Dataset Information

Preclinical Rodent Toxicity Studies for Long Term Use of Ceftriaxone.

ABSTRACT: A 6-month rodent toxicology and pharmacokinetic (PK) study was performed to provide supportive safety data for long-term use of intravenous ceftriaxone in a clinical trial in patients with amyotrophic lateral sclerosis (ALS). Ceftriaxone was administered by subcutaneous injection at up to 2 g/kg/day to Sprague-Dawley Crl:CD (SD) rats. Ceftriaxone was found to be safe and well tolerated. Specifically, no significant differences in body weight and food consumption were observed between the treatment and control groups. With the exception of in red cell parameters decrease, there were no ceftriaxone-related changes in hematology, coagulation, clinical chemistry and urinalysis parameters. Injection site trauma and associated reversible anemia, likely due to chronic blood loss at the injection site, were all attributable to subcutaneous route of administration. Cecum dilatation and some skin changes were reversible after recovery period, while bile duct dilatation, observed only in a few animals, persisted. Changes in the non-glandular stomach do not have a human correlate. The no-observed-adverse-effect dose level (NOAEL) was 0.5 g/kg/day ceftriaxone in both sexes. Ceftriaxone showed rapid absorption with half-life values ranging between 1 and 1.5 hours. Additionally, there was no evidence of accumulation and a virtually complete elimination by 16 hours after the last dose. Overall there were no toxicologically meaningful drug-related animal findings associated with the long-term administration (6 months) of ceftriaxone. These results support safety of long-term use of ceftriaxone in human clinical trials.

SUBMITTER: Ratti E

PROVIDER: S-EPMC4685718 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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Preclinical Rodent Toxicity Studies for Long Term Use of Ceftriaxone.

Ratti Elena E Berry James D JD Greenblatt David J DJ Loci Lorena L Ellrodt Amy Swartz AS Shefner Jeremy M JM Cudkowicz Merit E ME

Toxicology reports 20150101

A 6-month rodent toxicology and pharmacokinetic (PK) study was performed to provide supportive safety data for long-term use of intravenous ceftriaxone in a clinical trial in patients with amyotrophic lateral sclerosis (ALS). Ceftriaxone was administered by subcutaneous injection at up to 2 g/kg/day to Sprague-Dawley Crl:CD (SD) rats. Ceftriaxone was found to be safe and well tolerated. Specifically, no significant differences in body weight and food consumption were observed between the treatme ...[more]

PMID: 26705515

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Project description:The constant use of disease modifying anti rheumatic drugs affects the functioning of multiple organs inside the body. Some drugs are more toxic than others. The present case control investigation was designed to evaluate the comparative toxicity of methotrexate and leflunomide on multiple organs in rheumatoid arthritis patients. For this purpose, 100 subjects with confirmed rheumatoid arthritis condition were recruited form tertiary care center. Whereas 50 age matched controls were recruited from the local healthy population. Participants of the study were categorized into three groups with equal numbers of subjects in each group (n = 50). Group 1 comprised rheumatoid arthritis patients on methotrexate treatment, group 2 included rheumatoid arthritis patients on leflunomide treatment and group 3 were healthy subjects. Cardiac and respiratory response was evaluated by monitoring blood pressure, pulse and breathing rate and spot oxygen saturation. Stress on liver was estimated by measuring change in liver enzymes (alanine transaminase, aspartate aminotransferase, and alkaline phosphatase) and total bilirubin. While, degree of renal impairment was assessed by calculating glomerular filtration rate, serum creatinine, urinary urea and uric acid. For statistical interpretation, data was subjected to independent student "t" test and analysis of variance (one way ANOVA) for mean variations. Both methotrexate and leflunomide elevated the systolic and diastolic blood pressure and pulse rate. Leflunomide maintained the oxygen saturation at 96.7%, whereas methotrexate exerted serious effect on spot oxygen saturation by reducing it significantly to 93.25% than healthy subjects. Hepatotoxicity manifested by sustained use of leflunomide was perceptible in this study group. Whereas, both methotrexate and leflunomide influenced renal function as indicated by marked increase in blood urea nitrogen (P = 0.001), serum creatinine (P = 0.007) and reduced glomerular filtration rate (P<0.0001). However, use of methotrexate demonstrated significant (P<0.0001) reduction in serum uric acid and urinary urea levels. Methotrexate is more injurious to heart, blood vessels and kidneys than leflunomide but it is less noxious to hepatic parenchyma. Contrarily, leflunomide usage is comparatively better option for respiratory, cardiovascular, and renal health but dangerous to liver. Thus, a single drug can't be prescribed for the treatment of rheumatoid arthritis for longer management of arthritis patients.

Dataset Information

Preclinical Rodent Toxicity Studies for Long Term Use of Ceftriaxone.

Publications

Preclinical Rodent Toxicity Studies for Long Term Use of Ceftriaxone.

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