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  • 1995-1999  (106)
  • 1985-1989
  • 1955-1959
  • 1998  (106)
  • Chemical Engineering
  • Nuclear reactions
  • 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
    Mixing in Stars and the Evolution of the 3He Abundance (1998)
    Springer
    Space science reviews 84 (1998), S. 199-206 
    Details
    ISSN: 1572-9672
    Keywords: Nuclear reactions ; Nucleosynthesis ; Abundances ; Stars:Evolution ; Interior ; Rotation
    Source: Springer Online Journal Archives 1860-2000
    Topics: Physics
    Notes: Abstract We first recall the observational and theoretical facts that constitute the so-called 3He problem. We then review the chemical anomalies that could be related to the destruction of 3He in red giants stars. We show how a simple consistent mechanism can lead to the destruction of 3He in low mass stars and simultaneously account for the low 12C/13C ratios and low lithium abundances observed in giant stars of different populations. This process should both naturally account for the recent measurements of 3He/H in galactic HII regions and allow for high values of 3He observed in some planetary nebulae. We propose a simple statistical estimation of the fraction of stars that may be affected by this process.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1005027519798
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  • 34
    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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  • 35
    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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  • 36
    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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  • 37
    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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  • 38
    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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  • 39
    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.
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    URL: http://dx.doi.org/10.1023/A:1011929910782
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  • 40
    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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  • 41
    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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  • 42
    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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  • 43
    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.
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    URL: http://dx.doi.org/10.1023/A:1011942530288
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  • 44
    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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  • 45
    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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    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.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1011918425629
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  • 47
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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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    URL: http://dx.doi.org/10.1023/A:1011980432646
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  • 48
    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.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1011938112599
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  • 49
    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.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1011932800729
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  • 50
    Electronic Resource
    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.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1011922209757
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    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.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1011974226596
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  • 52
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    Electronic Resource
    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.
    Type of Medium: Electronic Resource
    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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  • 54
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    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.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1006023328617
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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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  • 56
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    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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  • 57
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    Electronic Resource
    Transportation of hazardous wastes (1998)
    New York, NY [u.a.] : Wiley-Blackwell
    Process Safety Progress 17 (1998), S. 61-67 
    Details
    ISSN: 1066-8527
    Keywords: Chemistry ; Chemical Engineering
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology , Process Engineering, Biotechnology, Nutrition Technology
    Notes: Risk assessments have been performed to determine the risk associated with the transportation of hazardous wastes through a city. In the course of these assessments, a number of modeling issues arose relating to transportation accident rates, the characterization of incidents, the effect of thermal radiation, the impact of exposure to toxic chemicals, and the threshold for acceptable risk. This paper discusses these issues.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1002/prs.680170112
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  • 58
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    Electronic Resource
    Process safety update (1998)
    New York, NY [u.a.] : Wiley-Blackwell
    Process Safety Progress 17 (1998), S. S3 
    Details
    ISSN: 1066-8527
    Keywords: Chemistry ; Chemical Engineering
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology , Process Engineering, Biotechnology, Nutrition Technology
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1002/prs.680170202
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  • 59
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    Electronic Resource
    Burst resistant ribbon wound pressure vessels for ammonia plants (1998)
    New York, NY [u.a.] : Wiley-Blackwell
    Process Safety Progress 17 (1998), S. 98-103 
    Details
    ISSN: 1066-8527
    Keywords: Chemistry ; Chemical Engineering
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology , Process Engineering, Biotechnology, Nutrition Technology
    Notes: This paper presents the design of ribbon wound pressure vessels useful for Ammonia, Urea and Methanol plants. The design is to create a thin shell of 1/5 the total wall thickness required, weld it to the end pieces, and wind 4 to 8 mm thick ribbons of 80 mm width at an angle of 15 to 30 degrees on the inner shell, using a prestress. The ribbons are welded at the ends and an even number of layers are wound cross-helically on to the shell. With more than 7000 vessels over the pressure range of 50 to 350 atmospheres in use in the various chemical industries in China over the past 30 years, their safety record has been excellent. Of particular interest has been the application of this technology in the Ammonia and Urea plants, where the design allows fabrication of these vessels at substantial reduction in cost, and early delivery, when compared to the mono wall technology.
    Additional Material: 6 Ill.
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    URL: http://dx.doi.org/10.1002/prs.680170205
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  • 60
    Electronic Resource
    Electronic Resource
    Safety surveys - looking at key activities in depth (1998)
    New York, NY [u.a.] : Wiley-Blackwell
    Process Safety Progress 17 (1998), S. 20-22 
    Details
    ISSN: 1066-8527
    Keywords: Chemistry ; Chemical Engineering
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology , Process Engineering, Biotechnology, Nutrition Technology
    Notes: Most audits try to look at a representative selection of the plant procedures and equipment. An alternative is a survey, a look in depth at selected procedures (such as those for testing alarms and trips, issuing permits-to-work, controlling modifications, taking samples or testing relief devices) or selected equipment (such as level glasses or equipment for handling LPG). If the procedure or equipment is well-chosen, surveys may make a bigger contribution to safety, per person-hour, than a conventional audit.
    Additional Material: 1 Tab.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1002/prs.680170106
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  • 61
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    Pressure relief system documentation: Equipment based relational database is key to OSHA 1910.119 compliance (1998)
    New York, NY [u.a.] : Wiley-Blackwell
    Process Safety Progress 17 (1998), S. 39-42 
    Details
    ISSN: 1066-8527
    Keywords: Chemistry ; Chemical Engineering
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology , Process Engineering, Biotechnology, Nutrition Technology
    Notes: Under OSHA 1910.119, all Process Safety Management (PSM) facilities are required to keep their pressure relief system design information current. This article demonstrates why a pressure relief system design verification effort must be based on an equipment list, rather than a relief device list, in order to ensure that every piece of equipment is adequately protected. The formerly common practice of simply checking the design bases of all existing relief devices is deficient is deficient since this technique does not systematically ensure that every piece of equipment is protected.The “Berwanger Method” is a step by step process for designing or analyzing a pressure relief system to meet OSHA 1910.119 Process Safety Information (PSI) and Process Hazard Analysis (PHA) mandates. The method uses a relational database which tracks the relationships between protected equipment, potential overpressure scenarios, and protective devices.The challenge facing an operating company does not end once the design basis has been “verified” - the design basis information must also be maintained and be readily accessible to avoid costly reinvention of the wheel down the road. The “Berwanger Method” also addresses these maintenance issues.
