plasma samples were assayed for NEF, HO-NEF and mCPP by a validated HPLC method. Single oral doses up to 200 mg of nefazodone were well tolerated by all subjects. Maximum plasma levels of NEF and HO-NEF were generally attained within 1 h after administration of nefazodone. HO-NEF and mCPP plasma levels were about 1/3 and 〈1/10 those of NEF, respectively. There were no apparent gender-related pharmacokinetic differences in any group of subjects. NEF and HO-NEF pharmacokinetics were dose dependent in all four subject groups; a superproportional increase in AUC and an increase in t1/2 with increasing dose was obtained, indicative of nonlinear pharmacokinetics. Relative to normal subjects, elderly and cirrhotic subjects exhibited increased systemic exposure to NEF and HO-NEF, as reflected by AUC, at all doses of nefazodone; subjects with moderate renal impairment did not. Elderly and cirrhotic patients may require lower doses of NEF to achieve and maintain therapeutic effectiveness.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00192383
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  • 19
    Electronic Resource
    Electronic Resource
    Steady-state pharmacokinetics of nefazodone in subjects with normal and impaired renal function (1995)
    Springer
    European journal of clinical pharmacology 49 (1995), S. 229-235 
    Details
    ISSN: 1432-1041
    Keywords: Nefazodone ; Renal impairment ; pharmacokinetics ; antidepressive agents
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract The steady-state pharmacokinetics of nefazodone (NEF) and its metabolites hydroxynefazodone (HO-NEF) and m-chlorophenylpiperazine (mCPP) were compared in subjects with normal and impaired renal function. Patients: The Study was of parallel group design which included 7 subjects with normal (NOR) renal function, CLCR≥72 ml·min−1·1.73 m−2, 6 with moderate (MOD) renal impairment, CLCR 31–60 ml·min−1·1.73 m−2 and 9 with severe (SEV) renal impairment, CLCR≤30 ml·min−1·1.73 m−2. Subjects in each renal function group received a 100-mg oral dose of nefazodone hydrochloride BID for 7 days and a single morning dose on day 8. Starting 48 h after the last 100-mg dose, 200-mg doses were administered on a similar schedule to 3, 4 and 3 subjects from each renal function group (NOR, MOD and SEV, respectively). Single trough blood samples just prior to each morning dose (Cmin) and serial samples after the dose on day 8 were obtained at each dose level for pharmacokinetic analysis. Plasma samples were assayed by a specific HPLC method for NEF, HO-NEF and mCPP. The CMIN data indicated that steady state was attained by the third day of BID administration of both the 100- and 200-mg doses of nefazodone, regardless of degree of renal function. Both NEF and HO-NEF attained steady-state Cmax within 2 h after administration of nefazodone; tmax for mCPP was less defined and more delayed. HO-NEF and mCPP plasma levels were about 1/3 and 〈1/10 those of NEF, respectively, regardless of the status of renal function. Steady-state systemic exposure of NEF and HO-NEF, as reflected by AUC and Cmax, and elimination t1/2 values did not differ significantly among renal function groups. Conclusion: The study results suggest that dose adjustments may not be necessary, but nefazodone should be used with caution in the presence of severe renal impairment.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00192384
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  • 20
    Electronic Resource
    Electronic Resource
    Relationship of changes in felodipine pharmacokinetics to haemodynamics during chronic oral treatment of congestive heart failure patients (1995)
    Springer
    European journal of clinical pharmacology 49 (1995), S. 203-210 
    Details
    ISSN: 1432-1041
    Keywords: Felodipine ; pharmacokinetics ; haemodynamics ; congestive heart failure
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract In congestive heart failure patients the kinetics of felodipine, a dihydropyridine calcium antagonist, show interpatient differences after acute i.v. administration that disappear after 8 weeks oral treatment with a change in kinetics in the patients with the largest clearances (CL) and the smallest volumes of distribution (V SS). Pharmacokinetic and haemodynamic data were combined to construct a haemodynamic-pharmacokinetic model. This model shows that the differences between the patients in i.v. pharmacokinetics are consistent with a difference in plasma flow distribution between liver and poorly perfused tissues. In patients in whom kinetics changed, felodipine treatment is supposed to cause a redistribution of flow from liver to peripheral tissues, accompanied by a decreased work load of the heart and a larger increase in VO2max during therapy than in the other patients, whose workload increased. This suggests a better therapeutic response in the patients whose kinetics changed. As change in kinetics is related to felodipine CL and CL to liver plasma flow, felodipine CL or even indocyanine CL might be predictive for the therapeutic effect of felodipine.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00192380
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  • 21
    Electronic Resource
    Electronic Resource
    The tolerability, pharmacokinetics and lack of effect on plasma cholesterol of 447C88, an AcylCoA:Cholesterol Acyl Transferase (ACAT) inhibitor with low bioavailability, in healthy volunteers (1995)
    Springer
    European journal of clinical pharmacology 49 (1995), S. 243-249 
    Details
    ISSN: 1432-1041
    Keywords: Cholesterol acyltransferase ; Hypocholesterolaemic ; 447C88 ; volunteers ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract 447C88 (N-Heptyl-N′-(2,4 difluoro-4-6-(2(-4-(2,2 dimethylpropyl)phenyl)ethyl)phenyl)urea) is an inhibitor of human microsomal AcylCoA:Cholesterol acyltransferase (ACAT) with an IC50 of 10.2 ng·ml−1 (23 nM). It is poorly absorbed but 5 mg·kg−1·day−1 completely abolishes the rise in plasma cholesterol in cholesterol-fed rats. In this study, twelve healthy, male volunteers received single, oral doses of 25, 50, 100, 200, 400 and 800 mg of 447C88 (n+8) or placebo (n+4) with food in a double-blind study with at least a week between occasions. The 400 mg dose was repeated after an overnight fast. Subsequently, fourteen different volunteers received a single 200 mg dose of 447C88 (n+8) or placebo (n+6) with food and, a week later, the same dose twice daily for 10 days; all doses were given with food. All doses were well tolerated with no significant changes in vital signs, full blood counts or plasma biochemical profiles. Plasma concentrations of 447C88 were unquantifiable after the fasting dose and low after all other doses. Mean Cmax and AUC were 1.8 ng·ml−1 and 9.0 ng·ml−1·h after 200 mg rising to 5.4 ng·ml−1 and 23.8 ng·ml−1·h respectively after 800 mg; t1/2 was 1.3 to 5.2 h. After 10 days dosing, plasma 447C88 concentrations were higher in the evening than the morning probably due to administration of the evening dose with more food. There were no significant changes in plasma triglcerides or total, LDL- or HDL-cholesterol after dosing with 447C88.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00192386
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  • 22
    Electronic Resource
    Electronic Resource
    Whole-blood pharmacokinetics and metabolic effects of the topical carbonic anhydrase inhibitor dorzolamide (1995)
    Springer
    European journal of clinical pharmacology 47 (1995), S. 453-460 
    Details
    ISSN: 1432-1041
    Keywords: Dorzolamide ; Glaucoma ; carbonic anhydrase ; pharmacokinetics ; renal effects
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Following a single-dose, open-label, pilot pharmacokinetic study in six subjects, the systemic pharmacokinetics and metabolic effects of dorzolamide after topical ocular administration were investigated in a double-blind, randomised, placebo-controlled study in 12 healthy volunteers. The subjects received a controlled diet on the 5 days before treatment initiation and throughout the study. For 14 days, a bilateral q.i.d. regimen of 3% dorzolamide, consisting of approximately 7.7 μg per day (21.3 μmol) dorzolamide hydrochloride, or placebo was given. Blood and urine electrolytes and acid-base profiles were measured 1 day prior to treatment and on days 1, 7 and 14 of treatment, and 24-h urine samples were collected daily. Topically applied dorzolamide was slowly taken up in erythrocytes and eliminated with a half life of approximately 120 days. Compared to the pre-study values, no significant treatment effect was observed in either the daily profiles or the 14-day cumulative sodium, potassium and citrate excretions. Two other volunteers given acetazolamide (125 mg q.i.d.) and assessed with the identical set of observations demonstrated marked metabolic changes. In spite of the prolonged and marked inhibition of carbonic anhydrase in red blood cells by dorzolamide, clinically significant metabolic and renal effects were not observed. The ocular tolerability profile was acceptable to all subjects.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00196861
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  • 23
    Electronic Resource
    Electronic Resource
    Elimination of amrinone during continuous veno-venous haemofiltration after cardiac surgery (1995)
    Springer
    European journal of clinical pharmacology 48 (1995), S. 57-59 
    Details
    ISSN: 1432-1041
    Keywords: Amrinone ; continuous veno-venous haemofiltration ; drug monitoring ; pharmacokinetics ; low cardiac output syndrom ; elimination ; renal failure
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract We studied the elimination of amrinone during continuous veno-venous haemofiltration (CVVHF) in three anuric patients after cardiac surgery. The patients had developed low cardiac output followed by acute prerenal failure. Plasma amrinone levels measured by HPLC were fitted to a two-compartment model. We found significant amrinone clearance, with a mean sieving coefficient (S) of 0.44%, which correlates with the protein-unbound, pharmacologically effective fraction of amrinone. The AUC of the arterial plasma concentration-time curve was decreased by 49.8%. All pharmacokinetic parameters showed wide interindividual variation. To ensure the therapeutic effect of amrinone and to avoid toxic adverse effects monitoring of plasma amrinone levels is necessary.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00202173
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  • 24
    Electronic Resource
    Electronic Resource
    Paracetamol disposition in Thai patients during and after treatment of falciparum malaria (1995)
    Springer
    European journal of clinical pharmacology 48 (1995), S. 65-69 
    Details
    ISSN: 1432-1041
    Keywords: Paracetamol ; Malaria ; pharmacokinetics ; phase II conjugation ; glucuronidation ; sulphation
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Investigations in animals have suggested that conjugation of paracetamol may be reduced in malaria. We have measured plasma concentrations and the urinary excretion of paracetamol and its phase II metabolites in eight Thai patients during uncomplicated falciparum malaria and in convalescence, following a 1000 mg single oral dose. The apparent oral clearance (Malaria, 3.6; Convalescence, 3.9; ml·min−1·kg−1), the elimination half-life (Malaria, 3.8; Convalescence, 3.7 h) and apparent volume of distribution (Malaria, 1.2; Convalescence, 1.2; l·kg−1) of paracetamol were similar during malaria and convalescence. In addition, the urinary excretion of paracetamol and its major phase II metabolites and their formation clearances from paracetamol were not significantly different between the two study phases. These data show that clinical malaria infection has no effect on the conjugation of paracetamol in man.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00202175
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  • 25
    Electronic Resource
    Electronic Resource
    The acetylation phenotype: does it contribute to the non-linearity of the metabolite pharmacokinetics of metamizol? (1995)
    Springer
    European journal of clinical pharmacology 48 (1995), S. 79-80 
    Details
    ISSN: 1432-1041
    Keywords: Metamizol ; Acetylation phenotype ; metabolites ; pharmacokinetics ; dose-linearity
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00202178
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  • 26
    Electronic Resource
    Electronic Resource
    Relative bioavailability of nicotine from a nasal spray in infectious rhinitis and after use of a topical decongestant (1995)
    Springer
    European journal of clinical pharmacology 48 (1995), S. 71-75 
    Details
    ISSN: 1432-1041
    Keywords: Nicotine ; Rhinitis ; pharmacokinetics ; nasal spray ; xylometazoline ; drug interaction
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract The relative bioavailability of nicotine from a nasal spray was assessed in 15 smokers suffering a common cold and rhinitis according to generally accepted criteria. The patients were given a single dose of 2 mg nicotine from the nasal spray with and without concurrent administration of a nasal vasoconstrictor decongestant, xylometazoline, in randomised order. Control session measurements were made in the disease-free state. Applying strict bioequivalence criteria, we found that common cold/rhinitis slightly reduced the bioavailability of nicotine, both in its rate and extent; the geometric mean of the ratio of Cmax, AUC and tmax were 0.81, 0.93 and 1.36, respectively. The nasal vasoconstrictor, xylometazoline, normalised the extent of the bioavailability of nicotine, but further prolonged the time for absorption to almost twice that measured in the disease-free state, increasing the tmax ratio to 1.72. The results suggest that a minor proportion of people stopping smoking with the help of a nicotine nasal spray may experience a minor reduction in the effect of the spray during common cold/rhinitis. However, the nicotine self-titration behaviour found with most smoking cessation products (except the nicotine patch) will automatically lead to an adjustment of the dosage to achieve the desired effect.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00202176
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  • 27
    Electronic Resource
    Electronic Resource
    Effects of liver disease on the pharmacokinetics of intravenous and oral chlordesmethyldiazepam (1995)
    Springer
    European journal of clinical pharmacology 48 (1995), S. 265-268 
    Details
    ISSN: 1432-1041
    Keywords: Chlordesmethyldiazepam ; Liver disease ; pharmacokinetics ; i.v./p.o. administration
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract We studied the pharmacokinetics of a single 0.5-mg i.v. dose of chlordesmethyldiazepam in 8 patients with liver disease and in 12 age-matched healthy controls. The kinetics were also studied of a single 1-mg oral dose in the patients with liver disease. After i.v. administration the kinetics of total chlordesmethyldiazepam in patients with liver disease differed from those in controls: elimination half-life was almost twice that in controls (395 and 204 h), as a consequence of a marked reduction in total clearance (0.13 and 0.25 ng·ml−1·h−1), whereas the apparent volume of distribution was similar in patients and controls (4.7 and 3.9 1/kg−1). The free fraction of the drug in patients was higher (5.5%) than in controls (2.9%). Correction for differences in protein binding revealed clearance in the patients was one-fifth (1.8 and 10.5 ng ml−1·kg−1) and volume of distribution one-half (65.0 and 118.4 1·kg−1) that in controls. The systemic availability of oral chlordesmethyldiazepam was high (110%) in spite of a relatively slow absorption rate. These results indicate a need for caution in the administration of chlordesmethyldiazepam to patients with liver disease.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00198309
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  • 28
    Electronic Resource
    Electronic Resource
    Effects of a finnish sauna on the pharmacokinetics and haemodynamic actions of propranolol and captopril in healthy volunteers (1995)
    Springer
    European journal of clinical pharmacology 48 (1995), S. 133-137 
    Details
    ISSN: 1432-1041
    Keywords: Sauna ; Propranolol ; Captopril ; pharmacokinetics ; blood pressure
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract The effects of a Finnish sauna on propranolol pharmacokinetics and on the pharmacodynamics of propranolol and captopril were studied in healthy, young volunteers (2 males, 6 females) in a double-blind, cross-over trial. The subjects received single oral doses of placebo. propranolol (40 mg) or captopril (12.5 mg) in sauna and control sessions at a one-week interval. The sauna sessions consisted of three repetitive 10-min stays in a sauna (85–100°C, relative humidity 25–35%) separated by two 5-min rest periods in a cool room. Sauna bathing started 35, 50 and 65 min after ingestion of the drugs. Venous blood for plasma propranolol measurement were collected before and 15, 30, 45, 60, 75, 90 min and 2, 3, 4, 5, 7 and 24 h after drug intake. The sauna significantly increased the maximum concentration (Cmax 41 vs. 28 ng·ml−1) of propranolol and the mean plasma propranolol concentration 60 and 90 min, and 2 and 3 h after drug administration. It also significantly increased the AUC0–5h (119 vs 71 μg·h·l-1) of propranolol from 0 to 5 hours tmax, t1/2β and AUC0–24h of propranolol did not differ between the control and sauna sessions. The higher propranolol levels during and after the cessation of sauna bathing did not lead to significant changes in blood pressure or heart rate compared to the control period. Captopril had no major effects on these parameters during the post-sauna phase. The results suggest that a sauna may increase the plasma propranolol concentration, but that did not notably affect the blood pressure or heart rate in healthy, young volunteers during the post-sauna phase.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00192738
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  • 29
    Electronic Resource
    Electronic Resource
    Pharmacokinetic interactions of alcohol and acetylsalicylic acid (1995)
    Springer
    European journal of clinical pharmacology 48 (1995), S. 151-153 
    Details
    ISSN: 1432-1041
    Keywords: Ethanol ; Acetylsalicylic acid ; ibuprofen ; paracetamol ; non-steroidal anti-inflammatory drugs ; interactions ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract This study assessed the influence of acetylsalicylic acid (ASA, 1.0 g), ibuprofen (0.8 g) and paracetamol (1.0 g) on the single-dose kinetics of ethanol in 12 healthy volunteers ingesting the drug and a standardised 1840-kJ breakfast 1 h before intake of ethanol. It also assessed the influence of ethanol on the single-dose kinetics of 1.0 g ASA in ten fasting healthy volunteers. Plasma concentrations of ethanol were measured by gas chromatography, and those of the drugs by liquid chromatography. There was no effect of ASA, ibuprofen or paracetamol on the single-dose kinetics of ethanol, but concurrent intake of ethanol reduced the peak concentration of ASA by 25%.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00192741
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  • 30
    Electronic Resource
    Electronic Resource
    Influence of piroxicam coadministration on pharmacodynamic parameters and the plasma concentration/effect relationship of recombinant hirudin (CGP 39393) (1995)
    Springer
    European journal of clinical pharmacology 48 (1995), S. 241-246 
    Details
    ISSN: 1432-1041
    Keywords: Recombinat hirudin ; Piroxicam ; activated partial thromboplastin time ; pharmacokinetics ; drug interaction
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Recombinant hirudins are currently under investigation for use in myocardial infarction and unstable angina. In this study the influence of piroxicam on the pharmacodynamics and pharmacokinetics of a recombinant hirudin preparation (CGP 39393) administered intravenously was determined. Twelve healthy, male volunteers received piroxicam 10 mg and matching placebo once daily for 12 days according to a double-blind, randomised cross-over design. On the 12th day, the dose of piroxicam was followed by a 6-hour infusion of hirudin 0.1 mg·kg−1·h−1. Plasma concentrations and urinary excretion of hirudin and repeated measurements of the activated partial thromboplastin time (APTT), bleeding time and platelet adhesion index were assessed up to 24 h after the start of the infusion. The maximum APTT was 83 s (placebo) and 84 s (piroxicam), 3 to 4 h after the start of the infusion, and was comparable on both study days. The AUD0–24 (APTT) came to 913 s·h·kg−1 under placebo and it was slightly increased to 1,017 s·h·kg−1 after piroxicam; the 95%-confidence interval according to MOSES ranged from 0.97 to 1.24, and the point estimator was 1.10. Bleeding time was significantly prolonged from 290 s under placebo to 345 s under piroxicam before the start of the infusion of hirudin. No further prolongation was found during or after the infusion. No change was observed in the platelet adhesion index. Responsiveness parameters according to a sigmoidal Emax-model were obtained from the hirudin-plasma concentration/effect (i.e. APTT-prolongation)-curves after placebo and piroxicam. Maximal APTT-prolongation (Emax; i.e. peak APTT minus the baseline value) was 53 s after placebo and 52 s after piroxicam. The EC50 was 34 nmol·l−1 after placebo and 40 nmol·h·l−1 after piroxicam. The AUC0 of hirudin was to 539 nmol·h·l−1·kg−1 under placebo and 557 nmol·h·l−1·kg−1 after piroxicam coadministration; the 95%- confidence interval according to MOSES ranged from 0.95 to 1.14, and the point estimator was 1.03. No period effect was detected. There were no significant differences between the other pharmacokinetic parameters except Vss, which was increased slightly from 0.23 l to 0.27 l under piroxicam. The results do not show a clinically relevant pharmacodynamic and/or pharmacokinetic interaction between hirudin and piroxicam.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00198305
