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  • Electronic Resource  (160)
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  • 1998  (160)
  • Physical Chemistry
  • pharmacokinetics
  • 1
    Electronic Resource
    Electronic Resource
    High-dose topotecan with granulocyte-colony stimulating factor in fluoropyrimidine-refractory colorectal cancer: A phase II and pharmacodynamic study (1998)
    Springer
    Annals of oncology 9 (1998), S. 173-180 
    Details
    ISSN: 1569-8041
    Keywords: colorectal cancer ; granulocyte-colony stimulating factor ; pharmacokinetics ; phase II ; topotecan
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Purpose: The premise for the study was that topotecan (TPT) resistance in preclinical studies is associated with low level expression of the p-glycoprotein (Pgp) multi-drug transporter conferred by the multi-drug resistant (MDR) phenotype, which might be overcome in clinical practice by administering moderately (2.3-fold) higher doses of TPT that have been shown to be feasible with granulocyte colony-stimulating factor (G-CSF) support. This phase II study evaluated the anti-tumor activity of TPT administered at its highest possible solid tumor dose with G-CSF in patients with fluoropyrimdine-refractory advanced colorectal carcinoma. The study also sought to identify pharmacodynamic (PD) determinants of both activity and toxicity. Patients and methods: TPT was administered as a 30-minute infusion daily for five days every three weeks at a dose of 3.5 mg/m2/day to patients with advanced colorectal carcinoma who developed progressive disease either during treatment with fluoropyrimidine-based chemotherapy for advanced disease or within six months after receiving fluoropyrimdine-based adjuvant chemotherapy. This dose of TPT was previously determined to be the maximal tolerated dose (MTD) with G-CSF support in a phase I study involving solid tumor patients with similar risk factors for myelosuppression. Plasma sampling was performed during course 1 to characterize the pharmacokinetic (PK) and PD behavior of TPT. Results: Seventeen patients who received 89 courses of TPT and G-CSF were evaluable for toxicity; 16 patients were evaluable for anti-tumor response. Toxicity, particularly myelosuppression, was substantial. At the 3.5 mg/m2/day dose level, absolute neutrophil counts (ANC) were less than 500/µl for longer than five days in 17% of courses involving seven of 17 (41%) patients. Severe neutropenia associated with fever occurred in 12.3% of courses; and platelet counts below 25,000/µl were noted in 26.9% of courses. These toxicities resulted in dose reductions in seven of 17 (41%) patients. Nevertheless, 90% of the planned total dose of TPT was administered. No major responses were observed, though minor activity was noted in several patients. Both the median time to progression and the median survival time were short – 2.5 and four months, respectively. Although interindividual variability in the disposition of total TPT was observed, the lack of objective responses precluded PD assessments related to disease activity. Total TPT exposure was significantly higher than drug exposure achieved in similar patients at an identical dose in a previous phase I study of TPT and G-CSF, which may explain why more severe myelosuppressive effects occurred in the present study. There were no PD relationships evident between relevant PK parameters and the percent decrements in platelets and ANCs during course 1, although patients with severe toxic effects (ANC below 500/µl for more than five days and/or platelets 〈25,000/µl) had higher drug exposure than patients with less severe toxicity (P 〈 0.018 and P = 0.09, respectively). Conclusions: Based on these results, the true response rate of TPT at its solid tumor MTD with G-CSF support is unlikely to approach 20%. Although a response rate of less than 20% might be viewed as significant in this disease setting and might be confirmed with sufficient statistical certainty by treating additional patients, the substantial toxicity, inconvenience, and cost associated with this high dose TPT/G-CSF regimen does not warrant the acceptance of a lower level of anti-tumor activity as a criterion for further development.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1008266630701
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  • 2
    Electronic Resource
    Electronic Resource
    UGT1A1 genotypes and glucuronidation of SN-38, the active metabolite of irinotecan (1998)
    Springer
    Annals of oncology 9 (1998), S. 845-847 
    Details
    ISSN: 1569-8041
    Keywords: genetic polymorphism ; glucuronidation ; irinotecan ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Background: Irinotecan (CPT-11) is metabolized by esterase to form a SN-38, which is further conjugated by UGT1A1. Genetic polymorphism has been shown in a promoter region of UGT1A1 and is related to its activity. We investigated whether there might be an inter-individual difference in pharmacokinetics of SN-38 and its glucuronide, depending on the genotypes of UGT1A1. Patients and methods: Nine male patients with lung cancer were treated with irinotecan (50 mg/m2) and carboplatin. Pharmacokinetic parameters were calculated with full sampling plasma data. Genotypes were determined by analyzing the sequence of TATA box of UGT1A1 of genomic DNA from the patients. Results: The genotyping analysis revealed one heterozygote (6/7) and one homozygote (7/7) for (TA)7TAA allele (UGT1A1*28). The remaining seven patients were homozygote for (TA)6TAA allele (6/6, wild type). The metabolic ratios (SN-38/SN-38 glucuronide) in the patient with 7/7 genotype were uncharacteristically higher than those in the patients with other genotypes (6/6 and 6/7). Biliary index was 6980 versus 2180 ± 1110 (range 840–3730) in patients with 7/7 versus 6/6 genotypes, respectively. Conclusion: These results support the idea that the patient with 7/7 genotype has an impaired capacity for glucuronidation of SN-38.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1008438109725
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  • 3
    Electronic Resource
    Electronic Resource
    A phase I and pharmacologic study of DMP 840 administered by 24-hour infusion (1998)
    Springer
    Annals of oncology 9 (1998), S. 101-104 
    Details
    ISSN: 1569-8041
    Keywords: DMP 840 ; pharmacodynamics ; pharmacokinetics ; phase I
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Purpose: DMP 840, a novel bisnaphthalimide, has demonstrated promising schedule dependent anti-tumor activity in vitro and in vivo against several tumor cell lines. A phase I study was conducted to evaluate the effect of a 24-hour infusion schedule repeated every three weeks, on the therapeutic efficacy of DMP 840. Patients and methods: Fourteen patients with refractory solid tumor malignancies were treated with DMP 840 at doses of 20, 40, 50 and 60 mg/m2. Results: A combination of neutropenia, thrombocytopenia and stomatitis were dose-limiting at doses of 50 and 60 mg/m2 in both minimally- and extensively-pretreated patients. In contrast, all courses at lower dose levels were well tolerated. Pharmacokinetic analysis demonstrated that DMP 840 had a prolonged terminal half life (median 39 hours; range 25–86) and that dose-limiting events were significantly related to several indices of systemic DMP 840 exposure (P 〈 0.01, Wilcoxon Rank Sum test). Conclusion: The recommended dose of DMP 840 for further disease oriented evaluations is 40 mg/m2 administered over 24 hours every three weeks. The infusion duration evaluated in this study did not result in a substantial increase in the tolerable dose compared to shorter, less cumbersome schedules.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1008260515869
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  • 4
    Electronic Resource
    Electronic Resource
    Feasibility and pharmacokinetic study of a chimeric anti-CD20 monoclonal antibody (IDEC-C2B8, rituximab) in relapsed B-cell lymphoma (1998)
    Springer
    Annals of oncology 9 (1998), S. 527-534 
    Details
    ISSN: 1569-8041
    Keywords: CD20 ; chimeric IDEC-C2B8 ; lymphoma ; monoclonal antibody ; pharmacokinetics ; feasibility study
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Background: In clinical trials in the USA, IDEC-C2B8 (a mouse-humanchimeric anti-CD20 monoclonal antibody) has demonstrated high response rateswith only mild toxic effects in relapsed B-cell lymphoma at a dose of fourweekly 375 mg/m2 infusions. The aim of the present trial wasto determine whether or not this dose is practically applicable to Japanesepatients with relapsed B-cell lymphoma with respect to safety,pharmacokinetics and efficacy. Patients and methods: Patients with relapsed CD20+ B-cell lymphomareceived intravenous infusions of IDEC-C2B8 once a week for four weeks. Atotal of 12 patients (four at 250 mg/m2 and eight at 375mg/m2) were enrolled. Results: All 11 eligible patients treated with either dose leveltolerated IDEC-C2B8 well. Commonly observed adverse drug reactions weregrades 1 or 2 non-hematologic toxicities during the infusion, consistingmostly of flu-like symptoms and skin reactions. All of the observedhematologic toxicities were of grade 3 or less, and transient. A rapid andsustained B-cell decrease in peripheral blood was observed, but noinfectious episodes were encountered. Human anti-mouse and anti-chimericantibodies were not detected. Of the 11 eligible patients (eight withfollicular, two with diffuse large-cell and one with mantle cell lymphoma),two showed a complete response and five showed a partial response, and allof the seven responders had lymphoma with follicular histology. Apharmacokinetic analysis showed that the elimination half-life (T1/2) ofIDEC-C2B8 was 445 ± 361 hours, and that the serum antibody levelsincreased in parallel with the course of infusions, and in most patients wasstill measurable at three months. Conclusions: The dose of four weekly 375 mg/m2 infusionsof IDEC-C2B8 is safe and effective in Japanese patients with relapsed B-celllymphoma. Further studies evaluating IDEC-C2B8 are warranted.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1008265313133
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  • 5
    Electronic Resource
    Electronic Resource
    Basal activity profiles of NPH and [Nɛ-palmitoyl Lys (B29)] human insulins in subjects with IDDM (1998)
    Springer
    Diabetologia 41 (1998), S. 116-120 
    Details
    ISSN: 1432-0428
    Keywords: Keywords Insulin ; pharmacokinetics ; acylated insulin ; NPH ; insulin therapy ; glucose turnover
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary [Ne-palmitoyl Lys (B29)] human insulin is a fatty acid-acylated derivative of insulin with extended action compared to unmodified insulin when infused intravenously (i. v.) secondary to its binding to circulating albumin. The duration and activity profile of the acylated (A) and NPH (B) insulins were assessed following subcutaneous (s. c.) doses of (A) 6 nmol/kg and (B) 1.2 nmol/kg (equivalent to 0.2 U/kg) in 9 subjects with IDDM. After overnight i.v infusion of regular human insulin, morning glucose was (A) 6.9 ± 0.1 and (B) 6.8 ± 0.1 mmol/l. After the s. c. injection, i. v. human insulin or glucose was infused to maintain near-basal glycaemia and tracer glucose to assess hepatic glucose production (HGP). An activity profile was deduced for each study by expressing the glucose infusion rate at each time point, as a fraction (%) of the basal (measured) HGP, and the i. v. insulin infusion rate as a fraction (%) of the basal requirement. The two fractions are combined by adding the fractional glucose infusion rate and subtracting the fractional insulin infusion rate. Infusion rates of i. v. insulin in the morning were (A) 0.96 ± 0.096 and (B) 1.22 ± 0.09 pmol · kg–1· min–1. After insulin injection, i.v insulin requirements decreased and were below 10 % of basal between 100 and 150 min. A constant activity profile of 0 % represents a perfect substitution of the basal i. v. insulin infusion by the s. c. dose. The actual profile is defined by deviations from this (above) and was –17 ± 11, 7 ± 10, –9 ± 6 and –18 ± 18 % for [Ne-palmitoyl Lys (B29)] human insulin and 17 ± 12, 5 ± 6, –9 ± 15, 22 ± 18 % for NPH insulin at 3, 6, 9 and 12 h after s. c. injection. HGP was similar for the two insulins, demonstrating similar metabolic actions and profiles both peripherally and at the liver. [Diabetologia (1998) 41: 116–120]
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s001250050876
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  • 6
    Electronic Resource
    Electronic Resource
    Impact of early cyclosporin average blood concentration on early kidney transplant failure (1998)
    Springer
    Transplant international 11 (1998), S. 46-52 
    Details
    ISSN: 1432-2277
    Keywords: Key words Cyclosporin ; pharmacokinetics ; kidney transplantation ; Kidney transplantation ; cyclosporin ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract This retrospective study served to examine the correlation between the degree of cyclosporin (CyA) exposure, as estimated by a single pharmacokinetic (PK) profile performed at 1 week post-transplant, and the outcome of 290 consecutive renal transplants performed over a 6-year period. For this retrospective analysis patients were stratified into four historical groups based on 12- versus 24-h PK studies and on the use of radioimmunoassay versus fluorescence polarization immunoassay methods for estimates of CyA concentrations. Four PK measures – trough concentration (C0), average concentration values (Cav; i. e., the dosing interval-corrected area under the concentration-time curve), maximum concentration (Cmax), and time to maximum concentration (tmax) – were examined as predictors of patient, graft, and rejection-free survival rates for each of the four groups individually and for all groups combined. Patients with an initial Cav≥ 550 ng/ml had higher 1-year (88 %) and 6-year (66 %) graft survival rates than patients with Cav 〈 550 ng/ml, who had 1- and 6-year graft survival rates of 80 % and 59 %, respectively (P = NS). Statistically significant differences were observed in graft survival rates between patients with Cav 〈 550 versus Cav≥ 550 ng/ml at 30 (88 % vs 96 %; P 〈 0.02), 60 (85 % vs 94 %; P 〈 0.007), 90 (85 % vs 94 %; P 〈 0.02), and 180 (83 % vs 92 %; P 〈 0.05) days. Moreover, patients with Cav 〈 550 ng/ml displayed more severe rejection episodes, as judged by Banff classification, than patients who displayed Cav≥ 550 ng/ml (grades II and III; 71 % vs 50 %; P = 0.036). In contrast, the C0, Cmax, and tmax values did not correlate with patient, graft, or rejection-free survival rates. The pharmacokinetic parameter of Cav correlated strongly with early graft survival and may, therefore, be a useful predictor of those renal transplant patients who may require more intensive post-transplant monitoring of CyA concentrations by serial PK studies to improve graft survival.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s001470050101
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  • 7
    Electronic Resource
    Electronic Resource
    Pharmacokinetic and phase I studies of brequinar (DUP 785; NSC 368390) in combination with cisplatin in patients with advanced malignancies (1998)
    Springer
    Investigational new drugs 16 (1998), S. 19-27 
    Details
    ISSN: 1573-0646
    Keywords: phase I ; brequinar ; DUP 785 ; cisplatin ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Brequinar (DUP 785; NSC 368390) is a quinoline carboxylic acid derivative that inhibits pyrimidine synthesis at the level of dihydro-orotate dehydrogenase and revealed synergy with cisplatin in preclinical models. In this study investigating the pharmacokinetic and toxicity of brequinar in combination with cisplatin, patients were initially treated with weekly brequinar, in combination with an every-three-week administration of cisplatin. Due to toxicity, the schedule was modified to a 28-day cycle with brequinar given on days 1, 8, 15, and cisplatin on day 1. A total of 24 patients (16 male, 8 female; median age 57; median performance status 1) received 69 courses of therapy. Six dose levels were explored, with cisplatin/ brequinar doses, respectively, of 50/500, 50/650, 50/860, 60/860, 75/650, and 75/860 mg/m2. The serum concentration versus time curves for brequinar were biphasic. A comparison of the pharmacokinetic results after the first and third doses of brequinar indicate that the presence of 50, 60, and 75 mg/m2cisplatin did not change the protein binding and the pharmacokinetics of brequinar in any of the three brequinar-dose groups. Total cisplatin plasma pharmacokinetic followed a triphasic-shape curve and unbound cisplatin decayed at a very rapid rate. Since pharmacokinetic parameters for total cisplatin in this study were similar to those reported in the literature, the presence of brequinar is unlikely to alter the pharmacokinetics of cisplatin. Main dose-limiting toxicities included myelosuppression (including neutropenia and thrombocytopenia) and mucositis. Cisplatin/brequinar doses of 50/500, 50/650, 50/860, 60/860, 75/650, and 75/860 mg/m2, were associated with dose limiting toxicity in 0/3, 1/3, 1/3, 1/3, 2/4, 2/5, and 4/6 patients, respectively. This study shows that co-administration of brequinar and cisplatin does not affect the pharmacokinetic properties of either drug and that the MTDs of cisplatin/brequinar combinations are 60/860 mg/m2 or 75/650 mg/m2. From this study, we conclude that full dose of 75 mg/m2 cisplatin (day 1) can be administered with 650 mg/m2 brequinar (days 1, 8 and 15) without significant modifications of individual drug pharmacokinetic parameters.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1016066529642
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  • 8
    Electronic Resource
    Electronic Resource
    Phase I clinical and pharmacokinetic trial of the podophyllotoxin derivative NK611 administered as intravenous short infusion (1998)
    Springer
    Investigational new drugs 16 (1998), S. 319-324 
    Details
    ISSN: 1573-0646
    Keywords: NK611 ; dimethylaminoetoposide ; Phase I ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Background: NK611 is a novel podophyllotoxin derivative. Compared with etoposide, NK611 carries a dimethyl-amino group at the D-glucose moiety. The antitumor activity of NK611 showed to be equal or superior to etoposide in a variety of in vitro and in vivo tumor models. The aim of our present study was to determine the maximum tolerated dose and the dose-limiting toxicities of NK611 administered as intravenous infusion over 30 min every 28 days. Patients and methods: 45 patients (7 female, 38 male; median age 54 [range 37–73]) were enrolled. In a first stage, NK611 was administered without hematopoietic growth factor support; in a second stage, G-CSF was used for further dose escalation. Toxicities were assessed using WHO-criteria. Results: Initially, the dose was escalated from 60 mg/m2 to 120 mg/m2. In a second patient cohort, doses were further escalated with G-CSF support with doses ranging from 140 mg/m2 to 250 mg/m2. Dose-limiting toxicities were granulocytopenia and thrombocytopenia. Non-hematologic toxicities consisted of alopecia, mild nausea, and infection. Four partial responses were observed: two at 200 mg/m2 (pleural mesothelioma, response duration 7 months, and non-small cell lung cancer, response duration 13 months), and two at 250 mg/m2 (hepatocellular carcinoma, response duration 7 months, and non-small cell lung cancer, response duration 2 months). Pharmacokinetic analyses were performed in all patients. Using an open 3-compartment model, the terminal half-life (t1/2γ) was 14.7 ± 3.7 h. The AUC at 250 mg/m2 was determined to be 330 ± 147 μg/mlh, the plasma clearance of NK611 was 16.2 ± 8.2 ml/min · m2 and the Vss was 16.8 ± 3.3 l/m2. Protein binding of NK611 was 98.7%. Conclusion: the recommended dose for clinical Phase II studies is 120 mg/m2 without G-CSF support and 200 mg/m2 with G-CSF support.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1006293830585
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  • 9
    Electronic Resource
    Electronic Resource
    Pharmacokinetics and Relative Bioavailability of Carboxyamido-Triazole with Respect to Food and Time of Administration: Use of a Single Model for Simultaneous Determination of Changing Parameters (1998)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 26 (1998), S. 673-687 
    Details
    ISSN: 1573-8744
    Keywords: carboxyamido-triazole ; bioavailability ; chronopharmacology ; pharmacokinetics ; food
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Carboxyamido-triazole (CAI) is an anti-invasive, antimetastatic, antiangiogenic agent in clinical development for cancer treatment. It has been postulated that food might enhance the oral absorption of micronized CAI based on an apparent discrepancy in steady state maximum concentrations when taken without regard to meals vs. fasting. The purpose of this study was to determine if a standardized meal affects the absorption and pharmacokinetics of this agent. Twelve patients with refractory cancers and good end organ function were randomized to receive two doses of CAI (250 mg/m 2 ) with and without a standardized high fat meal. One cohort of 6 patients received these doses at 9 AM, and the remaining 6 patients received CAI at 9 PM. Blood was obtained prior to each dose, and serially thereafter. A series of pharmacokinetic (PK) models were fit to the concentration–time data. PK parameters were ultimately calculated using a model which allows simultaneous estimation of parameters from both test doses using nonlinear least squares analysis with ADAPT II. This model estimates independent absorption rate constants and relative fraction absorbed for each condition. AUC 0–t was determined using the trapezoidal method, extrapolated to infinity, and used to calculate the relative bioavailability. No significant differences in PK parameters were noted between the morning and evening cohorts. However, the relative bioavailability, as measured by AUC 0–∞, of CAI was significantly increased when administered with a high fat meal compared to fasting (138.9 vs. 52.2 μg * hr/ml; p=0.0005). The magnitude of the increase in relative bioavailability of CAI taken with food could have profound implications for patients who may inadvertently take this medication shortly after eating.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1020750923542
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  • 10
    Electronic Resource
    Electronic Resource
    A preliminary study of the pharmacokinetics of fenoprofen enantiomers following intravenous administration of the racemate to cats (1998)
    Springer
    Veterinary research communications 22 (1998), S. 203-208 
    Details
    ISSN: 1573-7446
    Keywords: anti-inflammatory ; cat ; enantiomer ; fenoprofen ; NSAID ; pharmacokinetics ; racemic ; stereoselectivity
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1006077406388
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  • 11
    Electronic Resource
    Electronic Resource
    Some Pharmacokinetic Parameters and Dosage Regimens for a Long-Acting Formulation of Oxytetracycline in 6- to 8-Month-Old Male Calves (1998)
    Springer
    Veterinary research communications 22 (1998), S. 533-544 
    Details
    ISSN: 1573-7446