    Additional Material: 6 Ill.
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    URL: http://dx.doi.org/10.1002/prs.680170109
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  • 62
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    A detailed reaction study of phosphorus trichloride and water (1998)
    New York, NY [u.a.] : Wiley-Blackwell
    Process Safety Progress 17 (1998), S. 49-60 
    Details
    ISSN: 1066-8527
    Keywords: Chemistry ; Chemical Engineering
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology , Process Engineering, Biotechnology, Nutrition Technology
    Notes: This paper reports on a comprehensive literature search and small scale experimental work on the reaction characteristics of phosphorous trichloride and water. More than 30 tests were conducted, including both closed and open test cells. The water to phosphorus trichloride molar ratio was varied from 1 to 25. When in contact, water and phosphorus trichloride will form two liquid layers with a reaction starting at the interface. The impact of variables on reaction rates including the interface surface area, layer depth, and stirring were investigated experimentally. A reaction rate model that fits all the measured data is presented. Case studies illustrating the use of this data for emergency relief systems and vent containment design are presented in reference. [1].
    Additional Material: 10 Ill.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1002/prs.680170111
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  • 63
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    The influence of the geometry of the hot surfaces on the autoignition of vapor/air mixture: Some experimental and theoretical results (1998)
    New York, NY [u.a.] : Wiley-Blackwell
    Process Safety Progress 17 (1998), S. 68-73 
    Details
    ISSN: 1066-8527
    Keywords: Chemistry ; Chemical Engineering
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology , Process Engineering, Biotechnology, Nutrition Technology
    Notes: Two major accidents in the 80's: the summit Tunnel Fire, England and Piper Alpha disaster, an offshore platform in the North Sea; and very recently, possible explosion of the Boeing, TWA flight 800 at New York, makes it imperative that further research into the mechonisms of the ignition of flammable vapor/air mixture in contact with hot surfaces needs to be done. There have been a number of studies of ignition by hot surfaces, but in all these studies the ignition sources were wire, sphere or strip, i.e., most of them were flat surfaces. But to the authors' knowledge, other variables which affect the ignition mechanism such as irregular geometrical shapes have not been studied. The purpose of this paper is to examine how the degree of confinement (or, configuration), size and orientation, of the heated surface affects the ignition temperature of the flammable vapors. The results were obtained by experimentnal and by computational fluid dynamics.
    Additional Material: 13 Ill.
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    URL: http://dx.doi.org/10.1002/prs.680170113
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  • 64
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    Electronic Resource
    Process safety update (1998)
    New York, NY [u.a.] : Wiley-Blackwell
    Process Safety Progress 17 (1998), S. S3 
    Details
    ISSN: 1066-8527
    Keywords: Chemistry ; Chemical Engineering
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology , Process Engineering, Biotechnology, Nutrition Technology
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1002/prs.680170102
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    KG: New data and analysis (1998)
    New York, NY [u.a.] : Wiley-Blackwell
    Process Safety Progress 17 (1998), S. 9-15 
    Details
    ISSN: 1066-8527
    Keywords: Chemistry ; Chemical Engineering
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology , Process Engineering, Biotechnology, Nutrition Technology
    Notes: The design and deflagration pressure relief vents is based on correlations developed for various types of combustible materials and for enclosures of different strengths. The primary guideline for deflagration vent design in the US is NFPA 68 Guide for Venting of Deflagrations [5]. That document gives guidance for the design of vents for enclosures containing flammable gases, specifically hydrogen, coke oven gas, propane, and methane. Application of the guide to other gases is achieved using the KG value. Values of KG are published for a relatively small number of gases, as seen in Table D-1 of NFPA 68. This work present KG data on several additional gases obtained in a laboratory scale test vessel along with analysis of the results with respect to published values of fundamental burning velocity.
    Additional Material: 9 Ill.
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    URL: http://dx.doi.org/10.1002/prs.680170104
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    NFPA 30: An update and a look into the future (1998)
    New York, NY [u.a.] : Wiley-Blackwell
    Process Safety Progress 17 (1998), S. 23-31 
    Details
    ISSN: 1066-8527
    Keywords: Chemistry ; Chemical Engineering
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology , Process Engineering, Biotechnology, Nutrition Technology
    Notes: In May 1996, the Flammable and Combustible Liquids Code Committee of the National Fire Protection Association (NFPA) proposed for adoption by the Association a new edition of NFPA 30, Flammable and Combustible Liquids Code. This new edition was the culmination of two and one-half years' work by the Committee and included one of the most significant changes to that document in some twenty years: the incorporation of mandatory fire protection criteria for warehouses and other inside areas that store flammable and combustible liquids in containers and portable tanks.
    Additional Material: 2 Ill.