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  • 31
    Electronic Resource
    Electronic Resource
    Pharmacokinetics of fluconazole after oral administration in children with human immunodeficiency virus infection (1995)
    Springer
    European journal of clinical pharmacology 48 (1995), S. 291-293 
    Details
    ISSN: 1432-1041
    Keywords: Fluconazole ; absorption ; pharmacokinetics ; HIV infection ; children
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract The objective of this study was to determine the pharmacokinetics of fluconazole after oral administration in children with human immunodeficiency virus (HIV) infection. After an overnight fast, a single dose of either 2 mg·kg−1 or 8 mg·kg−1 was administered in a suspension; five children received 2 mg·kg−1 and four 8 mg·kg−1 (ages 5–13 years). Blood samples were collected at various times on day 1, and once daily on days 2–7 after the dose. Fluconazole serum concentrations were measured by gas chromatography. At the dose of 2 mg·kg−1, the Cmax, AUC (0–∞), and t1/2 ranged from 2.3–4.4 μg·ml−1, 84.9–136 μg·h·ml−1, and 19.8–34.8 h, respectively. At the dose of 8 mg·kg−1 the Cmax, AUC (0–∞), and t1/2 ranged from 5.4–12.1 μg·ml−1, 330–684 μgh·ml−1, and 25.6–42.3 h, respectively. When compared with published data in healthy adults, fluconazole achieved similar serum concentrations in the present group of children, indicating a nearly complete degree of absorption.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00198314
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  • 32
    Electronic Resource
    Electronic Resource
    Humoral and haemodynamic effects of idrapril calcium, the prototype of a new class of ACE-inhibitors, in essential hypertensive patients (1995)
    Springer
    European journal of clinical pharmacology 48 (1995), S. 339-343 
    Details
    ISSN: 1432-1041
    Keywords: Idrapril ; ACE-inhibition ; Hypertension ; essential ; active renin ; angiotensin II ; blood pressure ; pharmacodynamics ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Idrapril is the prototype of a new class of ACE inhibitors, characterised by the presence of a hydroxdmic group. Six untreated in-patients with essential hypertension were given single oral doses of the calcium salt of idrapril, idrapril calcium (200 mg) and placebo according to a double blind, randomised experimental design. Supine and upright blood pressure, heart rate, plasma idrapril serum ACE, active renin and angiotensin II were measured at timed intervals for 24 hours after dosing. Plasma idrapril reached a peak after 2 hours (3.01 μ·ml−1), and by 12 hours the compound had al most disappeared (67 ng·ml−1). Derived t1/2 was 1.4–2.2 h. ACE activity was suppressed [from 77.9 to 3.3 after 2 hours and 11.8 after 12 hours nmol−1·min−1·ml] and angiotensin II production inhibited [from 8.8 to 3.1 (after 1 hour) and 7.5 (after 12 hours) pg·ml−1] for up to 12 h, while active renin rose up to 24 h [from 12.3 to 20.1 (after 8 hours) and 17.5 (after 24 hours) pg·ml−1]. Compared to placebo, idrapril calcium significantly lowered both supine blood pressure starting at 4 hours (idrapril calcium 140/93 mmHg; placebo 157/101 mmHg) up to 24 hours (idrapril calcium 142/91 mmHg; placebo: 155/97 mmHg), and upright blood pressure starting at 3 hours (idrapril calcium 135/95 mmHg; placebo 147/100 mmHg) up to 24 hours (idrapril calcium 132/92 mmHg; placebo 145/100 mmHg). Idrapril calcium appears to be an effective ACE inhibitor in essential hypertension, with a hypotensive action for up to 24 h.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00194948
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  • 33
    Electronic Resource
    Electronic Resource
    Relative bioavailability of cyclosporin from conventional and microemulsion formulations in heart-lung transplant candidates with cystic fibrosis (1995)
    Springer
    European journal of clinical pharmacology 48 (1995), S. 285-289 
    Details
    ISSN: 1432-1041
    Keywords: Cyclosporin ; Cystic fibrosis ; pharmacokinetics ; bioavailability ; formulation ; transplantation
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Patients with cystic fibrosis absorb cyclosporin poorly and erratically. We have compared the relative bioavailability of cyclosporin from conventional and microemulsion formulations in 5 adult heart-lung transplant candidates with cystic fibrosis. Relative bioavailability was compared at two dose levels (200 mg and 800 mg). A randomized 4-period cross-over study was performed with at least a 7 days washout period between each single dose pharmacokinetic study. Blood cyclosporin concentrations were measured by a selective monoclonal antibody-based radioimmunoassay. The bioavailability of cyclosporin from the microemulsion formulation was 1.84 (95% C.I. 1.05 to 3.22; P−0.04) and 2.09 (95% C.I. 0.95 to 4.61; P−0.06) times higher compared with the conventional formulation at 200 mg and 800 mg respectively. Cmax following the microemulsion formulation was 3.38 (C.I. 1.14 to 10.59; P−0.04) and 2.77 (C.I. 1.48 to 5.19; P−0.01) times higher compared with the conventional formulation at 200 mg and 800 mg respectively. The higher Cmax following the microemulsion formulation was accompanied by shorter tmax. An enhancement of cyclosporin absorption with the microemulsion formulation was demonstrated in each patient for at least one dose level. We conclude that rate and extent of cyclosporin absorption from the microemulsion formulation is greater compared with the conventional formulation in patients with cystic fibrosis. The potential therapeutic and economic benefits of the micro-emulsion formulation should be evaluated in cystic fibrosis patients following heart-lung transplantation.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00198313
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  • 34
    Electronic Resource
    Electronic Resource
    Pharmacokinetic-pharmacodynamic (PK-PD) modeling for a new antihypertensive agent (neutral metalloendopeptidase inhibitor SCH 42354) in patients with mild to moderate hypertension (1995)
    Springer
    European journal of clinical pharmacology 48 (1995), S. 351-359 
    Details
    ISSN: 1432-1041
    Keywords: Atrial natriuretic peptide ; Hypertension ; SCH 42354 ; blood pressure ; neutral metalloendopeptidase ; pharmacodynamics ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract SCH 42354, a neutral metalloendopeptidase (NEP) inhibitor, is the pharmacologically active form of the prodrug SCH 42495. It exerts antihypertensive effects by potentiating atrial natriuretic peptide (ANP) activity through inhibition of its hydrolysis by NEP. The objective of this study was to characterize the pharmacokinetics (PK) and pharmacodynamics (PD) of SCH 42354 in hypertensive males. SCH 42495 12.5 to 400 mg was administered orally to hypertensive men twice daily in a double-blind, placebo controlled multiple-dose parallel group design. Plasma SCH 42354 concentration and diastolic blood pressure (DBP) data were used to develop a PK-PD model using two approaches. In the first (non-integrated) approach, the “link” model was used to predict effect-site concentrations, and was applied to data obtained at the 300 and 400 mg BID doses only; data at the other (lower) doses were not amenable to modeling because of high variability. Effect-site concentration and DBP data were then fit to a sigmoid Emax PD model. For the 300 mg BID dose, PD parameters were: maximum effect (Emax), 8.1mmHg; no-drug effect (Eo), 3.6 mmHg; concentration corresponding to 50% of maximum response (EC50), 0.87 μg·ml−1; and gamma, 3.9. In the second (time-integrated) approach, plasma SCH 42354 concentration and effect data obtained over the entire dose range were integrated with respect to time. Average plasma concentration and DBP data were then fit to a simple Emax PD model. PD parameters obtained over the dose range were: Emax, 10.3 mmHg; Eo, 2.0 mmHg; and EC50, 0.7 μg·ml−1. These were similar to the estimates obtained from the first approach, demonstrating that the integrated (average) data allow PK-PD modeling over the (entire) dose range. The analysis showed that, at steady-state, a 400 mg BID dose of SCH 42495 produced an approximate 10 mmHg decrease in DBP in hypertensive males; the average plasma SCH 42354 concentration attained at this dose was approximately 1.8 μg·ml−1.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00194950
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  • 35
    Electronic Resource
    Electronic Resource
    The effect of pH on the buccal and sublingual absorption of captopril (1995)
    Springer
    European journal of clinical pharmacology 48 (1995), S. 373-379 
    Details
    ISSN: 1432-1041
    Keywords: Captopril ; sublingual ; pharmacokinetics ; pharmacodynamics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract The effect of pH on the buccal and sublingual absorption of captopril was evaluated using in vitro techniques and human studies. Partitioning of captopril into n-octanol was lowest over the pH range 5 to 8 and highest at pH values 3, 4 and 9. Using the buccal absorption technique, the partitioning of captopril (2 mg) was examined in six healthy male volunteers from buffered solutions (pH 3, 4, 5, 6, 7, 8, and 9). Lowest buccal partitioning occurred at pH 3 while maximal buccal partitioning occurred at pH 7. These data clearly indicated that the buccal absorption of captopril did not obey the classical pH/partition hypothesis suggesting that mechanisms other than passive diffusion were involved in its absorption. Captopril pharmacokinetic and pharmacodynamic parameters were determined after administration of buffered sublingual captopril (pH 7, optimal pH for absorption as determined from the buccal partitioning data) and unbuffered sublingual captopril. The study was performed in eight healthy volunteers in a randomised single-blind cross-over fashion. The tmax for captopril was found to be approximately 11 minutes earlier after buffered versus unbuffered sublingual administration and AUC0–30 min increased by approximately 30% in the case of buffered captopril. Cpmax, AUC0–180 min and relative bioavailability did not differ between the buffered and unbuffered administration. Pharmacodynamic parameters (BP, heart rate and plasma renin activity) did not differ significantly between buffered and unbuffered sublingual administration. The increased rate of captopril absorption after buffered sublingual administration was small and is likely to offer little therapeutic advantage over conventional sublingual formulation.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00194953
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  • 36
    Electronic Resource
    Electronic Resource
    Plasma and red blood cell pharmacokinetics of pimobendan enantiomers in healthy Chinese (1995)
    Springer
    European journal of clinical pharmacology 47 (1995), S. 537-542 
    Details
    ISSN: 1432-1041
    Keywords: Pimobendan ; enantiomers ; pharmacokinetics ; stereoselectivity ; demethyl pimobendan ; metabolites
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract The pharmacokinetics of enantiomers of pimobendan and their demethylated metabolites in plasma and red cells were studied in 8 normal healthy volunteers. After racemic pimobendan 5 mg IV, the plasma concentration-time curve followed a two-compartment open-model with elimination half-lives of 1.81 h and 1.86 h for (+)- and (−)-pimobendan, respectively. The clearances and volumes of distribution postequilibrium were 13.5 ml · min−1 · kg−1, 14.4 ml · min−1 · kg−1; 1.74 l · kg−1 and 2.34 l · kg−1 for (+)- and (−)-pimobendan, respectively. Plasma protein binding (n=3) of (+)-, (−)-pimobendan, (+)- and (−)-demethylated metabolites was 97.6, 97.6, 92.2 and 92.5%, respectively. The plasma concentration-time curve also followed a two-compartment open model after oral administration of 7.5 mg racemic pimobendan. The absolute bioavailabilities of (+)- and (−)-pimobendan were 0.51 and 0.55. Peak levels of (+)-and (−)-pimobendan, both at 1.2 h, were 15.8 and 16.8 ng · ml−1, respectively. The (+)- and (−)-pimobendan concentrations in red cells were determined and their pharmacokinetics were estimated using red blood cell data. Interesting phenomena were observed: the peak concentrations of (+)- and (−)-pimobendan in red blood cells were about 5.5- and 9.2-times higher than in plasma, and the AUCs were correspondingly elevated. The volume of distribution of the central compartment of (−)-pimobendan in red cell was significantly smaller than that of (+)-pimobendan. (0.24 vs. 0.42 l · kg−1.) Similar phenomena were found after IV administration. These all indicated stereoselective partitioning or distribution of (−)-pimobendan into red cells. Since the elimination half-life of (+)- and (−)-pimobendan in red cells was similar (3.07 vs 2.97 h), the highly significant difference in clearance between (+)- and (−)-pimobendan (3.7 vs 2.3 ml · min−1 · kg−1) was solely due to the stereoselective distribution of (−)-pimobendan into the red blood cells. This stereoselective property of the (−)-isomer may be the explanation of a previous report that (−)-pimobendan produced a 1.5-times larger contractile force in detergent-skinned preparations of cardiac muscle from guinea pig and dog than the (+)-isomer.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00193708
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  • 37
    Electronic Resource
    Electronic Resource
    A phase II and pharmacokinetic study of 6S-leucovorin plus 5-fluorouracil in patients with colorectal carcinoma (1995)
    Springer
    Investigational new drugs 13 (1995), S. 149-155 
    Details
    ISSN: 1573-0646
    Keywords: leucovorin ; colorectal cancer ; pharmacokinetics ; chemotherapy
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Leucovorin (LV) is commonly used as a modulator of 5-fluorouracil (5-FU) cytotoxicity. In patients with colon cancer, the addition of LV to 5-FU improves response rates, and in some trials has improved survival in advanced disease and in the adjuvant setting. Leucovorin is generally administered as a racemic mixture, but the isomers differ substantially in pharmacokinetics and biological activity, with 6S-LV the predominant active component. The current study was undertaken to determine the effect of 6R on the pharmacokinetics of 6S-LV, and to characterize the toxicity and antitumor effect of 5-FU when administered with 6S-LV to patients with advanced colorectal carcinoma. Thirty patients were treated with weekly 5-FU plus high dose 6S-LV. To determine the effects of 6R-LV on the pharmacokinetics of 6S-LV, 20 patients were randomly assigned to receive either 250 mg/m2 6S-LV or 500 mg/m2 6R,S-LV as a 2 hour IV infusion on day −2, and the other preparation on day −1, with pharmacokinetics measured each day. The presence of 6R-LV had no effect on the AUC, Clp, Cmax, or terminal phase t1/2 of 6S-LV. The overall response rate was 40% (C.I. 23–60%). The most frequent toxicities were gastrointestinal. In this small cohort, scheduled and delivered dose intensity was positively associated with response (p=0.05). These results show that there is no pharmacokinetic advantage to the use of 6S-LV rather than 6R,S-LV as a modulator of 5-FU.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00872864
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  • 38
    Electronic Resource
    Electronic Resource
    Some pharmacokinetic parameters of doxycycline in East African goats after intramuscular administration of a long-acting formulation (1995)
    Springer
    Veterinary research communications 19 (1995), S. 425-432 
    Details
    ISSN: 1573-7446
    Keywords: doxycycline ; goat ; intramuscular ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract A compartmental and non-compartmental study was carried out on five adult goats following intramuscular administration of doxycycline at 20 mg/kg bodyweight. The concentration of the drug in serum was determined by a microbiological assay employingBacillus cereus varmycoides (ATCC 11778) as the test organism. The mean serum concentration (C max) and the time of maximum concentration (T max) were 1.87 µg/ml and 0.85 h, respectively. Using compartmental analysis, the plasma concentration-time curve of doxycycline best fitted a three-compartment open model with first-order absorption. A three-phase disposition of doxycycline was found, the terminal elimination half-life being approximately 40 h. The statistical moment theory was mainly used for non-compartmental analysis. The value obtained for the mean residence time (MRT) was 16.41 h. The mean values for the volume of distribution at steady state (V dss), determined by compartmental and non-compartmental analyses, were 8.73 and 13.19 L/kg, respectively. There were no statistically significant differences when the major pharmacokinetic parameters were compared. It was concluded that the pharmacokinetic behaviour of doxycycline in goats after intramuscular administration is characterized by a three-compartment model with a slow terminal elimination phase. Based on current knowledge, this could be due to enterohepatic recycling and/or flip-flop kinetics. The study indicated that a single intramuscular administration of 20 mg/kg of doxycycline may only provide therapeutic concentrations for up to 24 h owing to slow absorption at the injection site.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01839322
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  • 39
    Electronic Resource
    Electronic Resource
    Pharmacokinetics of Antimony in Patients Treated with Sodium Stibogluconate for Cutaneous Leishmaniasis (1995)
    Springer
    Pharmaceutical research 12 (1995), S. 113-116 
    Details
    ISSN: 1573-904X
    Keywords: antimony ; sodium stibogluconate ; pentavalent antimonials ; pharmacokinetics ; cutaneous leishmaniasis ; antimony in whole blood ; urinary excretion of antimony ; interpatient variability
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The pharmacokinetics of Sb was examined in 29 patients with cutaneous leishmaniasis following the intramuscular administration of a dose of sodium stibogluconate equivalent to 600 mg of Sb. Blood was sampled at different time intervals from each patient and Sb was measured in whole blood by electrothermal atomic absorption spectrophotometry after an appropriate dilution with Triton X-100. The 24-hr urine- was also collected and analyzed similarly. The blood concentration-time data conformed to the one-compartment open model with mean and (SEM) of the apparent first-order rate constants for absorption (ka) and elimination (kd) of 1.71 (0.15) and 0.391 (0.016) hr−1, respectively. The maximum concentration of Sb achieved was 8.77 (0.39) mg/L and the peak time was 1.34 (0.09) hr. The total body clearance (TBC) and the volume of distribution (Vd) were 17.67 (1.38) L/hr and 45.7 (2.6) L, respectively, assuming a complete absorption. The fraction of dose of Sb excreted in the urine was 0.80 (0.07) and the renal clearance was 12.7 (1.16) L/hr. The frequency distribution pattern of the area-under-the-curve (AUC) appears to be bimodal and separates patients into those with low exposure to Sb (AUC = 11.7-29.04 mg.hr/L) (i.e., rapid eliminators) and those with high exposure to Sb (AUC = 31.5-49.1 mg.hr/ L) (i.e., slow eliminators). This may explain the variability observed in the response to treatment of leishmaniasis with sodium stibogluconate.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1016251023427
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  • 40
    Electronic Resource
    Electronic Resource
    Assessment of Toxicokinetics and Toxicodynamics Following Intravenous Administration of Etoposide Phosphate in Beagle Dogs (1995)
    Springer
    Pharmaceutical research 12 (1995), S. 117-123 
    Details
    ISSN: 1573-904X
    Keywords: BMY-40481 ; etoposide phosphate ; etoposide ; pharmacokinetics ; pharmacodynamics ; dogs
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The toxicokinetics and toxicodynamics of etoposide phosphate (BMY-40481), a water soluble phosphate ester derivative of etoposide, were investigated in beagle dogs (N = 4) following 5 min i.v. infusion doses equivalent to 57, 114 and 461 mg/m2 of etoposide. The doses were administered in sequence starting with the low dose. There was a 28 day wash-out period between the doses. Serial blood samples were collected over 32 hr and the levels of intact BMY-40481 and etoposide in plasma were measured using validated HPLC assays. Hematology profiles were obtained at pre-dose, and twice a week post-dose for 28 days to correlate systemic exposure to etoposide and hematologic toxicity. Following i.v. administration, plasma concentrations of BMY-40481 declined rapidly. For the 3 doses, mean t1/2 of BMY-40481 ranged from 0.11 - 0.17 hr (6.6-11 min). The mean Cmax and AUC values of BMY-40481 ranged from 1.72 - 40.5 µg/ml and 0.16 - 4.14 hr.µg/ml, respectively. Both systemic clearance and steady state volume of distribution of BMY-40481 decreased significantly at the high dose. In contrast, the mean Cmax and AUC values of etoposide ranged from 5.46 - 39.4 µg/ml and 2.28 - 22.6 hr.µg/ml, respectively. Cmax occurred at the end of infusion (5 min) at all dose levels, indicating that etoposide was rapidly formed from BMY-40481. The apparent systemic clearance (range: 342 - 435 ml/min/m2) and apparent steady state volume of distribution (range: 21.5 - 26.6 1/m2) of etoposide were dose-independent. The AUC of etoposide was significantly correlated with hematologic toxicity, i.e., percent decreases in white blood count (WBC), absolute neutrophil count (ANC) and platelets. The relationship was best described by the sigmoid Emax model for WBC and ANC, and by a simple linear model for platelets. Hemoglobin showed slight decreases which did not correlate with etoposide AUC. In summary, BMY-40481 is rapidly and extensively converted to etoposide; etoposide exhibits linear kinetics; and except for hemoglobin, hematologic toxicity is significantly correlated with etoposide exposure.
