Clinical pharmacology and safety evaluation of timentin

Jackson, D.; Cockburn, Andrew; Cooper, D L; Langley, P. F.; Tasker, Tim; White, David J.

doi:10.1016/0002-9343(85)90128-7

Cited by 18 publications

(9 citation statements)

References 5 publications

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“…Nevertheless, one group concluded that effective concentrations of clavulanic acid are maintained longer in patients with renal dysfunction, and that sufficient amounts should remain to protect the ticarcillin from p-lactamase degradation with extension of the normal dosing interval. 6 The results of our study do not support this contention.…”

Section: Discussioncontrasting

confidence: 78%

Comparison of Ampicillin‐Sulbactam and Ticarcillin‐Clavulanic Acid in Patients With Chronic Renal Failure: Effects of Differential Pharmacokinetics on Serum Bactericidal Activity

Hardin,

Butler,

Ross

et al. 1994

Pharmacotherapy

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Study Objectives. To evaluate the pharmacodynamic antibacterial activity of ticarcillin‐clavulanic acid (T‐C) and ampicillin‐sulbactam (A‐S) combinations against reference bacterial strains in patients with end‐stage renal disease maintained on long‐term hemodialysis.Design. Randomized, crossover, controlled study.Setting. National Institutes of Health‐funded general clinical research unit in a Veterans Administration Medical Center.Patients. Nine adult men with end‐stage renal disease maintained on long‐term hemodialysis. Two subjects did not complete the study due to problems of vascular access, and another withdrew for personal reasons.Interventions. On a nondialysis day, each subject was randomly administered either T‐C 3.1 g or A‐S 3 g as a slow intravenous infusion over 30 minutes. Serial blood samples were collected for measurement of antibiotic serum concentrations and determination of serum bactericidal titers. Following a washout period, the study was repeated with the alternative antibiotic combination.Measurements and Main Results. The mean observed apparent β‐half‐life of clavulanic acid was substantially shorter than that for the other three drugs. The bactericidal activity of both A‐S and T‐C against non‐β‐lactamase‐producing (Nβ‐LP) strains of S. aureus and E. coli was consistently high, as indicated by geometric mean SBTs of at least 1:5 at 24 hours. Against β‐lactamase‐producing (β‐LP) S. aureus, the geometric mean SBTs for A‐S were at least 1:25 throughout the study period, while the geometric mean SBTs for T‐C decreased over 24 hours from 1:29 to 1:6. Against β‐LP E. coli, the bactericidal activities for both A‐S and T‐C were poor, with geometric mean peak SBTs of only 1:6 and 1:3, respectively. The geometric mean SBT for T‐C against this E. coli strain had declined to 1:1 at 6 hrs.Conclusion. Increasing the dosing interval for T‐C in patients with end‐stage renal disease may lead to periods of insufficient clavulanic acid to protect ticarcillin from β‐lactamase degradation.

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Section: Discussioncontrasting

confidence: 78%

Comparison of Ampicillin‐Sulbactam and Ticarcillin‐Clavulanic Acid in Patients With Chronic Renal Failure: Effects of Differential Pharmacokinetics on Serum Bactericidal Activity

Hardin,

Butler,

Ross

et al. 1994

Pharmacotherapy

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“…Hepatocytic glycogen accumulation is known to occur following exposure to certain chemicals. In the case of clavulanate treatment, it was suggested that the increase in hepatic glycogen in the rats represents an adaptive response to the extensive hepatic metabolism of this compound (Jackson et al 1985). The incidences of pancreatic exocrine gland hyperplasia were increased in all dosed groups of males (controls 4/50, 3 mg/kg 10/49, 10 mg/kg 11/50, 30 mg/kg 12/50).…”

Section: Pathologymentioning

confidence: 99%

Characterization of the toxicity, mutagenicity, and carcinogenicity of methacrylonitrile in F344 Rats and B6C3F1 mice