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    URL: http://dx.doi.org/10.1002/prs.680170107
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    Risk based prioritization of maintenance repair work (1998)
    New York, NY [u.a.] : Wiley-Blackwell
    Process Safety Progress 17 (1998), S. 32-38 
    Details
    ISSN: 1066-8527
    Keywords: Chemistry ; Chemical Engineering
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology , Process Engineering, Biotechnology, Nutrition Technology
    Notes: This paper describes the development of a risk ranked Inspection Recommendation procedure that is used by one of Exxon's chemical plants to prioritize repairs that have been identified during equipment inspection.As part of the Company's Safety Management Practices initiative in the late 1980's a procedure was put into place to ensure that an Inspector's repair recommendations were properly addressed by the organization. The initial procedures were successful at “systematizing” the documentation and stewardship-to-completion of the Inspector's recommendation, however, there were complications with the original process: (1)The Inspector made a simple High, Medium or Low assessment of the priority/criticality of the recommendation. Frequently, this resulted in disagreements with Operations about the true priority of the recommendation.(2)If there was agreement on the priority of the recommendation, there was still disagreement on the relative rank within the priority-which high priority was the highest priority?(3)With limited funds to spend on repairs, it was (and is) important to make sure that the money was being spent on the highest risk items that had the greatest risk reduction/cost benefit ratio.To address these concerns, the procedure was modified to incorporate a risk assessment of the recommendation by both the Inspector and Operations. In the new procedure, the Inspector describes the deficiency that he/she finds and assesses the probability of failure within a certain time-frame. Operations must assess the consequences, from an environmental, safety and economics standpoint, were the failure to occur. These assessments are combined in the typical risk equation (risk = probability × consequences) to arrive at a severity index which serves to rank the recommendation relative to the other recommendations. Because Operations participates in the assessment there is very little disagreement about the priority of the recommendation. The severity index puts the recommendations in order so it is quite clear which are the highest priority recommendations. This process has helped to focus the entire organization on those deficiencies that represent the greatest risk with the result that less time and money is spent correcting items that have a low risk/cost benefit ratio, allowing these savings to be used to reduce the higher risks in the plant.
    Additional Material: 4 Ill.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1002/prs.680170108
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    Short communication: Estimating the minimum ignition energy of hybrid mixtures (1998)
    New York, NY [u.a.] : Wiley-Blackwell
    Process Safety Progress 17 (1998), S. 124-126 
    Details
    ISSN: 1066-8527
    Keywords: Chemistry ; Chemical Engineering
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology , Process Engineering, Biotechnology, Nutrition Technology
    Notes: A simple analytical method is presented for estimating the hybrid minimum ignition energy (HMIE) of dust-gas mixtures, based on the assumed generality of Bartknecht's well-known test data for mixtures of propane with a series of dusts in air. Since the HMIE equation requires input data which might be unavailable, the use of conservative default methods is discussed.
    Additional Material: 1 Ill.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1002/prs.680170208
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    Flammability hazards of lower aliphatic aldehydes at elevated pressure and temperature (1998)
    New York, NY [u.a.] : Wiley-Blackwell
    Process Safety Progress 17 (1998), S. 138-148 
    Details
    ISSN: 1066-8527
    Keywords: Chemistry ; Chemical Engineering
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology , Process Engineering, Biotechnology, Nutrition Technology
    Notes: A large and potentially hazardous decrease in aldehyde autoignition temperature (AIT) occurs with increased pressure. The AIT-pressure curve determined in a 5 L stainless steel sphere was similar for propionaldehyde and butyraldehyde in air, falling from about 185°C at atmospheric pressure to 90°C at 140 psia. Reduction of oxygen concentration had little effect on propionaldehyde AIT. At 100°C and 140 psia, autoignitions accompanied by at least a doubling of pressure were observed above 4% oxygen. In the presence of a few grams of free liquid, propionaldehyde vapor ignited in air at initial conditions significantly below the AIT. The mechanism appears to involve rapid Fe-catalyzed exothermic liquid-phase oxidation leading to autoignition of the adjacent heated gas layer. An acetaldehyde vapor-air mixture in the presence of free liquid and rust exploded at room temperature when air pressure was increased to 95 psia; this result is discussed with reference to a cylinder overpressurization that occurred while making up an ostensibly sub-LFL calibration mixture with compressed air. Propionaldehyde's limiting oxygen concentration (LOC) was investigated in the near-autoignition region using the same 5L apparatus; the findings are discussed with reference to an overpressurization incident in an air-liquid partial oxidation reactor. The general results are used to illustrate the application of LOC in partial oxidation processes subject to autoignition and to discuss elements of the current ASTM draft test method for LOC, which does not address test difficulties associated with condensable and/or reactive gas systems.
    Additional Material: 16 Ill.
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    URL: http://dx.doi.org/10.1002/prs.680170211
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    Process safety update (1998)
    New York, NY [u.a.] : Wiley-Blackwell
    Process Safety Progress 17 (1998), S. F3 
    Details
    ISSN: 1066-8527
    Keywords: Chemistry ; Chemical Engineering
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology , Process Engineering, Biotechnology, Nutrition Technology
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1002/prs.680170302
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    Multivariate hazard identification and ranking system (1998)
    New York, NY [u.a.] : Wiley-Blackwell
    Process Safety Progress 17 (1998), S. 157-170 
    Details
    ISSN: 1066-8527
    Keywords: Chemistry ; Chemical Engineering
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology , Process Engineering, Biotechnology, Nutrition Technology
    Notes: Risk analysis in chemical process industries is an elaborate exercise involving several steps from preliminary hazard identification to development of credible accident scenarios, to preparation of strategies for prevention or control of damage.All this requires substantial inputs of time and money. In order to get an approximate yet workable assessment of risk at much lesser costs, indices have been developed which link typical findings of elaborate risk analysis to scales of risk. The scales, in turn, provide workable measures of hazards/risks/safety.In the past, indices have been reported for swift risk assessment - the noteworthy among them include Dow fire and explosion index, Mond fire, explosion and toxicity index, IFAL index, and mortality index. A few rapid ranking techniques have also been proposed.This paper presents a new system of methodologies for Hazard Identification and Ranking (HIRA). The system consists of two indices: one for fire and explosion hazards and another for the hazard due to likely release of toxic chemical. The magnitudes of these indices indicate the severity of the likely accident; in terms of the size of the impacted area.HIRA has been applied to a typical chemical process industry - a sulfolane plant - and its performance has been compared with that of the Dow's and the Mond's indices. The study reveals that HIRA is more sensitive and accurate than the other indices.
    Additional Material: 12 Ill.