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    URL: http://dx.doi.org/10.1023/A:1016203107497
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  • 41
    Electronic Resource
    Electronic Resource
    The Effect of Food on Pharmacokinetics of Zalcitabine in HIV-Positive Patients (1995)
    Springer
    Pharmaceutical research 12 (1995), S. 1462-1465 
    Details
    ISSN: 1573-904X
    Keywords: pharmacokinetics ; food ; interaction ; zalcitabine ; HIV infection
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. The purpose of this study was to determine the effect of food on the pharmacokinetics of zalcitabine in HIV-positive patients. Methods. Twenty patients received single oral 1.5 mg doses of zalcitabine with and without a standard breakfast in an open-label, randomized crossover study with at least a one week washout period between treatments. Serial blood and urine samples were collected over 24 hours and assayed for zalcitabine by a modified GC/MS method. Results. Administration with food delayed and prolonged absorption resulting in a decrease of approximately 39% in maximal plasma concentrations compared to dosing under fasting conditions. Comparison of plasma AUC values indicated a small (14%) reduction in bioavailability when given with food. Approximately 59% and 45% of the dose were excreted unchanged in the urine under fasting and fed conditions, respectively. Conclusions. The results of this study show that the administration of zalcitabine with food results in a mild reduction in bioavailability. Although these changes are not expected to be of clinical importance, further studies must be conducted for confirmation.
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    URL: http://dx.doi.org/10.1023/A:1016275118710
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  • 42
    Electronic Resource
    Electronic Resource
    A Novel Oligodeoxynucleotide Inhibitor of Thrombin. II. Pharmacokinetics in the Cynomolgus Monkey (1995)
    Springer
    Pharmaceutical research 12 (1995), S. 1943-1947 
    Details
    ISSN: 1573-904X
    Keywords: GS-522 ; oligodeoxynucleotide ; thrombin ; pharmacokinetics ; monkey
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. To determine the pharmacokinetics of GS-522, an oligodeoxynucleotide (GGTTGGTGTGGTTGG) inhibitor of thrombin, after constant infusion and bolus administration in the cynomolgus monkey. Methods. Using a stability indicating HPLC method, the GS-522 plasma concentration versus time data were obtained after constant infusion (0.1, 0.3, 0.5 mg/kg/min) and bolus administration (11.25 and 22.5 mg/kg). Plasma data after bolus administration was fit to a three-compartment model. Results. The half-lives for the α and β phases were 1.4 and 5.4 min, respectively. Steady state GS-522 concentrations were reached within 10 minutes after initiation of constant infusions. Termination of infusions resulted in a rapid elimination of GS-522 with an average elimination half-life equal to 1.5 min. The Vss calculated from both the constant infusion and bolus data approximated the blood volume of the monkey. Substitution of the phosphodiester backbone at the 3′ end of GS-522 with two phosphorothioate linkages did not substantially effect the elimination half-life upon termination of infusion. Conclusions. These data in conjunction with published biodistribution data suggest that oligodeoxynucleotides are rapidly cleared from plasma by tissue uptake and that little efflux back into blood takes place. Additionally, strategies designed to increase oligodeoxynucleotide resistance to exonucleases will not dramatically increase plasma half-lives.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1016295907266
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  • 43
    Electronic Resource
    Electronic Resource
    Regional Drug Delivery II: Relationship Between Drug Targeting Index and Pharmacokinetic Parameters for Three Non-Steroidal Anti-Inflammatory Drugs Using the Rat Air Pouch Model of Inflammation (1995)
    Springer
    Pharmaceutical research 12 (1995), S. 1987-1996 
    Details
    ISSN: 1573-904X
    Keywords: drug targeting index ; regional administration ; pharmacokinetics ; rat air pouch model ; inflammation ; non-steroidal anti-inflammatory drugs ; diclofenac ; piroxicam ; S[ + ]ibuprofen ; albumin flux
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. To quantify the advantage gained by direct administration to a target site for two non-steroidal anti-inflammatory drugs (NSAIDs) piroxicam and diclofenac in the rat air pouch model of inflammation. To derive a model relating drug targeting index (DTI) to the pharmacokinetic parameters of the target and systemic sites, and to compare predictions with observations. Methods. DTI was calculated based on area under the concentration time curve at target (pouch) and systemic site (venous blood) following administration into and sampling from both sites. A model was derived relating DTI to systemic clearance, target permeability, plasma protein binding and fraction of the targeted dose that is systemically available. Results. Both NSAIDs exhibited linear pharmacokinetics over the dose ranges studies. They differed primarily in total body clearance which was approximately 16 fold greater for diclofenac (213 ml hr−l per 250 g) than piroxicam (13 ml hr−l per 250 g). Observed DTIs (11, 114 and 276 for piroxicam, S[ + ]ibuprofen [studied previously] and diclofenac) were ranked in order of total body clearance but were approximately 7.5 fold lower than predicted (101, 700 and 2214 respectively). Conclusions. The discrepancy was explained by the influx of the plasma binding protein, albumin, into the target site due to increased vascular permeability associated with the inflammatory response. The originally derived equation for DTI, which assumed only unbound drug diffuses across the target site, was modified to take into account the simultaneous flux of bound drug.
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    URL: http://dx.doi.org/10.1023/A:1016212510900
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  • 44
    Electronic Resource
    Electronic Resource
    Effects of Gender, Pregnancy, and Anesthesia on the Pharmacokinetics of Zidovudine in Rats (1995)
    Springer
    Pharmaceutical research 12 (1995), S. 1647-1651 
    Details
    ISSN: 1573-904X
    Keywords: zidovudine ; gender ; anesthesia ; pregnant ; pharmacokinetics ; rats
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. The effects of gender, pregnancy and anesthesia on the pharmacokinetics of zidovudine (AZT) were studied in rats. Methods. Unanesthetized male (MR), female (FR) and pregnant (day 20, PR) rats received 50 mg/kg AZT via a jugular vein cannula. Female (FRA), pregnant (day 20, PRA) and pregnant (day 20, PRR) rats maintained under ketamine: acepromazine:xylazine anesthesia also received 50 mg/kg AZT. Two fetuses were removed at each sampling time from the PRR group. Plasma samples were collected and analyzed by RIA. Results. With the exception of a lower non-renal clearance in female rats, there were no gender differences in the disposition of AZT. No significant differences were noted in total clearance, non-renal clearance or volume of distribution between pregnant and female rats, however, significant differences in renal clearance values were evident. Anesthesia resulted in decreased total, renal and non-renal clearances in female and pregnant rats. The removal of fetuses during the experiments did not alter the total clearance of AZT in pregnant rats, however, renal clearance and volume of distribution were decreased by cesarian section. Conclusions. The rat appears to be a suitable laboratory animal model for investigating AZT disposition during pregnancy. However, results of pharmacokinetic studies when animals are maintained under anesthesia with ketamine :acepromazine:xylazine must be interpreted with caution.
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    URL: http://dx.doi.org/10.1023/A:1016293017318
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  • 45
    Electronic Resource
    Electronic Resource
    Design for Cell-Specific Targeting of Proteins Utilizing Sugar-Recognition Mechanism: Effect of Molecular Weight of Proteins on Targeting Efficiency (1995)
    Springer
    Pharmaceutical research 12 (1995), S. 209-214 
    Details
    ISSN: 1573-904X
    Keywords: protein targeting ; sugar recognition ; pharmacokinetics ; molecular weight ; liver
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Hepatic targeting of proteins utilizing the sugar-recognition mechanism was investigated in mice after intravenous injection. Five proteins with different molecular weights, i.e., bovine γ-globulins (IgG), bovine serum albumin (BSA), recombinant human superoxide dismutase (SOD), soybean trypsin inhibitor (STI), and chicken egg white lysozyme (LZM), were modified with 2-imino-2-methoxyethyl 1-thiogalactoside to obtain galactosylated proteins (Gal-IgG, Gal-BSA, Gal-SOD, Gal-STI, and Gal-LZM). The numbers of galactose residues were 38, 20, 11, 6, and 5 for Gal-IgG, Gal-BSA, Gal-SOD, Gal-STI, and Gal-LZM, respectively. All galactosylated proteins were dose-dependently taken up by the liver and the relative amount accumulated in the liver was decreased with an increase of the administered dose. At low doses (0.05 and 0.1 mg/kg), Gal-IgG, Gal-BSA, and Gal-SOD could be taken up by the liver up to more than 70–80% of dose within 10 min after intravenous injection, but the maximum amounts accumulated in the liver were approximately 40 and 30% of the dose for Gal-STI and Gal-LZM, respectively. Pharmacokinetic analysis revealed that the hepatic uptake clearance (CLliver) was quite different around the molecular weight of 32 kDa and correlated with the amount delivered to the liver; Gal-IgG, Gal-BSA, and Gal-SOD has a large CLliver that is close to the hepatic plasma flow rate (85 ml/hr), whereas those of Gal-STI and Gal-LZM were approximately 10 ml/hr at low doses. As for the total amount accumulated in the liver, high glomerular filtration rate of Gal-STI and Gal-LZM was also shown to cause insufficient delivery to the liver apart from being caused by their low CLliver.
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    URL: http://dx.doi.org/10.1023/A:1016222808484
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  • 46
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    Electronic Resource
    Evaluation of Intestinal Absorption into the Portal System in Enterohepatic Circulation by Measuring the Difference in Portal–Venous Blood Concentrations of Diclofenac (1995)
    Springer
    Pharmaceutical research 12 (1995), S. 880-883 
    Details
    ISSN: 1573-904X
    Keywords: portal–venous blood concentration difference ; enterohepatic circulation ; diclofenac ; portal system ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. We evaluated the first-pass effects in vivo by the intestine and liver during enterohepatic circulation (EHC) by simultaneously measuring the portal and venous plasma concentrations of the rat. Methods. The venous and upper portal blood vessels were cannulated through the jugular and the pyloric veins, respectively, to obtain simultaneously blood samples from both sites. After diclofenac was injected as a bolus through the jugular vein, the concentrations of diclofenac in the portal and jugular veins were measured at time intervals. The absorption rate from the intestinal tract into the portal system was determined using the portal–venous difference in plasma concentrations of diclofenac, considering 40% partitioning of diclofenac into erythrocytes. Results. After one hour, the plasma concentration in the portal vein was always higher than that in the jugular vein in awakening rats with intact EHC (portal–venous blood concentration difference). No portal–venous difference was observed in awakening rats with bile-duct cannulation. Therefore, it was concluded that this portal–venous concentration difference was not due to the hepatic clearance but to diclofenac reabsorption from the intestinal tract. Conclusions. Appropriately 40% of the dose of diclofenac was reabsorbed over 8 hours from the intestinal tract into the portal system. By comparing the reabsorbed amounts in the portal system and in the systemic circulation, the hepatic extraction ratio in vivo (FH) of diclofenac was estimated to be 63%.
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    URL: http://dx.doi.org/10.1023/A:1016217221977
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  • 47
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    Electronic Resource
    Effect of Corticosteroid Binding Globulin on the Pharmacokinetics of Prednisolone in Rats (1995)
    Springer
    Pharmaceutical research 12 (1995), S. 902-904 
    Details
    ISSN: 1573-904X
    Keywords: corticosteroid binding globulin ; transcortin ; pharmacokinetics ; free hormone hypothesis ; prednisolone ; methylprednisolone
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. The effect of exogenous corticosteroid binding globulin (CBG) on the pharmacokinetics of intravenous prednisolone was determined in rats to test the “free hormone hypothesis.” Methods. A dose of CBG to yield 95% binding with 1000 ng/ml of prednisolone in vitro in rat plasma or saline was administered before dosing 2 mg/kg of prednisolone hemisuccinate or methylprednisolone intravenously. Drug concentrations in plasma samples were assayed by HPLC. Results. Single administration of CBG decreased apparent prednisolone clearance by 56% (155 to 66 ml/min/kg) and reduced apparent Vss by 35% (4.1 to 2.7 L/kg) (p〈0.001). Methylprednisolone pharmacokinetics, studied as a negative control because the drug does not bind to CBG, did not change. Conclusions. The corticosteroid bound to CBG does not appear to be available for removal by clearance organs.
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    URL: http://dx.doi.org/10.1023/A:1016225423795
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  • 48
    Electronic Resource
    Electronic Resource
    Metabolism of Dynorphin A 1-13 in Human Blood and Plasma (1995)
    Springer
    Pharmaceutical research 12 (1995), S. 1165-1170 
    Details
    ISSN: 1573-904X
    Keywords: dynorphin Al-13 ; opioid peptides ; metabolism ; pharmacokinetics ; HPLC
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. A detailed investigation of the metabolic routes and rates of Dyn A1-13 in human blood and plasma was performed. Methods. Human plasma was incubated at 37°C with dynorphin A 1-13 (Dyn Al-13, 15-20 µM). The generated dynorphin fragments were separated by a new ion-pair chromatographic method and identified by matrix assisted laser desorption mass spectroscopy. The kinetic behavior of parent compound and metabolites was evaluated in the absence and presence of enzyme inhibitors. Results. The major plasma metabolites of Dyn Al-13 were Dyn A1-12, A2-12, A4-12 and A4-8. Further metabolites were Dyn A2-13, A3-13, A3-12, A5-12, A6-12, A7-12, Al-10, A2-10, A2-8 and A3-8. At 37°C, Dyn Al-13 had a half-life of less than one minute in plasma and blood. Plasma half-lives of major metabolites ranged between 0.5 and 4 min. Inter-and intra-individual differences in healthy volunteers were 30% (c.v.). Dyn Al-13 is mainly metabolized by carboxypeptidases to Dyn Al-12 (80%) and by aminopeptidases to Dyn A2-13 (15%). Dyn A1-12 and Dyn A2-13 are predominantly converted into Dyn A2-12 (67% of Dyn Al-13). Subsequent metabolic steps yield Dyn A3-12 (16%), Dyn A4-12 (37%) and Dyn A4-8 (33%). Aminopeptidases generate Dyn A2-12, A3-12, A4-12, A5-12. ACE metabolizes Dyn Al-12 (19%), A2-12 (33%), A3-12 (34%) and A4-12 (46%). Bestatin-sensitive endopeptidases (possibly endopeptidase 24.11) metabolize 30% of Dyn A2-12. Dyn A4-8 is formed via Dyn A4-12 (23% of Dyn A4-12) and Dyn A2-10 (37% of Dyn A2-10). Conclusions. The combination of enzyme inhibition experiments and noncompartmental kinetic analysis proved to be a powerful tool for the detailed evaluation of the metabolic fate of Dyn Al-13 in human blood and plasma.