    Keywords: calves ; dosage regimen ; oxytetracycline ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract A two-way crossover study was conducted in crossbred male calves (6–8 months old) to determine the bioavailability, pharmacokinetics and dosage regimens for a long-acting formulation of oxytetracycline (OTC-LA). The half-lives of oxytetracycline after intravenous and intramuscular administration were 7.8 h and 24 h, respectively. The volume of distribution and total body clearance values of the drug were 0.86±0.07 L and 76.1±3.3 (ml/h)/kg, respectively. The maximum concentration of the drug in the serum (4.7–7.4 μg/ml) was achieved 8–10 h after intramuscular administration. The minimum therapeutic serum concentration of drug of ≥0.5 μg/ml was maintained between 15 min and 84 h after intramuscular administration. The intramuscular bioavailability of the drug was 89.1±4.2%. The dosage regimens to maintain the minimum therapeutic serum concentrations of OTC following intramuscular administration of OTC-LA were computed.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1006193703979
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  • 12
    Electronic Resource
    Electronic Resource
    The Pharmacokinetics and Efficacy of Long-Term Low-Level and Split-Dose Administration of Albendazole Through In-Feed Formulations against Ovine and Caprine Parasitic Gastroenteritis (1998)
    Springer
    Veterinary research communications 22 (1998), S. 467-477 
    Details
    ISSN: 1573-7446
    Keywords: albendazole ; anthelmintic ; goat ; in-feed ; metabolite ; pharmacokinetics ; sheep
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Two trials were conducted against natural and experimentally induced parasitic gastroenteritis in sheep and goats using an in-feed formulation of albendazole to evaluate its therapeutic and prophylactic efficacy. In the first trial, albendazole was incorporated in feed pellets to deliver an average daily dose of 0.7 mg/kg body weight in order to evaluate its prophylactic efficacy. In the second trial, feed pellets were offered to deliver an average total dose of 8.0 mg/kg body weight in two equal split doses in order to evaluate its curative efficacy. Sustained plasma concentrations of the active compound, albendazole sulphoxide, and its metabolite albendazole sulphone, sufficient to prevent establishment of infection, were achieved when the animals were allowed to feed on medicated pellets for 10 consecutive days. The bioavailability of the metabolites of albendazole following the administration of a therapeutic dose in two split doses of the in-feed formulation was sufficient to remove established adult nematodes. The concentrate feed pellets could be used for self-medicating small ruminants for therapeutic use as well as for prophylaxis based on their strategic use appropriate to the epidemiology of the parasitic disease.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1006127132161
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  • 13
    Electronic Resource
    Electronic Resource
    Plasma, Urinary and Biliary Residues in Cattle Following Intramuscular Injection of Nortestosterone Laurate (1998)
    Springer
    Veterinary research communications 22 (1998), S. 479-491 
    Details
    ISSN: 1573-7446
    Keywords: cattle ; nortestosterone ; pharmacokinetics ; residues
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The synthetic androgen 19-nortestosterone (β-NT) has been used illegally as a growth promoter in cattle production in the European Union. Elimination of β-NT and its metabolites in plasma, urine and bile was studied in three cattle with cannulated gallbladders following intramuscular injection at a single site of 500 mg of the laurate ester (NTL) containing 300.5 mg β-NT. Using enzyme immunoassay quantification, plasma Cmax of free β-NT was 0.5±0.15 μg/L (mean±SEM). Concentrations of free β-NT in plasma were consistently greater than the assay limit of quantification (0.12 μg/L) for 32.7±13.42 days. Mean residence time for free β-NT in plasma was 68.5±20.75 days. Following sample preparation by immunoaffinity chromatography, high-resolution GC-MS was used to quantify β-NT and α-NT in urine and bile. β-NT was detected irregularly in urine from two of the three animals post injection. The principal metabolite present in the urine, α-NT, was detected for 160.3±22.67 days post injection. Cmax for α-NT in urine was 13.7±5.14 μg/L. Mean urinary AUC0–183 days for α-NT was 845.7±400.90 (μg h)/L. In bile, α-NT was the only metabolite detected for 174.3±8.67 days post treatment. Cmax for α-NT in bile was 40.8±12.70 μg/L and mean biliary AUC0–183 days for α-NT was 1982.6±373.81 (μg h)/L. Concentrations of α-NT in bile samples were greater than those in urine samples taken at the same time. The mean ratio of biliary:urinary AUC0–183 days was 3.0±0.72. It is concluded that bile is a superior fluid for detection of α-NT following injection of NTL, owing to the longer period during which residues may be detected after administration.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1006179116231
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  • 14
    Electronic Resource
    Electronic Resource
    Comparative Disposition Kinetics of Albendazole in Sheep Following Oral and Intraruminal Administration (1998)
    Springer
    Veterinary research communications 22 (1998), S. 545-551 
    Details
    ISSN: 1573-7446
    Keywords: albendazole ; metabolites ; pharmacokinetics ; route of administration ; sheep
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The pharmacokinetics of albendazole was studied in sheep following single oral and intraruminal administration at nematocidal dose rates. The disposition curves of its metabolites indicated increased uptake of the drug in sheep following intraruminal as compared to oral dosing (p〈0.05). The increased bioavailability of benzimidazole anthelmintics given by the intraruminal route could be exploited for optimizing the use of anthelmintic for sustained parasite control in small ruminants.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1006145820818
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  • 15
    Electronic Resource
    Electronic Resource
    Lumping of Whole-Body Physiologically Based Pharmacokinetic Models (1998)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 26 (1998), S. 21-46 
    Details
    ISSN: 1573-8744
    Keywords: pharmacokinetics ; whole body physiologically based model ; lumping ; system theory ; barbiturates
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Lumping is a common pragmatic approach aimed at the reduction of whole-body physiologically based pharmacokinetic (PBPK) model dimensionality and complexity. Incorrect lumping is equivalent to model misspecification with all the negative consequences to the subsequent model implementation. Proper lumping should guarantee that no useful information about the kinetics of the underlying processes is lost. To enforce this guarantee, formal standard lumping procedures and techniques need to be defined and implemented. This study examines the lumping process from a system theory point of view, which provides a formal basis for the derivation of principles and standard procedures of lumping. The lumping principle in PBPK modeling is defined as follows: Only tissues with identical model specification, and occupying identical positions in the system structure should be lumped together at each lumping iteration. In order to lump together parallel tissues, they should have similar or close time constants. In order to lump together serial tissues, they should equilibrate very rapidly with one another. The lumping procedure should include the following stages: (i) tissue specification conversion (when tissues with different model specifications are to be lumped together); (ii) classification of the tissues into classes with significantly different kinetics, according to the basic principle of lumping above; (iii) calculation of the parameters of the lumped compartments; (iv) simulation of the lumped system; (v) lumping of the experimental data; and (vi) verification of the lumped model. The use of the lumping principles and procedures to be adopted is illustrated with an example of a commonly implemented whole-body physiologically based pharmacokinetic model structure to characterize the pharmacokinetics of a homologous series of barbiturates in the rat.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1023272707390
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  • 16
    Electronic Resource
    Electronic Resource
    Population Pharmacokinetic Analysis of Mizolastine and Validation from Sparse Data on Patients Using the Nonparametric Maximum Likelihood Method (1998)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 26 (1998), S. 133-161 
    Details
    ISSN: 1573-8744
    Keywords: mizolastine ; pharmacokinetics ; population analysis ; zero-order absorption ; heteroscedastic variance ; NPML ; validation ; predictive distributions
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract A population analysis of the kinetics of mizolastine was performed from concentrations on 449 allergic patients, using the nonparametric maximum likelihood method (NPML). A two-compartment open model with zero-order absorption was used to describe the kinetics of mizolastine after oral administration. A heteroscedastic variance model was assumed for the error. To explain the kinetic variability, eight covariates were introduced in the analysis: gender, pharmaceutical dosage form, age, body weight, serum creatinine concentration, creatinine renal clearance, plasma levels of hepatic transaminases ASAT and ALAT. Their relationships to the kinetic parameters were studied by means of the estimated distribution of each kinetic parameter conditional on different levels of each covariate. An important interindividual kinetic variability was found for all parameters. Moreover, several kinetic parameters among which the duration of absorption were found to be influenced by pharmaceutical dosage form and gender. Body weight and creatinine renal clearance were found to have a little influence on the oral clearance and the smallest disposition rate constant. This population analysis was validated on a separate group of 247 other patients. For each observed concentration of this sample, a predictive distribution was computed using the individual covariates. Predicted concentrations and standardized prediction errors were deduced. The mean and variance of the standardized prediction errors were, respectively, 0.21 and 2.79. Moreover, in the validation sample, the predicted cumulative distribution function of each observed concentration was computed. Empirical distribution of these values was not significantly different from a uniform distribution, as expected under the assumption that the population model estimated by NPML is adequate.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1020505722924
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  • 17
    Electronic Resource
    Electronic Resource
    Rapid Attainment of Steady State Plasma Drug Concentrations Within Precise Limits (1998)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 26 (1998), S. 319-328 
    Details
    ISSN: 1573-8744
    Keywords: anesthetic techniques ; continuous infusion ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract We describe a method of rapidly obtaining a specified steady state plasma concentration of an intravenous drug within precise limits. The technique requires an initial bolus to raise the plasma concentration to the upper limit followed by a series of constant-rate infusions each of which is associated with a minimum plasma concentration equal to the tower limit. The infusion rate is stepped down when the plasma concentration returns to the upper limit. Computer simulation, based on the method, is used to generate plasma concentration–time curves with fluctuations of up to 10% about selected steady state concentrations of amrinone, esmolol, lidocaine, midazolam, propofol, and theophylline. The utility of this general approach to intravenous dosing and potential limitations of the method are discussed.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1023285426388
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  • 18
    Electronic Resource
    Electronic Resource
    Fourth-Generation Model for Corticosteroid Pharmacodynamics: A Model for Methylprednisolone Effects on Receptor/Gene-Mediated Glucocorticoid Receptor Down-Regulation and Tyrosine Aminotransferase Induction in Rat Liver (1998)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 26 (1998), S. 289-317 
    Details
    ISSN: 1573-8744
    Keywords: methylprednisolone ; pharmacokinetics ; pharmacodynamics ; indirect response models ; glucocorticoid receptor ; tyrosine aminotransferase ; Northern hybridization ; mRNA ; down-regulation ; receptor recycling
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract A fourth-generation pharmacokinetic/pharmacodynamic (PK/PD) model for receptor/genemediated effects of corticosteroids was developed. Male adrenalectomized Wistar rats received a 50 mg/kg iv bolus dose of methylprednisolone (MPL). Plasma concentrations of MPL, hepatic glucocorticoid receptor (GR) messenger RNA (mRNA) and GR density, tyrosine aminotransferase (TAT) mRNA, and TAT activity in liver were determined at various time points up to 72 hr after MPL dosing. Down-regulation of GR mRNA and GR density were observed: GR mRNA level declined to 45–50% of the baseline in 8–10 hr, and slowly returned to predose level in about 3 days; GR density fell to 0 soon after dosing and returned to the baseline in two phases. The first phase, occurring in the first 10 hr, entailed recovery from 0 to 30%. The second phase was parallel to the GR mRNA recovery phase. Two indirect response models were applied for GR mRNA dynamics regulated by activated steroid-receptor complex. A full PK/PD model for GR mRNA/GR down-regulation was proposed, including GR recycling theory. TAT mRNA began to increase at about 1.5 hr, reached the maximum at about 5.5 hr, and declined to the baseline at about 14 hr after MPL dosing. TAT induction followed a similar pattern with a delay of about 1–2 hr. A transcription compartment was applied as one of the cascade events leading to TAT mRNA and TAT induction. Pharmacodynamic parameters were obtained by fitting seven differential equations piecewise using the maximum likelihood method in the ADAPT II program. This model can describe GR down-regulation and the precursor/product relationship between TAT mRNA and TAT in receptor/gene-mediated corticosteroid effects.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1023233409550
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  • 19
    Electronic Resource
    Electronic Resource
    Optimal Experimental Design for Precise Estimation of the Parameters of the Axial Dispersion Model of Hepatic Elimination (1998)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 26 (1998), S. 595-615 
    Details
    ISSN: 1573-8744
    Keywords: optimal design ; hepatic elimination models ; parameter estimation ; protein binding ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The axial dispersion model of hepatic drug elimination is characterized by two dimensionless parameters, the dispersion number, DN , and the efficiency number, RN , corresponding to the relative dispersion of material on transit through the organ and the relative efficiency of elimination of drug by the organ, respectively. Optimal design theory was applied to the estimation of these two parameters based on changes in availability (F) of drug at steady state for the closed boundary condition model, with particular attention to variations in the fraction of drug unbound in the perfusate (fuB ). Sensitivity analysis indicates that precision in parameter estimation is greatest when F is low and that correlation between RN and DN is high, which is desirable for parameter estimation, when DN lies between 0.1 and 100. Optimal design points were obtained using D-optimization, taking into account the error variance model. If the error variance model is unknown, it is shown that choosing Poisson error model is reasonable. Furthermore, although not optimal, geometric spacing of fuB values is often reasonable and definitively superior to a uniform spacing strategy. In practice, the range of fuB available for selection may be limited by such practical considerations as assay sensitivity and acceptable concentration range of binding protein. Notwithstanding, optimal design theory provides a rational approach to precise parameter estimation.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1023229318017
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  • 20
    Electronic Resource
    Electronic Resource
    Single-Dose Pharmacokinetics of Rifapentine in Women (1998)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 26 (1998), S. 75-85 
    Details
    ISSN: 1573-8744
    Keywords: rifapentine ; pharmacokinetics ; gender differences ; female
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Gender can be an important variable in the absorption and disposition of some drugs. In this open-label study, 15 healthy, nonsmoking women received a single 600-mg oral dose of rifapentine. Plasma samples were obtained at frequent intervals for up to 72 hr after the dose to determine the pharmacokinetic (PK) parameters of rifapentine and its active metabolite, 25-desacetyl-rifapentine. Peak plasma rifapentine concentrations (Cmax ) were observed 5.9 hr after ingestion of the single dose. The mean area under the rifapentine plasma concentration–time curve [AUC(0 → ∞ )] was 325 μg · hr ml and the mean elimination half-life (t1/2 ) was 16.3 hr. Plasma concentrations for the 25-desacetyl metabolite peaked at 15.4 hr after the rifapentine dose and declined with a terminal half-life of 17.3 hr. These rifapentine and 25-desacetyl-rifapentine PK data in women were compared to data generated previously in healthy men. Striking similarities in the PK profiles of parent drug and metabolite were found in the two populations. Mean differences in rifapentine CL/F (12%) and t1/2 (2%) were small. The only adverse event reported in the female subjects was discoloration of the urine. Based on these PK and safety data, no dosage adjustments for rifapentine based on gender are recommended.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1023276808298
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  • 21
    Electronic Resource
    Electronic Resource
    Pharmacokinetic and Pharmacodynamic Evaluation for Tissue-Selective Inhibition of Cholesterol Synthesis by Pravastatin (1998)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 26 (1998), S. 329-347 
    Details
    ISSN: 1573-8744
    Keywords: HMG-CoA reductase inhibitors ; pravastatin ; tissue-selectivity ; cholesterol synthesis ; pharmacokinetics ; pharmacodynamics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The tissue-selective inhibition of cholesterol synthesis by pravastatin was evaluated pharmacokinetically and pharmacodynamically. Plasma, tissue, urine, and bile concentrations were measured after iv bolus injection of pravastatin to rats at various doses. The total body clearance and steady state volume of distribution decreased with increasing dose. A saturable biliary excretion was also observed. The time course of plasma and liver concentrations was described by a three-compartment model, consisting of a central compartment, a deep compartment with an nonsaturable uptake process, and a shallow compartment with saturable uptake and nonsaturable elimination processes. It suggests that a mechanism for the decrease in the total body clearance and distribution volume might be explained by a saturation of pravastatin uptake into the liver. Plasma concentration data after oral administration was also fitted to the same model by connecting an absorption compartment to the shallow compartment. The inhibitory activity of pravastatin against cholesterol synthesis in liver could be related to the concentration in the shallow compartment via a sigmoidal Emax model and the obtained pharmacodynamic parameters were comparable to those in vitro. Results suggest that the carrier-mediated hepatic uptake of pravastatin is actually responsible for the hepatoselective inhibition of cholesterol synthesis under physiological conditions.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1023237510458
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  • 22
    Electronic Resource
    Electronic Resource
    Mathematical Formalism and Characteristics of Four Basic Models of Indirect Pharmacodynamic Responses for Drug Infusions (1998)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 26 (1998), S. 385-408 
    Details
    ISSN: 1573-8744
    Keywords: pharmacodynamics ; pharmacokinetics ; indirect response models ; infusions ; inhibition ; stimulation
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Indirect response models require differential equations to describe the nonlinear inhibition or stimulation of the production or loss (kout ) of the response variable. Partially integrated solutions for these models developed previously for iv bolus or biphasic pharmacokinetics were extended to consider drug infusions for limited or extended durations. Qualitative examination was made of the role of infusion rate and duration, type and rate of drug disposition, Imax or Smax capacity factors, IC50 or SC50 sensitivity factors, and kout values. Properties of the response curves characterized include curve shapes, maximum or minimum response, onset rate, steady-state, and return to baseline. Some comparisons were made with behavior of iv bolus doses. These relationships provide both a formal and practical basis for better understanding of the time-course of basic indirect response models.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1021060000789
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  • 23
    Electronic Resource
    Electronic Resource
    Integrated Pharmacokinetic–Pharmacodynamic Model for Acetaminophen, Ibuprofen, and Placebo Antipyresis in Children (1998)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 26 (1998), S. 559-579 
    Details
    ISSN: 1573-8744
    Keywords: acetaminophen ; age ; antipyretic ; fever ; ibuprofen ; pediatrics ; pharmacokinetics ; pharmacodynamics ; temperature