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    URL: http://dx.doi.org/10.1002/prs.680170303
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    Experiences with non-destructive testing of static equipment in ammonia plants at DSM (1998)
    New York, NY [u.a.] : Wiley-Blackwell
    Process Safety Progress 17 (1998), S. 200-208 
    Details
    ISSN: 1066-8527
    Keywords: Chemistry ; Chemical Engineering
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology , Process Engineering, Biotechnology, Nutrition Technology
    Additional Material: 14 Ill.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1002/prs.680170309
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    Analysis of hydrogen fluoride release at Texas city (1998)
    New York, NY [u.a.] : Wiley-Blackwell
    Process Safety Progress 17 (1998), S. 213-218 
    Details
    ISSN: 1066-8527
    Keywords: Chemistry ; Chemical Engineering
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology , Process Engineering, Biotechnology, Nutrition Technology
    Notes: On October 31, 1987 a crane lifting a heat exchanger convection section failed and severed a 4″ loading line and a 2″ pressure relief line to an HF alkylation reactor settler drum at a petroleum refinery in Texas City, Texas. Vapors were emitted under pressure for about two hours and the vessel was plugged and drained aproximately 44 hours later. A plume from this accidental release passed through residential areas, damaging some vegetation (brown lawns), and spawning a class action law suit. An extensive analysis was conducted to determine the total inventory loss and to model the blowdown process and the concentrations of HF in the plume. Since the discharge rate was decreasing with time, a peak concentration of HF in the emitted vapors occurred just before the water spray mitigation system became fully operative. Consequently, the mitigation efforts were more effective late in the response when concentrations were already low. The predicted plume concentrations are consistent with observed vegetation damage effects, with concentrations below Emergency Response Planning Guideline Level 3 past 3/4 mile from the source. These results support a policy of sheltering in place during such an event.
    Additional Material: 8 Ill.
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    URL: http://dx.doi.org/10.1002/prs.680170311
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    Peroxide drum explosion and fire (1998)
    New York, NY [u.a.] : Wiley-Blackwell
    Process Safety Progress 17 (1998), S. 225-231 
    Details
    ISSN: 1066-8527
    Keywords: Chemistry ; Chemical Engineering
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology , Process Engineering, Biotechnology, Nutrition Technology
    Notes: A fifty-five gallon steel drum of a liquid organic peroxide pressurized and ruptured in the mix room of a manufacturing plant. The head of the drum blew off and the ejected material ignited. The resulting fire was extinguished by the building sprinkler system and operating personnel. Although there were no injuries, the fire caused significant damage in the mix room. The investigation of this incident, its likely cause, and the corrective actions will be discussed.
    Additional Material: 9 Ill.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1002/prs.680170313
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    Making RMP hazard assessment meaningful (1998)
    New York, NY [u.a.] : Wiley-Blackwell
    Process Safety Progress 17 (1998), S. 238-242 
    Details
    ISSN: 1066-8527
    Keywords: Chemistry ; Chemical Engineering
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology , Process Engineering, Biotechnology, Nutrition Technology
    Notes: The Brazoria County Petrochemical Council, 13 companies that are working together to enhance relations between industry and the community, united in a joint effort at complying with the EPA's Risk Management Program. One of the significant issues the group had to address was the need to develop meaningful hazard assessment for presentation to the public. The EPA's “Table Look-Up Approach” found in the Offsite Consequence Analysis Guidance document is certainly a good tool; however, the built-in conservatism results in over-estimates of potential hazard areas. Much more meaningful results are shown to be obtained using one of the hazard release models.The value of using a credible scenario with realistic meteorological data is demonstrated through the consistently smaller areas predicted by the PHAST Model for planning purposes. Realistic scenarios/failure modes and realistic model parameters are important so that the risk to the public is not overstated. Proprietary models such as PHAST are invaluable in providing more meaningful consequences for planning purposes.
    Additional Material: 2 Tab.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1002/prs.680170404
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    The effects of valve wheel size, operation position and in-line pressures on required torque for gate valves (1998)
    New York, NY [u.a.] : Wiley-Blackwell
    Process Safety Progress 17 (1998), S. 263-271 
    Details
    ISSN: 1066-8527
    Keywords: Chemistry ; Chemical Engineering
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology , Process Engineering, Biotechnology, Nutrition Technology
    Notes: Some of the hazards encountered by process plant operators involve the operation of in-line valves to control, start, and to stop flow. Torque required to operate valves may vary according to valve wheel size, in-line pressure, and valve flange position (open/closed). This study determined how valve wheel size, in-line pressure and valve position (open/closed) affect torque required to actuate a valve. Data were gathered with each combination of size, pressure and position for 336 valves in an operating petrochemical process facility. The results indicate that the main effects of valve wheel size, the in-line pressure, and open/closed valve position significantly affect operational torque requirements. In addition, the interaction between position and pressure was significant for operational torque. The implication of these results is that operators are exposed to operational torque requirements that exceed maximum acceptable capabilities that have been determined in previous studies.
    Additional Material: 12 Ill.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1002/prs.680170407
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    Measures taken to ensure safe operation of an ammonia storage tank (1998)
    New York, NY [u.a.] : Wiley-Blackwell
    Process Safety Progress 17 (1998), S. 288-296 
    Details
    ISSN: 1066-8527
    Keywords: Chemistry ; Chemical Engineering
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology , Process Engineering, Biotechnology, Nutrition Technology
    Notes: An ammonia storage tank was built at the BASF Antwerp site in 1969 on land reclaimed from the sea. After several years of operation uneven foundation settlement, of up 2, occurred. In order to assure stability of this area for the next operation period (at least 10 years) measures were taken to ensure continued safe operation. One key measure was strain gauge monitoring at the location of maximum stress.