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    URL: http://dx.doi.org/10.1023/A:1016211910107
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  • 49
    Electronic Resource
    Electronic Resource
    Pharmacokinetic Studies of Methotrexate in Plasma and Synovial Fluid Following IV Bolus and Topical Routes of Administration in Dogs (1995)
    Springer
    Pharmaceutical research 12 (1995), S. 1474-1477 
    Details
    ISSN: 1573-904X
    Keywords: methotrexate ; pharmacokinetics ; synovial fluid ; poloxamer gel ; muscle tissue
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. The pharmacokinetic properties of methotrexate (MTX) in the plasma and synovial fluid (SF) after bolus IV and topical administration were studied in dogs to assess the feasibility of topical delivery of MTX for the treatment of rheumatoid arthritis. Methods. A MTX gel in Poloxamer 407 containing an absorption enhancer was formulated and topically applied on the elbow and stifle joints of dogs. SF was collected by inserting a needle with syringe into the joint space. Drug concentrations in the plasma, SF and muscle tissues were determined using a HPLC method with fluorimetric detection. Results. Peak MTX concentrations in SF occurrred at 38 ± 5 min following bolus IV dose, indicating the presence of a substantial diffusion barrier between the plasma and SF. The plasma/SF concentration ratios of 1.16 ± 0.25 were maintained after the attainment of distribution equilibrium between the two compartments. The t1/2 values in the plasma (11.2 ± 1.2 hr) and SF (12.7 ± 3.7 hr) were similar during the elimination phase, while the MRT in SF (3.24 ± 0.21 hr) was longer than that in plasma (2.56 ± 0.20 hr), probably due to the slow distribution of MTX to SF. After topical dose, MTX concentrations in plasma reached the steady state at ~4 hr, lasting for ~20 hr.The bioavailability of MTX from the gel was 11.8 ± 3.3% of the applied dose, but muscle tissues beneath the gel application site had significantly higher levels of MTX than untreated muscle tissues. There was no statistical difference in SF concentrations of MTX between drug treated and untreated joints 24 hr after topical dose. Conclusions. Topical delivery of MTX in a hydrophilic gel achieved a sustained C/t profile in plasma and higher drug levels in muscle tissues underneath the dosing site, implicating the potential therapeutic value of the topical formulation. Methods. A MTX gel in Poloxamer 407 containing an absorption enhancer was formulated and topically applied on the elbow and stifle joints of dogs. SF was collected by inserting a needle with syringe into the joint space. Drug concentrations in the plasma, SF and muscle tissues were determined using a HPLC method with fluorimetric detection. Results. Peak MTX concentrations in SF occurrred at 38 ± 5 min following bolus IV dose, indicating the presence of a substantial diffusion barrier between the plasma and SF. The plasma/SF concentration ratios of 1.16 ± 0.25 were maintained after the attainment of distribution equilibrium between the two compartments. The t1/2 values in the plasma (11.2 ± 1.2 hr) and SF (12.7 ± 3.7 hr) were similar during the elimination phase, while the MRT in SF (3.24 ± 0.21 hr) was longer than that in plasma (2.56 ± 0.20 hr), probably due to the slow distribution of MTX to SF. After topical dose, MTX concentrations in plasma reached the steady state at ~4 hr, lasting for ~20 hr.The bioavailability of MTX from the gel was 11.8 ± 3.3% of the applied dose, but muscle tissues beneath the gel application site had significantly higher levels of MTX than untreated muscle tissues. There was no statistical difference in SF concentrations of MTX between drug treated and untreated joints 24 hr after topical dose. Conclusions. Topical delivery of MTX in a hydrophilic gel achieved a sustained C/t profile in plasma and higher drug levels in muscle tissues underneath the dosing site, implicating the potential therapeutic value of the topical formulation.
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    URL: http://dx.doi.org/10.1023/A:1016231303689
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  • 50
    Electronic Resource
    Electronic Resource
    Intra- and Inter-Subject Variabilities of CGP 33101 after Replicate Single Oral Doses of Two 200-mg Tablets and 400-mg Suspension (1995)
    Springer
    Pharmaceutical research 12 (1995), S. 1878-1882 
    Details
    ISSN: 1573-904X
    Keywords: CGP 33101, intra-subject variability ; inter-subject variability ; pharmacokinetics ; healthy subjects ; bioavailability
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. The purpose of this study was to use a replicate designed trial to assess the overall, intra- and inter-subject variabilities in pharmacokinetic parameters of CGP 33101 after oral administration of tablets relative to that of powder suspended in water, and to determine the relative proportion of the intra-subject variance to the overall variability. Methods. Sixteen healthy subjects were randomly assigned to four groups to receive tablets and suspension twice in four different treatment sequences. The plasma concentration-time profile of CGP 33101 was characterized in terms of Cmax, Tmax, and AUC. Bioavailability of tablets relative to suspension and intra- and inter-subject variability were assessed by statistical analysis. Results and Conclusions. The overall variabilities in absorption kinetics of CGP 33101 in healthy subjects were small with CV's of the population mean values for AUC and Cmax less than 26% for both tablets and suspension. Contribution of intra-subject variability to the overall variability was also small (~20%). Both the overall and intra-subject variabilities of AUC and Cmax after suspension were larger than after the tablets. However, the differences in variability between tablets and suspension were not statistically significant (p 〉 0.05). The tablet formulation was bioequivalent to suspension in terms of rate and extent of absorption based on 90% conventional confidence intervals (for AUC and Cmax) and Wilcoxon rank-sum test (for Tmax).
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1016275402723
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  • 51
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    Electronic Resource
    Effect of Probenecid on the Enantioselective Pharmacokinetics of Oxprenolol and Its Glucuronides in the Rabbit (1995)
    Springer
    Pharmaceutical research 12 (1995), S. 1964-1967 
    Details
    ISSN: 1573-904X
    Keywords: enantioselectivity ; pharmacokinetics ; oxprenolol ; oxprenolol glucuronides ; probenecid ; active renal secretion
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. To study the effect of probenecid on the stereoselective pharmacokinetics of oxprenolol and its glucuronides in the rabbit. Methods. An oral dose of 50 mg/kg racemic oxprenolol was given to nine rabbits twice, in random sequence with and without the concurrent administration of probenecid. Oxprenolol enantiomers were determined in plasma and urine by an enantioselective HPLC method. Oxprenolol glucuronides were measured in plasma and urine after enzymatic hydrolysis. Results. The disposition of the oxprenolol enantiomers in rabbits is stereoselective, mainly due to a difference in metabolism. Renal excretion is only a minor elimination route for unchanged oxprenolol, and the renal clearances of the enantiomers are similar. Pre-treatment with probenecid did not affect the plasma concentrations of the oxprenolol enantiomers, but there was a slight decrease in their urinary excretion. The plasma concentrations of the oxprenolol glucuronides are much higher than those of the parent enantiomers, and those of (S)-glucuronide are about twice those of its antipode. About 10% of the oxprenolol dose is excreted in the urine as glucuronides. The renal clearances of both glucuronides are similar, and markedly higher than the creatinine clearance. After probenecid, the mean glucuronide plasma levels were markedly higher, with for both glucuronides a more than twofold increase in mean AUC. Probenecid decreased the renal clearance of both glucuronides to about 30%. Moreover, it decreased slightly the formation clearance of (S)-glucuronide, while the formation clearance of (R)-glucuronide was not significantly influenced. Conclusions. Our results show that in the rabbit, both oxprenolol glucuronide diastereomers are actively secreted by the kidney, and that this process is inhibited by probenecid.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1016204309083
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  • 52
    Electronic Resource
    Electronic Resource
    Microdialysis Sampling to Determine the Pharmacokinetics of Unbound SDZ ICM 567 in Blood and Brain in Awake, Freely-Moving Rats (1995)
    Springer
    Pharmaceutical research 12 (1995), S. 291-294 
    Details
    ISSN: 1573-904X
    Keywords: brain microdialysis ; blood microdialysis ; pharmacokinetics ; free drug concentration ; SDZ ICM 567
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The free concentrations of the serotoninergic 5-HT3 antagonist SDZ ICM 567 in blood and in the central nervous system were examined in awake, freely-moving rats using blood and brain microdialysis coupled to liquid chromatography. Microdialysis probes were implanted in the jugular vein and in the frontal cortex and dialysis samples were simultaneously collected from both sites. Pharmacokinetic parameters were calculated after a 10 mg/kg intravenous dose of [14C]SDZ ICM 567. The elimination half lives measured in whole blood, brain and blood microdialysates were similar (≃1.7 h). The AUC0–5h corresponding to the unbound drug was 462 ± 142 ng · ml−1 · h in blood dialysate, not significantly different from the AUC corresponding to the free concentration in whole blood, i.e. 586 ± 63 ng · ml−1 h. The free fraction in blood obtained in vitro by equilibrium dialysis (21%) or by microdialysis (19%) was not statistically different from that obtained in vivo (17%) in microdialysis experiments. The unbound concentrations (AUC0–5h) of SDZ ICM 567 in the brain cortex were 86 ± 24 ng · ml−l - h, lower than those expected from unbound blood concentrations, suggesting an active transport out of the central nervous system. Finally, microdialysis sampling allowed the determination of pharmacokinetic parameters of SDZ ICM 567 in blood and brain as well as the estimation of the free fraction of drug in blood.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1016247413935
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  • 53
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    Electronic Resource
    The Influence of Regional Deposition on the Pharmacokinetics of Pulmonary-Delivered Human Growth Hormone in Rabbits (1995)
    Springer
    Pharmaceutical research 12 (1995), S. 356-359 
    Details
    ISSN: 1573-904X
    Keywords: growth hormone ; pulmonary ; pharmacokinetics ; gamma scintigraphy ; drug delivery ; rabbit
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The pulmonary deposition and pharmacokinetics of human growth hormone (hGH), administered by aerosol and instillate, in formulations containing 99mTc-DTPA (for gamma scintigraphic imaging) have been studied in five male New Zealand White rabbits. Gamma scintigraphy indicated that the peripheral:central deposition tended to be greater for aerosol (1.54) than for instillate (0.8). Two gamma scintigraphic methods were used to quantify dose deposited by aerosol, which permitted bioavailabilities to be determined. The bioavailable fraction for aerosolized hGH (45%) was greater than for instilled hGH (16%). This was attributed to the differential effects of mucociliary clearance. Absorption rate limited pharmacokinetics prevailed for both hGH formulations with post-peak half-lives approximately 10-fold greater than the intravenous elimination half-life of 40 min. Apparent absorption rate constants resulting from instillation and aerosolization were equivalent (0.0012 min−1and 0.0020 min−1respectively), however lung-to-blood transfer rate constants for aerosol delivery (0.00071 min −l) were greater than for instillation (0.00018 min−1).
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1016292232513
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  • 54
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    Electronic Resource
    Pharmacokinetic/Pharmacodynamic Evaluation of Deflazacort in Comparison to Methylprednisolone and Prednisolone (1995)
    Springer
    Pharmaceutical research 12 (1995), S. 1096-1100 
    Details
    ISSN: 1573-904X
    Keywords: pharmacokinetics ; pharmacodynamics ; corticosteroids ; metabolites ; prodrug
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. The pharmacokinetics and pharmacodynamics of deflazacort after oral administration (30 mg) to healthy volunteers were determined and compared with those of 20 mg of methylprednisolone and 25 mg of prednisolone. Methods. Methylprednisolone, prednisolone and the active metabolite of deflazacort, 21-desacetyldeflazacort, were measured in plasma using HPLC. For the assessment of pharmacodynamics, differential white blood cell counts were obtained over 24 hours. An integrated pharmacokinetic-pharmacodynamic (PK-PD) model was applied to link corticosteroid concentrations to the effect on lymphocytes and granulocytes. Results. Deflazacort is an inactive prodrug which is converted rapidly to the active metabolite 21-desacetyldeflazacort. Maximum concentrations of 21-desacetyldeflazacort averaged 116 ng/ml and were observed after 1.3 h. The average area under the curve was 280 ng/ml · h, and the terminal half-life was 1.3 h. 21-Desacetyldeflazacort was cleared significantly faster than both methylprednisolone and prednisolone. The PK-PD-model was suitable to describe time course and magnitude of the observed effects. The results were consistent with reported values for glucocorticoid receptor binding affinities for the investigated compounds. Conclusions. Due to the short pharmacokinetic half-life of its active metabolite, pharmacodynamic effects of deflazacort are of shorter duration than those of methylprednisolone and prednisolone. The PK-PD model allows good prediction of pharmacodynamic effects based on pharmacokinetic and receptor binding data.
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    URL: http://dx.doi.org/10.1023/A:1016287104656
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  • 55
    Electronic Resource
    Electronic Resource
    Liposomal Formulations of Cyclosporin A: Influence of Lipid Type and Dose on Pharmacokinetics (1995)
    Springer
    Pharmaceutical research 12 (1995), S. 1189-1198 
    Details
    ISSN: 1573-904X
    Keywords: cyclosporins ; liposomal membranes ; lipid dose ; rat ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. Liposomal formulations of Cyclosporin A (CyA)3 have been described in more than 30 publications to substitute Cremophor EL (CrEL), a triricinoleate ester of ethoxylated glycerol, as drug carrier. However, conflicting reports did not allow to draw consistent conclusions about the influence of liposomes on CyA pharmacokinetics (PK) and pharmacodynamics. Methods. A series of liposomal CyA-formulations with varying liposome composition and lipid dose but constant CyA dose was compared in rats. Data were analysed with a PK-model taking into account the varying volume of distribution with the varying lipid concentration in blood. Results. Surface properties and lipid type of liposomes are not important PK predictors of liposomal CyA, at least for small dosages of liposomes. Rather, the absolute lipid amount and the lipophilicity of cyclosporins are critical factors influencing the PK of liposomal CyA. The higher the concentration of lipid in blood and the greater the lipophilicity of cyclosporin is, the higher are the concentrations of CyA in blood. Conclusions. These relations may explain the inconsistent literature results. Together with earlier observations from our group the above findings indicate, that CyA is not caged in the liposomal membranes. Reports in literature, which claim lower clearance and a lower volume of distribution of CyA in obese rats compared to lean rats, support our assumption about the involved mechanisms. A semi-quantitative model of CyA distribution is presented, which points to the variable free fraction of CyA in plasma as the crucial factor for all previously reported phenomena in liposomal CyA formulations.