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract A descriptive profile for antipyretic drug action has been documented for children. However, a linked pharmacokinetic–pharmacodynamic (PK/PD) model is central to the understanding of antipyretic drug action in febrile children. This was examined for previously reported data from 178 febrile children who received a single oral dose of acetaminophen (APAP) (12.5 mg/kg), ibuprofen (IBU) (5 or 10 mg/kg), or placebo. Rectal temperatures and plasma levels (μg/ml) of APAP and IBU were measured for up to 12 hr after drug administration. Nonlinear regression analyses were applied to these measurements and yielded simultaneous solutions of an integrated one-compartment PK, link, and SigmoidEmax effect model in 102/153 febrile children given APAP or IBU. The PK parameters (tlag ,ka , β,T1 / 2β ,AUC0–∞ ,Vd/F,andClp/F) were not different than those reported previously, except the APAPka was significantly lower. The link component yieldedkeo s of 0.58±0.06 (X±SE), 0.70±0.11 and 0.57 ± 0.11 hr -1 for APAP, IBU05, and IBU10, respectively: the SigmoidEmax component yieldedEC50 s (μg/ml) and sigmoidicity (γ) of 4.63±0.39 and 3.98±0.42 for APAP, 11.33±1.35 and 3.97±0.58 for IBU05 and 12.83±1.89 and 4.27±0.63 for IBU10. On visual inspection of the efficacy–time profiles of the febrile children, a number of them had an apparent linear function (slope; Δ°C/hr) and/or a sinusoidal cyclic function “confounding” standard approaches to PD analysis. Thus, the temperature profiles of 91/102 children given APAP or IBU required the addition of a slope (Δ°C/hr) and/or a sinusoidal cyclic function to the SigmoidEmax component to fit the data satisfactorily. All 22 children given a placebo also required a slope and/or a cyclic function in their PD model. The residual Δ°Cs (observed-predicted) of the placebo group were not significantly different from 0. Thus, no placebo antipyretic effect was observed. Dose dependency of IBUAUC0–∞ was confirmed; doubling the dose from 5 to 10 mg/kg increased theAUC0→∞ by only 1.5-fold. The confounding effect of initial temperature (Tempi ) on antipyretic efficacy in all treatment groups except placebo was also confirmed to expose nonlinear pharmacodynamics. A significant (p=0.03) contribution ofTempi (but not age) on the value of the slope function was found. There was no consistent effect of age orTempi , on the cyclic component of the integrated model of antipyresis. In addition, a multiple linear relationship of age andTempi was observed with a large number of the PK, link, and PD variables in those who received IBU. Dose, age, andTempi interacted with β in a significant multiple linear relationship withAUC0–∞ . The effects of IBU dose, age, andTempi are pervasive and cascade down the chain of events leading to the PD response. The etiology of pyresis may create the slope function, the magnitude of which may be partially due to the underlying disease. In some cases, the cyclic function may be explained by temperature regulation. Regardless of their cause, both confound analysis of drug action and make the simple, unmodified SigmoidEMax effect model less than satisfactory for interpretation of antipyretic drug effects. The influence of Tempi on the magnitude of antipyretic drug response is also a finding with major impact on PD investigations of antipyretic medications. In children receiving IBU, dose and age are also confounders, in addition toTempi . A multiplicity of covariables must be taken into account when developing appropriate dosing regimens for these antipyretics in febrile children.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1023225217108
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  • 24
    Electronic Resource
    Electronic Resource
    Dose-Dependence and Repeated-Dose Studies for Receptor/Gene-Mediated Pharmacodynamics of Methylprednisolone on Glucocorticoid Receptor Down-Regulation and Tyrosine Aminotransferase Induction in Rat Liver (1998)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 26 (1998), S. 619-648 
    Details
    ISSN: 1573-8744
    Keywords: methylprednisolone ; pharmacokinetics ; pharmacodynamics ; indirect pharmacodynamic response models ; glucocorticoid receptor ; Northern hybridization ; mRNA ; down-regulation ; tyrosine aminotransferase ; dose dependence ; tolerance
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Dose-dependent and repeated-dose effects of methylprednisolone (MPL) on down-regulation of glucocorticoid receptor messenger RNA (GR mRNA) and GR density, as well as tyrosine aminotransferase (TAT) mRNA and TAT induction by receptor/gene-mediated mechanisms in rat liver were examined. A previously developed pharmacokinetic/pharmacodynamic (PK/PD) model was used to design these studies which sought to challenge the model. Three groups of male adrenalectomized Wistar rats received MPL by iv injection: low-dose (10 mg/kg at Time 0), high-dose (50 mg/kg at Time 0), and dual-dose (50 mg/kg at Time 0 and 24 hr). Plasma concentrations of MPL, and hepatic content of free GR, GR mRNA, TAT mRNA, and TAT activity were determined. The P-Pharm program was applied for population analysis of MPL PK revealing low interindividual variation in CL and Vc values (3–14%). Two indirect response models were applied to test two competing hypotheses for GR mRNA dynamics. Indirect Pharmacodynamic Response Model I (Model A) where the complex in the nucleus decreases the transcription rate of GR mRNA better described GR mRNA/GR down-regulation. Levels of TAT mRNA began to increase at 1–2 hr, reached a maximum at 5–6 hr, and declined to the baseline at 12–14 hr after MPL dosing. The induction of TAT activity followed a similar pattern with a delay of about 1–2 hr. The low-dose group had 50–60% of the TAT mRNA and TAT induction compared to the high-dose group. Since the GR density returned to about 70% of the baseline level before the second 50 mg/kg dose at 24 hr, tolerance was found for TAT mRNA/TAT induction where only 50–60% of the initial responses were produced. Our fourth-generation model describes the dose dependence and tolerance effects of TAT mRNA/TAT induction by MPL involving multiple-step signal transduction controlled by the steroid regimen, free GR density, and GR occupancy. This model may provide the foundation for studying other induced proteins or enzymes mediated by the similar receptor/nuclear events.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1020746822634
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  • 25
    Electronic Resource
    Electronic Resource
    Characterization of Pharmacodynamic Recession Slopes for Direct and Indirect Response Models (1998)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 26 (1998), S. 409-436 
    Details
    ISSN: 1573-8744
    Keywords: pharmacodynamic recession slope ; Hill function ; k · m product ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Direct pharmacologic effects are known to recede over time with largely linear slopes (Levy's k · m product, J. Pharm. Sci. 53: 342, 1964) and indirect responses have similar behavior. Pharmacodynamic slope properties were examined mathematically for the Hill function with monoexponential drug disposition and simulations were carried out for other pharmacokinetic functions. Both types of pharmacodynamic profiles exhibit a single terminal inflection point (fp) when drug concentrations exceed the EC50 (that concentration causing one-half maximum effect, Emax ). For direct effects it was found that Cfp (the drug concentration at fp) =EC50 , the determinants of inflection time were identified, and Slopefp = −λzγEmax /4 where λz is the terminal disposition slope and γ is the Hill coefficient. These characteristics were explored for the four basic indirect response models which also exhibit recession profiles with slight sigmoidity and a single terminal inflection point at higher doses. The drug concentration at inflection Cfp is ≤IC50 or SC50 (drug concentrations causing half-maximal inhibition or stimulation), while the inflection response (Rfp ) attains constant values at larger doses. Indirect Response Models I, III, and IV have nearly linear return slopes for a wide range of doses which are governed by the disposition slope λz of the drug, loss constant kout of the response, maximum inhibition (Imax ) or stimulation (Smax ) factors, and a unique fractional constant (0〈G≤1). Model II exhibits more complex behavior with recession slopes which are less likely to be parallel for various doses. Most indirect responses are expected to show nearly linear recession slopes which are parallel for moderate to large doses and mainly governed by an identical combination of pharmacokinetic (λz ), system (kout ), and dynamic capacity factors (Imax or Smax ).
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1021012117627
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  • 26
    Electronic Resource
    Electronic Resource
    Effects of Intestinal and Hepatic Metabolism on the Bioavailability of Tacrolimus in Rats (1998)
    Springer
    Pharmaceutical research 15 (1998), S. 1609-1613 
    Details
    ISSN: 1573-904X
    Keywords: tacrolimus ; bioavailability ; metabolism ; intestine ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. Tacrolimus, an immunosuppressive agent, has poor and variable bioavailability following oral administration in clinical use. We investigated the contribution of intestinal metabolism to the first pass effect of tacrolimus in rats. Methods. Tacrolimus was administered intravenously, intraportally or intraintestinally to rats. Blood samples were collected over a 240-min period, and blood tacrolimus concentrations were measured. The extraction ratios of tacrolimus in the intestine and liver were investigated. In addition, the metabolism of tacrolimus in the everted sacs of the small intestine was examined. Results. The rate of absorption of tacrolimus in the intestine was rapid, and tacrolimus was almost completely absorbed after intestinal administration. The bioavailability of tacrolimus was about 40% and 25% after intraportal and intraintestinal administration, respectively, indicating that tacrolimus is metabolized in both the intestine and the liver. In addition, tacrolimus was significantly metabolized in the everted sacs of the rat intestine. Conclusions. The present study suggested that the metabolism of tacrolimus in the intestine contributes to its extensive and variable first pass metabolism following the oral administration.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1011967519752
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  • 27
    Electronic Resource
    Electronic Resource
    Human Drug Absorption Kinetics and Comparison to Caco-2 Monolayer Permeabilities (1998)
    Springer
    Pharmaceutical research 15 (1998), S. 47-52 
    Details
    ISSN: 1573-904X
    Keywords: permeability ; oral absorption ; Caco-2 cells ; pharmacokinetics ; human
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. This study aims to assess the drug absorption kinetics of three drugs and compare their resulting first-order intestinal permeation rate constants to their Caco-2 monolayer permeabilities. Methods. In vitro dissolution — in vivo absorption analysis was conducted on four formulations of each ranitidine HC1, metoprolol tartrate, and piroxicam to yield apparent and "true” human clinical permeation rate constants. Drug permeability coefficients through Caco-2 monolayers were also determined. Results. In vitro dissolution — in vivo absorption analysis revealed different relative and absolute contributions of dissolution and intestinal permeation to overall drug absorption kinetics for various drug formulations and yielded estimates of each drug's true and apparent human intestinal permeation rate constant [k p = 0.225 hr−1, 0.609 hr−l, and 9.00 hr−1 for ranitidine, metoprolol, and piroxicam, respectively]. A rank order relationship was observed for both the apparent and true permeation rate constant with Caco-2 monolayer permeability. The decrease in the true permeation rate constant relative to the apparent permeation rate constant was most significant (almost three-fold) for the least permeable compound, ranitidine. Conclusions. There were marked differences in the permeation kinetics of ranitidine, metoprolol, and piroxicam. The possibility of an association between absorption kinetics from dosage forms in humans and Caco-2 monolayer permeability may allow for a direct kinetic interpretation of human oral absorption from Caco-2 monolayer permeability values.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1011992518592
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  • 28
    Electronic Resource
    Electronic Resource
    Rapid Determination of Oral Pharmacokinetics and Plasma Free Fraction Using Cocktail Approaches: Methods and Application (1998)
    Springer
    Pharmaceutical research 15 (1998), S. 93-97 
    Details
    ISSN: 1573-904X
    Keywords: cocktail dosing ; pharmacokinetics ; plasma free fraction ; ultrafiltration ; HPLC/APCI/MS
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. To apply cocktail approaches for protein binding (PB) and pharmacokinetics (PK) within a discovery program as a means of providing timely systemic exposure (AUC and Cmax) data. Methods. For PB data, a procedure of cocktail ultrafiltration, mixed matrix sample preparation and single quadrupole atmospheric pressure ionization LC/MS analysis was used. In vivo PK studies consisted of 4 experimental compounds and a control compound dosed orally at 1 mg/kg (5 mg/kg total dose), with plasma samples obtained at 0.5, 1, 2, 4 and 8 h post dose. For PB and in vivo PK analysis, a control compound was tested within each cocktail to ensure consistent reproducibility. Results. Approximately 2 weeks were spent comparing single and cocktail approaches to determine the feasibility of this method for this project. Comparisons of cocktail data with single compound data revealed no significant differences between the approaches. The oral AUC values ranged from 0.01 to 9.28 μg⋅hr/ml and the Cmax values ranged from 0.04 to 2.17 μg/ml. Free fractions of the 44 compounds studied ranged from 0.006 to 0.271. Using the free fraction values to correct for free AUC and Cmax results in ranges of 0.001 to 0.473 μg⋅hr/ml, and 0.001 to 0.119 μg/ml, respectively. Conclusions. All 44 compounds tested had similar potencies in vivo. Thus, these results suggest that a respective 400 and 100-fold range in AUC and Cmax corrected for free fraction exist in the presence of comparable in vivo activity. The ability to generate this type of data in a timely manner allowed the selection of a candidate with low peripheral exposure relative to the effective dose. The free fraction and PK data on the 44 compounds described was collected within three work days by 2 lab scientists.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1011909022226
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  • 29
    Electronic Resource
    Electronic Resource
    Elucidation of Human Amphotericin B Pharmacokinetics: Identification of a New Potential Factor Affecting Interspecies Pharmacokinetic Scaling (1998)
    Springer
    Pharmaceutical research 15 (1998), S. 1630-1636 
    Details
    ISSN: 1573-904X
    Keywords: amphotericin B ; pharmacokinetics ; human ; gender-differences ; disposition function differences ; interspecies scaling
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. To elucidate the pharmacokinetics of amphotericin B in rats, mice and humans, and to perform interspecies scaling to humans using allometry. Methods. Plasma concentrations following intravenous bolus administration in rats, and mice were determined by HPLC. Human pharmacokinetic parameters elucidated from literature data were validated in a preliminary study involving a patient receiving daily infusion dose for 27 days. A critical literature review was conducted to identify appropriate pharmacokinetic parameter values in other species for interspecies scale-up. Interspecies allometric scale-up was performed across mice, rats, rabbits and dogs and the resulting predictions in humans were compared to observed values. Results. A triexponential decline in rat, mouse and human plasma concentrations were observed. No gender differences in rat pharmacokinetics were observed. In contrast to allometry, mouse CL was smaller (82 vs 116 ml/h/kg) and T0.5 (33 vs 20 h) was longer compared to rat. In the preliminary human study, Cpeak and Cmin values remained relatively constant over the duration of therapy, and a CL, MRT, T0.5, Vss and Vdarea of 26 ml/h/kg, 10 and 23 days, 6.2 and 20 L/kg, respectively, were estimated. The relative contributions of the terminal phase area in rat, mouse and human were 75%, 92% and 31%, respectively. Interspecies allometric scale-up predictions of human CL (41 ml/h/kg), CLu (467 ml/h/kg) and Vss (3.3 L/kg) were similar to reported values, whereas poor predictions of human Vuss (33 L/kg), Vdarea (4.1 L/kg) and T0.5 (3 days) were obtained. Conclusions. Insignificant accumulation in humans inspite of the long terminal T0.5 was rationalized to be due to the small terminal-phase area contribution. While human CL and Vss were sucessfully predicted in the interspecies scaling, poor predictions of human Vdarea and T0.5 were obtained, which was attributed to disposition pattern differences between humans and other species, a potential new critical factor affecting interspecies scale-up.
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    URL: http://dx.doi.org/10.1023/A:1011923704731
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  • 30
    Electronic Resource
    Electronic Resource
    Immediate and Long-Term Effects of 5,7-Dihydroxytryptamine on Rat Striatal Serotonergic Neurons Measured Using In Vivo Voltammetry (1998)
    Springer
    Neurochemical research 23 (1998), S. 1-6 
    Details
    ISSN: 1573-6903
    Keywords: 5,7-Dihydroxytryptamine ; intracerebroventricular administration ; serotonin release ; in vivo voltammetry ; pharmacokinetics ; striatum
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The immediate and long-term effects of the selective serotonergic neurotoxin 5,7-dihydroxytryp-tamine (5,7-DHT) on rat striatal serotonergic neurons were examined after its intracerebroventricular administration using in vivo voltammetry. Extracellular concentration of 5-hydroxyindoles increased immediately following intracerebroventricular 5,7-DHT injection (200 μg in 24 μl, 18 min), peaked at 1.5-2 h, and returned to normal by 4 h. 5,7-DHT diffused to the contralateral striatum in detectable amounts 9 to 12 min after the start of injection and returned to basal levels by 1.5 h. Three to 6 days after 5,7-DHT lesions, 5-hydroxytryptophan administration produced an increase in striatal 5-hydroxyindoles that was greater than that produced in pre-lesioned rats. This effect was maximal at 14 to 17 days post-lesion, and remained even after 50 days. The short-term effect of 5,7-DHT may be attributable to increased serotonin release, inhibition of uptake, or monoamine oxidase inhibition. The long-term effect of 5,7-DHT lesions may attributable to increased synthesis of serotonin or decreased reuptake in remaining serotonergic neurons.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1022460216822
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  • 31
    Electronic Resource
    Electronic Resource
    Nephrologic complications of drug therapy in the elderly (1998)
    Springer
    Geriatric nephrology and urology 8 (1998), S. 29-44 
    Details
    ISSN: 1573-7306
    Keywords: aged ; contrast sensitivity ; drug toxicity ; hyperkalemia ; pharmacokinetics ; renal failure
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1008203008239
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  • 32
    Electronic Resource
    Electronic Resource
    Guide for judicious use of the paracetamol absorption technique in a study of gastric emptying rate of liquids (1998)
    Springer
    Journal of gastroenterology 33 (1998), S. 785-791 
    Details
    ISSN: 1435-5922
    Keywords: Key words: gastric emptying rate ; paracetamol (acetaminophen) ; pharmacokinetics ; rate of absorption
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract: The paracetamol absorption technique, a widely used method for evaluating the gastric emptying rate of liquids, appears to be performed inappropriately, resulting from a lack of consideration of pharmacokinetics in paracetamol absorption. This review suggests that appropriate study designs and logical choice of the parameters for the rate of paracetamol absorption are the cornerstone of reliable investigation of gastric emptying using the paracetamol method.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s005350050177
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  • 33
    Electronic Resource
    Electronic Resource
    A phase I and pharmacokinetic trial of terephthalamidine (NSC 57155) as a 120-hour continuous infusion (1998)
    Springer
    Investigational new drugs 16 (1998), S. 57-67 
    Details
    ISSN: 1573-0646
    Keywords: phase I ; pharmacokinetics ; terephthalamidine ; NSC 57155 ; phthalanilides
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract In this phase I study, terephthalamidine was administered as a 120-hour continuous infusion repeated every 21 days. Thirteen patients received 27 courses of terephthalamidine at four dose levels (14, 28, 46, and 70 mg/m2/day). Dose-limiting toxicity consisted of profound and intractable anorexia, weight loss and prostration in all patients. Toxicity was delayed and accompanied by hyponatremia and hypokalemia. No hematologic or other toxicity was documented. One patient with adenocarcinoma of the lung had a 40% decrease in mediastinal lymph nodes and resolution of a pleural effusion lasting 2 months. Pharmacokinetic analysis by HPLC was performed in all patients during their first course. The harmonic mean terminal half-life for terephthalamidine was 23 hours with a plasma clearance of 1.7 l/hr/m2. Both plasma concentrations achieved during infusion (r2 = 0.9) and area under the curve (AUC) (r2 = 0.8) were proportional to increase in dose (p 〈 0.002). Renal excretion accounted for 64% of the total cumulative dose, with an average renal clearance of 1.16 l/hr/m2. Due to the unacceptable toxicity seen at all doses with this schedule, no further studies are recommended unless the mechanism of toxicity is better understood and can be prevented.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1006003718255
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  • 34
    Electronic Resource
    Electronic Resource
    Effect of Particle Size and Charge on the Disposition of Lipid Carriers After Intratumoral Injection into Tissue-isolated Tumors (1998)
    Springer
    Pharmaceutical research 15 (1998), S. 128-132 
    Details
    ISSN: 1573-904X
    Keywords: pharmacokinetics ; tissue-isolated tumor ; liposome ; emulsion ; intratumoral injection
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. Pharmacokinetic properties of various lipid carriers (liposome and emulsions) after intratumoral injection were studied in perfusion experiments using tissue-isolated tumor preparations of Walker 256 carcinosarcoma. Methods. Four types of lipid carriers, large emulsion (254 nm), small emulsion (85 nm), neutral liposomes (120 nm) and cationic liposomes (125 nm) were prepared. We quantified their recovery from the tumor, leakage from the tumor surface and venous outflow after intratumoral injection into perfused tissue-isolated tumors, and analyzed venous appearance curves based on a pharmacokinetic model. Results. In contrast to the small emulsion and neutral liposomes, which immediately appeared in the venous outflow perfusate following intratumoral injection, the appearance of the cationic liposomes and the large emulsion was highly restricted, clearly demonstrating that intratumoral clearance of these formulations can be greatly retarded by the cationic charge and large particle size, respectively. The venous appearance rate-time profiles were fitted to equations derived from a two-compartment model by nonlinear regression analysis. When the calculated parameters were compared among these four formulations, the venous appearance rate did not exhibit such a large difference; however, the rate of transfer from the injected site to the compartment which involves clearance by venous outflow was all very different. Conclusions. The results of this study indicate that the determining factor which alters the pharmacokinetic properties of these lipid carriers after intratumoral injection is not the rate of transfer from the interstitial space to the vascular side but the rate of intratumoral transfer from the injection site to the well-vascularized region.