    Additional Material: 19 Ill.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1002/prs.680170410
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    Recent developments in the Baker-Strehlow VCE analysis methodology (1998)
    New York, NY [u.a.] : Wiley-Blackwell
    Process Safety Progress 17 (1998), S. 297-301 
    Details
    ISSN: 1066-8527
    Keywords: Chemistry ; Chemical Engineering
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology , Process Engineering, Biotechnology, Nutrition Technology
    Notes: The Baker-Strehlow methodology was developed to provide an objective approach to prediction of blast pressures from vapor cloud explosions. The complete methodology was first published in 1994 [1]. Since then, it has evolved through ongoing research and use in VCE hazard analyses, facility siting studies and accident investigations. This article gives a brief overview of a paper on recent developments in the Baker-Strehlow methodology presented at the 31st Loss Prevention Symposium in Houston on March 9-13, 1997. Because the entire paper is too lengthy to be presented here, the following discussions may be lacking in some details. A copy of the complete paper can be obtained from the American Institute of Chemical Engineers (AIChE).Since the Baker-Strehlow method was first published, it has been used extensively in VCE hazard assessments in refineries and chemical plants. As expected, many practical lessons have been learned during the course of the hazard assessments, and the Baker-Strehlow method has evolved as a result. The changes have been evolutionary, not revolutionary. In keeping with the goals of the original study in which the methodology was developed, all changes have been incorporated with the intent of achieving an objective methodology to provide consistent prediction of VCE blast effects.The revisions to the Baker-Strehlow method resulting from experience gained during plant walk-downs and hazard assessments include: Systematic identification of “potential explosion sites” or “PESs,”Selection of the level of confinement for mixed zones of 2D and 3D confinement,Deciding on flame expansion when confinement is elevated above the vapor cloud,Selecting the reactivity for a fuel that is a mixture of fuels with differing reactivities,Predicting blast loads when there are multiple PES's within a vapor cloud considering different ignition source locations.
    Additional Material: 4 Ill.
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    URL: http://dx.doi.org/10.1002/prs.680170411
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    Safety, health and loss prevention in AIChE (1998)
    New York, NY [u.a.] : Wiley-Blackwell
    Process Safety Progress 17 (1998), S. 83-85 
    Details
    ISSN: 1066-8527
    Keywords: Chemistry ; Chemical Engineering
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology , Process Engineering, Biotechnology, Nutrition Technology
    Notes: Safety, health and loss prevention are major areas of interst for the American Institute of Chemical Engineers (AIChE). There has been an evolution of these concerns over the years in the Institute just as it has in industry. This article chronicles this evolution.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1002/prs.680170203
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    Masthead (1998)
    New York, NY [u.a.] : Wiley-Blackwell
    Process Safety Progress 17 (1998) 
    Details
    ISSN: 1066-8527
    Keywords: Chemistry ; Chemical Engineering
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology , Process Engineering, Biotechnology, Nutrition Technology
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1002/prs.680170101
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    Improving the effect of atmospheric stability class for dispersion modeling (1998)
    New York, NY [u.a.] : Wiley-Blackwell
    Process Safety Progress 17 (1998), S. 1-8 
    Details
    ISSN: 1066-8527
    Keywords: Chemistry ; Chemical Engineering
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology , Process Engineering, Biotechnology, Nutrition Technology
    Notes: Recent guidelines released by the U.S. EPA define a worst-case scenario as a release under stable atmospheric conditions defined as Pasquil-Gifford stability class F. Unfortunately, very few tests at F stability have been available heretofore to provide a basis for models. Recent test data with propane releases by the German research organization TUV provide a set of 60 experiments conducted specifically to define the effects of atmospheric stability class on dispersion. Of these, 25 tests were at F stability. A comparable number were at each other stability class A through E. In addition 23 tests were at wind speeds under 1.5 m/s in stable atmospheres. This paper reports on adjustments made to our models based on these new data by reducing the originally-postulated sensitivity to stability class. In spite of considerable scatter in the TUV data, particularly between two different types of propane analyzers, the model allows us to extract information by averaging over the tests.
    Additional Material: 15 Ill.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1002/prs.680170103
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    Vent access restriction for solids handling systems (1998)
    New York, NY [u.a.] : Wiley-Blackwell
    Process Safety Progress 17 (1998), S. 16-19 
    Details
    ISSN: 1066-8527
    Keywords: Chemistry ; Chemical Engineering
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology , Process Engineering, Biotechnology, Nutrition Technology
    Notes: A multi-disciplinary team developed a guideline for determining access restriction zones around vented solids handling equipment. The guideline provides a method for ensuring the discharge from a vented explosion will not cause injury to personnel. The steps in this method include: calculating the extent of external hazards from vented explosions; identifying potential areas where personnel could be exposed to a hazard; identifying ways to eliminate or reduce the hazard area; and establishing and documenting any access restrictions needed. Hazard zone calculations use the latest knowledge from research into fireball size, flame length and external pressure equations in VDI 3673. The guideline provides guidance for using this information. Options for mitigating or reducing external hazards from vented explosions are also described. As part of the project, the team audited several solids handling systems to look for potential oversights in existing restricted access areas. Some of the team's learnings from these audits are reviewed.
    Additional Material: 2 Ill.
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    URL: http://dx.doi.org/10.1002/prs.680170105
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    Team situation awareness for process control safety and performance (1998)
    New York, NY [u.a.] : Wiley-Blackwell
    Process Safety Progress 17 (1998), S. 43-48 
    Details
    ISSN: 1066-8527
    Keywords: Chemistry ; Chemical Engineering
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology , Process Engineering, Biotechnology, Nutrition Technology
    Notes: This paper defines situation awareness (SA) and discusses its importance to operator-machine system safety and functioning in the context of process control activities. Specifically, identified are relationships of human detection of critical process cues converying the status of automated control systems and operator interpretation of the meaning and relevance of such information to the potential for negative incidents in chemical processing. Beyond individual operator SA in interacting with control systems, intra- and inter- work team SA are discussed for supporting individual attainment of process control responsibilities. Factors critical to team SA are discussed. “Road blocks” to team SA are also analytically examined. Lastly, methods for assessing individual and team SA are reviewed and vehicles for relating outcomes of these methods to changes in process control operator and team behavior to improve human-machine system safety and performance are relayed.