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    URL: http://dx.doi.org/10.1023/A:1016220211925
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  • 56
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    Electronic Resource
    Third-generation model for corticosteroid pharmacodynamics: Roles of glucocorticoid receptor mRNA and tyrosine aminotransferase mRNA in rat liver (1995)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 23 (1995), S. 163-181 
    Details
    ISSN: 1573-8744
    Keywords: methylprednisolone ; pharmacokinetics ; pharmacodynamics ; glucocorticoid receptor ; tyrosine aminotransferase ; Northern hybridization ; mRNA
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract A third-generation pharmacokinetic/pharmacodynamic model was proposed for receptor/genemediated corticosteroid effects. The roles of the messenger RNA (mRNA) for the glucocorticoid receptor (GR) in hepatic GR down-regulation and the mRNA for hepatic tyrosine aminotransferase (TAT) induction by methylprednisolone (MPL) were examined. Male adrenalectomized Wistar rats received 50 mg/kg MPL iv. Blood and liver samples were collected at various time points for a period of 18 hr. Plasma concentrations of MPL, free hepatic cytosolic GR densities, GR mRNA, TAT mRNA, and TAT activities in liver were determined. Plasma MPL profile was biexponential with a terminal t1/2 of 0.57 hr. Free hepatic GR density rapidly disappeared from cytoplasm after the MPL dose and then slowly returned to about 60% of starting level after 16 hr. Meanwhile, GR mRNA level fell to 45% of baseline within 2 hr postdosing, and remained at that level for at least 18 hr. The GR down-regulation of GR mRNA and protein turnover rate were modeled. The TAT mRNA began to increase at about 2 hr, reached a maximum at about 5 hr, and declined to baseline by 14 hr. TAT induction followed a similar pattern, except the induction was delayed about 0.5 hr. Pharmacodynamic parameters were obtained by fitting seven differential equations in a piecewise fashion. The cascade of corticosteroid steps were modeled by a series of inductions for steroid-receptor-DNA complex, two intermediate transit compartments, TAT mRNA, and TAT activity. Results indicate that GR mRNA and TAT mRNA are major controlling factors for the receptor/gene-mediated effects of corticosteroids.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF02354270
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  • 57
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    Electronic Resource
    Bayesian design criteria: Computation, comparison, and application to a pharmacokinetic and a pharmacodynamic model (1995)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 23 (1995), S. 101-125 
    Details
    ISSN: 1573-8744
    Keywords: Bayesian designs ; Bayesian estimation ; prior distribution ; pharmacokinetics ; pharmacodynamics ; E max model ; nonlinear models
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract In this paper 3 criteria to design experiments for Bayesian estimation of the parameters of nonlinear models with respect to their parameters, when a prior distribution is available, are presented: the determinant of the Bayesian information matrix, the determinant of the preposterior covariance matrix, and the expected information provided by an experiment. A procedure to simplify the computation of these criteria is proposed in the case of continuous prior distributions and is compared with the criterion obtained from a linearization of the model about the mean of the prior distribution for the parameters. This procedure is applied to two models commonly encountered in the area of pharmacokinetics and pharmacodynamics: the one-compartment open model with bolus intravenous single-dose injection and theE max model. They both involve two parameters. Additive as well as multiplicative gaussian measurement errors are considered with normal prior distributions. Various combinations of the variances of the prior distribution and of the measurement error are studied. Our attention is restricted to designs with limited numbers of measurements (1 or 2 measurements). This situation often occurs in practice when Bayesian estimation is performed. The optimal Bayesian designs that result vary with the variances of the parameter distribution and with the measurement error. The two-point optimal designs sometimes differ from the D-optimal designs for the mean of the prior distribution and may consist of replicating measurements. For the studied cases, the determinant of the Bayesian information matrix and its linearized form lead to the same optimal designs. In some cases, the pre-posterior covariance matrix can be far from its lower bound, namely, the inverse of the Bayesian information matrix, especially for theE max model and a multiplicative measurement error. The expected information provided by the experiment and the determinant of the pre-posterior covariance matrix generally lead to the same designs except for theE max model and the multiplicative measurement error. Results show that these criteria can be easily computed and that they could be incorporated in modules for designing experiments.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF02353788
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  • 58
    Electronic Resource
    Electronic Resource
    A semicompartmental modeling approach for pharmacodynamic data assessment (1995)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 23 (1995), S. 307-322 
    Details
    ISSN: 1573-8744
    Keywords: effect-site link model ; semicompartmental model ; model misspecification ; pharmacokinetics ; pharmacodynamics ; nonlinear regression
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract A new method is proposed for modeling the temporal aspects of the pharmacodynamic-pharmacokinetic relationship of drugs. A semicompartmental solution to the effect-site link model of Sheiner et al. (1) formed the basis for this new approach. This semicompartmental solution does not require the specification of a compartmental model for the pharmacokinetic response and may offer an advantage when model misspecification is present in using standard compartmental models. A Monte Carlo simulation study was conducted to evaluate the performance of the semicompartmental modeling approach. This method is easily implemented in standard nonlinear regression packages.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF02354287
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  • 59
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    Electronic Resource
    Pharmacokinetics and Anticonvulsant Effect of a New Hypnotic, CL 284,846, in Rats (1995)
    Springer
    Pharmaceutical research 12 (1995), S. 1592-1597 
    Details
    ISSN: 1573-904X
    Keywords: anticonvulsant ; CL 284,846 ; CL 284,859 ; pentylenetetrazol ; pharmacokinetics ; pharmacodynamics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. CL 284,846 (CL846) is an investigational non-benzodiazepine agent with hypnotic, anxiolytic, myorelaxant and anticonvulsant properties. This study assessed the pharmacokinetics and anticonvulsant action of CL846 in female Sprague-Dawley rats. Methods. CL846 pharmacokinetics were examined after either an iv bolus dose (2.5 mg/kg) or a 6-hr infusion (0.4 mg/kg/hr). CL846 pharmacodynamics were evaluated with a pentylenetetrazol (PTZ) infusion 5 min after a CL846 in bolus dose (0 to 10 mg/kg). CL846 and the derived metabolite CL 284,859 (CL859) concentrations in serum and brain tissue were determined by HPLC with fluorescence detection. Results. Both the steady-state volume of distribution (1636 ± 162 and 1804 ± 293 ml/kg, after bolus and infusion administration, respectively) and systemic clearance (19.1 ± 7.1 and 22.2 ± 4.3 ml/min/kg for bolus and infusion administration, respectively) were high. No differences in pharmacokinetic parameters were noted between the two modes of administration. The relationship between anticonvulsant effect and brain/serum concentrations was well described by an Emax model. CL846 was as effective as triazolam in antagonizing PTZ-induced seizures. Conclusions. Under the conditions of the present study, CL846 pharmacokinetics were linear and stationary. Further evaluation of the anticonvulsant properties of CL846 is warranted, including the potential development of tolerance, which is well known for benzodiazepines.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1016224629614
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  • 60
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    Electronic Resource
    MicroPharm-K, a Microcomputer Interactive Program for the Analysis and Simulation of Pharmacokinetic Processes (1995)
    Springer
    Pharmaceutical research 12 (1995), S. 1225-1230 
    Details
    ISSN: 1573-904X
    Keywords: pharmacokinetics ; nonlinear minimisation ; computer program ; software ; estimation ; simulation
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. The microcomputer program, MicroPharm-K (MP-K) was developed for pharmacokinetic modeling, including analysis of experimental data and estimation of relevant parameters, and simulation. The intention was to provide a user-friendly, interactive, event-driven program for PC computers. Methods. The data are ascribed to a predefined model from a library including various routes of administration, oral or intra-venous, bolus or infusion, and various compartmental interpretations, 1 to 3. Single and multiple administrations are supported. The program provides initial estimates of the parameters in most cases, and the parameters are then fitted to the model by non linear model fitting using either the Simplex, Evol, Gauss-Newton, Levenberg-Marquardt or Fletcher-Powell algorithms. The non linear model fitting is based on the maximum likelihood method, and the criterion to minimize is either the weighted least squares (Chi2 criterion) or the extended least squares. Graphical representations of non-fitted or curve-fitted data are immediately available (including log-scale representation), as well as pharmacokinetic typical parameters such as area under the curve, clearance, volumes, time-rate constants, transfer rate constants, etc. Results. Simulated and experimental data were analysed and the results were similar to those obtained by other programs. Conclusions. This non linear fitting program has been proved in our laboratory to be a very effective package for pharmacokinetic studies, including estimation and simulation. Because it is easy-to-use and runs on basic computers, the program could also be used for educational purposes.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1016280430580
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  • 61
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    Electronic Resource
    Absorption and Presystemic Metabolism of Nefazodone Administered at Different Regions in the Gastrointestinal Tract of Humans (1995)
    Springer
    Pharmaceutical research 12 (1995), S. 1716-1721 
    Details
    ISSN: 1573-904X
    Keywords: nefazodone ; site of absorption ; intubation ; pharmacokinetics ; P450 metabolism
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. The absorption and disposition of nefazodone (NEF) and its metabolites hydroxynefazodone (HO-NEF), m-chlorophenylpiperazine (mCPP) and triazole dione (dione) were assessed in 10 healthy subjects following infusion of NEF solution into the proximal and distal regions of the intestine vs administration of NEF solution orally by mouth. Methods. NEF HC1 (400 mg) was infused over 5 hours into the proximal or distal intestine through a nasogastric tube, or orally ingested in 10 divided doses over 4.5 hours. The three treatments in the three-period crossover design were separated by one week. Results. The bioavailability of NEF, based on AUC(INF), from proximal and distal regions relative to that from oral administration was 97% and 106%, respectively. NEF was absorbed equally well from all three treatments with median Tmax of 5.0 hours which coincided with the duration of infusion. Mean Cmax of NEF was not different between proximal and oral administrations, however, mean Cmax after distal instillation was 40% lower than that after oral administration. Exposure to HO-NEF, mCPP and dione, following proximal instillation was also comparable to that after oral administration. AUC(INF) of HO-NEF and dione was significantly lower after distal instillation compared to that after oral administration but AUC(INF) of mCPP was not. Cmax of all metabolites was significantly lower after distal administration in comparison to oral treatment. Terminal half-life for NEF, HO-NEF and mCPP after distal administration was longer than the other two treatments. Conclusions. NEF is absorbed throughout the length of the gastrointestinal tract which supports the development of an extended-release formulation of NEF. The exposure to the metabolites (relative to NEF) was lower from the distal intestinal site compared to the proximal and oral site which may be explained by a reduced first pass of NEF by the cytochrome P450 3A4 in the distal intestine.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1016265705932
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  • 62
    Electronic Resource
    Electronic Resource
    Contribution of Parenchymal and Non-Parenchymal Liver Cells to the Clearance of Hepatocyte Growth Factor From the Circulation in Rats (1995)
    Springer
    Pharmaceutical research 12 (1995), S. 1737-1740 
    Details
    ISSN: 1573-904X
    Keywords: hepatocyte growth factor ; receptor-mediated endocytosis ; pharmacokinetics ; liver
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. The distribution of 125I-hepatocyte growth factor (HGF) to either liver parenchymal cells (PC) or non-parenchymal cells (NPC) was investigated in rats. Methods. After injection of a trace amount of 125I-HGF, the distribution of radioactivity determined by microautoradiography closely resembled that of 125I-epidermal growth factor which distributes mainly to PC. Results. The uptake clearance of 125I-HGF estimated by determining the radioactivity of isolated liver cells was three times higher for PC than for NPC. This suggests that HGF distributes mainly to PC at relatively low doses. On the other hand, the uptake clearance by PC fell on coadministering an excess (80 µg/kg) of unlabeled HGF, while no change was observed for NPC, indicating that a saturable process for the hepatic handling of HGF exists only in PC where the HGF receptor is expressed. Conclusions. At such a dose the uptake clearance was comparable for both PC and NPC showing that HGF distributes to both cell types although NPC have few HGF receptors. Since the distribution to NPC was relatively non-specific and heparin-sensitive, it may be that heparin-like substances, which are believed to exist on PC and/ or the extracellular matrix, also exist on NPC.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1016273907749
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  • 63
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    Electronic Resource
    The Problem of Racemization in the Stereospecific Assay and Pharmacokinetic Evaluation of Ketorolac in Human and Rats (1995)
    Springer
    Pharmaceutical research 12 (1995), S. 1652-1657 
    Details
    ISSN: 1573-904X
    Keywords: ketorolac ; racemization ; inversion ; stereospecific assay ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. A comparison of a previously reported indirect (precolumn derivatization) assay for ketorolac (KT) and a new direct method described here was made to establish the conditions under which KT may undergo racemization and to explain the observed discrepancies in the pharmacokinetics of KT reported in the literature. Methods. A previously reported pre-column derivatization method and a new direct method were employed to determine the effect of pH and ionic strength on racemization. Using the conditions where no racemization occurred, the pharmacokinetics in humans and rats, and protein binding of KT enantiomers were determined. Results. Under the chromatographic conditions employed for the direct assay, no racemization was observed. Under high pH and ionic strength, however, both methods resulted in KT racemization. The indirect method resulted in rapid and complete racemization due to the strong basic conditions required for derivatization. In both humans and rats, the pharmacokinetics of racemic KT were stereoselective with the R enantiomer being predominant (AUC S/R: humans, 0.26; Rats: 0.45). This is likely due to more extensive plasma protein binding of S than its antipode (unbound S/R: 1.35). Conclusions. The discrepancies in the literature may be explained by rapid racemization of KT that occurs during sample preparation for the pre-column derivatization method. Considerations should be given to the possibility of racemization during the assay development and validation.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1016245101389
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  • 64
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    Electronic Resource
    Prolonged Circulation of Recombinant Human Granulocyte–Colony Stimulating Factor by Covalent Linkage to Albumin Through a Heterobifunctional Polyethylene Glycol (1995)
    Springer
    Pharmaceutical research 12 (1995), S. 1883-1888 
    Details
    ISSN: 1573-904X
    Keywords: albumin ; granulocyte-colony stimulating factor ; polyethylene glycol ; protein conjugate ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. Recombinant human granulocyte-colony stimulating factor (rhG-CSF) was covalently conjugated to both rat and human serum albumin (RSA and HSA respectively) to increases the circulating half life (t1/2) of rhG-CSF. Methods. Conjugates of RSA (MW 67,000) and HSA (MW 66,000) were prepared by linking the two proteins through a heterobifunctional maleimido-carboxyl polyethylene glycol (PEG) and were tested in the rat. The conjugates were injected intravenously (IV) at the equivalent dose of 50 µg/kg of rhG-CSF, and white blood cell (WBC) counts and plasma concentrations of drug were determined. A comparison of pharmacokinetic parameters was made between rhG-CSF, the conjugates RSA-PEG-rhG-CSF and HSA-PEG-rhG-CSF, and a non-covalent mixture of rhG-CSF and HSA. Results. The albumin-rhG-CSF conjugates are eliminated more slowly from the circulation. The clearance values are reduced from 0.839 ± 0.121 ml/mm/kg for rhG-CSF to 0.172 ± 0.013 ml/min/kgfor RSA-PEG-rhG-CSF and 0.141 ± 0.005 ml/mm/kg for HSA-PEG-rhG-CSF. WBC counts increased in both absolute number and duration as compared to rhG-CSF alone. The albumin rhG-CSF conjugates had enhanced serum stability relative to free rhG-CSF. The rate of degradation of the albumin conjugates incubated in rat serum at 37°C decreased five fold. Conclusions. The results from the study show that specific conjugation of rhG-CSF to albumin decreases plasma clearance in vivo, causes increased WBC response, and increases serum stability as compared to free rhG-CSF.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1016227519561
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    Electronic Resource
    Evidence for the Lack of a Human Metabolic Isotope Effect of a Deuterium Analog of Fluphenazine (1995)
    Springer
    Pharmaceutical research 12 (1995), S. 1388-1390 
    Details
    ISSN: 1573-904X
    Keywords: fluphenazine ; stable isotope ; deuterium labeled ; mass spectrometry ; schizophrenics ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1016298329188
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  • 66
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    Electronic Resource
    Pharmacokinetics of Oral Extended-Release Dosage Forms. I. Release Kinetics, Concentration, and Absorbed Fraction (1995)
    Springer
    Pharmaceutical research 12 (1995), S. 720-728 
    Details
    ISSN: 1573-904X
    Keywords: extended-release ; in vivo release kinetics ; pharmacokinetics ; absorbed fraction ; in vitro/in vivo correlation absorption rate
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract In this study, we derive pharmacokinetic models for oral extended-release (OER) drug products with defined in vivo release kinetics (IVRK) and a compartmental system. Fitting the model to clinical data, we were able to examine the correlation between released and absorbed fractions. Furthermore, we found that absorbed fractions of OER products can be expressed by absorption rate and release duration only. The expression is unchanged in different compartmental systems with the same IVRK, implying that the IVRK drives the pharmacokinetic system of an OER product. The apparent absorption rate constant of an OER product can be estimated by solving an implicit equation using observed concentrations. We also propose a new method for calculating absorbed fractions, which is more accurate than Loo-Riegelman method. Ultimately, these methods may permit optimally designed OER products.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1016215827004
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  • 67
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    Electronic Resource
    Comprehensive Pharmacokinetics of Urinary Human Follicle Stimulating Hormone in Healthy Female Volunteers (1995)
    Springer
    Pharmaceutical research 12 (1995), S. 844-850 
    Details
    ISSN: 1573-904X
    Keywords: urinary human FSH ; pharmacokinetics ; immunoassay ; in vitro bioassay ; immunoassay:bioassay ratio
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. The study determined the pharmacokinetics of urinary human follicle stimulating hormone (u-hFSH) in 12 down-regulated healthy female volunteers. Methods. Following pituitary desensitization, baseline FSH serum levels were measured over a 24-hour period. Then each subject received, in random order, single doses of u-hFSH (Metrodin®), 75 IU, 150 IU and 300 IU iv, and 150 IU im on four occasions separated by washout periods of one week. Blood and urine samples were collected at preset times. FSH levels were measured by a immuno-radiometric assay and an in vitro rat granulosa cells aromatase bioassay. Results. All doses of u-hFSH were well tolerated. After an iv bolus, the pharmacokinetics of FSH were well described by a two-compartment open model. Immunoassay data showed that the total exposure to FSH was proportional to the administered dose. Mean total clearance of FSH was approximately 0.5 L·h−1 and renal clearance was 0.14 L·h−1. The volume of distribution at steady-state was around 8 liters. The distribution half-life was 2 h and the terminal half-life nearly one day. After im injection, almost two thirds of the administered dose was available systemically. The in vitro bioassay confirmed this pharmacokinetic analysis. Conclusions. The estimation of the elimination half-life of around one day indicates that the maximal effect of a given dose of u-hFSH administered daily cannot be observed until 3 to 4 days of repeated administration. This indicates that, on a pure pharmacokinetic basis, physicians should wait at least 4 days to assess the efficacy of a given dose of u-hFSH and that they should not modify dosage too frequently.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1016204919251