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    URL: http://dx.doi.org/10.1023/A:1011921324952
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  • 35
    Electronic Resource
    Electronic Resource
    Estimation of Oral Bioavailability of a Long Half-Life Drug in Healthy Subjects (1998)
    Springer
    Pharmaceutical research 15 (1998), S. 1782-1786 
    Details
    ISSN: 1573-904X
    Keywords: bioavailability ; pharmacokinetics ; squalene synthase inhibitor ; prodrug
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. To estimate and compare the oral bioavailability of a drug (BMS-187745) administered as single doses of oral solution of either the parent drug or its prodrug (BMS-188494). Methods. A single-dose, two-period, three-treatment, control-balanced, residual-effect, incomplete block crossover study was completed in 16 healthy male subjects. All subjects received a 10 mg IV infusion of BMS-187745, and a single oral dose of either BMS-187745 (PO1) or BMS-188494 (PO2). A model is proposed to calculate the oral bioavailability of BMS-187745 which has a long half-life; incomplete data points were available to characterize its elimination phase. The plasma concentration-time data obtained following IV infusion of parent drug, and after administration of either PO1 or PO2 treatment were fitted simultaneously with systemic pharmacokinetic parameters shared by both the oral and IV routes of administration. Results. The best simultaneous fittings of the plasma concentration-time data were obtained by using a biexponential pharmacokinetic model with a first-order absorption rate constant. The mean bioavailability (F) values of BMS-187745 estimated by the proposed model were 26.5% and 2.6% when given as oral solution of its prodrug and as the parent drug. The coefficient of variation (CV) of these F values are reasonable, ranging from 38−40%. In contrast, F calculated by the model-independent AUC method exhibited high CV, ranging from 111−120%. Conclusions. The oral bioavailability values estimated by the proposed model were more reasonable compared to those calculated by the model-independent AUC method. The proposed approach may be useful for estimating bioavailability of long half-life drugs when incomplete data points are available to characterize their elimination phase.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1011977116543
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  • 36
    Electronic Resource
    Electronic Resource
    Risedronate Gastrointestinal Absorption Is Independent of Site and Rate of Administration (1998)
    Springer
    Pharmaceutical research 15 (1998), S. 228-232 
    Details
    ISSN: 1573-904X
    Keywords: risedronate ; gastrointestinal absorption ; gastrointestinal site ; bisphosphonate ; administration rate ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. Two studies were conducted to compare the absorption of risedronate administered as a solution to three different gastrointestinal sites (study A) and to determine the extent of absorption of risedronate solution administered by rapid and slow infusion to the second part of the duodenum (study B). Methods. Each study was designed as a single-dose, crossover (three periods, study A; two periods, study B) trial in healthy male subjects, with a 14-day washout period between dosing. Subjects fasted overnight before drug administration and for 4 hours after drug administration. In study A, a risedronate solution of 40 mg in 30 mL of water was administered directly into the stomach, the second part of the duodenum, or the terminal ileum over 1 minute via a nasoenteral tube in a three-period crossover design. In study B, a risedronate solution of 40 mg in 30 mL of water was administered directly into the second part of the duodenum over 1 minute and over 1 hour in a randomized, two-period crossover design. Serum and urine samples were obtained for 48 hours after dosing for risedronate analysis. Results. Eight subjects completed each study. No statistically significant site-specific differences in any pharmacokinetic parameter were observed (study A). Based on the area under the serum concentration-time profile and the amount of drug excreted in the urine unchanged, the extent of risedronate absorption did not differ significantly following a rapid or a slow infusion (study B). Only minor symptomatic complaints were reported by subjects, such as headaches and body aches. Conclusions. These studies indicate that the rate and extent of risedronate absorption are independent of the site of administration along the gastrointestinal tract, and that the extent of absorption is not affected by the rate of administration.
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    URL: http://dx.doi.org/10.1023/A:1011910517200
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  • 37
    Electronic Resource
    Electronic Resource
    Use of the Stable Isotopes Technique to Evaluate the Bioavailability of a Pharmaceutical Form of Magnesium in Man (1998)
    Springer
    Pharmaceutical research 15 (1998), S. 347-351 
    Details
    ISSN: 1573-904X
    Keywords: magnesium ; absolute bioavailability ; stable isotopes ; pharmacokinetics ; ICP-MS
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1011947525377
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  • 38
    Electronic Resource
    Electronic Resource
    Blood-Brain Barrier Equilibration of Codeine in Rats Studied with Microdialysis (1998)
    Springer
    Pharmaceutical research 15 (1998), S. 570-575 
    Details
    ISSN: 1573-904X
    Keywords: microdialysis ; codeine ; morphine ; blood-brain barrier ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. The purpose of the study was to investigate the distribution of codeine across the blood-brain barrier (BBB) in rats by micro-dialysis (MD). Methods. Rats were administered intravenous infusion of codeine in doses of (1) 10 mg/kg, (2) 20 mg/kg for 10 min, and (3) an exponential infusion for 2 h aiming at a plasma concentration of 2500 ng/ml, in a crossover design (n = 6). Microdialysis was used to determine codeine unbound concentrations in blood and brain extracellular fluid (ECF). Total brain tissue and plasma concentrations were also determined. Nalorphine was used as a calibrator for measurement of in vivo recovery. Results. Relative recovery and retrodialysis loss of codeine and nalorphine were similar both in vitro and in vivo. Codeine was rapidly transported into the brain ECF with identical influx and efflux clearance across the BBB. The AUC ratios of brain to blood were 0.99 ± 0.25 and 0.95 ± 0.16 for Dose 1 and 2, respectively. The Css ratio of brain to blood was 1.06 ± 0.12 for the exponential infusion. The half-lives were 25 ± 4 min, 22 ± 2 min in blood and 27 ± 5 min, 25 ± 5 min in brain for Dose 1 and Dose 2, respectively. Total brain tissue concentrations were 3.6 ± 1.2-fold higher than the unbound concentrations in brain. Codeine was demethylated to morphine with an unbound AUCbIood,morphine/AUCblood,codeine ratio of 7.7 ± 5.1% in blood. No morphine was detected in brain MD, but total concentrations were possible to measure. Conclusions. Codeine rapidly reached a distributional equilibrium with equal unbound concentrations in blood and brain. The brain transport of codeine did not show any dose-dependency.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1011929910782
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  • 39
    Electronic Resource
    Electronic Resource
    Pulmonary Bioavailability of a Phosphorothioate Oligonucleotide (CGP 64128A): Comparison with Other Delivery Routes (1998)
    Springer
    Pharmaceutical research 15 (1998), S. 583-591 
    Details
    ISSN: 1573-904X
    Keywords: administration ; antisense ; bioavailability ; gastrointestinal ; intra-peritoneal ; intra-tracheal ; ISIS 3521 ; oligonucleotide ; oral ; pharmacokinetics ; subcutaneous
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. Phosphorothioate antisense oligodeoxynucleotides are promising therapeutic candidates. When given systemically in clinical trials they are administered via slow intravenous infusion to avoid their putative plasma concentration-dependent haemodynamic side-effects. In this study, we have evaluated alternative parenteral and non-parenteral administration routes which have the potential to enhance the therapeutic and commercial potential of these agents. Methods. The delivery of CGP 64128A by intravenous, subcutaneous, intra-peritoneal, oral and intra-tracheal (pulmonary) routes was investigated in rats using radiolabelled compound and supported by more specific capillary gel electrophoretic analyses. Results. Intravenously administered CGP 64128A exhibited the rapid blood clearance and distinctive tissue distribution which are typical for phosphorothioate oligodeoxynucleotides. Subcutaneous and intra-peritoneal administration resulted in significant bioavailabilities (30.9% and 28.1% over 360 min, respectively) and reduced peak plasma levels when compared with intravenous dosing. Administration via the gastrointestinal tract gave negligible bioavailability (〈2%). Intra-tracheal administration resulted in significant but dose-dependent bioavailabilities of 3.2, 16.5 and 39.8% at 0.06, 0.6 and 6.0 mg/kg, respectively. Conclusions. Significant bioavailabilities of CGP 64128A were achieved following subcutaneous, intra-peritoneal and intra-tracheal administration. Pulmonary delivery represents a promising mode of non-parenteral dosing for antisense oligonucleotides. The dose-dependent increase in pulmonary bioavailability suggests that low doses may be retained in the lungs for local effects whereas higher doses may be suitable for the treatment of a broader spectrum of systemic diseases.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1011934011690
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  • 40
    Electronic Resource
    Electronic Resource
    Skin Mini-Erosion Sampling Technique: Feasibility Study with Regard to Serial Glucose Measurement (1998)
    Springer
    Pharmaceutical research 15 (1998), S. 883-888 
    Details
    ISSN: 1573-904X
    Keywords: transdermal access ; skin erosion ; transdermal ; dermal interstitial fluid ; sampling ; glucose ; monitoring ; diabetes mellitus ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. To describe a dermally non-invasive serial sampling technique and to test its clinical feasibility with regard to glucose measurement. Methods. A standardized skin mini-erosion devoid of the epidermal barrier, and covered by an artificial one, was formed by a suctioning technique. Interstitial fluid (IF) was extracted serially by brief application of negative pressure, and its glucose content compared with that in capillary or venous blood samples. Results. The procedure caused no discomfort. The epidermis regenerated rapidly after experimentation. There were no complications. In non-diabetic subjects (n = 13) the mean of all IF values measured daily for 6 days was 6.2 ± 0.1 mmol/1 (±SE). The corresponding capillary blood glucose value was 5.6 ± 0.1 mmol/1, and the venous glucose value was 5.4 ± 0.1 mmol/1. The differences between IF glucose values and invasive control values remained within narrow limits throughout. The 2SD limits of agreement for the differences were 1.44 mmol/1 (IF vs. capillary blood samples) and 1.76 mmol/1 (IF vs venous samples) respectively. The OGTT curves suggested glucose kinetics to be similar in IF and in capillary blood. In diabetic subjects, the mean of IF values determined serially during one day was 15.3 ± 1.0 mmol/1 (range, 6.7−21.8 mmol/1), and the corresponding mean capillary value was 12.0 ± 0.9 mmol/1 (range, 3.3−17.2 mmol/1). The ICC for all paired photometric observations was 0.948. Conclusions. The results suggest the new sampling technique to be a feasible approach for clinical and experimental purposes. A functionally integrated sampling patch is entering the clinical testing stage.
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    URL: http://dx.doi.org/10.1023/A:1011924631680
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  • 41
    Electronic Resource
    Electronic Resource
    Pharmacokinetics and Biodistribution of a Nucleotide-Based Thrombin Inhibitor in Rats (1998)
    Springer
    Pharmaceutical research 15 (1998), S. 904-910 
    Details
    ISSN: 1573-904X
    Keywords: GS522 ; oligodeoxynucleotide ; pharmacokinetics ; tritiated ; biodistribution ; rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. To characterize the pharmacokinetic and tissue distribution profiles of a nucleotide-based thrombin inhibitor (GS522, phosphodiester oligonucleotide, GGTTGGTGTGGTTGG) following intravenous administration to rats. Methods. Pharmacokinetic study: 10 mg/kg, 20 mg/kg, 30 mg/kg (6 animals/dose) were administered to rats by rapid injection into the femoral vein. Blood samples were collected over a 45 minute period. Plasma concentrations of GS522 were determined using capillary gel electrophoresis with laser-induced fluorescence detection. Biodistribution Study: l0mg/kg (400μl, 31.46 μCi/ml) of 3H-GS522 was administered to rats by rapid injection into the femoral vein. The animals were sacrificed by decapitation at 1, 5, 10, 30, 60, 360 minutes post-dose (3 rats/point). Brain, blood, duodenum, eyes, heart, kidney, liver, lungs, muscle, pancreas, skin, spleen and vein samples were collected, processed and quantitated using liquid scintillation counting. Results. The pharmacokinetic profile declines in multiexponential manner, exhibiting extremely fast distribution and elimination (t1/2 = 7.6−9.0 min, Cl = 22.0−28.0 ml/min, V = 83.9−132.4 ml/kg). GS522 follows linear pharmacokinetics, with the area under the curve being proportional to the dose (Rsq = 0.9744). Highest radioactivity levels were detected in kidney, liver and blood (39.7, 15.7 and 15.3% dose/ respective organ). Less than 1% of the dose was detected in the heart, spleen and lungs, and 〉0.3% of the dose was found in the brain and eyes. The oligonucleotide associated radioactivity was uniformly distributed between the brain regions (left and right lobe and cerebellum). Six hours following the dose administration a statistically significant increase (p 〈 0.05) in radioactivity levels was observed in the brain, eyes, skin, liver, pancreas and vein. Conclusions. The pharmacokinetic and biodistribution profiles of GS522 following intravenous administration to rats at three doses were characterized. The oligonucleotide associated radioactivity was widely distributed in tissues. The amount of radioactivity sharply decreased with time in most tissues. Kidney, liver and muscle were the main sites of accumulation. The oligonucleotide associated radioactivity did not cross the blood brain barrier to an appreciable extent. In addition, a statistically significant increase (p 〈 0.05) in the radioactivity levels observed in select tissues suggested a re-uptake mechanism for intact oligonucleotide or its degradation products.
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    URL: http://dx.doi.org/10.1023/A:1011980716659
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  • 42
    Electronic Resource
    Electronic Resource
    Lack of In Vivo/In Vitro Correlations for 50 mg and 250 mg Primidone Tablets (1998)
    Springer
    Pharmaceutical research 15 (1998), S. 1085-1089 
    Details
    ISSN: 1573-904X
    Keywords: primidone ; bioavailability ; human ; pharmacokinetics ; in vitro dissolution
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. To determine if large differences in the in vitro dissolution profiles for primidone tablets would result in significant bioavailability differences. Methods. Two separate bioavailability studies were conducted. The first study used 18 healthy subjects and compared the bioavailability of an old 50 mg tablet formulation, a new 50 mg tablet formulation, and a suspension containing 50 mg/ml of primidone. The second study enrolled 24 subjects who were to receive a new 250 mg tablet formulation, two lots of an old 250 mg tablet formulation and a 250 mg tablet from a second manufacturer. In vitro dissolution was conducted over 90 minutes, using USP 23 Apparatus 2 at 50 rpm, with 900 ml of water. Results. Dissolution at 90 minutes for the old and new 50 mg tablets was approximately 20% and 100%, respectively. The dissolution of the four 250 mg tablets ranged from approximately 30% to 100%. The 50 mg tablet that dissolved slower had a longer Tmax and a 14% lower Cmax than the more rapidly dissolving tablet, but the AUC(0−∞) values differed by only 3%. Only nine subjects completed the 250 mg study because of side effects. The differences in Cmax and AUC(0−∞) among the four 250 mg tablets were less than 7%. Conclusions. Even though there were large differences in the in vitro dissolution of the 50 mg and the 250 mg primidone tablets, the two 50 mg tablets were shown to be bioequivalent, as were the four 250 mg tablets.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1011942530288
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  • 43
    Electronic Resource
    Electronic Resource
    Guar Gum-Based Sustained Release Diltiazem (1998)
    Springer
    Pharmaceutical research 15 (1998), S. 1196-1201 
    Details
    ISSN: 1573-904X
    Keywords: guar gum ; sustained release ; extended release ; diltiazem ; dissolution ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. This study was performed to examine the use of guar gum to sustain the release of diltiazem under in vitro and in vivo conditions. Methods. Guar gum tablet formulations were prepared and evaluated under a variety of in vitro dissolution conditions. The formulations, along with Dilacor XR®, were administered to a group of eight fasted, healthy volunteers in a four period crossover study. Results. Varying the lot of guar gum as well as using guar from different suppliers had little effect on diltiazem dissolution. Also, dissolution of diltiazem from guar gum tablets was essentially independent of stir speed under normal conditions (USP Apparatus II). The stability of guar-based formulations under stressed conditions (40°C/75% relative humidity for 3 months) was also established. All four formulations gave similar plasma concentrations over time in the healthy volunteers pharmacokinetic study. Conclusions. Guar gum-based matrix tablets represent a simple and economical alternative to existing diltiazem sustained release dosage forms.
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    URL: http://dx.doi.org/10.1023/A:1011931622536
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  • 44
    Electronic Resource
    Electronic Resource
    Pharmacokinetic and Pharmacoimmunodynamic Interactions Between Prednisolone and Sirolimus in Rabbits (1998)
    Springer
    Pharmaceutical research 15 (1998), S. 1888-1894 
    Details
    ISSN: 1573-904X
    Keywords: prednisolone ; sirolimus ; immunosuppressant ; interaction ; pharmacokinetics ; pharmacodynamics ; rabbit
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. To assess pharmacokinetic and pharmacoimmunodynamic interactions between prednisolone (Pred, 1 mg/kg) and sirolimus (Sir, 0.25 mg/kg) in rabbits. Methods. After intravenous administration, plasma concentrations of Pred and corticosterone, and Sir blood concentrations were followed for 24 hours along with blood granulocyte and T-helper cell counts. Ex vivo and in vitro whole blood lymphocyte proliferation marked lymphocyte reactivity. Results. Pred terminal half-life and clearance were 1.1 hr and 0.72 l/ hr/kg with no difference after Sir. Sir values were 13 hr and 0.16 1/hr/ kg and Pred produced no changes. Corticosterone production (0−12hr) was suppressed by 55% after Pred alone or combined, while Sir did not cause adrenal suppression. Blood T-helper cells and granulocytes displayed circadian rhythms after placebo. Over 12 hr, T-helper cell counts were decreased by Pred (40%) and Sir (19%) while granulocyte numbers increased by 56% and 23%. After coadministration, cell numbers were similar to Pred alone. Pred and Sir decreased lymphocyte reactivity by 41% and 56% over 24 hr and their combination reached 85% inhibition with additive interaction. In vitro studies showed antagonistic or synergistic interactions depending on drug concentration ratios. Conclusions. At therapeutic concentrations, Sir and Pred do not significantly interact pharmacokinetically and have additive pharmacoimmunodynamics. Thus, the therapeutic application of this combination is promising.
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    URL: http://dx.doi.org/10.1023/A:1011966308791
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  • 45
    Electronic Resource
    Electronic Resource
    Pharmacokinetics and Leukocyte Responses of Recombinant Human Interleukin-10 (1998)
    Springer
    Pharmaceutical research 15 (1998), S. 1895-1901 
    Details
    ISSN: 1573-904X
    Keywords: IL-10 ; cytokines ; protein ; immunosuppression ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. To study the pharmacokinetics and ex vivo leukocyte responses of recombinant human IL-10 (rHuIL-10) following single SC and IV dosing. Methods. A randomized two-way cross-over study was undertaken in 17 healthy volunteers in which rHuIL-10 was administered as 25 μg/ kg SC and IV doses. Blood samples were collected for 48 hr after dosing to determine serum IL-10 concentrations. Inhibitory activity of IL-10 on ex vivo production of inflammatory cytokines (TNF-α and IL-1β) by LPS-treated peripheral blood cells were measured over 96 hr. Results. A physiologically-relevant modeling approach was developed to determine the pharmacokinetics for two routes of administration (SC and IV). The IV dose showed polyexponential disposition with CL of 65 mL/kg/hr, Vss of 70 mL/kg, and t1/2 of 1.94 hr. Absolute bioavailability averaged 42% for SC dosing which produced lower but sustained concentrations. Substantial and prolonged suppression of TNF-α and IL-1β production was achieved during IL-10 treatment. The Hill Function was used to account for the joint concentration-dependent immunosuppressive action of rHuIL-10 after both IV and SC doses. The IC50 values were about 0.03 ng/mL and Imax values were about 0.85 for both TNF-α and IL-lβ suppression. The degree of change as well as the duration of leukocyte response was greater after SC administration than after IV administration. Conclusions. rHuIL-10 shows favorable PK/PD characteristics especially by theSC route of administration which produced prolonged suppression of cytokine production (ex vivo) which may be applicable in various immune-related disorders.