    Additional Material: 1 Ill.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1002/prs.680170110
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    Masthead (1998)
    New York, NY [u.a.] : Wiley-Blackwell
    Process Safety Progress 17 (1998) 
    Details
    ISSN: 1066-8527
    Keywords: Chemistry ; Chemical Engineering
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology , Process Engineering, Biotechnology, Nutrition Technology
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1002/prs.680170201
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    Determination, prevention and mitigation of potential hazards due to the handling of powders during transportation, charging, discharging and storage (1998)
    New York, NY [u.a.] : Wiley-Blackwell
    Process Safety Progress 17 (1998), S. 74-81 
    Details
    ISSN: 1066-8527
    Keywords: Chemistry ; Chemical Engineering
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology , Process Engineering, Biotechnology, Nutrition Technology
    Notes: The knowledge of the ingition behavior of dust-air mixtures due to electrical sparks (MIE, Minimum Ignition Energy) and hot surfaces (MIT, Minimum Ignition Temperature) is important for risk assessments in chemical production plants. The ignition behavior determines the extent and hence the cost of preventive protection measures.This paper describes the use of the minimum ignition energy and minimum ignition temperature as very important safety indexes in practice.Based on the latest results from large scale experiments on pneumatic filling of silos with polymeric materials and new results of full scale filling tests using Flexible Intermediate Bulk Containers (FIBC) manufactured from a variety of materials, guidance can be given to ensure safe operation in different situations such as filling, emptying operations, type of powder handled.The aim of this paper is to assist people dealing with product. It reflects the present state of the art and current knowledge of the assessment and measures associated with powder handling.
    Additional Material: 12 Ill.
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    URL: http://dx.doi.org/10.1002/prs.680170114
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    Integrating hazard analysis into the implementation of advanced process control (1998)
    New York, NY [u.a.] : Wiley-Blackwell
    Process Safety Progress 17 (1998), S. 104-106 
    Details
    ISSN: 1066-8527
    Keywords: Chemistry ; Chemical Engineering
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology , Process Engineering, Biotechnology, Nutrition Technology
    Notes: In mid-1997, an Advanced Process Control (APC) scheme was implemented at a resins manufacturing complex with the goal of minimizing flare fuel gas usage while maintaining sufficient energy (BTU/SCF flare gas) to be in environmental regulatory compliance. Prior to APC implementation, the flare system was manually controlled by plant operators with minor attention paid to the minimization of fuel gas usage. Since implementation, APC has saved the plant thousands of dollars in fuel gas costs and reduced unnecessary combusted fuel gas emissions.Hazard analysis techniques were used in the development of the control scheme. An overview of the APC used, the economic evaluation, and the hazard analysis techniques used in the project are presented here.
    Additional Material: 1 Ill.
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    URL: http://dx.doi.org/10.1002/prs.680170206
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    Models for domino effect analysis in chemical process industries (1998)
    New York, NY [u.a.] : Wiley-Blackwell
    Process Safety Progress 17 (1998), S. 107-123 
    Details
    ISSN: 1066-8527
    Keywords: Chemistry ; Chemical Engineering
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology , Process Engineering, Biotechnology, Nutrition Technology
    Notes: In the risk assessment parlance, especially with reference to chemical process industries, the term “domino effect” is used to denote “chain of accidents,” or situations when a fire/explosion/missile/toxic load generated by an accident in one unit in an industry causes secondary and higher order accidents in other units. The multi-accident catastrophe which occurred in a refinery at Vishakhapatnam, India, on September 14, 1997, claiming 60 lives and causing damages to property worth over Rs 600 million, is the most recent example of the damage potential of domino effect.But, even as the domino effect has been documented since 1947, very little attention has been paid towards modeling this phenomena. In this paper we have provided a conceptual framework based on sets of appropriate models to forecast domino effects, and assess their likely magnitudes and adverse impacts, while conducting risk assessment in a chemical process industry. The utilizability of the framework has been illustrated with a case study.
    Additional Material: 8 Ill.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1002/prs.680170207
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  • 88
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    Electronic Resource
    Masthead (1998)
    New York, NY [u.a.] : Wiley-Blackwell
    Process Safety Progress 17 (1998) 
    Details
    ISSN: 1066-8527
    Keywords: Chemistry ; Chemical Engineering
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology , Process Engineering, Biotechnology, Nutrition Technology
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1002/prs.680170301
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  • 89
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    Fire tests of rack storage of water miscible liquids in plastic containers (1998)
    New York, NY [u.a.] : Wiley-Blackwell
    Process Safety Progress 17 (1998), S. 149-154 
    Details
    ISSN: 1066-8527
    Keywords: Chemistry ; Chemical Engineering
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology , Process Engineering, Biotechnology, Nutrition Technology
    Notes: This article deals with fire protection for water miscible flammable liquids stored in plastic containers packaged in boxes located on pallets. A series of fire tests was conducted with palletized rack storage arrangements using in-rack sprinkler protection at various levels. The intent of the paper is to present data from this test series for these types of commodities. The paper will identify various existing water miscible flammable liquid products stored in this fashion and provide background information for protecting this type of storage as it relates to NFPA 30 Flammable and Combustible Liquids Code. The test data indicates that further research work is needed in the area of plastic containers for use with the storage of combustible and flammable liquids. Included in the paper are discussions concerning possible protection strategies and suggestions for future research which would benefit those involved in risk management of this type of commodity.
    Additional Material: 4 Ill.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1002/prs.680170212
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  • 90
    Electronic Resource
    Electronic Resource
    Application of the flammability diagram for evaluation of fire and explosion hazards of flammable vapors (1998)
    New York, NY [u.a.] : Wiley-Blackwell
    Process Safety Progress 17 (1998), S. 176-183 
    Details
    ISSN: 1066-8527
    Keywords: Chemistry ; Chemical Engineering
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology , Process Engineering, Biotechnology, Nutrition Technology
    Notes: The safest method to prevent fires and explosions of flammable mixtures in the first place. This method requires detailed knowledge of the flammability region as a function of the fuel, oxygen, and nitrogen concentrations. A triangular flammability diagram is the most useful tool to display the flammability region, and to determine if a flammable mixture is present during plant operations.This paper describes how to draw and use a flammability diagram. A procedure to estimate the flammability region using the available and sometimes limited data is discussed. The paper also shows how to use the flammability diagram with plant operations involving inerting and purging, and from bringing vessels into and out of service. A compilation of flammability diagrams for 30 materials, based on previously published data is provided.An automated apparatus for acquiring data for a flammability diagram is described. The apparatus consists of a 20-L sphere with an automated gas mixing system, a fuse-wire ignition system, and a high speed pressure measurement and data acquisition system. Data derived from the apparatus includes flammability limits, maximum pressure during combustion, and the maximum pressure rate. The effect of fuse-wire ignitor dynamics on the results is studied. A flammability diagram for methane drawn from data obtained from the apparatus, is presented.