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  • 68
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    Electronic Resource
    Soft Drugs 19. Pharmacokinetics, Metabolism and Excretion of a Novel Soft Corticosteroid, Loteprednol Etabonate, in Rats (1995)
    Springer
    Pharmaceutical research 12 (1995), S. 875-879 
    Details
    ISSN: 1573-904X
    Keywords: soft corticosteroid ; loteprednol etabonate ; pharmacokinetics ; metabolism ; excretion
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. Pharmacokinetics, metabolism and excretion of loteprednol etabonate (LE) were investigated in rats. Methods. The pharmacokinetic studies were performed by iv injections of LE (1-20 mg/ kg). In the metabolism and excretion studies, 0.5-10 mg/kg of LE were iv administered, bile and urine samples were collected for 6 hr. Results. The pharmacokinetic of LE showed a rapid, dose-dependent elimination with a total blood clearance (CLtotal) of higher than 60 ml/min/kg. The metabolism and excretion of LE also showed a marked dose-dependency. At 6 hr after iv of LE (0.5-10 mg/kg), the total recoveries (LE and the metabolites, AE & A, in bile and urine) were 99.35-26.72%. However, only about 2% of LE was excreted from the body through the urine. There were 0.93-2.12% and 0.66-0.26% of AE, and 75.67-19.69% and 20.74-2.77% of A excreted in the bile and urine, respectively. The excretion of A was dose dependent, and significantly higher at the lower dose. Using the (% of total excretion) vs. (log dose) plots, it could be predicted that almost all of the administered LE will be metabolized, and excreted as A when the systemic dose is lower than 0.25 mg/kg. Conclusions. The results indicate that LE absorbed systemically, after topical administration, can be rapidly transformed to the inactive metabolites, and eliminated from the body mainly through the bile and urine.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1016265105139
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  • 69
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    Electronic Resource
    Sumatriptan Absorption from Different Regions of the Human Gastrointestinal Tract (1995)
    Springer
    Pharmaceutical research 12 (1995), S. 138-143 
    Details
    ISSN: 1573-904X
    Keywords: sumatriptan ; gastrointestinal tract ; absorption ; metabolism ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Sumatriptan exhibits low oral bioavailability partly due to presystemic metabolism, which may vary with regional differences in metabolic activity throughout the gastrointestinal tract. This study evaluated sumatriptan absorption in humans after administration orally and by oroenteric tube into the jejunum and cecum. Because the site of cecal administration varied, pharmacokinetic parameters for sumatriptan and its major metabolite were compared statistically only after oral and jejunal administration. One-half of the oral dose was recovered in the urine as parent (3%) and metabolite (46%). Sumatriptan was absorbed throughout the gastrointestinal tract; absorption was similar after oral and jejunal administration, and less after cecal administration. The metabolite AUC and the AUC ratio (metabolite/parent) were significantly lower after jejunal compared to oral administration; the AUC ratio was two-fold lower after cecal administration. Results suggest that presystemic metabolism of sumatriptan varies throughout the gastrointestinal tract and/or regional differences exist in the absorption of metabolite formed within the gastrointestinal tract.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1016211409315
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  • 70
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    Electronic Resource
    Effect of Norfloxacin on Theophylline Disposition: A Comparison with Other Fluoroquinolones (1995)
    Springer
    Pharmaceutical research 12 (1995), S. 257-262 
    Details
    ISSN: 1573-904X
    Keywords: norfloxacin ; theophylline ; pharmacokinetics ; drug–drug interactions ; ciprofloxacin ; enoxacin
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The effects of norfloxacin (NOR), at steady-state plasma concentrations of 0–32 mg · 1−1, on the plasma clearance of a 6 mg · kg-1 iv bolus dose of theophylline (THEO) in the male Sprague-Dawley rat have been studied. The effects were characterised by a Ki value (Ki = 12 µM), which was comparable with Ki values obtained previously under identical conditions for ciprofloxacin, but higher than that obtained for enoxacin. The distributional characteristics, volume of distribution and liver to plasma concentration ratio, were very similar for the three compounds. The only marked pharmacokinetic differences were in hepatic clearance, where there was a rank order NOR 〉 ciprofloxacin 〉 enoxacin, a reverse of the order in the reduction of THEO clearance seen in clinical studies. The advantages of using the steady-state experimental design described here are that equivalent concentrations are utilised to compare related drugs and differences in pharmacokinetics are accounted for, to allow a direct comparison of potency. This information, together with additional pharmacokinetic considerations, suggests that the different effects on THEO clearance seen in the clinic for NOR, ciprofloxacin and enoxacin are not solely due to differences in inhibitory potency, but also involve differences in hepatic clearance and hence systemic availability of the fluoroquinolones.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1016287128048
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  • 71
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    Electronic Resource
    Pharmacokinetics of 1 -(2-Deoxy-2-fluoro-β-L-arabino-furanosyl)-5-methyluracil (L-FMAU) in Rats (1995)
    Springer
    Pharmaceutical research 12 (1995), S. 1350-1353 
    Details
    ISSN: 1573-904X
    Keywords: l-(2-deoxy-2-fluoro-β-L-arabinofuranosyl)-5-methyluracil ; L-FMAU ; nucleoside ; pharmacokinetics ; hepatitis B virus
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. The objective of this study was to characterize the pharmacokinetics of 1 -(2-deoxy-2-fluoro-β-L-arabinofuranosyl)-5-methyluracil (L-FMAU), a nucleoside analogue with potent activity against the hepatitis B virus and the Epstein-Barr virus, in rats. Methods. Three doses of L-FMAU were administered intravenously (10, 25, and 50 mg/kg) to rats, and L-FMAU concentrations in plasma and urine were measured by HPLC. Pharmacokinetic parameters were generated by using area-moment analysis. Results. There were no significant differences in the pharmacokinetic parameters between the three doses (α 〈 0.05). Thus, the disposition of L-FMAU was linear over the dosage of 10 to 50 mg/kg. Plasma concentrations of L-FMAU declined rapidly with a terminal phase half-life of 1.33 ± 0.45 h (mean ± SD). Total clearance of L-FMAU was moderate, averaging 1.15 ± 0.28 L/h/kg. The fraction of compound excreted unchanged in urine was 0.59 ± 0.13. No glucuronide metabolite was found in the urine. The steady-state volume of distribution was 1.12 ± 0.26 L/kg indicating intracellular distribution of the compound. The fraction of L-FMAU bound to plasma proteins was approximately 15% and was independent of nucleoside concentration. Conclusions. The pharmacokinetics of L-FMAU in rats were independent of dose over the dosage range of 10 to 50 mg/kg.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1016234009624
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  • 72
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    Electronic Resource
    Use of Parent Drug and Metabolite Data in Bioavailability Assessment of a Novel Diltiazem HC1 Once-Daily Product (1995)
    Springer
    Pharmaceutical research 12 (1995), S. 2071-2074 
    Details
    ISSN: 1573-904X
    Keywords: absorption rate ; bioavailability ; bioequivalence ; diltiazem ; metabolites ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1016241317260
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  • 73
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    Pharmacokinetic Study of Zeolite A, Sodium Aluminosilicate, Magnesium Silicate, and Aluminum Hydroxide in Dogs (1995)
    Springer
    Pharmaceutical research 12 (1995), S. 270-274 
    Details
    ISSN: 1573-904X
    Keywords: Zeolite A ; silicon ; aluminum ; bioavailability ; pharmacokinetics ; sodium aluminosilicate ; magnesium trisilicate ; aluminum hydroxide ; dog
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Zeolite A is a synthetic zeolite which may have therapeutic utility in osteoporotic individuals because of its ability to stimulate bone formation. A study of Zeolite A (30 mg/kg), sodium aluminosilicate (16 mg/kg), magnesium trisilicate (20 mg/kg), and aluminum hydroxide (675 mg) was designed in beagle dogs. The purpose of this study was to compare the oral bioavailability of silicon and aluminum from Zeolite A, sodium aluminosilicate, magnesium trisilicate, and aluminum hydroxide in dogs. Twelve female dogs received each compound as a single dose separated by one week in a randomized, 4-way, crossover design. Plasma samples were drawn at time 0 and for 24 hours after dosing. The concentrations of silicon and aluminum were determined by graphite furnace atomic absorption. The mean plasma silicon AUC values (±S.D.) were 9.5 ± 4.5, 7.7 ± 1.6, 8.8 ± 3.0, 6.1 ± 1.9 mg · hr/L and the mean plasma silicon Cmax values (±S.D.) were 1.07 ± 1.06, 0.67 ± 0.27, 0.75 ± 0.31, 0.44 ± 0.17 mg/L for Zeolite A, sodium aluminosilicate, magnesium trisilicate, and aluminum hydroxide respectively. Although mean silicon AUC and Cmax values were elevated when compared to baseline after administration of the silicon containing compounds, only the AUC from Zeolite A reached statistical significance (p = 0.041). The mean plasma silicon Tmaxvalues (±S.D.) were 7.9 ± 6.4, 5.8 ± 4.6, 6.9 ± 6.3 and 8.5 ± 3.4 hrs for Zeolite A, sodium aluminosilicate, magnesium trisilicate and aluminum hydroxide respectively. These values were not statistically different. The mean plasma aluminum AUC values for Zeolite A, sodium aluminosilicate, magnesium trisilicate and aluminum hydroxide (±S.D.) were 342 ± 111, 338 ± 167, 315 ± 69, 355 ± 150 µg · hr/L and the mean aluminum Cmax values (±S.D.) were 29 ± 9, 27 ± 14, 24 ± 5 µg/L, 29 ± 11 respectively. The plasma aluminum Tmax values (±S.D.) were 3.5 ± 4.1, 4.2 ± 4.3, 5.7 ± 7.3 and 5.0 ± 4.7 hrs for Zeolite A, sodium aluminosilicate, magnesium trisilicate, and aluminum hydroxide respectively. There was no statistically significant absorption of aluminum from the aluminum containing treatments.
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    URL: http://dx.doi.org/10.1023/A:1016291228957
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    Pharmacodynamics and pharmacokinetics of clentiazem and diltiazem in closed-chest anesthetized dogs (1995)
    Springer
    Cardiovascular drugs and therapy 9 (1995), S. 685-692 
    Details
    ISSN: 1573-7241
    Keywords: clentiazem ; diltiazem ; pharmacodynamics ; pharmacokinetics ; cardiac function
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary In the present study we investigated the relationship between pharmacodynamic and pharmacokinetic properties of the benzothiazepine-like calcium antagonists, clentiazem and diltiazem. Experiments were carried out in closed-chest anesthetized dogs, instrumented for hemodynamic recording and blood sampling. Clentiazem and diltiazem bolus injections (400 µg/kg) were administered intravenously, and subgroups of animals were sacrificed at 15, 30, 60, or 120 minutes Clentiazem and diltiazem plasma and myocardial levels were determined by high performance liquid chromatography (HPLC). Clentiazem elicited a more marked reduction in mean arterial pressure (−17% for clentiazem vs. −12% for diltiazem), along with an attenuation of the expected positive reflex chronotropic response. Pharmacokinetic analysis revealed that clentiazem had a greater volume of distribution (33±16 l vs. 15±9 l for diltiazem), while the half-life of elimination (t1/2β) was similar (55±21 minutes vs. 59±23 minutes). The kinetic disposition profile of both drugs was analyzed through myocardial/plasma concentration ratios. In the distribution phase (0–15 minutes), this ratio was similar (26±2 for clentiazem vs. 18±5 diltiazem), suggesting that the myocardium was not a preferential site of distribution for either drugs. Data collected within the elimination phase indicate significant myocardial retention for clentiazem; at the end of the study period, the myocardial/plasma concentration ratio was twofold higher for clentiazem. The observed retention of clentiazem in the myocardium may be responsible for attenuation of the baroreflex. Clentiazem increased potency was confirmed by the fact that its hypotensive and cardioinhibitory effects were observed at lower plasma concentrations.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00878551
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  • 75
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    Morphology and evolutionary implications of the annual cycle of secretion and sperm storage in spermathecae of the salamander Ambystoma opacum (Amphibia: Ambystomatidae) (1995)
    New York, NY : Wiley-Blackwell
    Journal of Morphology 223 (1995), S. 35-46 
    Details
    ISSN: 0362-2525
    Keywords: Life and Medical Sciences ; Cell & Developmental Biology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Biology , Medicine
    Notes: Females of the marbled salamander, Ambystoma opacum, store sperm in exocrine glands called spermathecae in the roof of the cloaca. Eggs are fertilized by sperm released from the spermathecae during oviposition. Some sperm remain in the spermathecae following oviposition, but these sperm degenerate within a month and none persists more than 6 mo after oviposition. Thus, sperm storage between successive breeding seasons does not occur. Apical secretory vaculoes are abundant during the fall mating season and contain a substance that is alcian blue+ at pH 2.5. Production of secretory vacuoles decreases markedly after oviposition, and the glands are inactive by the summer months. Ambystoma opacum is a terrestrial breeder, and some mating occurs prior to arrival at pond basins where oviposition occurs. Mating prior to arrival at the ovipository site may prolong the breeding season, leading to fitness implications for both males and females. Females have opportunities for more matings, and the possibilities for sperm competition in the spermathecae are enhanced. © 1995 Wiley-Liss, Inc.
    Additional Material: 5 Ill.
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    URL: http://dx.doi.org/10.1002/jmor.1052230106
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    Annual changes in fine structure of inner epithelial lining of the ovary of a marine sculpin, Alcichthys alcicornis (Teleostei: Scorpaeniformes), with internal gametic association (1995)
    New York, NY : Wiley-Blackwell
    Journal of Morphology 223 (1995), S. 85-97 
    Details
    ISSN: 0362-2525
    Keywords: Life and Medical Sciences ; Cell & Developmental Biology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Biology , Medicine
    Notes: Alcichthys alciocornis has a viscous ovarian fluid in the ovarian cavity, which plays an important role in its unique mode of reproduction called internal gametic association (i.e., internal insemination and sperm-egg association but a delay in the physiological fertilization until spawning). Seasonal changes in fine structure of the inner epithelial lining and capillary endothelium of the ovary revealed that ovarian fluid originated as a result of the secretory activity of the tissues. The ovarian cavity of A. alcicornis is lined with an ovigerous lamella epithelium and an ovarian wall epithelium. During the spawning period, both epithelia actively secreted proteinaceous substances which seemed to constitute the ovarian fluid. The substances appear to be synthesized in the rough-surfaced endoplasmic reticulum from the material which was transported from the blood capillary, taken into the epithelial cells by endocytosis, accumulated in secretory vesicles via Golgi apparatus in the cells, and finally released into the ovarian cavity by exocytosis. Microapocrine secretion was also observed to occur in both epithelia. Secretory activity of both epithelia by exocytosis and microapocrine secretion showed distinct seasonal changes. Active exocytosis and microapocrine secretion were observed during the spawning period (April-May). These activities slightly declined during the degeneration period (May-June) and were lost during the early recovery period (July). During the mid to late recovery period (October-March), there was some exocytosis but no microapocrine secretion. © 1995 Wiley-Liss, Inc.
    Additional Material: 10 Ill.
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    URL: http://dx.doi.org/10.1002/jmor.1052230108
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    Surface morphology of hamster (Mesocricetus auratus) decidual cells in vitro (1995)
    New York, NY : Wiley-Blackwell
    Journal of Morphology 223 (1995), S. 167-174 
    Details
    ISSN: 0362-2525
    Keywords: Life and Medical Sciences ; Cell & Developmental Biology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Biology , Medicine
    Notes: Cell surface morphology of hamster decidual cells isolated from day 8 implantation swellings was studied, using both phase-contrast and scanning electron microscopy. Two kinds of cells, fibroblastic and epithelioid, were identified in cultures examined by phase-contrast microscopy. Fibroblastic cells were spindle-shaped, having pointed or blunt terminals on one end and bifid or webbed projections at the other end. Epithelioid cells, on the other hand, were flat and discoid, having a distinctively ruffled plasma membrane. Further, the plasma membrane of epithelioid cells formed rope-like or flange-like processes. The significance of such adaptations is discussed. © 1995 Wiley-Liss, Inc.
    Additional Material: 9 Ill.
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    URL: http://dx.doi.org/10.1002/jmor.1052230205
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    Skeletal morphogenesis in the urodele skull: II. Effect of developmental stage in thyroid hormone-induced remodeling (1995)
    New York, NY : Wiley-Blackwell
    Journal of Morphology 223 (1995), S. 149-166 
    Details
    ISSN: 0362-2525
    Keywords: Life and Medical Sciences ; Cell & Developmental Biology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Biology , Medicine
    Notes: This study investigates the effect of developmental stage on thyroid hormone (TH)-mediated remodeling in the skeletal tissues of hemidactyliine plethodontid urodeles. Rate of morphogenesis was quantified in 17 metamorphic tissues for three different size-age classes of Eurycea bislineata larvae immersed in a metamorphic dosage of T4. Extent of morphogenesis after a 3-week immersion was also quantified in these tissues plus four larval ones for the full size range of E. bislineata larvae and for less complete size ranges of E. wilderae, E. longicauda guttolineata, Gyrinophilus porphyriticus, and Pseudotriton ruber larvae. Although all tissues respond more slowly with decreasing size/age, two tissue-specific effects are evident in all species. Larval ossifications are less inducible than metamorphic ossifications, and progressive metamorphic events are more retarded and, in some cases, more prone to abnormal morphogenesis than regressive ones. The first effect agrees with the prediction that tissues that naturally remodel at metamorphosis are more responsive to a metamorphic dosage of TH than those that respond at a larval stage and lower TH. The second effect agrees with the prediction that progressive morphogenesis is more likely to be impaired at small size than regressive morphogenesis, although the frequent discrepancies between individuals of similar size implicate developmental age more than size in this effect. Collectively, these two effects provide only equivocal support for the hypothesis that direct development in plethodontids evolved via precocious TH activity. However, the unexpected transition from ceratobranchial replacement to ceratobranchial shortening in medium-sized larvae suggests that the former pathway requires a longer period of cell specification at low TH. Since ancestral plethodontids appear to have been distinguished by an exceptionally long larval period with exceptionally low TH activity, this developmental prerequisite may in turn be partly responsible for their singular evolution of ceratobranchial replacement. © 1995 Wiley-Liss, Inc.
    Additional Material: 6 Ill.
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    URL: http://dx.doi.org/10.1002/jmor.1052230204
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    Atomic force microscopy of the morphology of the matrix and mineral components of the otolith of Hyperoglyphe antarctica (1995)
    New York, NY : Wiley-Blackwell
    Journal of Morphology 223 (1995), S. 203-214 
    Details
    ISSN: 0362-2525
    Keywords: Life and Medical Sciences ; Cell & Developmental Biology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Biology , Medicine
    Notes: The sagittal otolith of Hyperoglyphe antarctica (Centrolophidae: Teleostei) has a prismatic structure in which the anti-sulcal growth axes of each prism consist of a series of nested cones each composed of a mineral layer followed by an organic matrix layer. Broken sections show the mineral layers to be composed of stacks of crystals. Otolith matrix that has been decalcified and air-dried, or critical-pont-dried, retains a periodic structure of repeating high and low matrix density. At high magnifications, both broken whole crystal surfaces and decalcified matrix surfaces have a granular structure. Chloroxbleached whole otoliths also show a granular crystalline structure. At higher magnifications, the air-dried matrix showed a parallel fiber structure with similar dimensions to keratin fibers. © 1995 Wiley-Liss, Inc.