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    URL: http://dx.doi.org/10.1023/A:1011918425629
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    Electronic Resource
    Influence of Different Fat Emulsion-Based Intravenous Formulations on the Pharmacokinetics and Pharmacodynamics of Propofol (1998)
    Springer
    Pharmaceutical research 15 (1998), S. 442-448 
    Details
    ISSN: 1573-904X
    Keywords: propofol ; pharmacokinetics ; pharmacodynamics ; rats ; EEG ; fat emulsion
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. The influence of different intravenous formulations on the pharmacokinetics and pharmacodynamics of propofol was investigated using the effect on the EEG (11.5-30 Hz) as pharmacodynamic endpoint. Methods. Propofol was administered as an intravenous bolus infusion (30 mg/kg in 5 min) or as a continuous infusion (150 mg/kg in 5 hours) in chronically instrumented male rats. Propofol was formulated as a 1% emulsion in an Intralipid 10%®-like fat emulsion (Diprivan-10®, D) or as a 1%- or 6% emulsion in Lipofundin® MCT/LCT-10% (Pl% and P6%, respectively). EEG was recorded continuously and arterial blood samples were collected serially for the determination of propofol concentrations using HPLC. Results. Following bolus infusion, the pharmacokinetics of the various propofol emulsions could adequately be described by a two-compart-mental pharmacokinetic model. The average values for clearance (Cl), volume of distribution at steady-state (Vd,ss) and terminal half-life (t1/2, λ2) were 107 ± 4 ml/min/kg, 1.38 ± 0.06 l/kg and 16 ± 1 min, respectively (mean ± S.E., n = 22). No significant differences were observed between the three propofol formulations. After continuous infusion these values were 112 ± 11 ml/min/kg, 5.19 ± 0.41 l/kg and 45 ± 3 min, respectively (mean±S.E., n = 20) with again no statistically significant differences between the three propofol formulations. Comparison between the bolus- and the continuous infusion revealed a statistically significant difference for both Vd,ss and t1/2, λ2 (p 〈 0.05), whereas Cl remained unchanged. In all treatment groups infusion of propofol resulted in a burst-suppression type of EEG. A profound hysteresis loop was observed between blood concentrations and EEG effect for all formulations. The hysteresis was minimized by a semi-parametric method and resulted in a biphasic concentration-effect relationship of propofol that was described non-parametrically. For P6% a larger rate constant onset of drug effect (t,1/2, keo) was observed compared to the other propofol formulations (p〈0.05). Conclusions. The pharmacokinetics and pharmacodynamics of propofol are not affected by to a large extent the type of emulsion nor by the concentration of propofol in the intravenous formulation.
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  • 47
    Electronic Resource
    Electronic Resource
    Effect of GF120918, a Potent P-glycoprotein Inhibitor, on Morphine Pharmacokinetics and Pharmacodynamics in the Rat (1998)
    Springer
    Pharmaceutical research 15 (1998), S. 599-605 
    Details
    ISSN: 1573-904X
    Keywords: morphine ; morphine-3-glucuronide ; P-glycoprotein ; pharmacokinetics ; pharmacodynamics ; antinociception ; central nervous system ; analgesia
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. The objective of this study was to evaluate the effect of a potent P-gp inhibitor, GF120918, on the systemic pharmacokinetics and antinociceptive pharmacodynamics of a single intravenous dose of morphine in rats. Methods. Male Sprague-Dawley rats received either 500 mg base/kg/d GF120918 or vehicle for 4 days by gavage, or no pretreatment. On day 4, morphine was administered as a 1- or 2-mg/kg i.v. bolus. Antinociception, expressed as percent of maximum possible response (%MPR), was evaluated over 300 min after morphine administration. Serial blood samples were collected and analyzed for morphine and morphine-3-glucuronide (M3G) by HPLC. Results. Morphine clearance and distribution volume were not altered significantly by GF120918. M3G AUC in the GF120918-treated rats was approximately 2-fold higher than in vehicle-treated rats. For both morphine doses, %MPR and the area under the effect-time curve at 300 min were significantly higher in the GF120918-treated rats. A pharmacokinetic/pharmacodynamic effect model accurately described the effect-concentration data for the rats that received 1-mg/kg morphine; ke0 was significantly smaller for GF 120918- vs. vehicle-treated and control rats (0.060 ± 0.028 vs. 0.228 ± 0.101 vs. 0.274 ± 0.026 min−1, p=0.0023). EC50 and γ were similar between treatment groups. Conclusions. Pretreatment with GF 120918 enhanced morphine antinociception, as assessed by the hot-lamp tail-flick assay, and elevated systemic M3G concentrations in rats. The differential pharmacologic response to morphine in the GF120918-treated animals could not be attributed to alterations in systemic morphine pharmacokinetics.
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    URL: http://dx.doi.org/10.1023/A:1011938112599
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    Electronic Resource
    Electronic Resource
    Receptor Occupancy in Myocardium, Adrenal Cortex, and Brain by TH-142177, a Novel AT1 Receptor Antagonist in Rats, in Relation to Its Plasma Concentration and Hypotensive Effect (1998)
    Springer
    Pharmaceutical research 15 (1998), S. 911-917 
    Details
    ISSN: 1573-904X
    Keywords: angiotensin II receptor antagonist ; TH-142177 ; rat tissues ; ex vivo receptor occupancy ; pharmacokinetics ; pharmacodynamics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. To study the relationship between angiotensin II (All) receptor occupancy ex vivo in tissues plasma concentration and hypotensive effect of a novel All receptor antagonist, TH-142177 and losartan in rats. Methods. At 2, 8 and 24 hr after oral administration of TH-142177 and losartan in rats, All receptors in myocardium, adrenal cortex and cerebral cortex were determined by radioligand binding assay using [125I]Sar1,Ile8-AII. Plasma concentrations of both drugs and metabolite in rats were also measured using validated HPLC assays. Further, systolic blood pressure (SBP) in conscious renal hypertensive rats treated orally with TH-142177 and losartan were measured by using a tail cuff plethysmographic method. Results. Oral administration of TH-142177 (1.8 and 5.5 μmol/kg) and losartan (6.5 and 21.7 μmol/kg) in rats brought about dose-dependent decreases in [125I]Sar1,Ile8-AII binding sites (Bmax) in myocardium and adrenal cortex. The extent of receptor occupancy by both drugs in adrenal cortex was maximal at 2 hr later but that in myocardium at 8 hr later. Further, the receptor occupancy was more sustained in myocardium than adrenal cortex. The ex vivo binding affinity of TH-142177 for All receptors in these tissues was roughly three times higher than that of losartan. Also, cerebral cortical [125I]Sar1,Ile8-AII binding was significantly reduced by oral administration of losartan but not by TH-142177. The time course of All receptor occupancy by both drugs in adrenal cortex appeared to be in parallel with that of their plasma concentrations, while the time course in myocardium correlated with that of their hypotensive effects rather than plasma concentrations. Conclusions. TH-142177 produced a relatively selective and sustained occupancy ex vivo of All receptors in myocardium and adrenal cortex of rats with approximately three times greater potency than losartan. Its time course of myocardial receptor occupancy was in parallel with that of hypotensive effect rather than plasma concentration.
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  • 49
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    Electronic Resource
    Correction for Non-Ideal Tracer Pharmacokinetic Disposition by Disposition Decomposition Analysis (DDA) (1998)
    Springer
    Pharmaceutical research 15 (1998), S. 1469-1473 
    Details
    ISSN: 1573-904X
    Keywords: drug tracer ; labeling ; pharmacokinetics ; erythropoietin ; iodination
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. Pharmacokinetic (PK) studies assume that the tracer's PK is equivalent to the parent compound. This assumption is often violated. The aim of this work is to present a method enabling the ideal tracer PK, i.e. the PK of the parent compound, to be predicted from the non-ideal tracer. Methods. The procedure uses a disposition decomposition-recomposition (DDR) that assumes that the labeling mainly changes the elimination kinetics while the distribution kinetics is not significantly affected. In the DDR procedure an elimination rate constant correction factor (kCOR) is determined from a simultaneously fitting to plasma concentration data resulting from an i.v. injection of both the tracer and the parent compound. The correction factor is subsequently used to predict the ideal tracer PK behavior from the disposition function (i.v. bolus response) of the non ideal tracer. Results. The DDR method when applied to plasma level data of erythropoietin (r-HuEPO) and its iodinated tracer (l25I-r-HuEPO) from a high (4000U/kg) and a low (400U/kg) dosing of r-HuEPO in newborn lambs (n = 13) resulted in excellent agreements in the elimination rate corrected dispositions in all cases (r = 0.995, SD = 0.0095). The correction factor did not show a dose dependence (p 〉 0.05). The correction factors were all larger than 1 (kCOR = 1.94, SD = 0.519) consistent with a reduction in the EPO elimination by the iodination labeling. Conclusions. The DDR tracer correction methodology produces a better differentiation of the PK of endogenously produced compounds by correcting for the non-ideal PK behavior of chemically produced tracers.
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    URL: http://dx.doi.org/10.1023/A:1011922209757
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  • 50
    Electronic Resource
    Electronic Resource
    Correlation of Plasma Clearance of 54 Extensively Metabolized Drugs Between Humans and Rats: Mean Allometric Coefficient of 0.66 (1998)
    Springer
    Pharmaceutical research 15 (1998), S. 1474-1479 
    Details
    ISSN: 1573-904X
    Keywords: plasma clearance ; unbound plasma clearance ; inter-species scale-up in plasma clearance ; allometric analysis ; pharmacokinetics ; rat vs. human
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. To evaluate the distribution of allometric exponents for relationship of total plasma clearance of 54 extensively metabolized drugs, with wide-ranging linear clearance values, between humans and rats, to provide a rationale for the observed data, and to discuss potential significance of the findings. Methods. Human and rat plasma clearance values of 54 drugs with markedly different physicochemical properties were obtained from the literature. Standard allometric analysis was performed for each drug using both rat and human data. Unbound vs. total plasma clearances were obtained for 15 out of 54 drugs and their correlations between humans and rats were compared. Results. The mean ± SD of the allometric exponent for the 54 drugs studied is 0.660 ± 0.190. The median clearance ratio based on unit body weight is 7.41 and the median exponent is 0.645. Excluding two outliers the correlation coefficient of plasma clearance between humans and rats was 0.745 (p 〈 0.0001). For the 15 drugs, use of unbound plasma clearance approach seems to significantly improve the correlation coefficient compared to total plasma clearance (0.940 vs. 0.841). Conclusions. The present study indicates that on average, humans and rats may eliminate extensively metabolized drugs at a rate similar to that expected from the allometric or body surface area relationship of basal metabolic rate between the two species. A simple statistical distribution hypothesis is used to rationalize the species difference in plasma drug clearance. Rat may serve as an useful animal model to predict (unbound) plasma clearance of drugs in humans.
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    URL: http://dx.doi.org/10.1023/A:1011974226596
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    Combined Use of Carboxyl-Directed Protein Pegylation and Vector-Mediated Blood-Brain Barrier Drug Delivery System Optimizes Brain Uptake of Brain-Derived Neurotrophic Factor Following Intravenous Administration (1998)
    Springer
    Pharmaceutical research 15 (1998), S. 576-582 
    Details
    ISSN: 1573-904X
    Keywords: pegylation ; blood-brain barrier ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. Peptide drug delivery to the brain requires optimization of (a) plasma pharmacokinetics and (b) blood-brain barrier (BBB) permeability. In the present studies, plasma pharmacokinetics are improved with protein pegylation and BBB transport is facilitated with the use of vector-mediated drug delivery using the OX26 monoclonal antibody (MAb) to the rat transferrin receptor, which undergoes receptor-mediated transcytosis through the BBB in vivo. Methods. A conjugate of OX26 and streptavidin (SA), designated OX26/SA, was prepared in parallel with the carboxyl-directed pegylation of brain-derived neurotrophic factor (BDNF). A novel bifunctional polyethyleneglycol (PEG) was used in which a hydrazide (Hz) was attached at one end and a biotin moiety was attached to the other end. This allowed for conjugation of BDNF-PEG-biotin to OX26/SA. Results. The brain uptake of BDNF-PEG-biotin was increased following conjugation to OX26/SA to a level of 0.144 ± 0.004% injected dose per g brain and a BBB permeability-surface area product of 2.0 ± 0.2 μL/min/g. Conclusions. These studies demonstrate that peptide drug delivery to the brain can be achieved with advanced formulation of protein-based therapeutics. The formulation is intended to (a) minimize rapid systemic clearance of the peptide, and (b) allow for vector-mediated drug delivery through the BBB in vivo. Following this dual formulation, the brain uptake of a neurotrophin such as BDNF achieves a value that is approximately 2-fold greater than that of morphine, a neuroactive small molecule.
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    URL: http://dx.doi.org/10.1023/A:1011981927620
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    Electronic Resource
    Preliminary observations on the pharmacokinetics of CDRI compound 81/470 in calves (1998)
    Springer
    Veterinary research communications 22 (1998), S. 67-72 
    Details
    ISSN: 1573-7446
    Keywords: anthelmintic ; benzimidazole ; calf ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1005939328885
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    Electronic Resource
    The disposition kinetics of albendazole following the administration of single and divided doses to cattle and buffalo (1998)
    Springer
    Veterinary research communications 22 (1998), S. 87-96 
    Details
    ISSN: 1573-7446
    Keywords: anthelmintic ; albendazole ; buffalo ; cattle ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Concentrations of albendazole sulphoxide and its sulphone metabolite in plasma in cattle and buffalo were measured by high-performance liquid chromatography after single and divided intraruminal administration of albendazole at the recommended nematocidal and fasciolicidal dose rates of 7.5 and 15.0 mg/kg body weight, respectively. No significant differences in the plasma concentrations of the metabolites or their pharmacokinetic parameters were observed between cattle or buffalo at either dose rate. Pharmacokinetic analysis and the disposition curve of the metabolites indicated increased uptake of the drug in both cattle and buffalo when the same total amount of the drug was given in divided doses compared to a single dose (p〈0.05). The divided dose schedules of administration could possibly be exploited to extend the life of the available benzimidazole anthelmintics.
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    The effect of feed quality on the kinetic disposition of orally administered triclabendazole in sheep (1998)
    Springer
    Veterinary research communications 22 (1998), S. 257-263 
    Details
    ISSN: 1573-7446
    Keywords: anthelmintics ; Fasciola ; nutrition ; pharmacokinetics ; sheep ; triclabendazole
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The effect of two qualities of feed on the kinetic disposition of triclabendazole (TCBZ) metabolites was investigated in sheep (n = 4) following oral administration of TCBZ at 10 mg/kg body weight. The same sheep were given sequentially two qualitatively different diets: a low-quality (LQ) diet based on wheat straw ad libitum, and a high-quality (HQ) diet based on barley+alfalfa. The triclabendazole sulphoxide (TCBZSO) and triclabendazole sulphone (TCBZSO2) concentrations were determined in blood samples taken serially from the jugular vein between 5 min and 9 days after TCBZ administration. The parent drug TCBZ was not detected in any of the samples. The quality of feed affected the kinetics of both TCBZ metabolites. The rate of appearance (Tlag and Tmax) in the jugular blood was slower and the formed amount (AUC) of TCBZSO was slightly higher when the sheep were on the LQ diet (Tlag = 7.74 h; Tmax = 27.91 h; AUC = 1042 μg.h/ml) than when they were offered the HQ diet (Tlag = 1.90 h; Tmax = 16.01 h; AUC = 832.4 μg.h/ml). The MRT of TCBZSO was about 40% longer with the LQ diet than with the HQ diet. Similarly, the rate of appearance of TCBZSO2 in plasma of sheep was slower when they were on the LQ diet than when they were on the HQ diet, suggesting an impairment of the hepatic enzymatic activity involved in the oxidation of TCBZSO to TCBZSO2.
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    URL: http://dx.doi.org/10.1023/A:1006095400309
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    Electronic Resource
    Pharmacokinetics of antipyrine in rats with different resistance to hypoxia in cold stress (1998)
    Springer
    Bulletin of experimental biology and medicine 126 (1998), S. 1098-1099 
    Details
    ISSN: 1573-8221
    Keywords: pharmacokinetics ; antipyrine ; individual resistance to hypoxia ; cold stress
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Abstract It is shown that the parameters of antipyrine pharmacokinetics during cold exposure depend on individual resistance to hypoxia. High-resistant rats are characterized by less intense metabolism and more rapid normalization of pharmacokinetic parameters than lowresistant rats characterized by shortened elimination half-time corresponding to a more rapid metabolism of xenobiotics under conditions of cold stress.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF02447243
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  • 56
    Electronic Resource
    Electronic Resource
    Kinetics of liquid phase synthesis of tert-amyl methyl ether from tert-amyl alcohol and methanol catalyzed by ion exchange resin (1998)
    New York, NY : Wiley-Blackwell
    International Journal of Chemical Kinetics 30 (1998), S. 137-143 
    Details
    ISSN: 0538-8066
    Keywords: Chemistry ; Physical Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: Synthesis of tert-amyl methyl ether (TAME) from methanol (MeOH) and tert-amyl alcohol (TAA) in the liquid phase was studied by using an ion exchange resin, Amberlyst15 (A15) in the H+ form. Experiments were carried out in a stirred batch reactor under atmospheric pressure. The effects of catalyst size, agitation speed, temperatures, feed ratio and water on the reaction rate were investigated. Both of intraparticle and external diffusion effects could be neglected in this system. The dehydration of TAA could be decreased by increasing the ratio of MeOH/TAA and the reaction rates were greatly inhibited by water.A kinetic model which considered the inhibition of water was proposed. The experimental results agreed well with the model. © 1998 John Wiley & Sons, Inc. Int J Chem Kinet: 30: 137-143, 1998.
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    Electronic Resource
    Proton transfer involving nucleic acids: A temperature-jump study of the systems sulphonephthaleins-double stranded poly(A) and sulphonephthaleins-double stranded poly(C) (1998)
    New York, NY : Wiley-Blackwell
    International Journal of Chemical Kinetics 30 (1998), S. 161-169 
    Details
    ISSN: 0538-8066
    Keywords: Chemistry ; Physical Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: The kinetics of proton transfer between poly(A - AH) (partially protonated double-stranded polyadenylic acid) and CPR (chlorophenol red), and between poly(C - H - C) (partially protonated double-stranded polycytidylic acid) and the indicators CPR, BCP (bromocresol purple), and BCG (bromocresol green) have been investigated at 25°C and ionic strength 0.1 M (NaClO4) by the temperature-jump method. The acidic proton of poly(C - H - C) is engaged in a hydrogen bond (N3H+----N3) which is believed to contribute to stabilizing the double-strand conformation, whereas the acidic proton of poly(A - A - H) does not form hydrogen bonds. The analysis of the dependence of the relaxation times on the concentrations of the reactants has enabled the evaluation of the rate constants for the direct proton transfer and for the protolysis paths. The rate constants for proton recombination with the deprotonated forms of the polynucleotides and the indicators are of the order of magnitude expected for diffusion controlled processes involving oppositely charged ions (k2=(0.2-1.6)×1010 M-1s-1). The direct proton transfer from poly(C - H - C) to BCG is thermodynamically disfavored and its rate constant, k1, is lower than k2 by about three orders of magnitude. The (thermodynamically favored) proton transfers from poly(A - A - H) to CPR and from poly(C - H - C) to CPR and BCP are characterized by similar values of k1. This result indicates that the hydrogen bonds in poly(C - H - C) are very weak and suggests that the stabilization of the double-stranded conformation of this polynucleotide could be ascribed to the large number of hydrogen bonds rather than to their specific strength. © 1998 John Wiley & Sons, Inc. Int J Chem Kinet: 30: 161-169, 1998.