    Additional Material: 18 Ill.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1002/prs.680170305
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  • 91
    Electronic Resource
    Electronic Resource
    A model for the calculation and the verification of closed cup flash points for multicomponent mixtures (1998)
    New York, NY [u.a.] : Wiley-Blackwell
    Process Safety Progress 17 (1998), S. 86-97 
    Details
    ISSN: 1066-8527
    Keywords: Chemistry ; Chemical Engineering
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology , Process Engineering, Biotechnology, Nutrition Technology
    Notes: Regulatory issues related to material safety have made the accurate measurement and/or prediction of flash points essential. The flash point is one of the major physical properties used to determine the fire and explosion hazards of a liquid. Flash points are used by virtually all governmental entities worldwide to define “flammable” and “combustible” materials for shipping and safety regulations.A model is described here for the calculation of closed cup flash points for multicomponent, single liquid phase, mixtures. The model is based upon rigorous vapor/liquid equilibrium calculations supplemented with information about the lower flammable limits (LFL's) and heats of combustion (ΔHc's) for the mixture's constituent components. The closed cup flash points predicted with this model are typically within ± 5°C of the experimentally reported values. Such a model is useful as a means of verifying experimental data and as a tool for screening product formulations prior to experimental flash point determination. The model should considerably enhance the safety evaluation portion of the product development cycle, thus leading to shortened product time-to-market cycles. While flash points calculated with this model are in excellent agreement with experiment, experimental determination is still encouraged for critìcal safety applications.
    Additional Material: 15 Ill.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1002/prs.680170204
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  • 92
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    Electronic Resource
    Emergency planning: Critical evaluation of proposed AEGLs for ammonia (1998)
    New York, NY [u.a.] : Wiley-Blackwell
    Process Safety Progress 17 (1998), S. 134-137 
    Details
    ISSN: 1066-8527
    Keywords: Chemistry ; Chemical Engineering
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology , Process Engineering, Biotechnology, Nutrition Technology
    Notes: National Advisory Committee's Acute Exposure Guideline Levels (AEGLs) for ammonia are critically evaluated. The technical bases for concern about AEGL-2 and AEGL-3 values derived by the committee are summarized recommendations made.
    Additional Material: 2 Ill.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1002/prs.680170210
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  • 93
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    Electronic Resource
    Investigation of an explosion and flash fire in a fixed bed reactor (1998)
    New York, NY [u.a.] : Wiley-Blackwell
    Process Safety Progress 17 (1998), S. 127-133 
    Details
    ISSN: 1066-8527
    Keywords: Chemistry ; Chemical Engineering
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology , Process Engineering, Biotechnology, Nutrition Technology
    Notes: An explosion and flash fire in a fixed bed reactor occurred at a municipal wastewater treatment plant (WWTP). Two employees were injured in the accident. The accident occurred in an ozone treatment building where ozone was used to treat odors from the offgas of the sludge concentration units. Excess ozone manually was routed to the fixed bed reactor (ozone destruct unit) where the ozone is catalytically transformed into oxygen before being discharged to the atmosphere.An investigation of the accident was conducted to determine the root cause of the explosion and flash fire and identify corrective actions which the WWTP management could undertake to prevent a recurrence. This investigation included site inspections, interview with the injured employees, sampling and analysis of various materials, an explosion dynamics analysis, and a root cause analysis.It was concluded that cooling oil from one of the ozone generation units entered the main ozone gas line due to a crack in one of the reactor's dielectric tubes. The cooling oil was vented into the ozone destruct unit when an employee opened a ball valve on the main ozone gas line. The cooling oil, essentially a saturated hydrocarbon mixture, reacted exothermically when it contacted the manganese dioxide catalyst. The exothermic reaction resulted in an explosion which propelled the access panel outwards and dispersed the catalyst pellets. A flash fire followed the explosion. The flash fire burned two employees and caused thermal damage to a nearby control panel.Although this accident was the first of its kind at this facility, this was not the first time that the ozone generator had experienced a failure of a dielectric tube. Thus, there was a significant probability that a dielectric tube failure could leak cooling oil into the main ozone gas line. This failure event could, in turn, result in another explosion and flash fire. The WWTP staff neither designed nor fabricated the ozone generator-destructor system. Therefore, it did not seem appropriate for the WWTP staff to modify the ozone system. Instead, it was recommended that the ozone destruct unit be taken out of service. The WWTP management acted on this recommendation.
    Additional Material: 3 Ill.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1002/prs.680170209
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  • 94
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    Investigation of a steam explosion in a petroleum product storage tank (1998)
    New York, NY [u.a.] : Wiley-Blackwell
    Process Safety Progress 17 (1998), S. 171-175 
    Details
    ISSN: 1066-8527
    Keywords: Chemistry ; Chemical Engineering
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology , Process Engineering, Biotechnology, Nutrition Technology
    Notes: An explosion occurred in a petroleum product storage tank at a refinery. The liquid petroleum product was a heavy oil used as an asphalt extender. There were no injuries, but the cleanup was costly. The storage tank was one of several which received the product stream from a dehydration unit. The accident occurred shortly after the refinery was brought back on-line following a shutdown for schduled maintenance.This was the first incident of this kind to occur at this facility. Analysis of the process data and eyewitness observations indicated that the dehydration tower, which was supposed to be maintained at a minimum of 100°C during the shutdown, was allowed to drift below 100°C for an unknown period of time. This deviation enabled liquid water to enter the storage tank. Three operational factors contributed to the accident. Corrective actions were recommended to prevent a recurrence of a similar incident.