    Additional Material: 7 Ill.
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    URL: http://dx.doi.org/10.1002/jmor.1052230208
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    Cellular ultrastructure and catecholamine histofluorescence of the heart of the Australian lungfish, Neoceratodus forsteri (1995)
    New York, NY : Wiley-Blackwell
    Journal of Morphology 223 (1995), S. 191-201 
    Details
    ISSN: 0362-2525
    Keywords: Life and Medical Sciences ; Cell & Developmental Biology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Biology , Medicine
    Notes: Ultrastructural descriptions of the dipnoan heart are lacking. Many ultrastructural features of the heart of the Australian lungfish, Neoceratodus forsteri, resemble those of other lower vertebrates. The epicardial cells appear to be adapated for the exchange of material with the pericardial fluid. The most prominent features of the endocardial cells are numerous moderately electron-dense vesicles found within the cytoplasm. These organelles might have an endocrine function. The myocardiocytes are typically small. The banding pattern of the sarcomere is shared with most fish. The intercalated disc has a convoluted path and consists of desmosomes and fascia adherens. Caveolae are a prominent feature of the sarcoplasm. The sarcoplasmic reticulum is sparse, and T-tubules are lacking. Atrial myocardial dense bodies occur in vast numbers throughout the atrium and are occasionally seen in the ventricle. These vesicles are chromaffin-positive but fail to show catecholamine fluorescence. They are likely to contain peptides related to ANP. Subendothelial cells exhibiting catecholamine-specific fluorescence are scattered throughout the atrium. Ultrastructurally these cells contain many chromaffin-positive granules. Chromaffin cells represent another cell type with a probable endocrine function within the heart of N. forsteri. © 1995 Wiley-Liss, Inc.
    Additional Material: 4 Ill.
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    URL: http://dx.doi.org/10.1002/jmor.1052230207
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    Masthead (1995)
    New York, NY : Wiley-Blackwell
    Journal of Morphology 223 (1995) 
    Details
    ISSN: 0362-2525
    Keywords: Life and Medical Sciences ; Cell & Developmental Biology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Biology , Medicine
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1002/jmor.1052230301
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    Morphology of complex lymphoepithelial organs of the anal canal (“anal tonsil”) in the bottlenose dolphin, Tursiops truncatus (1995)
    New York, NY : Wiley-Blackwell
    Journal of Morphology 223 (1995), S. 263-268 
    Details
    ISSN: 0362-2525
    Keywords: Life and Medical Sciences ; Cell & Developmental Biology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Biology , Medicine
    Notes: A complex of lymphoepithelial organs, the “anal tonsils,” is a consistent structure in the anal canal of the bottlenose dolphin, Tursiops truncatus. This complex occurs as a circumferential cluster of discrete tonsil like aggregations of lymphoid tissues, together with epithelial ducts (“crypts”) and occasional mucus secretory units in the extreme lower portion of the intestinal tract. These structures are concentrated in the segment lined by stratified squamous epithelium and extend for a variable distance cephalad from the anal aperture. The tonsils appear to be most active, judged by the amount of lymphoid tissue present, in young animals. Depletion of lymphocytes and cystic enlargement of the crypts, probably representing functional as well as morphological involution, is a consistent feature of older animals. © 1995 Wiley-Liss, Inc.
    Additional Material: 5 Ill.
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    URL: http://dx.doi.org/10.1002/jmor.1052230304
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    Prenatal development of the integument in Delphinidae (Cetacea: Odontoceti) (1995)
    New York, NY : Wiley-Blackwell
    Journal of Morphology 223 (1995), S. 269-287 
    Details
    ISSN: 0362-2525
    Keywords: Life and Medical Sciences ; Cell & Developmental Biology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Biology , Medicine
    Notes: The prenatal development of epidermis, dermis, and hypodermis was studied in embryos of different ago of two delphinid species (Stenella attenuata, Delphinus delphis), using light and transmission electron microscopical methods. The delphinid embryo is covered by a multilayered tissue formed by four different epidermal generations (periderm, stratum intermedium-I, str. intermedium-II, str. spinosum) produced by the str. basale. The first layer appears at about 40-50 mm of body length, the second type (s.i.-I) about 60-160 mm, and the third type (s.i.-II) is present at 160-500 mm. The first spinosal cells are produced at 225-260 mm body length; thenceforth, the epidermis increases continuously in thickness. Epidermal ridge formation begins about 400-mm body length. The development of the dermis is characterized by the early production of thin connective tissue fibers (40- 70-mm body length) and simultaneously the cutaneuous muscle matures in structure. Vascular development intensifies between embryos of 150-225 mm, and collagen production increases markedly in fetuses of 225-260-mm length. These events are paralledled by an increase in dermal thickness. The first elastic fibers can be recognized in the skin from the abdomen at about 600-mm body length. The development of the hypodermis is marked by very rapid and constantly progressing growth, beginning about 60-mm body length. The first typical fat cells appear in animals of 360-400 mm. Regional differences are obvious for all skin layers with regard to the flippers, where structural maturation proceeds more rapidly than in dorsal or abdominal regions. © 1995 Wiley-Liss, Inc.
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    URL: http://dx.doi.org/10.1002/jmor.1052230305
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    Design of the predatory legs of water bugs (Hemiptera: Nepidae, Naucoridae, Notonectidae, Gerridae) (1995)
    New York, NY : Wiley-Blackwell
    Journal of Morphology 223 (1995), S. 289-302 
    Details
    ISSN: 0362-2525
    Keywords: Life and Medical Sciences ; Cell & Developmental Biology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Biology , Medicine
    Notes: Functional comparative morphology of predatory legs in five species of water bugs (Ilyocoris cimicoides, Nepa cinerea, Ranatra linearis, Notonecta glauca, and Gerris lacustris) has been investigatd adn the following peculiarities of leg design were revealed.1Subcoxal articulation may be monoaxial (G. lacustris, N. glauca), or, in contrast to walking leg type, biaxial (N. cinerea, R. linearis, I. cimicoides); the first axis is oriented along the coxa (torsion axis), the second one is perpendicular to the first (non-torsion axis).2In contrast to walking leg type, which is characterized by cross suspension of the axis of coxal rotation in thoracal skeleton, this axis in G. lacustris is placed vertically. Non-torsion coxal axis in R. linearis is oriented strongly transversal. This axis directs the leg strike forward.3Legs in the majority of species are planar: Torsion axes of the coxa, femur, and tibia are placed in the same plane. Axes of rotation of consequent joints in I. cimicoides are reciprocally sloped. Therefore, the end of the leg outlines the spiral trajectory, when all angles of joints are opening (closing). This is an adaptation for clinging to the stems of water plants.4Passive adduction of the femur in the trochanter-femoral joint in N. glauca allows it to go around protuberances of the body wall, when the leg is sliding along them; recurrent femur movement during releasing from the obstacele is active due to the rt.fe muscle.5Only R. linearis has predatory legs, which permit the high-speed pursuit of potential prey; other species realize this function using the swimming legs, whereas the forelegs are used for the manipulation movements.6Muscle arrangement in the prothorax of different species reflects both leg construction and constructional constraints of body design. Powerful flexor muscles (co1, co2, co3, co5, fl.ti, et.ti in R. linearis; fl.ta, fl.ti in N. glauca; fl.ti in I. cimicoides) have long tendons and short muscle bundles, which originate on the leg wall. As a result, the powerful force is developed along the muscle tendon.7Some features of the predatory leg are common for the species studies: elongation of coxae, thickening of femora, and increase of the degree of junction of tibia and tarsus. The muscles, which move the distal segment of the leg, are reinforced and the sclerite of the fl.ti tendon is enlarged. The joint angle of the distal segment is increased to 120°. © 1995 Wiley-Liss, Inc.
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    URL: http://dx.doi.org/10.1002/jmor.1052230306
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    Allometry and developmental integration of body growth in a piranha, Pygocentrus nattereri (Teleostei: Ostariophysi) (1995)
    New York, NY : Wiley-Blackwell
    Journal of Morphology 223 (1995), S. 341-355 
    Details
    ISSN: 0362-2525
    Keywords: Life and Medical Sciences ; Cell & Developmental Biology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Biology , Medicine
    Notes: Piranhas, like many teleosts, change their diets on both ontogenetic and phylogenetic time scales. Prior studies have suggested that pervasive morphological changes in body form on a phylogenetic time scale may be related to changes in diet, but previous reports have found little shape change in piranhas on an ontogenetic time scale. We re-examine the post-transformational allometry of body form in one piranha, Pygocentrus nattereri (Kner), using the method of thin-plate splines decomposed by their partial warps. We find substantial evidence of allometry, primarily elongation of the mid-body relative to the more anterior and posterior regions, elongation of the postorbital and nape regions relative to the more anterior head and posterior body, and deepening of the head relative to the body. In addition to these pervasive changes throughout the body, there are some that are more localized, especially elongation of the postorbital region relative to eye diameter and snout, and an even more localized elongation of the snout relative to eye diameter. Initial dietary transitions are associated with changes in head and jaw proportions, but rates of shape change decelerate through growth, so that the final transition to a diet increasingly dominated by small whole fish appears associated with change largely in overall body size. © 1995 Wiley-Liss, Inc.
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    URL: http://dx.doi.org/10.1002/jmor.1052230309
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    Ultrastructurally different muscle cell types in Eisenia foetida (Annelida, Oligochaeta) (1995)
    New York, NY : Wiley-Blackwell
    Journal of Morphology 224 (1995), S. 87-96 
    Details
    ISSN: 0362-2525
    Keywords: Life and Medical Sciences ; Cell & Developmental Biology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Biology , Medicine
    Notes: Muscles in the body wall, intestinal wall, and contractile hemolymphatic vessels (pseudohearts) of an oligochaete anelid (Eisenia foetida) were studied by electron microscopy. The muscle cells in all locations, except for the outer layer of the pseudohearts, are variants of obliquely striated muscle cells. Cells comprising the circular layer of the body wall possess single, peripherally located myofibrils that occupy most of the cytoplasm and surround other cytoplasmic organelles. The nuclei of the cells lie peripherally to the myofibrils. The sarcomeres consist of thin and thick myofilaments that are arranged in parallel arrays. In one plane of view, the filaments appear to be oriented obliquely to Z bands. Thin myofilaments measure 5-6 nm in diameter. Thick myofilaments are fusiform in shape and their width decreases from their centers (40-45 nm) to their tips (23-25 nm). The thin/thick filament ratio in the A bands is 10. The Z bands consist of Z bars alternating with tubules of the sarcoplasmic reticulum. Subsarcolemmal electron-dense plaques are found frequently. The cells forming the longitudinal layer of the body wall musculature are smaller than the cells in the circular layer and their thick filaments are smaller (31-33 nm centrally and 21-23 nm at the tips). Subsarcolemmal plaques are less numerous. The cells forming the heart wall inner layer, the large hemolymphatic vessels, and the intestinal wall are characterized by their large thick myofilaments (50-52 nm centrally and 27-28 nm at the tips) and abundance of mitochondria. The cells forming the outer muscular layer of the pseudohearts are smooth muscle cells. These cells are richer in thick filaments than vertebrate smooth muscle cells. They differ from obliquely striated muscle cells by possessing irregularly distributed electron-dense bodies for filament anchorage rather than sarcomeres and Z bands and by displaying tubules of smooth endoplasmic reticulum among the bundles of myofilaments. © 1995 Wiley-Liss, Inc.
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    URL: http://dx.doi.org/10.1002/jmor.1052240110
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    Internal fertilization, testis and sperm morphology in glandulocaudinae fishes (Teleostei: Characidae: Glandulocaudinae) (1995)
    New York, NY : Wiley-Blackwell
    Journal of Morphology 224 (1995), S. 131-145 
    Details
    ISSN: 0362-2525
    Keywords: Life and Medical Sciences ; Cell & Developmental Biology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Biology , Medicine
    Notes: In this report, the gonads of 32 glandulocaudine species, representing 18 genera, are compared with 11 outgroup characiform species. Through the presence of spermatozoa within the ovarian cavity, internal fertilization of the female is confirmed for the 16 genera for which mature ovaries were available. No outgroup ovary studied contains spermatozoa. All mature glandulocaudine testes have a large portion of the posterior testis, which is devoid of developing germ cells and spermatocysts (aspermatogenic), devoted to sperm storage, with the degree of partitioning in that region varying greatly within the group. All outgroup species examined have spermatozoa with spherical nuclei. With the exception of the species of the genus Planaltina, which also have spherical nuclei, all glandulocaudines have elongated nuclei, which vary among the species from 3.6 μm to 31.6 μm in length. Distinct sperm packets (spermatozeugmata) are formed in five genera by two different methods. In the genera Xenurobrycon, Tyttocharax, and Scopaeocharax, all of the tribe Xenurobryconini, the spermatozeugmata are formed within the spermatocysts and released fully formed. In all genera of the tribe Glandulocaudini, which includes Glandulocauda and Mimagoniates, loose spermatozoa are released which cluster into spermatozeugmata within the posterior storage areas. These morphological specializations are discussed within a phylogenetic framework as adaptations for internal fertilization and are hypothesized to be independently derived. © 1995 Wiley-Liss, Inc.
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    URL: http://dx.doi.org/10.1002/jmor.1052240203
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    Presence of interdigitating cells in thymus of the sea bass, Dicentrarchus labrax L. (Teleost) (1995)
    New York, NY : Wiley-Blackwell
    Journal of Morphology 224 (1995), S. 199-203 
    Details
    ISSN: 0362-2525
    Keywords: Life and Medical Sciences ; Cell & Developmental Biology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Biology , Medicine
    Notes: Interdigitating cells in the thymus of the sea bass, Dicentrarchus labrax, occur principally in the internal zone and in the border with the external zone. Ultrastructurally, the most characteristic cytological features of these cells are their low electron density, complicated labyrinthine membrane-membrane contacts, scantiness of cytoplasmic organelles, presence of Birbeck-like granules, juxtanuclear tubulo-vesicular complex, and phagocytic capacity. © 1995 Wiley-Liss, Inc.
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    URL: http://dx.doi.org/10.1002/jmor.1052240208
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    Morphological, histochemical, and ultrastructural characterization of the salivary glands and proboscises of three species of glossiphoniid leeches (Hirudinea: Rhynchobdellida) (1995)
    New York, NY : Wiley-Blackwell
    Journal of Morphology 225 (1995), S. 1-18 
    Details
    ISSN: 0362-2525
    Keywords: Life and Medical Sciences ; Cell & Developmental Biology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Biology , Medicine
    Notes: Morphological and ultrastructural features of the salivary glands and proboscises of Placobdella ornata, Placobdella parasitica, and Desserobdella picta were studied by light and electron microscopy. Chemical composition of the salivary cells was investigated using a variety of histochemical techniques. Placobdella ornata and P. parasitica have compact salivary glands with discrete pairs of anterior and posterior glands, while the salivary cells contain one mucous and three proteinaceous secretions. Salivary glands of D. Picta are diffusely arranged and contain two mucous and two proteinaceous secretions. A cobalt-lysine forward-filling technique revealed that individual salivary cells consist of a roughly spherical soma and an elongated ductule. The majority of the internal space in a salivary soma is densely packed with spherical secretory granules which displace the cytoplasm to the periphery of the cell. Bundles of individual ductules enter the base of the proboscis on opposite sides and extend anteriorly. The ductules, also packed with secretory granules, are surrounded by microtubules associated with agranular endoplasmic reticulum, and merge with deep invaginations of the proboscis cuticle. The secretory granules are released at the end of these invaginations or pores. Pores were found on the tip, along the body, and on the luminal wall of the proboscises in all three species. © 1995 Wiley-Liss, Inc.
    Additional Material: 24 Ill.
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    URL: http://dx.doi.org/10.1002/jmor.1052250102
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    In vivo strain in the humerus of pigeons (Columba livia) during flight (1995)
    New York, NY : Wiley-Blackwell
    Journal of Morphology 225 (1995), S. 61-75 
    Details
    ISSN: 0362-2525
    Keywords: Life and Medical Sciences ; Cell & Developmental Biology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Biology , Medicine
    Notes: Longitudinal and principal strain recordings were made in vivo at three sites (dorsal, anterior, and ventral) on the humeral midshaft of pigeons executing five modes of free flight: Take-off, level flight, landing, vertical ascent, and near-vertical descent. Strains were also recorded while the birds flew carrying weights that were 33%, 50%, or 100% of their body weight. The relative distribution of strain measured at the three surface midshaft sites and across the bone's cortex was found to be similar for all flight modes. Principal strains recorded in the dorsal and ventral humerus indicated considerable torsion produced by aerodynamic loading of the wing surface posterior to the bone. Measured torsional shear strains (maximum: 2,700-4,150 μ ε during level flight) were 1.5 times greater than longitudinal strains. In addition to torsion, the humerus is also subjected to significant dorsoventral bending owing to lift forces acting on the wing during the downstroke. Analysis of the cross-sectional distribution of longitudinal strains at the humeral midshaft cortex shows that the orientation of bending shifts in a regular manner during the downstroke, indicating that the wing generates progressively more thurst (vs. lift) later in the downstroke. This shift is less during take-off and vertical ascent when greater lift is required. Peak principal and longitudinal strains increased by an average of only 50% from landing to vertical ascending flight and take-off (e.g., dorsal humerus: -1,503 to -2,329 μ ε) and did not exceed -2,600 μ epsiv; at any site, even when the birds flew carrying twice their body weight. Strains recorded when birds flew at two times their body weight (100% BW load) were similar in magnitude to those recorded during vertical ascent and take-off and likely represent those developed during maximal performance. Strains developed within the midshaft were maximal in the anterodorsal and posteroventral cortices, not at the dorsal, ventral, and anterior sites at which strain was recorded. Consequently, maximum strains experienced by the bone are probably 20-25% greater than those recorded (ca. 3,200 μ ε), indicating a safety factor of about 3.5 for compressive strain failure. The much higher shear strains, however, indicate a lower safety factor (1.9), in which the bone's torsional strength is its most critical design feature. Finally, the magnitude and distribution of strains developed in the humerus of pigeons are generally similar to those recorded in the humerus of large fruit-eating bats during flight. © 1995 Wiley-Liss, Inc.
