Safety of healthy subjects in first-in-human multiple-dose studies: A pooled analysis.

PURPOSE: Reflecting the extended scope of the valid EMA regulation, this analysis intends to contribute to the knowledge about risk for participants in first-in-human (FiH) multiple-dose studies. MATERIALS AND METHODS: All FiH multiple-dose studies in healthy subjects performed by the Bayer Department of Clinical Pharmacology, Cardiovascular, between 2006 and 2019 were analyzed. Study reports were reviewed for study designs, demographics, treatment-emergent adverse events (TEAEs), and safety laboratory results above the 1.5-fold of the upper limit of normal (aspartate aminotransferase (AST), alanine aminotransferase (ALT), creatine kinase (CK), amylase, lipase, glutamate dehydrogenase (GLDH), gamma glutamyl transpeptidase (GGT), total bilirubin, and creatinine in serum), and data were analyzed. RESULTS: 12 out of 16 studies were included. Indications for development were cardiovascular (7), pulmonary (3), kidney (1), and hematological (1) diseases. 496 healthy male subjects (mean age 33.8 years, mean BMI of 24.7 kg/m2) received treatment (370 active, 126 placebo). 293 subjects had at least 1 TEAE (59.1%): 231 (62.4%) after active treatment and 126 (49.2%) after placebo. Subjects with a maximum TEAE intensity of moderate did not differ between active and placebo. The only severe TEAE was unrelated to the study, the only serious TEAE on active treatment was not considered drug-related. Subjects had a significantly higher relative risk on active treatment versus placebo to experience an overall TEAE. No relevant differences between active and placebo for the analyzed laboratory increases were seen. CONCLUSION: Subjects were not exposed to an undue risk in the analyzed studies. Adverse events and laboratory value increases occur frequently under placebo treatment. The results can help in the risk stratification for and interpretation of other phase I studies.

Hepatotoxicity due to etanercept abated after dose reduction in a patient with pustular psoriasis and without compromised efficacy / Hepatotoxicidad por supresión del etanercept tras reducción de dosis en un paciente con psoriasis pustular y sin eficacia comprometida

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Atividades séricas da aspartato aminotransferase, creatina quinase e lactato desidrogenase de eqüinos submetidos ao teste padrão de exercício progressivo em esteira / Serum activities of aspartate aminotransferase, creatine kinase and lactate dehydrogenase in arabian horses submitted to standard incremental exercise test

Objetivou-se determinar a atividade sérica das enzimas aspartato aminotransferase (AST), creatina quinase (CK) e lactato desidrogenase (LDH) de cavalos da raça Árabe submetidos a exercício em esteira de alta velocidade. Onze eqüinos adultos da raça Árabe foram condicionados e submetidos ao Teste Padrão de Exercício Progressivo em esteira. Antes, imediatamente após o término do exercício, e nos momentos pós-exercício, 30min, 60min, 3h, 6h, 12h, 24h, 3 dias e 5 dias, foram coletadas amostras de sangue venoso para as determinações séricas das enzimas aspartato aminotransferase (AST), creatina quinase (CK) e lactato desidrogenase (LDH). As concentrações séricas da AST, da CK e da LDH elevam-se imediatamente e retornam a valores semelhantes ao de repouso 30 minutos após o término do Teste Padrão de Exercício Progressivo. A atividade enzimática da aspartato aminotransferase (AST) eleva-se de 12 horas a 24 horas, da creatina quinase (CK) de 3 horas a 6 horas e da lactato desidrogenase (LDH) 24 horas após o término do Teste Padrão de Exercício Progressivo.

The aim of this study was to determine the serum activities of enzymes aspartate aminotransferase, creatine kinase and lactate dehydrogenase in Arabian horses submitted to exercise on high-speed equine treadmill. Eleven mature Arabian horse were training and submitted to Standard Incremental Exercise Test on high-speed equine treadmill. Venous blood samples were taken before exercise, immediately and 30 min, 60min, 3h, 6h, 24h, 3 days and 5 days after exercise. The serum activity aspartate aminotransferase, creatine kinase and lactate dehydrogenase were determined. The serum activies of AST, CK and LDH increase immediately and returned to baseline value 30 minutes after exercise. The AST enzyme activity increased at 12 hours and 24 hours, CK at 3 hours and 6 hours, and LDH at 24 hours after Standard Incremental Exercise Test.

Thrombocytopenia in HIV-infected drug users in the HAART era.

The present case-control study compared 26 HIV+ drug users having persistent thrombocytopenia (TCP<150 000/mm(3)) with 54 available age, gender and HIV CDC classification matched controls with normal platelet counts. Participants were followed longitudinally over a 2-year period (1998-2000), and hematological alterations evaluated in relationship to antiretroviral treatment, drug use and nutritional (selenium) status. Demographic information and medical history, including antiretroviral treatment were obtained. Blood was drawn for complete cell blood count, T lymphocytes and viral load. Sixty-nine percent of the individuals with persistent TCP and 49% of the controls were receiving antiretrovirals. At baseline, no significant differences in CD4 existed between the two groups. Over time, CD4 cell count declined in the cases (P = 0.05) and a significantly higher proportion of the cases (38%) developed AIDS (CD4<200 cell/mm(3)), as compared to the controls (18%, P = 0.004). A high risk for development of thrombocytopenia was observed with specific drug use (heroin 2.96 times, P = 0.0007), selenium levels below 145 microg/l (6 times, P = 0.008), and abnormal liver enzyme (SGOT) levels (2 times, P = 0.002). Together, these results indicate a number of factors that may be sensitive predictors of thrombocytopenia, which, despite antiretroviral treatment, appears to be related to more rapid disease progression in drug users.