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    Electronic Resource
    A dual-phase oscillatory behavior in Belousov-Zhabotinsky system with vanillin as the substrate (1998)
    New York, NY : Wiley-Blackwell
    International Journal of Chemical Kinetics 30 (1998), S. 201-206 
    Details
    ISSN: 0538-8066
    Keywords: Chemistry ; Physical Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: Dual-phase oscillations are observed in Belousov-Zhabotinsky system with 4-hydroxy-3-methoxybenzaldehyde (vanillin) as the substrate and manganous sulphate or ammonium Ce(IV) sulphate as the catalyst. The nonoscillatory period of time between the two phases decreases with increase in the concentration of the catalyst and the substrate. Under uncatalyzed and ferroin catalyzed conditions the system exhibits single-phase oscillations. The first-phase oscillations are due to vanillin whereas the second-phase oscillations are brought about by 4-hydroxy-3-methoxybenzoic acid (vanillic acid) formed during the course of the first-phase reactions. The reactions are explained with relevant steps of the FKN mechanism. © 1998 John Wiley & Sons, Inc. Int J. Chem. Kinet 30: 201-206, 1998.
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    Electronic Resource
    Electronic Resource
    A wide range modeling study of dimethyl ether oxidation (1998)
    New York, NY : Wiley-Blackwell
    International Journal of Chemical Kinetics 30 (1998), S. 229-241 
    Details
    ISSN: 0538-8066
    Keywords: Chemistry ; Physical Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: A detailed chemical kinetic model has been used to study dimethyl ether (DME) oxidation over a wide range of conditions. Experimental results obtained in a jet-stirred reactor (JSR) at 1 and 10 atm, 0.2≤φ≤2.5, and 800≤T≤1300 K were modeled, in addition to those generated in a shock tube at 13 and 40 bar, φ=1.0 and 650≤T≤1300 K. The JSR results are particularly valuable as they include concentration profiles of reactants, intermediates, and products pertinent to the oxidation of DME. These data test the kinetic model severely, as it must be able to predict the correct distribution and concentrations of intermediate and final products formed in the oxidation process. Additionally, the shock-tube results are very useful, as they were taken at low temperatures and at high pressures, and thus undergo negative temperature dependence (NTC) behavior. This behavior is characteristic of the oxidation of saturated hydrocarbon fuels, (e.g., the primary reference fuels, n-heptane and iso-octane) under similar conditions. The numerical model consists of 78 chemical species and 336 chemical reactions. The thermodynamic properties of unknown species pertaining to DME oxidation were calculated using THERM. © 1998 John Wiley & Sons, Inc. Int J Chem Kinet 30: 229-241, 1998.
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    Electronic Resource
    Electronic Resource
    Micellar effect upon the reaction of hydroxide ion with coumarin (1998)
    New York, NY : Wiley-Blackwell
    International Journal of Chemical Kinetics 30 (1998), S. 273-276 
    Details
    ISSN: 0538-8066
    Keywords: Chemistry ; Physical Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: Cationic micelles of cetyltrimethylammonium bromide, CTABr, speed attack of hydroxide ion upon coumarin by a factor of c.a-2, due to a concentration effect. The first-order rate constants, kobs, at a given hydroxide ions concentration go through maxima with increasing surfactant concentration. The overall micellar effects in these cationic micelles can be treated in terms of the pseudo-phase ion exchange model. Analysis of the data shows that second-order rate constant at the micellar surface is smaller than the second-order rate constant in water. Anionic micelles of sodium dodecyi sulfate, SDS, inhibit the same reaction. © 1998 John Wiley & Sons, Inc. Int J Chem Kinet 30: 273-276, 1998.
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    Electronic Resource
    Kinetics and mechanism of the oxidation of diols by pyridinium bromochromate (1998)
    New York, NY : Wiley-Blackwell
    International Journal of Chemical Kinetics 30 (1998), S. 285-290 
    Details
    ISSN: 0538-8066
    Keywords: Chemistry ; Physical Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: The kinetics of oxidation of four vicinal diols, four nonvicinal diols, and one of their monoethers by pyridinium bromochromate (PBC) have been studied in dimethyl sulfoxide. The main product of oxidation is the corresponding hydroxyaldehyde. The reaction is first-order with respect to each the diol and PBC. The reaction is acid-catalyzed and the acid dependence has the form: kobs=a+b[H+]. The oxidation of [1,1,2,2-2H4]ethanediol exhibited a primary kinetic isotope effect (kH/k D=6.70 at 298 K). The reaction has been studied in 19 organic solvents including dimethyl sulfoxide and the solvent effect has been analyzed using multiparametric equations. The temperature dependence of the kinetic isotope effect indicates the presence of a symmetrical transition state in the rate-determining step. A suitable mechanism has been proposed. © 1998 John Wiley & Sons, Inc. Int J Chem Kinet 30: 285-290, 1998.
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    Electronic Resource
    Fast and reliable numerical methods to simulate complex chemical kinetic mechanisms (1998)
    New York, NY : Wiley-Blackwell
    International Journal of Chemical Kinetics 30 (1998), S. 349-358 
    Details
    ISSN: 0538-8066
    Keywords: Chemistry ; Physical Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: Models that simulate atmospheric photochemistry require the use of a stiff ordinary differential equations (ODEs) solver. Since the simulation of the chemical transformations taking place in the system takes up to 80 percent of the CPU time, the numerical solver must be computationally fast. Also, the residual error from the solver must be small. Because most accurate solvers are relatively slow, modelers continue to search for timely, yet accurate integration methods. Over the past years an extensive number of articles have been dedicated to this subject. One of the highly debated questions is whether one should construct specialized algorithms or instead use general methods for stiff ODEs. In the present article we use the second alternative. We apply three linearly (semi-)implicit methods from the classical stiff ODE literature which we modified to implement the sparse routines to solve the system of equations describing a complex kinetic mechanism. © 1998 John Wiley & Sons, Inc. Int J Chem Kinet 30: 349-358, 1998
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    Hydrogen autoignition at pressures above the second explosion limit (0.6-4.0 MPa) (1998)
    New York, NY : Wiley-Blackwell
    International Journal of Chemical Kinetics 30 (1998), S. 385-406 
    Details
    ISSN: 0538-8066
    Keywords: Chemistry ; Physical Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: The investigation of high-pressure autoignition of combustible mixtures is of importance in providing both practical information in the design of combustion systems and fundamental measurements to verify and develop chemical kinetic models. The autoignition characteristics of hydrogen-oxygen mixtures at low pressures have been explored extensively, whereas few measurements have been made at high pressures. The present measurements extend the range of pressures up to 4 MPa, where few measurements have yet been reported.Using a rapid compression machine equipped with a specially designed piston head, hydrogen autoignition pressure traces were measured at pressures above the second explosion limit (p=0.6-4 MPa, T=950-1050 K). The measured pressure records show a more gradual pressure increase during induction time in this regime than in the low-pressure regime, indicating that the energy release becomes significant at conditions over the second explosion limit.By comparing the measurements and a thermodynamic model which incorporates the heat transfer and energy release, a modified reaction rate constant for H2O2+H=HO2+H2, one of the most important reactions for hydrogen oxidation at high pressure, and the reaction with the largest uncertainty, is suggested in this work as k17=2.3 . 1013exp(-4000/T) cm3/mol-s. The modeled pressure history with the modified reaction rate agrees well with the measured values during the induction period over the range of conditions tested. © 1998 John Wiley & Sons, Inc. Int J Chem Kinet 30: 385-406, 1998
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    Kinetic study and modeling of the hetero-homogeneous pyrolysis and oxidation of isobutane around 800 K. Part II. Pyrolysis in pyrex reactors packed with platinum foils or PbO-treated pyrex rods (1998)
    New York, NY : Wiley-Blackwell
    International Journal of Chemical Kinetics 30 (1998), S. 439-450 
    Details
    ISSN: 0538-8066
    Keywords: Chemistry ; Physical Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: Isobutane pyrolysis has been studied at 20-200 torr initial pressures and 773-793 K, in a packed reactor treated with PbO and in a reactor packed with platinum foils. These packings strongly inhibit product formation and this effect is explained by the occurrence of the heterogeneous termination step:\documentclass{article}\pagestyle{empty}\begin{document}$ \rm H\cdot\mathrel{\mathop{\relbar\joinrel\longrightarrow}^{walls}} product $\end{document}at the reactor walls. The reaction has been modeled in the temperature and pressure range on the basis of a kinetic scheme which has been proposed for the homogeneous reaction and step (w) with the following values of kw:$$\eqalign{(k_{_{w}})_{_{\rm{PbO}}}&=3.7\ 10^{8}\ \rm{exp} \left[-{9000\over \rm{T}}\right]\rm{S}^{-1}\cr(k_{_{w}})_{_{\rm{Pt}}}&=15000\ \rm{S}^{-1}\ \rm{at\ any\ temperature}\cr}$$for both types of packing. The corresponding sticking coefficients of hydrogen atoms are:$$\eqalign{\gamma _{_{\rm{PbO}}} &=160\ \rm{exp} \left[-{9000\over \rm{T}}\right]\cr\gamma _{_{\rm{Pt}}} &=0.03\cr}$$© 1998 John Wiley & Sons, Inc. Int J Chem. Kinet 30: 439-450,1998
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    Rate constants for the gas-phase reactions of selected dibasic esters with the OH radical (1998)
    New York, NY : Wiley-Blackwell
    International Journal of Chemical Kinetics 30 (1998), S. 471-474 
    Details
    ISSN: 0538-8066
    Keywords: Chemistry ; Physical Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: Using a relative rate method, rate constants have been measured for the gas-phase reactions of the OH radical with the dibasic esters dimethyl succinate [CH3OC(O)CH2CH2C(O)OCH3], dimethyl glutarate [CH3OC(O)CH2CH2CH2C(O)OCH3], and dimethyl adipate [CH3OC(O)CH2CH2CH2CH2C(O)OCH3] at 298±3 K. The rate constants obtained were (in units of 10-12 cm3 molecule-1 s-1): dimethyl succinate, 1.4±0.6; dimethyl glutarate, 3.3±1.1; and dimethyl adipate, 8.4±2.5, where the indicated errors include the estimated overall uncertainty of ±25% in the rate constant for cyclohexane, the reference compound. The calculated tropospheric lifetimes of these dibasic esters due to gas-phase reaction with the OH radical range from 1.4 days for dimethyl adipate to 8.3 days for dimethyl succinate for a 24 h average OH radical concentration of 1.0×106 molecule cm-3. © 1998 John Wiley & Sons, Inc. Int J Chem Kinet: 30: 471-474, 1998
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    Kinetics and modeling of the thermal reaction of propene at 800 K. Part iii. Propene in the presence of small amounts of oxygen (1998)
    New York, NY : Wiley-Blackwell
    International Journal of Chemical Kinetics 30 (1998), S. 503-522 
    Details
    ISSN: 0538-8066
    Keywords: Chemistry ; Physical Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: The thermal reaction of propene was examined around 800 K in the presence of less than 20% oxygen. At initial time, the production of H2, CH4, C2H4, C2H6, allene, C3H8, 1,3-butadiene, butenes, 3- and 4-methylcyclopentene, a mixture of 1,4- and 1,5-hexadienes, methylcyclopentane (or dimethylcyclobutane), 4-methylpent-1-ene, and hex-1-ene, was observed along with hydrogen peroxide, CO, and small quantities of ethanal and CO2. Oxygen increases the initial production of hydrogen and of most hydrocarbons and, particularly, that of C6 dienes and of cyclenes. However, the production of allene, methylcyclopentane (or dimethylcyclobutane), and 4-methylpent-1-ene is practically not affected. A kinetic study confirms the mechanism proposed for the thermal reaction of propene. Formation of allene, thus, involves a four-center-unimolecular dehydrogenation of propene, that of 4-methylpent-1-ene is explained by an ene bimolecular reaction while methylcyclopentane (or dimethylcyclobutane) probably arises from a bimolecular process involving a biradical intermediate. Other products arise from a conventional chain radical mechanism.A kinetic scheme is proposed in which chains are primarily initiated by the bimolecular step:C3H6+O2→HO2·+C3H5·which competes with the second-order initiation of propene pyrolysis. Since allene production is not affected by oxygen, it is concluded that allyl radicals are not dehydrogenated by oxygen; but they oxidize in a branching step involving allylperoxyl radicals; r. radicals other than methyl, and allyl are dehydrogenated according to the conventional process:r·+O2→unsaturated+HO2·and account for the production of a large excess of C6 diolefins, methylcyclopentenes, and hydrogen peroxide, when r. stands for C6H11, the allyl adduct. Hydrogen peroxide gives rise to a degenerate branching of chains. Based on the proposed scheme, a modeling of the reaction is shown to account fairly well for the concentration-time profiles. Rate constants of many steps are evaluated and discussed. © 1998 John Wiley & Sons, Inc. Int J Chem Kinet: 30: 503-522, 1998
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    Branching ratios for BrO production from reactions of O(1D) with HBr, CF3Br, CH3Br, CF2ClBr, and CF2HBr (1998)
    New York, NY : Wiley-Blackwell
    International Journal of Chemical Kinetics 30 (1998), S. 555-563 
    Details
    ISSN: 0538-8066
    Keywords: Chemistry ; Physical Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: Laser-flash photolysis of RBr/O3/SF6/He mixtures at 248 nm has been coupled with BrO detection by time-resolved UV absorption spectroscopy to measure BrO product yields from O(1D) reactions with HBr, CF3Br, CH3Br, CF2ClBr, and CF2HBr at 298±3 K. The measured yields are: HBr, 0.20±0.04; CF3Br, 0.49±0.07; CH3Br, 0.44±0.05; CF2ClBr, 0.31±0.06; and CF2HBr, 0.39±0.07 (uncertainties are 2σ and include estimates of both random and systematic errors). The results are discussed in light of other available information or O(1D)+RBr reactions. © 1998 John Wiley & Sons, Inc. Int J Chem Kinet 30: 555-563, 1998
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    Determination of the rate constants for the gas-phase reactions of methyl butenol with OH radicals, ozone, NO3 radicals, and Cl atoms (1998)
    New York, NY : Wiley-Blackwell
    International Journal of Chemical Kinetics 30 (1998), S. 589-594 
    Details
    ISSN: 0538-8066
    Keywords: Chemistry ; Physical Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: Using a relative rate method, rate constants for the gas-phase reactions of 2-methyl-3-buten-2-ol (MBO) with OH radicals, ozone, NO3 radicals, and Cl atoms have been investigated using FTIR. The measured values for MBO at 298±2 K and 740±5 torr total pressure are: kOH=(3.9±1.2)×10-11 cm3 molecule-1 s-1, kO3=(8.6±2.9)×10-18 cm3 molecule-1 s-1, kNO3=(8.6±2.9)×10-15 cm3 molecule-1 s-1, and kCl=(4.7±1.0)×10-10 cm3 molecule-1 s-1. Atmospheric lifetimes have been estimated with respect to the reactions with OH, O3, NO3, and Cl. The atmospheric relevance of this compound as a precursor for acetone is, also, briefly discussed. © 1998 John Wiley & Sons, Inc. Int J Chem Kinet: 30: 589-594, 1998
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    Kinetic stability of 1,1,1-Trifluoroethane (1998)
    New York, NY : Wiley-Blackwell
    International Journal of Chemical Kinetics 30 (1998), S. 621-628 
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    ISSN: 0538-8066
    Keywords: Chemistry ; Physical Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: 1,1,1-Trifluoroethane has been decomposed in comparative rate single-pulse shock-tube experiments. The rate expression for elimination at ca. 2.5 bar and in the temperature range of 1050 to 1200 K has been found to be\documentclass{article}\pagestyle{empty}\begin{document}$ \it k\rm (CF_{3}\joinrel{\relbar\!\!\relbar}CH_{3}\relbar\!\!\rightarrow HF+CF_{2}=CH_{2})=7.0\times 10^{14}\ exp(-37260/T)s^{-1} $\end{document}The experimental conditions appear to be such that the unimolecular reaction is at the beginning of the fall-off region and we find that for step sizes down between 500 and 1000 cm-1 the high-pressure rate expression is in the range\documentclass{article}\pagestyle{empty}\begin{document}$ \it k\rm (CF_{3}\joinrel{\relbar\!\!\relbar}CH_{3}\relbar\!\!\rightarrow HF+CF_{2}=CH_{2})=2.0\times 10^{15}\ exp(-38300/T)\ to\ 4\ \times\ 10^{15}\ exp(-39000/T)s^{-1} $\end{document}where the smaller rate parameters refer to the larger step size down. The results are compared with those from an earlier study and the anomalously high A-factor is noted. It is suggested that the existing rate expressions for the fluorinated ethanes may need to be reevaluated. © 1998 John Wiley & Sons, Inc., Int J Chem Kinet: 30: 621-628, 1998
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    Rate constant for the gas-phase reaction of hydroxyl radical with the natural hydrocarbon bornyl acetate (1998)
    New York, NY : Wiley-Blackwell
    International Journal of Chemical Kinetics 30 (1998), S. 497-502 
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    ISSN: 0538-8066
    Keywords: Chemistry ; Physical Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: The gas-phase reaction of bornyl acetate (bicyclo[2,2,1]-heptan-2-ol-1,7,7-trimethyl-acetate) with hydroxyl radical has been studied. A relative method was used to determine the rate constant for this reaction, with n-octane as reference compound.Methyl nitrite photolysis experiments were carried out in an environmental smog chamber at atmospheric pressure and (294±2) K. The rate constant determined for bornyl acetate is k=(13.9±2.2)×10-12 cm3 molecule-1 s-1.The experimental rate constant has been compared with the rate constants calculated with the structure-activity relationship (SAR) and with the evolution trend of the acetate rate constants. © 1998 John Wiley & Sons, Inc. Int J Chem Kinet: 30: 497-502, 1998
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    Atmospheric chemistry of acetone: Kinetic study of the CH3C(O)CH2O2+NO/NO2 reactions and decomposition of CH3C(O)CH2O2NO2 (1998)
    New York, NY : Wiley-Blackwell
    International Journal of Chemical Kinetics 30 (1998), S. 475-489 
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    ISSN: 0538-8066
    Keywords: Chemistry ; Physical Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: Pulse radiolysis was used to study the kinetics of the reactions of CH3C(O)CH2O2 radicals with NO and NO2 at 295 K. By monitoring the rate of formation and decay of NO2 using its absorption at 400 and 450 nm the rate constants k(CH3C(O)CH2O2+NO)=(8±2)×10-12 and k(CH3C(O)CH2O2+NO2)=(6.4±0.6)×10-12 cm3 molecule-1 s-1 were determined. Long path length Fourier transform infrared spectrometers were used to investigate the IR spectrum and thermal stability of the peroxynitrate, CH3C(O)CH2O2NO2. A value of k-6≈3 s-1 was determined for the rate of thermal decomposition of CH3C(O)CH2O2NO2 in 700 torr total pressure of O2 diluent at 295 K. When combined with lower temperature studies (250-275 K) a decomposition rate of k-6=1.9×1016 exp (-10830/T) s-1 is determined. Density functional theory was used to calculate the IR spectrum of CH3C(O)CH2O2NO2. Finally, the rate constants for reactions of the CH3C(O)CH2 radical with NO and NO2 were determined to be k(CH3C(O)CH2+NO)=(2.6±0.3)×10-11 and k(CH3C(O)CH2+NO2)=(1.6±0.4)×10-11 cm3 molecule-1 s-1. The results are discussed in the context of the atmospheric chemistry of acetone and the long range atmospheric transport of NOx. © John Wiley & Sons, Inc. Int J Chem Kinet: 30: 475-489, 1998
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    The fluorine atom initiated oxidation of CF3CFH2 (HFC-134a) studied by FTIR spectroscopy (1998)
    New York, NY : Wiley-Blackwell
    International Journal of Chemical Kinetics 30 (1998), S. 541-554 
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    ISSN: 0538-8066