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    URL: http://dx.doi.org/10.1002/jmor.1052250106
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    Cephalometric correlates of echolocation in the chiroptera: II. Fetal development (1995)
    New York, NY : Wiley-Blackwell
    Journal of Morphology 225 (1995), S. 107-123 
    Details
    ISSN: 0362-2525
    Keywords: Life and Medical Sciences ; Cell & Developmental Biology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Biology , Medicine
    Notes: Cephalometry was used to detect patterns of cranial growth in fetal bats that were stained differentially for bone and cartilage. Three developmental features distinguish embryos of taxa that echolocate nasally from embryos of taxa that echolocate orally: (1) the basicranium is retained ventral to the cervical axis, (2) the rostrum is retained below the basicranial axis, and (3) the lateral semicircular canals are rotated caudally. Together, the first two actions align the fetal nasal cavity with what will be the long axis of the adult body in flight. The third action aligns the lateral semicircular canals with the horizontal. In contrast, skulls of oral-emitting taxa are constructed such that the oral cavity is aligned with the long axis of the body in flight. The evolution of head posture and skull form in microchiropteran bats has been constrained by the demands of vocalization, i.e., ultrasonic echolocation. Accordingly, the ontogeny of the microchiropteran skull has been canalized along two distinct developmental paths - oral-emitting and nasal-emitting Baupläne. © 1995 Wiley-Liss, Inc.
    Additional Material: 10 Ill.
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    URL: http://dx.doi.org/10.1002/jmor.1052250109
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    Masthead (1995)
    New York, NY : Wiley-Blackwell
    Journal of Morphology 225 (1995) 
    Details
    ISSN: 0362-2525
    Keywords: Life and Medical Sciences ; Cell & Developmental Biology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Biology , Medicine
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1002/jmor.1052250301
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    Effects of caffeine treatment on the fine structure, silica secretion, and shell morphology of the testate amoeba Assulina muscorum (1995)
    New York, NY : Wiley-Blackwell
    Journal of Morphology 225 (1995), S. 251-260 
    Details
    ISSN: 0362-2525
    Keywords: Life and Medical Sciences ; Cell & Developmental Biology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Biology , Medicine
    Notes: Assulina muscorum secretes morphologically altered shells when cultured in a medium with 5 mM caffeine. The siliceous scales, normally distributed in a regular overlapping pattern, are disorganized, thicker and wider than normal, and occasionally have incompletely silicified surfaces that appear irregular in profile in transmission electron microscopic ultrathin sections. The shape of the silica deposition vesicles (SDVs) in the cytoplasm is altered and they are less regularly arranged. The swollen appearances of the SDVs, and of nearby Golgi tubules, give additional evidence that caffeine affects the fine structural morphology of membranous secretory organelles and can disrupt their normal depositional activity. In addition to the greater thickness and width of the siliceous scales in caffeine-treated cells, the length and width of the shell are larger compared to controls, but the aspect ratio (length / width) is smaller. The latter is attributed to a larger increase in width relative to the increase in length of the caffeine-reated cells. Since some of the scales are deposited with the long axis laterally on the shell surface, in addition to being greater in width, this raises the interesting question of whether the morphology of the SDVs and the siliceous products influences the size and morphogenesis of the shell. Further research is needed to clarify the interaction of the SDVs with the cytoplasmic cytoskeletal system during shell morphogenesis. © 1995 Wiley-Liss, Inc.
    Additional Material: 12 Ill.
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    URL: http://dx.doi.org/10.1002/jmor.1052250302
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    Spinal cord central canal of the German shepherd dog: Morphological, histological, and ultrastructural considerations (1995)
    New York, NY : Wiley-Blackwell
    Journal of Morphology 224 (1995), S. 205-212 
    Details
    ISSN: 0362-2525
    Keywords: Life and Medical Sciences ; Cell & Developmental Biology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Biology , Medicine
    Notes: This study deals with some macroscopical, microscopical, and ultrastructural aspects of the spinal cord central canal of the German shepherd dog. The caudal end of the spinal cord is constituted by the conus medullaris, which may extend to the first sacral vertebra, the terminal ventricle, and the filum terminale. The latter structure is considered as internum (second to third sacral vertebrae) or externum (fifth caudal vertebra), according to its relation to the dura mater. Occasionally, there is a second anchorage which is close to the level of the sixth caudal vertebra. The central canal is surrounded by a ciliated ependymal epithelium, which differs depending upon the levels. The most caudal part of the filum terminale bears a columnar ciliated ependymal epithelium surrounded by two layers of glia and pia mater, which separate the central canal from the subarachnoid space. Microfil injections show a communication between the cavity and the subarachnoid space, as the plastic is able to pass through the ependymal epithelium. At the level of the terminal ventricle there are real separations of the ependymal epithelium, which seem to connect the lumen of the spinal canal with the subarachnoid space. These structures probably constitute one of the drainage pathways of the cerebrospinal fluid. The diameter of the central canal is related to the age of the animal. However, even in very old animals the spinal cord central canal reaches the tip of the filum terminale and remains patent until death. At the ultrastructural level the ependymal cells present villi, located on cytoplasmic projections, cilia, dense mitochondria, and oval nuclei. © 1995 Wiley-Liss, Inc.
    Additional Material: 5 Ill.
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    URL: http://dx.doi.org/10.1002/jmor.1052240209
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    Developing embryo and cyclic changes in the uterus of Peripatus (Macroperipatus) acacioi (Onychophora, Peripatidae) (1995)
    New York, NY : Wiley-Blackwell
    Journal of Morphology 224 (1995), S. 179-198 
    Details
    ISSN: 0362-2525
    Keywords: Life and Medical Sciences ; Cell & Developmental Biology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Biology , Medicine
    Notes: Female reproductive tracts of the viviparous neo-tropical onychophoran Peripatus acacioi have been examined at different times throughout the year, and the altering relationship between the developing embryo and the uterus is described. Depending on her age and time of year, the female may have one or two generations of embryos within her uterus. The uterine wall consists of a thin outer epithelium and basal lamina, three layers of muscles, and a thick basal lamina beneath an inner epithelium lining the uterus lumen. These layers are consistent along the length of the uterus apart from the inner epithelial lining, which varies according to position in the uterus and the developmental stage of embryos contained in the uterus. Early embryos are positioned along the length of the uterus and therefore have space in which to grow. During cleavage and segment formation, each embryo is contained within a fluid-filled embryo cavity that increases in size as the embryo grows. Morulae and blastulae are separated by lengths of empty uterus in which the epithelial lining appears vacuolated. Until the process of segment formation is complete, the embryos are attached to a placenta by a stalk and remain in the same part of the upper region of the uterus. As these embryos grow, the lengths of vacuolated cell-lined uterus between them decrease. Each embryo cavity is surrounded by the epithelial sac, the maternal uterine epithelium, which becomes overlaid by a thin layer of cells, the embryo sac, which is believed to be of embryonic origin. The placenta is a syncytial modification of the epithelial sac located at the ovarian end of each embryo cavity covered by the embryo sac and is analogous to the mammalian noninvasive epitheliochorial placenta. Segment-forming embryos have their heads directed toward the ovary. As the embryo gets longer during segment formation, its posture changes from coiled to flexed. Once segment formation is complete, the embryo loses contact with its stalk, an embryonic cuticle forms, and the embryo turns around so that its head is directed toward the vagina. The embryo escapes from its embryo sac and moves to the lower part of the uterus. In the lower part of the uterus, the straightened fetuses are first unpigmented but subsequently become pigmented as the secondary papillae on the body surface form and an adult-type cuticle forms beneath the embryonic cuticle. While the embryos are contained within their embryo cavities, nutrients are supplied by the placenta. Throughout development the mouth is open and in the mature fetus the gut is lined by peritrophic membrane and material is present in the gut lumen. Trachea have been observed only in fetuses that were ready for birth. Insemination, cyclical changes in the uterine epithelium, and the nature of the cuticle shed at parturition are discussed. © 1995 Wiley-Liss, Inc.
    Additional Material: 33 Ill.
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    URL: http://dx.doi.org/10.1002/jmor.1052240207
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    Mechanics of the avian propatagium: Flexion-extension mechanism of the avian wing (1995)
    New York, NY : Wiley-Blackwell
    Journal of Morphology 225 (1995), S. 91-105 
    Details
    ISSN: 0362-2525
    Keywords: Life and Medical Sciences ; Cell & Developmental Biology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Biology , Medicine
    Notes: The supporting elements of the avian propatagium were examined in intact birds and as isolated components, using static force-length measurements, calculated models, and airflow observations. The propatagial surface supported between Lig. propatagiale (LP) and brachium-antebrachium is equally resistant to distortion over the range of wing extension used in flight. The lengths LP assumes in flight occur across a nearly linear, low-stiffness portion of the force-length curve of its extensible pars elastica. In an artificial airflow, intact wings automatically extend; their degree of extension is roughly correlated with the airflow velocity. Comparisons between geometric models of the wing and the passive force-length properties of LPs suggest that the stress along LP blances the drag forces acting to extend the elbow. The mechanical properties (stiffness) of the LP vary and appear to be tuned for flight-type characteristics, e.g., changes in wing extension during flight and drag. Lig. limitants cubiti and LP combine to limit elbow extension at its maximum, a safety device in flight preventing hyperextension of the elbow and reduction of the propatagium's cambered flight surface. Calculations using muscle and ligament lengths suggest that M. deltoideus, pars propatagialis, via its insertions onto both the propatagial ligaments, controls and coordinates propatagial deployment, leading edge tenseness, and elbow/wing extension across the range of wing extensions used in flight. The propatagial ligaments and M. deltoideus, pars propatagialis, along with skeleto-ligamentous elbow/carpus apparatus, are integral components of the wing's extension control mechanism. © 1995 Wiley-Liss, Inc.
    Additional Material: 8 Ill.
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    URL: http://dx.doi.org/10.1002/jmor.1052250108
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    Comparative embryology of teleostean fishes. I. Development and staging of the american shad, Alosa sapidissima (Wilson, 1811) (1995)
    New York, NY : Wiley-Blackwell
    Journal of Morphology 225 (1995), S. 125-167 
    Details
    ISSN: 0362-2525
    Keywords: Life and Medical Sciences ; Cell & Developmental Biology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Biology , Medicine
    Notes: A new approach to devising embryological staging systems allows improved phylogenetic comparisons of developmental patterns. As in traditional approaches, morphological features provide the defining criteria for stages, but unlike traditional normal tables, each stage is defined by no more than one or two morphological criteria that are fundamental developmental features of all teleosts. Additional developmental features that occur concurrently with the defining criteria of a stage are treated as variables potentially uncoupled from the defining criteria for that stage. This system is well suited to detect phylogenetic heterochrony and promises to increase our understanding of conserved vs. labile features in teleostean embryology. In this study, I explain the defining criteria for American shad and then make comparisons with other clupeoids. The development of American shad includes 35 stages extending from fertilization to metamorphosis. Comparisons with other clupeoids indicate that the developmental pattern of shad is representative of the early ontogeny of many clupeoids during the embryonic and yolk sac periods and may be conservative for the group. However, several concurrent features, particularly hatching, formation of neuromasts, and opercular development, vary in developmental timing among clupeoids. Comparisons indicate that shad embryos delay the development of these concurrent features relative to other clupeoids. Modifications of the developmental pattern for different species of clupeoids are heterochronic but their phylogenetic and adaptive significance is unknown. © 1995 Wiley-Liss, Inc.
    Additional Material: 22 Ill.
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    URL: http://dx.doi.org/10.1002/jmor.1052250202
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    Fiber-type composition of hindlimb muscles in the turtle, Pseudemys (Trachemys) scripta elegans (1995)
    New York, NY : Wiley-Blackwell
    Journal of Morphology 225 (1995), S. 193-211 
    Details
    ISSN: 0362-2525
    Keywords: Life and Medical Sciences ; Cell & Developmental Biology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Biology , Medicine
    Notes: A description is provided of the fiber-type composition of several hindlimb muscles of the adult turtle, Pseudemys (Trachemys) scripta elegans. In addition, cross-section areas of each fiber type and an estimation of the relative (weighted) cross-section area (wCSA) occupied by the different fiber types are also provided. Seven muscles were selected for study, based on their suitability for future neurophysiological analysis as components of the segmental motor system, and on their homologies with muscles in other vertebrates. The test muscles were iliofibularis (ILF), ambiens (AMB), external gastrocnemius (EG), extensor digitorum communis (EDC), flexor digitorum longus (FDL), tibialis anterior (TA), and peroneus anterior (PA). Serial sections of these muscles were stained for myosin adenosine triphosphatase (ATPase), NADH-diaphorase, and alpha-glycerophosphate dehydrogenase (α-GPDH), thereby enabling fiber-type classification on the basis of indirect markers for contraction speed and oxidative (aerobic) vs. glycolytic (anaerobic) metabolism. All muscles contained three fiber types: Slow oxidative (SO; possibly including some non-twitch tonic fibers); fast oxidative glycolytic (FOG); and fast glycolytic (Fg). There were at least 30% FOG and 50% FOG + Fg fibers in the seven muscles, the extreme distributions being the predominantly glycolytic ILF vs. the predominantly oxidative FDL muscle (ILF - 15.5% SO, 35.2% FOG, 49.3% Fg vs. FDL - 49.1% SO, 41.1% FOG, 9.8% Fg). As in other species, the test muscles exhibited varying degrees of regional concentration (compartmentalization) of the different fiber types. This feature was most striking in ILF. Pronounced compartmentalization was also observed in AMB, EG, PA, TA, and EDC, whereas the distribution of fiber types in the highly oxidative FDL was homogeneous. In five of the seven muscles, fiber size was ranked with Fg 〉 FOF 〉 SO. In terms of wCSA, which provides a coarse-grain measure of the different fiber types' potential contribution to whole muscle peak force, all muscles exhibited a higher Fg and lower SO contribution to cross-section area than suggested by their corresponding fiber-type composition. The largest relative increases in wCSA vs. fiber-type composition were in the ILF and AMB muscles. We conclude that the turtle hindlimb provides some interesting possibilities for testing for a division of labor among different muscles during different movements (e.g., sustained vs. ballistic), and for study of the behavior of the different fiber (and motor unit) types under normal and perturbed conditions. The relationships between the present results and previous findings on homologous muscles of the mammalian (cat, rat) and reptilian (lizard) hindlimb are discussed. © 1995 Wiley-Liss, Inc.
    Additional Material: 8 Ill.
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    URL: http://dx.doi.org/10.1002/jmor.1052250205
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    Occurrence of ampulla in the ductus deferens of the Indian garden lizard Calotes versicolor daudin (1995)
    New York, NY : Wiley-Blackwell
    Journal of Morphology 225 (1995), S. 261-268 
    Details
    ISSN: 0362-2525
    Keywords: Life and Medical Sciences ; Cell & Developmental Biology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Biology , Medicine
    Notes: During the breeding season, the terminal end of the ductus deferens of Calotes versicolor appears swollen and is comparable to the ampulla of the mammalian ductus deferens. Its anatomy was studied from paraffin sections. It differentiates along its length into five zones. The first has thick smooth muscle and pesudostratified epithelium; the second has luminal trabeculae with an epithelium showing evidence of secretory activity; the third has the epithelial mucosa abutting against the smooth muscle in the form of pocketlike indentations; the fourth has crypts between epithelial folds; and the fifth zone is a sphincter. The anatomy of this ampullary region is indicative of secretory as well as spermatophagous roles. It undergoes seasonal change and appears to be androgen-dependent. © 1995 Wiley-Liss, Inc.
    Additional Material: 10 Ill.
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    URL: http://dx.doi.org/10.1002/jmor.1052250303
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  • 100
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    Perinatal changes in avian muscle: Implications from ultrastructure for the development of endothermy (1995)
    New York, NY : Wiley-Blackwell
    Journal of Morphology 225 (1995), S. 357-367 
    Details
    ISSN: 0362-2525
    Keywords: Life and Medical Sciences ; Cell & Developmental Biology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Biology , Medicine
    Notes: Endothermic heat production and the capacity to shiver develop soon after hatching in birds, permitting chicks to regulate their body temperature. Physiological studies have not clearly identified the developmental events causing this change in function. Here, we use electron microscopy to examine the development of structures involved in muscle activation, contraction, and metabolism coincident with the development of shivering thermogenesis. A stereological study was used to compare the ultrastructure of chicken iliofibularis before endothermic heat production was present (24 h before hatching) and 120 h later, when the iliofibularis had substantial capacity for shivering. Profound increases were found in the t-tubule system and terminal cisternae, mitochondrial cristae, and lipids. The number of triadic profiles increased 3.8-fold (7.6 ± 1.31/100 μm2 to 28.5 ± 2.90/100 μm2 fiber area). The surface area of cristae per mitochondrial volume doubled (12.0 ± 1.50 pm2/pm3 to 25.7 ± 1.84 μm2/μm3). Lipid droplets were rare in the iliofibularis of embryos about to hatch, but accounted for 4.4% of the muscle fiber volume in day 4 birds. We suggest that these ultrastructural changes more fully activate the iliofibularis, allow it to produce more heat both from calcium pumping and from contraction, and increase its endurance, thus permitting the muscle to be effective in thermogenesis. © 1995 Wiley-Liss, Inc.
    Additional Material: 4 Ill.
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    URL: http://dx.doi.org/10.1002/jmor.1052250307
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