Nyska

Ghanayem

2003

Arch Toxicol

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Methacrylonitrile is an unsaturated aliphatic nitrile. It is widely used in the preparation of homopolymers and copolymers, elastomers, and plastics, and as a chemical intermediate in the preparation of acids, amides, amines, esters, and other nitriles. Methacrylonitrile was nominated for study by the National Cancer Institute (USA) because of the potential for human exposure, structural similarity to the known carcinogen acrylonitrile, and a lack of toxicity and carcinogenicity data. Doses selected for the 2-year study were based on the results of the 13-week gavage studies. Groups of 50 male and 50 female animals were exposed by gavage to 0, 3, 10, or 30 mg/kg in F344 rats, and 0, 1.5, 3 or 6 mg/kg in B6C3F1 mice, 5 days per week for 2 years. Urinary excretion of N-acetyl- S-(2-cyanopropyl)- l-cysteine (NACPC) and N-acetyl- S-(2-hydroxypropyl)- l-cysteine (NAHPC) were measured as markers of exposure at various time points after methacrylonitrile administration, and demonstrated that exposure of animals to methacrylonitrile occurred as intended. Urinary excretion of NACPC and NAHPC increased in rats and mice in a dose-dependent manner. In contrast to observations in rats, the ratios of NACPC/creatinine were generally higher in female than in male mice. Further, the ratios of NAHPC/creatinine in rats were significantly greater at all time points and all doses than the corresponding ratios of NACPC/creatinine in male and female mice. In both rats and mice, survival was not affected by treatment. In rats, mean body weights of the 30 mg/kg groups were less than those of the vehicle controls after weeks 21 and 37 for males and females, respectively. No treatment-related effect on body weight was seen in mice. There were no neoplasms (in either species) or non-neoplastic lesions (mice only) that were attributed to methacrylonitrile administration. In rats, the incidences of olfactory epithelial atrophy and metaplasia of the nose were significantly greater in 30 mg/kg males and females than those in the vehicle controls. Increased incidences of cytoplasmic vacuolation occurred in the liver of males and females. Testing methacrylonitrile in a battery of short-term in vitro and in vivo tests showed no evidence of genotoxicity. In conclusion, under the conditions of these 2-year gavage studies, there was no evidence of a carcinogenic activity of methacrylonitrile in male or female F344/N rats or B6C3F1 mice. Methacrylonitrile-related non-neoplastic lesions were seen in the nose and liver of rats.

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“…Shortly thereafter, clavulanic acid was combined with ticarcillin, an intravenous carboxypenicillin (2,3). By the mid-1980s and early 1990s, clavulanic acid was joined in clinical practice by the penicillanic acid sulfone BLIs sulbactam and tazobactam (4,5,6,7). Sulbactam was combined with the intravenous aminopenicillin ampicillin, while tazobactam was combined with the intravenous ureidopenicillin piperacillin.…”

mentioning

confidence: 99%

Pharmacokinetics-Pharmacodynamics of Tazobactam in Combination with Ceftolozane in an In Vitro Infection Model

VanScoy

Mendes

Nicasio

et al. 2013

Antimicrob Agents Chemother

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Clinical pharmacology and safety evaluation of timentin

Cited by 18 publications

References 5 publications

Comparison of Ampicillin‐Sulbactam and Ticarcillin‐Clavulanic Acid in Patients With Chronic Renal Failure: Effects of Differential Pharmacokinetics on Serum Bactericidal Activity

Comparison of Ampicillin‐Sulbactam and Ticarcillin‐Clavulanic Acid in Patients With Chronic Renal Failure: Effects of Differential Pharmacokinetics on Serum Bactericidal Activity

Characterization of the toxicity, mutagenicity, and carcinogenicity of methacrylonitrile in F344 Rats and B6C3F1 mice

Pharmacokinetics-Pharmacodynamics of Tazobactam in Combination with Ceftolozane in an In Vitro Infection Model

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