    Keywords: Chemistry ; Physical Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: Experiments have been carried out on the oxidation of CF3CFH2 (HFC-134a). Reaction was initiated by continuous photolysis of F2 in the near-ultraviolet. The F atoms produced abstracted a hydrogen atom from CF3CFH2 initiating oxidation in gas mixtures containing O2 and made up to a total pressure of 700 torr with N2. Product yields were measured using Fourier-transform infrared (FTIR) spectroscopy. Experiments were performed with several different partial pressures of O2 present, and at three temperatures; 298, 323, and 357 K. The major products were HC(O)F, CF3C(O)F, and CF3O3CF3, consistent with H atom abstraction by O2 and CC bond scission being the dominant loss processes for CF3CFHO radicals:\documentclass{article}\pagestyle{empty}\begin{document}$ CF3CFHO+O2 \rightarrow CF3C(O)F+HO2 (4a) $\end{document}\documentclass{article}\pagestyle{empty}\begin{document}$ CF3CFHO+M \rightarrow CF3+HC(O)F+M (4b) $\end{document}The following expression was derived for the ratio of rate constants for these reactions:k4a/k4b=(3.8±1.6)×10-24 exp[(2400±500)/T]cm3 molecule-1 (viii)The main fate of the CF3 radicals was formation of CF3O3CF3 and small amounts of CF3OH were detected. The results of the present experiments in which F atoms were used to initiate reaction are in good agreement with those of previous studies in which Cl atoms were employed to initiate the oxidation of HFC-134a. © 1998 John Wiley & Sons, Inc. Int J Chem Kinet 30: 541-554, 1998
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    Photoreduction of IrCl62- complex in alcohol solutions and its reaction with hydroxyalkyl radicals (1998)
    New York, NY : Wiley-Blackwell
    International Journal of Chemical Kinetics 30 (1998), S. 711-719 
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    ISSN: 0538-8066
    Keywords: Chemistry ; Physical Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: The photochemistry of IrCl62- complex in simple alcohols have been studied using laser-flash photolysis. Single electron transfer from the solvent molecule to the light-excited complex has been shown to be the primary photochemical process. Quantum yields of the photoreduction of IrCl62- complex and the rate constants of its reaction with hydroxyalkyl radicals were determined at 200-330 K. Deviations of the rate constants from Debye-Smoluchowski equation for diffusion-controlled reactions are discussed. © 1998 John Wiley & Sons, Inc. Int J Chem Kinet: 30: 711-719, 1998
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    The hydroxyl radical reaction rate constant and atmospheric transformation products of 2-butanol and 2-pentanol (1998)
    New York, NY : Wiley-Blackwell
    International Journal of Chemical Kinetics 30 (1998), S. 745-752 
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    ISSN: 0538-8066
    Keywords: Chemistry ; Physical Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: The relative rate technique has been used to measure the hydroxyl radical (OH) reaction rate constant of +2-butanol (2BU, CH3CH2CH(OH)CH3) and 2-pentanol (2PE, CH3CH2CH2CH(OH)CH3). 2BU and 2PE react with OH yielding bimolecular rate constants of (8.1±2.0)×10-12 cm3molecule-1s-1 and (11.9±3.0)×10-12 cm3molecule-1s-1, respectively, at 297±3 K and 1 atmosphere total pressure. Both 2BU and 2PE OH rate constants reported here are in agreement with previously reported values [1-4]. In order to more clearly define these alcohols' atmospheric reaction mechanisms, an investigation into the OH+alcohol reaction products was also conducted. The OH+2BU reaction products and yields observed were: methyl ethyl ketone (MEK, (60±2)%, CH3CH2C((DOUBLEBOND)O)CH3) and acetaldehyde ((29±4)% HC((DOUBLEBOND)O)CH3). The OH+2PE reaction products and yields observed were: 2-pentanone (2PO, (41±4)%, CH3C((DOUBLEBOND)O)CH2CH2CH3), propionaldehyde ((14±2)% HC((DOUBLEBOND)O)CH2CH3), and acetaldehyde ((40±4)%, HC((DOUBLEBOND)O)CH3). The alcohols' reaction mechanisms are discussed in light of current understanding of oxygenated hydrocarbon atmospheric chemistry. Labeled (18O) 2BU/OH reactions were conducted to investigate 2BU's atmospheric transformation mechanism details. The findings reported here can be related to other structurally similar alcohols and may impact regulatory tools such as ground level ozone-forming potential calculations (incremental reactivity) [5]. © 1998 John Wiley & Sons, Inc. Int J Chem Kinet 30: 745-752, 1998
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    Reduction of iodine by hydroxylamine within the pH range 0.7-3.5 (1998)
    New York, NY : Wiley-Blackwell
    International Journal of Chemical Kinetics 30 (1998), S. 785-797 
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    ISSN: 0538-8066
    Keywords: Chemistry ; Physical Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: The reduction of iodine by hydroxylamine within the [H+] range 3×10-1-3×10-4 mol.L-1 was first studied until completion of the reaction. In most cases, the concentration of iodine decreased monotonically. However, within a narrow range of reagent concentrations ([NH3OH+]0/[I2]0 ratio below 15, [H+] around 0.1 mol.L-1, and ionic strength around 0.1 mol.L-1), the [I2] and [I3-] vs. time curves showed 2 and 3 extrema, respectively. This peculiar phenomenon is discussed using a 4 reaction scheme (I2+I-⇔I3-, 2 I2+NH3OH++H2O→HNO2+4 I-+5 H+, NH3OH++HNO2→N2O+2 H2O+H+, and 2 HNO2+2 I-+2 H+→2 NO+I2+2 H2O). In a flow reactor, sustained oscillations in redox potential were recorded with an extremely long period (around 24 h).The kinetics of the reaction was then investigated in the starting conditions. The proposed rate equation points out a reinforcement of the inhibition by hydrogen ions when [H+] is above 4×10-2 mol.L-1 at 25°C. A mechanism based on ion-transfer reactions is postulated. It involves both NH2OH and NH3OH+ as the reducing reactive species. The additional rate suppression by H+ at low pH would be connected to the existence of H2OI+ in the reactive medium. © 1998 John Wiley & Sons, Inc. Int J Chem Kinet 30: 785-797, 1998
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    Kinetics of the reactions of OH radicals with some oxygenated volatile organic compounds under simulated atmospheric conditions (1998)
    New York, NY : Wiley-Blackwell
    International Journal of Chemical Kinetics 30 (1998), S. 839-847 
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    ISSN: 0538-8066
    Keywords: Chemistry ; Physical Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: Some relative rate experiments have been carried out at room temperature and at atmospheric pressure. This concerns the OH-oxidation of some oxygenated volatile organic compounds including methanol (k1), ethanol (k2), MTBE (k3), ethyl acetate (k4), n-propyl acetate (k5), isopropyl acetate (k6), n-butyl acetate (k7), isobutyl acetate (k8), and t-butyl acetate (k9). The experiments were performed in a Teflon-film bag smog chamber. The rate constants obtained are (in cm3 molecule-1 s-1): k1=(0.90±0.08)×10-12; k2=(3.88±0.11)×10-12; k3=(2.98±0.06)×10-12; k4=(1.73±0.20)×10-12; k5=(3.56±0.15)×10-12; k6=(3.97±0.18)×10-12; k7=(5.78±0.15)×10-12; k8=(6.77±0.30)×10-12; and k9=(0.56±0.11)×10-12. The agreement between the obtained rate constants and some previously published data has allowed for most of the studied compounds to point out a coherent group of values and to suggest recommended values. Atmospheric implications are also discussed. © 1998 John Wiley & Sons, Inc. Int J Chem Kinet 30: 839-847, 1998
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    Reactivity of the bis[1-Hydroxy-2-(Salicylideneamino)Ethane]Manganese(II) complex toward hydrogen peroxide: Kinetics and intermediates of reaction (1998)
    New York, NY : Wiley-Blackwell
    International Journal of Chemical Kinetics 30 (1998), S. 889-897 
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    ISSN: 0538-8066
    Keywords: Chemistry ; Physical Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: Kinetic studies of the oxidation of the bis[1-hydroxy-2-(salicylideneamino)ethane]manganese(II) complex by hydrogen peroxide in acetonitrile solutions, at (30.0±0.2)°C, are described. A first-order dependence on the total manganese and the peroxide concentrations was verified, leading to the rapid formation of a Mn(III) intermediate, monitored by stopped-flow measurements, at 394 nm, with a rate constant kf=(1.15±0.03)×105 mol-1 dm3 s-1. The participation of hydroxyl radicals in the process was detected by spin-trapping EPR spectra. The final product was monitored both by EPR spectra, and spectrophotometrically by the slow decay of the intermediary Mn(III) species, with a rate constant kd=(2.60±0.09) s-1. It was identified as the corresponding mononuclear Mn(IV) complex, and characterized by different spectroscopic techniques. Comparative results of the reactivity of the starting complex versus molecular oxygen, leading to the same final product, were also discussed. © 1998 John Wiley & Sons, Inc. Int J Chem Kinet 30: 889-897, 1998
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    Determination of the isomerization rate constant HOCH2CH2CH2CH(OO·)CH3 →HOC·HCH2CH2CH(OOH)CH3. Importance of intramolecular hydroperoxy isomerization in tropospheric chemistry (1998)
    New York, NY : Wiley-Blackwell
    International Journal of Chemical Kinetics 30 (1998), S. 875-887 
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    ISSN: 0538-8066
    Keywords: Chemistry ; Physical Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: The rate constant of the title reaction is determined during thermal decomposition of di-n-pentyl peroxide C5H11O(—)OC5H11 in oxygen over the temperature range 463-523 K. The pyrolysis of di-n-pentyl peroxide in O2/N2 mixtures is studied at atmospheric pressure in passivated quartz vessels. The reaction products are sampled through a micro-probe, collected on a liquid-nitrogen trap and solubilized in liquid acetonitrile. Analysis of the main compound, peroxide C5H10O3, was carried out by GC/MS, GC/MS/MS [electron impact EI and NH3 chemical ionization CI conditions]. After micro-preparative GC separation of this peroxide, the structure of two cyclic isomers (3S*,6S*)3α-hydroxy-6-methyl-1,2-dioxane and (3R*,6S*)3α-hydroxy-6-methyl-1,2-dioxane was determined from 1H NMR spectra. The hydroperoxy-pentanal OHC(—)(CH2)2(—)CH(OOH)(—)CH3 is formed in the gas phase and is in equilibrium with these two cyclic epimers, which are predominant in the liquid phase at room temperature. This peroxide is produced by successive reactions of the n-pentoxy radical: a first one generates the CH3C·H(CH2)3OH radical which reacts with O2 to form CH3CH(OO·)(CH2)3OH; this hydroxyperoxy radical isomerizes and forms the hydroperoxy HOC·H(CH2)2CH(OOH)CH3 radical. This last species leads to the pentanal-hydroperoxide (also called oxo-hydroperoxide, or carbonyl-hydroperoxide, or hydroperoxypentanal), by the reaction HOC·H(CH2)2CH(OOH)CH3+O2→O(=)CH(CH2)2CH(OOH)CH3+HO2.The isomerization rate constant HOCH2CH2CH2CH(OO·)CH3→HOC·HCH2CH2CH(OOH)CH3 (k3) has been determined by comparison to the competing well-known reaction RO2+NO→RO+NO2 (k7). By adding small amounts of NO (0-1.6×1015 molecules cm-3) to the di-n-pentyl peroxide/O2/N2 mixtures, the pentanal-hydroperoxide concentration was decreased, due to the consumption of RO2 radicals by reaction (7). The pentanal-hydroperoxide concentration was measured vs. NO concentration at ten temperatures (463-523 K). The isomerization rate constant involving the H atoms of the CH2(—)OH group was deduced:\documentclass{article}\pagestyle{empty}\begin{document}$ k_{3}\rm =(6.4\pm 0.6)\times 10^{10}\hbox{exp}\{-(16,900\pm 700)\hbox{cal mol}^{-1}/RT\}s^{-1} $\end{document}or per H atom:\documentclass{article}\pagestyle{empty}\begin{document}$ k_{3\rm (H)}\rm =(3.2\pm 0.3)\times 10^{10}\hbox{exp}\{-(16,900\pm 700)\hbox{cal mol}^{-1}/RT\}s^{-1} $\end{document}The comparison of this rate constant to thermokinetics estimations leads to the conclusion that the strain energy barrier of a seven-member ring transition state is low and near that of a six-member ring. Intramolecular hydroperoxy isomerization reactions produce carbonyl-hydroperoxides which (through atmospheric decomposition) increase concentration of radicals and consequently increase atmospheric pollution, especially tropospheric ozone, during summer anticyclonic periods. Therefore, hydrocarbons used in summer should contain only short chains (〈C4) hydrocarbons or totally branched hydrocarbons, for which isomerization reactions are unlikely. © 1998 John Wiley & Sons, Inc. Int J Chem Kinet 30: 875-887, 1998
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  • 79
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    Modeling of the oxidation of n-octane and n-decane using an automatic generation of mechanisms (1998)
    New York, NY : Wiley-Blackwell
    International Journal of Chemical Kinetics 30 (1998), S. 949-959 
    Details
    ISSN: 0538-8066
    Keywords: Chemistry ; Physical Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: Detailed modeling of the oxidation of n-octane and n-decane in the gas phase was performed by using mechanisms written by means of a software recently developed in our laboratory. This computer-aided design of mechanisms permits the automatic generation of detailed oxidation and combustion kinetic models in the case of paraffins and isoparaffins [1]. For n-octane, the predictions of the model were compared with experimental results obtained by Dryer and Brezinsky by means of a turbulent plug flow reactor (1080 K, 1 atm) [2]. The experimental study of Balès-Guéret et al., performed in a perfectly stirred reactor (922-1033 K, 1 atm) [3], was used as a basis of comparison for the modeling of the oxidation of n-decane. Considering that no fitting of any kinetic parameter was done, the agreement between the computed and the experimental values is satisfactory both for conversions and for the distribution of the products formed. This modeling has required improvement in the generation of the secondary reactions of alkenes, which are the main primary products obtained during the oxidation of these two alkanes in the range of temperature studied and for which reaction paths are detailed. © 1998 John Wiley & Sons, Inc. Int J Chem Kinet 30: 949-959, 1998
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  • 80
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    Oxidation of L-glutamine by manganese(iii) in aqueous sulfuric acid, acetic acid, and pyrophosphate media: A kinetic and mechanistic study (1998)
    New York, NY : Wiley-Blackwell
    International Journal of Chemical Kinetics 30 (1998), S. 7-19 
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    ISSN: 0538-8066
    Keywords: Chemistry ; Physical Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: Manganese(III) solutions were prepared by known electrochemical methods in sulfuric acid, acetic acid, and pyrophosphate media. The nature of the oxidizing species present in manganese(III) solutions was characterized by spectrophotometric and redox potential measurements. Kinetics of oxidation of L-glutamine by manganese(III) in sulfuric acid (1.5 M), acetic acid (60% v/v), and pyrophosphate (pH=1.3) media at 313 K, 323 K, and 328 K, respectively, have been studied. Three different rate laws have been obtained for the three media. Effects of varying ionic strength, solvent composition, and added anions, such as fluoride, chloride, perchlorate, pyrophosphate, and bisulfate, have been investigated. There is evidence for the existence of free radicals as transient species. Activation parameters have been evaluated using Arrhenius and Eyring plots. Mechanisms consistent with the observed kinetic data have been proposed and discussed. © 1998 John Wiley & Sons, Inc. Int J Chem Kinet: 30: 7-19, 1998.
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    Study of the effects of concentration and pH on the dissociation kinetics of Fe(II)-fulvic acid complexes (1998)
    New York, NY : Wiley-Blackwell
    International Journal of Chemical Kinetics 30 (1998), S. 63-67 
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    ISSN: 0538-8066
    Keywords: Chemistry ; Physical Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: The effects of reagent concentration and the pH in the kinetic behavior of the dissociation of Fe(II)-fulvic acid complexes were studied using a spectrophotometric technique. The results show that this behavior is not strongly affected by the concentration of fulvic acid, the concentration of the metal cation on the ratio of these concentrations and that variations in pH are more important in the dissociation process. A possible explanation based in the relative influence of proton concentration on the stability of the complexes is proposed. © 1998 John Wiley & Sons, Inc. Int J Chem Kinet: 30: 63-67,1998.
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  • 82
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    Kinetics and mechanism of reaction of toluidine blue with acidic bromate (1998)
    New York, NY : Wiley-Blackwell
    International Journal of Chemical Kinetics 30 (1998), S. 111-120 
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    ISSN: 0538-8066
    Keywords: Chemistry ; Physical Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: The detailed kinetics of the reaction of toluidine blue {phenothiazine-5-ium, 3-amino-7(dimethylamino)-2-methyl chloride, tolonium chloride, TB+Cl-} with potassium bromate and with aqueous bromine reaction were studied. In most of the experiments, the kinetics were monitored by following the rate of consumption of TB+ at 590 nm with excess acid and bromate. The reaction exhibited complex kinetic behavior. Initial reaction was slow and after an induction time, the TB+ concentration decreased fast. It had first-order dependence on both TB+ and bromate, and second-order dependence on H+. Under excess bromate conditions, the stoichiometric ratio of TB+ to bromate was 1:1. Demethylated sulfoxides were found at the reaction products. Sharp increase in the overall potential synchronized with the increase in bromine levels and the fast depletion of [TB+]. The role of bromide ion and bromine in the reaction was established. A multi-step reaction mechanism is proposed consistent with the experimental results. © 1998 John Wiley & Sons, Inc. Int J Chem Kinet: 30: 111-120, 1998.
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  • 83
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    Kinetic study of the nitrosation of N-alkylureas in dioxane-acetic acid mixtures (1998)
    New York, NY : Wiley-Blackwell
    International Journal of Chemical Kinetics 30 (1998), S. 145-150 
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    ISSN: 0538-8066
    Keywords: Chemistry ; Physical Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: The rate constants were determined for the nitrosation reactions of the following substrates: Methyl (MU), Ethyl (EU),Propyl (PU)Butyl (BU), and Allylurea (AU). The rate equation found at a constant pH was: v=k[HNO2] [Urea]. The reactions were carried out in predominantly organic media(dioxane-acetic acid-water) with differing polarities. The proposed reaction mechanism involves the proton transfer from the protonated N-alkyl-N-nitrosourea to the acetate anion. As the polarity of the medium decreased, an approximation of the rate constants of the nitrosation of the different substrates was observed. This approximation can be interpreted as a function of the impediment generated by the R alkyl radical in the rate controlling step. Accordingly, the substrate reactivity will be associated with the ease in which the protonated N-alkyl-N nitrosurea can transfer the proton to the acetate anion. The results achieved in this study are in accordance with there activities observed in the nitrosation of these substrates in aqueous media MU≫(EU≈PU≈BU)〉AU. © 1998 John Wiley & Sons, Inc. Int J Chem Kinet 30: 145-150, 1998.
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  • 84
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    The pyrolysis of azetidine: Shock-tube kinetics similarities and contrasts with two analogs (1998)
    New York, NY : Wiley-Blackwell
    International Journal of Chemical Kinetics 30 (1998), S. 185-191 
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    ISSN: 0538-8066
    Keywords: Chemistry ; Physical Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: The kinetics of decomposition of azetidine {(CH2)3N(SINGLEBOND)H)} was measured using single-pulse shock-tube techniques, over the temperature range 855-1100 K, in high argon dilution. These data confirm and extend an earlier investigation that utilized the very low-pressure pyrolysis method. A brief survey of many reports regarding the interesting features of azetidine is presented. In two appendices the thermodynamic and kinetic data on trimethylene sulfide, oxide, and immine are intercompared. New ab-initio calculations are cited for the parent species and their fragmentation products. © 1998 John Wiley & Sons, Inc. Int J Chem Kinet 30: 185-191, 1998.