    Additional Material: 2 Ill.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1002/prs.680170304
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  • 95
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    Electronic Resource
    Dust explosion mitigation using Q-Rohr and exkop (1998)
    New York, NY [u.a.] : Wiley-Blackwell
    Process Safety Progress 17 (1998), S. 184-189 
    Details
    ISSN: 1066-8527
    Keywords: Chemistry ; Chemical Engineering
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology , Process Engineering, Biotechnology, Nutrition Technology
    Notes: Dust explosions have been with us for a long time. The first record of a dust explosion occurred in Turin, Italy, on December 14, 1785 [1]. The detailed record of this event is left to us by Count Morozzo. The event took place in Mr. Giacomelli's bakery. We know from his account that the weather was unseasonably dry, that a boy who worked in the bakery was using a shovel to stir and transfer the flour to a chute from a store room to the bakery and he had a lighted lamp to work by. The rest, as the saying goes, is history. No one was killed, and the building was saved by the sagacious fact of having plenty of windows. Since that first record, of course, there have been many explosions with much loss of life and significant economic consequences.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1002/prs.680170306
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  • 96
    Electronic Resource
    Electronic Resource
    The reactive system screening tool (RSST): An easy, inexpensive approach to the DIERS procedure (1998)
    New York, NY [u.a.] : Wiley-Blackwell
    Process Safety Progress 17 (1998), S. 190-195 
    Details
    ISSN: 1066-8527
    Keywords: Chemistry ; Chemical Engineering
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology , Process Engineering, Biotechnology, Nutrition Technology
    Notes: The RSST DIERS vent sizing methodology is revised to provide realistic design equations for reactive systems consistent with available large-scale experience. Using easy to obtain RSST data such as rate of temperature rise and rate of pressure rise excellent agreement is illustrated for hybrid, vapor and gassy reactive systems.
    Additional Material: 9 Ill.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1002/prs.680170307
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  • 97
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    Electronic Resource
    Making safety second nature (1998)
    New York, NY [u.a.] : Wiley-Blackwell
    Process Safety Progress 17 (1998), S. 196-199 
    Details
    ISSN: 1066-8527
    Keywords: Chemistry ; Chemical Engineering
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology , Process Engineering, Biotechnology, Nutrition Technology
    Notes: From the 1960s onwards, the chemical and oil industries developed and used a number of new safety techniques which, in time, became second nature to those who applied them. They included the use of QRA for deciding priorities, Hazop and audits for identifying problems, inherently safer design for avoiding hazards, and more thorough investigation of incidents for identifying underlying causes. However, it has not yet become second nature to remember the accidents of the past and the actions needed to prevent them happening again.I joined industry in 1944 and moved to production in 1952. Then, and for at least 15 years afterwards, safety was a non-technical subject that could be left to arts graduates and elderly foremen. There was concern that people should not be hurt - great attention was paid to the lost-time accident rate - but there was no realization, that it was a subject worthy of systematic study by experienced technologists.This view changed at the end of the 1960s. A new generation of plants had been built, operating at higher temperatures and pressures and containing larger inventories of hazardous chemicals; the result was a series of fires and explosions and a worsening fatal accident rate. Figure 1 shows the situation in ICI, at the time the UK, s largest chemical company. Other companies experienced a similar state of affairs.As a result in 1968, I was appointed one of the company's first technical safety advisers, an unusual appointment at the time for someone with my experience, and if the reason for my appointment had not been so obvious I would have wondered what I had done wrong. I and my colleagues tried to apply the same sort of systematic thinking to safety that we applied in our other professional work. We developed some new concepts and techniques and adopted others. A common feature of our ides, realized only in restrospect, was that they consisted of more than mere problem-solving techniques. Once people had got used to these new concepts and used them a few times, they began to look at a whole range of problems in a different way.
    Additional Material: 1 Ill.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1002/prs.680170308
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  • 98
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    Electronic Resource
    Process safety update (1998)
    New York, NY [u.a.] : Wiley-Blackwell
    Process Safety Progress 17 (1998), S. W3 
    Details
    ISSN: 1066-8527
    Keywords: Chemistry ; Chemical Engineering
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology , Process Engineering, Biotechnology, Nutrition Technology
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1002/prs.680170402
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  • 99
    Electronic Resource
    Electronic Resource
    Case studies of incidents in runaway reactions and emergency relief (1998)
    New York, NY [u.a.] : Wiley-Blackwell
    Process Safety Progress 17 (1998), S. 259-262 
    Details
    ISSN: 1066-8527
    Keywords: Chemistry ; Chemical Engineering
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology , Process Engineering, Biotechnology, Nutrition Technology
    Notes: Case histories of 65 incidents in runaway reactions and emergency relief in Taiwan were analyzed and classified into several categories according to their causes, materials involved, equipment types, reaction types, and ignition sources. The cases in reactors and storage tanks were examined in more detail owing to the higher probability or larger potential hazard in these two types of equipments. The most common consequence of the incidents are explosions, fires, and atmospheric release of toxic chemicals. The most severe case was a thermal explosion from an organic peroxide storage area which caused the death of 33 persons. Popping and direct releasing of process chemicals to the atmosphere from relieving devices cause the greatest environmental concerns to the community close to the plants. Runaway reactions in batch type reactors occur frequently due to various operational mistakes. Heat of reaction is the most frequent ignition source of runaway reactions and emergency relief.
    Additional Material: 1 Ill.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1002/prs.680170406
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  • 100
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    RMP hazard assessment for compliance with EPA's risk management program regulation: OxyChem's experience (1998)
    New York, NY [u.a.] : Wiley-Blackwell
    Process Safety Progress 17 (1998), S. 272-277 
    Details
    ISSN: 1066-8527
    Keywords: Chemistry ; Chemical Engineering
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology , Process Engineering, Biotechnology, Nutrition Technology
    Notes: EPA's Risk Management Program regulation, promulgated in June 1996 as 40 CFR Part 68 requires subject industries to submit Risk Management Plans by June 1999. This plan requires hazard assessment of the operations of a facility using worst case scenarios and alternative releases. EPA has provided an Off-site Consequence Analysis (OCA) guidance to help facilities in their hazard assessment.OxyChem will be significantly impacted by the RMP rule. This paper outlines OxyChem's general experience and its strategy in planning to comply with this rule. OxyChem's approach in the development of the scenarios required by the rule is described in this paper. Limitations involved in the use of EPA's look-up tables or a single modeling solution for conducting all of the OCA are discussed. A three tiered OCA approach is presented as a possible alternative.
    Additional Material: 4 Tab.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1002/prs.680170408
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