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  • 85
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    Oxidation of manganese(II) by ozone and reduction of manganese(III) by hydrogen peroxide in acidic solution (1998)
    New York, NY : Wiley-Blackwell
    International Journal of Chemical Kinetics 30 (1998), S. 207-214 
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    ISSN: 0538-8066
    Keywords: Chemistry ; Physical Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: Manganese(II) is oxidized by ozone in acid solution, k=(1.5±0.2)×103 M-1 s-1 in HClO4 and k=(1.8±0.2)×103M-1 s-1 in H2SO4. The plausible mechanism is an oxygen atom transfer from O3 to Mn2+ producing the manganyl ion MnO2+, which subsequently reacts rapidly with Mn2+ to form Mn(III). No free OH radicals are involved in the mechanism. The spectrum of Mn(III) was obtained in the wave length range 200-310 nm. The activation energy for the initial reaction is 39.5 kJ/mol. Manganese(III) is reduced by hydrogen peroxide to Mn(II) with k(Mn(III)+H2O2)=2.8×103M-1 s-1 at pH 0-2. The mechanism of the reaction involving formation of the manganese(II)-superoxide complex and reaction of H2O2 with Mn(IV) species formed due to reversible disproportionation of Mn(III), is suggested. © 1998 John Wiley & Sons, Inc. Int J Chem Kinet 30: 207-214, 1998.
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  • 86
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    Belousov-Zhabotinskii type oscillations with amino acids or peptides as organic substrates in the presence of Mn2+ and Fe(phen)32+ as coupled catalysts (1998)
    New York, NY : Wiley-Blackwell
    International Journal of Chemical Kinetics 30 (1998), S. 243-247 
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    ISSN: 0538-8066
    Keywords: Chemistry ; Physical Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: Nine amino acids, aspartic acid, glycine, serine, tyrosine, alanine, glutamic acid, threonine, cystine, phenylalanine, and two peptides, and two peptides, glycine-glycine peptide, glutamic acid-cystine-glycine peptide, give rise to damped oscillations of the Belousov-Zhabotinskii(BZ) type in a batch reactor. Both Mn2+ and Fe(phen)32 are essential for most of those oscillations; and the oscillations in [Mn3+] and [Fe(phen)33+] are also observed. The role of two metallic ions played in the oscillations are analyzed, showing that Mn2+ catalyzes the oxidation of the amino acids or peptides by BrO3- to produce some intermediates which effectively reduce Br2 to Br- catalyzed by Fe(phen)32+. © 1998 John Wiley & Sons, Inc. Int. J. Chem Kinet 30: 243-247, 1998.
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    Concerted mechanism of the reactions of 2,4-dinitrophenyl 4-cyanobenzoate with secondary alicyclic amines in aqueous ethanol (1998)
    New York, NY : Wiley-Blackwell
    International Journal of Chemical Kinetics 30 (1998), S. 267-272 
    Details
    ISSN: 0538-8066
    Keywords: Chemistry ; Physical Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: The title reactions are subjected to a kinetic analysis in 44 wt% ethanol-water, at 25.0°C, ionic strength 0.2 (KCl). With a large excess of amine over the substrate, pseudo-first-order rate coefficients (kobs) are obtained, which are linearly dependent on the amine concentration. The nucleophilic rate constants (kN) are determined from plots of kobs vs. amine concentration. The Brönsted-type plot obtained with the kN values is linear, with slope β=0.63. The magnitude of this slope suggests that the mechanism is concerted, as opposed to a stepwise process with rate-determining breakdown of a zwitterionic tetrahedral intermediate (T±), in which the value of β is usually 0.8-1.0. The pyridinolysis of the same substrate in the same solvent is stepwise with the breakdown of T± as the rate-determining step. The change to a concerted mechanism for the title reactions is attributed to the superior nucleofugality of the alicyclic amines, compared to the isobasic pyridines, which destabilizes kinetically the “intermediate” T± in such a way that it does not exist, and the mechanism becomes enforced concerted. © 1998 John Wiley & Sons, Inc. Int J Chem Kinet 30: 267-272, 1998.
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    Comment: A kinetic study of chlorine radical reactions with ketones by laser-photolysis technique by Olsson et al. (1998)
    New York, NY : Wiley-Blackwell
    International Journal of Chemical Kinetics 30 (1998), S. 309-310 
    Details
    ISSN: 0538-8066
    Keywords: Chemistry ; Physical Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: No abstract.
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    Critical considerations on the methods for evaluating kinetic parameters from nonisothermal experiments (1998)
    New York, NY : Wiley-Blackwell
    International Journal of Chemical Kinetics 30 (1998), S. 313-327 
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    ISSN: 0538-8066
    Keywords: Chemistry ; Physical Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: By surveying the most used methods for evaluating the kinetic parameters from nonisothermal experiments, a new classification scheme of the methods is proposed. For each method the number of principles and theoretical approximations required to derive the equation which grounds it, is considered as a comparison criterion. The methods are, finally, classified into classes of equivalence.As a result of the analysis it is also suggested that the activation energy, as calculated from nonisothermal data, should be given as a range of values instead of a unique value. © 1998 John Wiley & Sons, Inc. Int J Chem Kinet 30: 313-327, 1998.
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  • 90
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    Temperature dependence of the gas-phase reactions F+CHFO, CFO+F, and CFO+CFO (1998)
    New York, NY : Wiley-Blackwell
    International Journal of Chemical Kinetics 30 (1998), S. 329-333 
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    ISSN: 0538-8066
    Keywords: Chemistry ; Physical Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: The rate coefficients for the reactions CHFO+F, CFO+F and the self-reaction of CFO were determined over the temperature range of 222-298 K. A computer controlled discharge-flow system with mass spectrometric detection was used. The results are expressed in the Arrhenius form (with energies in J):CHFO+F→CFO+HF:k1(T)=(9.7±0.7)·10-12 exp[-(5940±150)/RT] cm3 molecule-1 s-1CFO+F+M→CF2O+M:FORMULA DISC=“MATH”〉k2(T)=(2.60±1.17)·10-10 exp[-(10110±1250)/RT cm3 molecule-1 s-1FORMULACFO+CFO→CF2O+CO:k3(T)=(3.77±2.7)·10-10 exp[-(8350±2800)/RT] cm3 molecule-1 s-1© 1998 John Wiley & Sons, Inc. Int J Chem Kinet 30: 329-333, 1998
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    Kinetics and mechanism of the pyrolysis of 1-chloro-1,1-difluoroethane in the presence of additives (1998)
    New York, NY : Wiley-Blackwell
    International Journal of Chemical Kinetics 30 (1998), S. 359-366 
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    ISSN: 0538-8066
    Keywords: Chemistry ; Physical Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: The thermal dehydrochlorination CF2ClCH3→CF2(DOUBLEBOND)CH2+HCl has been studied in a static system between 597 and 664 K in the presence of CCl4, C2Cl6, CF2(DOUBLEBOND)CH2, HCl, and CF3CH3. A kinetic radical and molecular reaction model has been developed. In addition to describing earlier results on the acceleration of the pyrolysis by CCl4 and the further acceleration by HCl, this model describes quantitatively up to conversions of 20% (i) the dependence of the catalytic effect of CCl4 at low concentrations, (ii) the stronger catalytic effect of C2Cl6, and (iii) the inhibitory effect of added CF2CH2 and CF3CH3 when CCl4 is used as a catalyst. © 1998 John Wiley & Sons, Inc. Int J Chem Kinet 30: 359-366, 1998
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  • 92
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    Kinetics and mechanism of oxidation of aspirin by bromamine-T, N-bromosuccinimide, and N-bromophthalimide (1998)
    New York, NY : Wiley-Blackwell
    International Journal of Chemical Kinetics 30 (1998), S. 407-414 
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    ISSN: 0538-8066
    Keywords: Chemistry ; Physical Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: The kinetics of the oxidation of aspirin (ASP) by bromamine-T (BAT), N-bromosuccinimide (NBS), and N-bromophthalimide (NBP) has been studied in aqueous perchloric acid at 303 K. The oxidation reaction follows identical kinetics with first-order in [oxidant], fractional-order in [ASP], and inverse fractional-order in [H+]. Under identical experimental conditions the extent of oxidation with different oxidizing agents is in the order: NBS 〉 BAT 〉 NBP. The rate decreased with decreasing dielectric constant of the medium. The variation of ionic strength and the addition of the reaction products and halide ions had no significant effect on the reaction rate. The solvent isotope effect was studied using D2O. Kinetic parameters were evaluated by studying the reaction at different temperatures. The reaction products were identified by GC-MS. The proposed reaction mechanism and the derived rate law are consistent with the observed kinetic data. Formation and decomposition constants for ASP-oxidant complexes have been evaluated. Decarboxylation, bromination, and loss of acetic acid gave 2,4,6-tribromophenol. © 1998 John Wiley & Sons, Inc. Int J Chem Kinet: 30: 407-414, 1998
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    Kinetic study and modeling of the hetero-homogeneous pyrolysis and oxidation of isobutane around 800 K. Part I. Pyrolysis in an unpacked pyrex reactor (1998)
    New York, NY : Wiley-Blackwell
    International Journal of Chemical Kinetics 30 (1998), S. 425-437 
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    ISSN: 0538-8066
    Keywords: Chemistry ; Physical Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: Isobutane pyrolysis is studied in an unpacked Pyrex reactor at 20-100 torr initial pressures and 750-793 K. Results are interpreted in terms of a long chain radical mechanism and the reaction is modeled. The reaction selectivity or ratio of the initial production rate of isobutene (or hydrogen) to that of propene (or methane) is practically given by the ratio of the rate constant of abstraction of a tertiary hydrogen atom of isobutane to that of a primary one. A sensitivity analysis clearly shows that self-inhibition is essentially due to methylallyl radicals produced by hydrogen abstraction from isobutene. The model has been manually adjusted to experimental results and most of the adjusted rate constants are in agreement with literature data. © 1998 John Wiley & Sons, Inc. Int J Chem Kinet: 30: 425-437, 1998
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    Kinetics and mechanism of isatin ring opening in aqueous binary mixtures of methanol and acetonitrile cosolvents (1998)
    New York, NY : Wiley-Blackwell
    International Journal of Chemical Kinetics 30 (1998), S. 463-469 
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    ISSN: 0538-8066
    Keywords: Chemistry ; Physical Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: Solvent effects on the kinetics of hydrolysis of isatin by sodium hydroxide have been investigated within the temperature range (30-55°C) in methanol-water and acetonitrile-water media of varying solvent compositions up to 70% (v/v) of the organic solvent component. The thermodynamic activation parameters were calculated and discussed in terms of solvation effects. The determined isokinetic temperatures, in both systems, revealed the existence of compensation effect arising from strong solute-solvent interactions; log k was correlated with both log [H2O] and the reciprocal of the dielectric constant. The first correlation was observed to be linear while the second was nonlinear. Finally a mechanism for the isatin ring opening was proposed, which accounts for the role and the effect of the solvent on the reaction rate. © 1998 John Wiley & Sons, Inc. Int J Chem Kinet: 30: 463-469, 1998
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  • 95
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    Reaction of 2,2′-azinobis (3-ethylbenzothiazoline-6-sulfonic acid (ABTS) derived radicals with hydroperoxides. Kinetics and mechanism (1998)
    New York, NY : Wiley-Blackwell
    International Journal of Chemical Kinetics 30 (1998), S. 565-570 
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    ISSN: 0538-8066
    Keywords: Chemistry ; Physical Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: Tert-Butyl hydroperoxide and hydrogen peroxide readily react with the radical cation derived from 2,2′-azinobis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS). The reaction is inhibited by ABTS and protons, and can be interpreted in terms of a mechanism comprising a partially reversible electron transferROOH+ABTS•+↔ ROO · + ABTS + H+ (1)followed by the self-reactions of the hydroperoxide derived radicals and reactions between them and another ABTS derived radical. A complete kinetic analysis allows an evaluation of the rate constant for reaction (1). A value of 0.2 M-1 s-1 was obtained for both compounds. The back reaction of process (1) is more relevant when tert-butyl hydroperoxide is employed. © 1998 John Wiley & Sons, Inc. Int J Chem Kinet 30: 565-570, 1998
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    Kinetic study of the Ce(iii)- or Mn(ii)-catalyzed Belousov-Zhabotinsky reactions with mixed organic acid/ketone substrates (1998)
    New York, NY : Wiley-Blackwell
    International Journal of Chemical Kinetics 30 (1998), S. 595-604 
    Details
    ISSN: 0538-8066
    Keywords: Chemistry ; Physical Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: In a stirred batch reactor, the Ce(III)- or Mn(II)-catalyzed Belousov-Zhabotinsky reaction with mixed organic acid/ketone substrates exhibits oscillatory behavior. The organic acids studied here are: dl-mandelic acid (MDA), dl-4-bromomandelic acid (BMDA), and dl-4-hydroxymandelic acid (HMDA), and the ketones are: acetone (Me2CO), methyl ethyl ketone (MeCOEt), diethyl ketone (Et2CO), acetophenone (MeCOPh), and cyclohexanone ((CH2)5CO). The effects of bromate ion, organic acid, ketone, metal-ion catalyst, and sulfuric acid concentrations on the oscillatory patterns are investigated. Both conventional and stopped-flow methods are applied to study the kinetics of the oxidation reactions of the above organic acids by Ce(IV) or Mn(III) ion. The order of relative reactivities of the oxidation reactions of organic acids in 1 M H2SO4 is Mn(III)(SINGLEBOND)HMDA reaction 〉 Ce(IV)(SINGLEBOND)HMDA reaction 〉 Mn(III)(SINGLEBOND)BMDA, reaction 〉 Mn(III)(SINGLEBOND)MDA reaction 〉 Ce(IV)(SINGLEBOND)BMDA reaction 〉 Ce(IV)(SINGLEBOND)MDA reaction. Spectrophotometric study of the bromination reactions of the above ketones shows that these reactions are zero-order with respect to bromine and first-order with respect to ketone and that ketone enolization is the rate-determining step. The order of relative rates of bromination or enolization reactions of ketones in 1 M H2SO4 is (CH2)5CO≫(MeCOEt, Et2CO, Me2CO)〉MeCOPh. © 1998 John Wiley & Sons, Inc. Int J Chem Kinet:30: 595-604, 1998
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    Electronic Resource
    Inhibition of chemical oscillations by bromide ion in the Briggs-Rauscher reaction (1998)
    New York, NY : Wiley-Blackwell
    International Journal of Chemical Kinetics 30 (1998), S. 641-646 
    Details
    ISSN: 0538-8066
    Keywords: Chemistry ; Physical Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: The addition of bromide ions to the component solutions of the Briggs- Rauscher oscillating system produces a variety of phenomena, depending on the sequence of the addition and on the initial bromide concentration. If the addition is made some minutes after the mixing of H2O2 and acidic IO3- and before adding malonic acid and Mn2+ ions, the oscillations last for five or six cycles, then suddenly ceases. If the addition is made immediately after the mixing of H2O2 and acidic IO3- and before adding malonic acid and Mn2+ ions, the oscillations do not start at all. The addition of bromide ions to an actively oscillating BR reaction causes a rapid suppression of the oscillations. Our observations may be accounted for by a mechanism involving the IBr species. © 1998 John Wiley & Sons, Inc. Int J Chem Kinet: 30: 641-646, 1998
    Additional Material: 4 Ill.
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  • 98
    Electronic Resource
    Electronic Resource
    Parabenzoquinone pyrolysis and oxidation in a flow reactor (1998)
    New York, NY : Wiley-Blackwell
    International Journal of Chemical Kinetics 30 (1998), S. 683-697 
    Details
    ISSN: 0538-8066
    Keywords: Chemistry ; Physical Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: An experimental and theoretical study of the pyrolysis and oxidation of parabenzoquinone has been performed. The experiments were conducted in an isothermal quartz flow reactor at atmospheric pressure in the temperature range 600-1500 K. The main variables considered are temperature, oxygen concentration, and presence of CO. A detailed reaction mechanism for the pyrolysis and oxidation chemistry of parabenzoquinone is proposed, which provides a good description of the experimental results. Both the experimental work and the kinetic mechanism proposed for the pyrolysis and oxidation of parabenzoquinone represent the first systematic study carried out for this important aromatic compound.Our pyrolysis results confirm that the primary dissociation channel for p-benzoquinone leads to CO and a C5H4O isomer, presumably cyclopentadienone. However, significant formation of CO2 during the pyrolysis may indicate the existence of a secondary dissociation channel leading to CO2 and a C5H4 isomer. Under oxidizing conditions, consumption of p-benzoquinone occurs mainly by dissociation at lower temperatures. As the temperature increases interaction of OC6H4O with the radical pool becomes more significant, occurring primarily through hydrogen abstraction reactions followed by ring opening reactions of the OC6H3O radical. © 1998 John Wiley & Sons, Inc. Int J Chem Kinet: 30: 683-697, 1998
    Additional Material: 9 Ill.
    Type of Medium: Electronic Resource
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  • 99
    Electronic Resource
    Electronic Resource
    Rate coefficients for the reactions of hydrogen atoms with 1-bromopropane, 2-bromopropane, 1-bromobutane, and 2-bromobutane (1998)
    New York, NY : Wiley-Blackwell
    International Journal of Chemical Kinetics 30 (1998), S. 721-727 
    Details
    ISSN: 0538-8066
    Keywords: Chemistry ; Physical Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: The rate coefficients for the reactions of hydrogen atoms with n-C3H7Br, s-C3H7Br, n-C4H9Br, and s-C4H9Br were determined in a discharge flow-reactor at 298 K and a pressure of 4 mbar. Molecular-beam sampling and subsequent mass-spectrometric detection with electron-impact ionisation was used for the measurement of the bromo-hydrocarbon concentration. The rate coefficients obtained are (in 1010 cm3 mol-1 s-1): 2.3±1.2 for n-C3H7Br, 2.3±1.2 for s-C3H7Br, 2.4±1.2 for n-C4H9Br, and 2.8±1.4 for s-C4H9Br. The results are compared with predictions from bond-energy bond-order (BEBO) calculations, where a reasonable agreement is found. Furthermore, also by BEBO calculations, the relative importance of bromine abstraction as compared to hydrogen abstraction is estimated. © 1998 John Wiley & Sons, Inc. Int J Chem Kinet: 30: 721-727, 1998
    Additional Material: 1 Ill.
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  • 100
    Electronic Resource
    Electronic Resource
    Rate constants for the reactions of methylvinyl ketone, methacrolein, methacrylic acid, and acrylic acid with ozone (1998)
    New York, NY : Wiley-Blackwell
    International Journal of Chemical Kinetics 30 (1998), S. 769-776 
    Details
    ISSN: 0538-8066
    Keywords: Chemistry ; Physical Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: Rate constants for the reaction of ozone with methylvinyl ketone (H2C(DOUBLEBOND)CHC(O)CH3), methacrolein (H2C(DOUBLEBOND)C(CH3)CHO), methacrylic acid (H2C(DOUBLEBOND)C(CH3)C(O)OH), and acrylic acid (H2C(DOUBLEBOND)CHC(O)OH) were measured at room temperature (296±2 K) in the presence of a sufficient amount of cyclohexane to scavenge OH-radicals. Results from pseudo-first-order experiments in the presence of excess ozone were found not to be consistent with relative rate measurements. It appeared that the formation of the so-called Criegee-intermediates leads to an enhanced decrease in the concentration of the two organic acids investigated. It is shown that the presence of formic acid, which is known to react efficiently with Criegee-intermediates, diminishes the observed removal rate of the organic acids. The rate constant for the reaction of ozone with the unsaturated carbonyl compounds methylvinyl ketone and methacrolein was found not to be influenced by the addition of formic acid. Rate constants for the reaction of ozone determined in the presence of excess formic acid are (in cm3 molecule-1 s-1): methylvinyl ketone (5.4±0.6)×10-18; methacrolein (1.3±0.14)×10-18; methacrylic acid (4.1±0.4)×10-18; and acrylic acid (0.65±0.13)×10-18. Results are found to be consistent with the Criegee mechanism of the gas-phase ozonolysis. © 1998 John Wiley & Sons, Inc. Int J Chem Kinet 30: 769-776, 1998
    Additional Material: 7 Ill.
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