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Human Pharmaceuticals (human + pharmaceuticals)
Selected AbstractsThe Industry View on Long-Term Toxicology Testing in Drug Development of Human PharmaceuticalsBASIC AND CLINICAL PHARMACOLOGY & TOXICOLOGY, Issue 2000Herman Van Cauteren The 1990's have seen a general acceptance that studies with a maximal duration of 6 months in rodents are all that is required for adequate safety assessment of developmental pharmaceutical agents. However, controversy has arisen concerning the most appropriate duration for chronic toxicity testing in non-rodents. Initial suggestions that 6 months duration was sufficient have been countered by findings noted in 12-month studies that were not seen in shorter-term studies. Retrospective analysis of available data eventually lead to a subsequent ICH recommendation that studies of 9 months duration would be now acceptable. However, until recently the FDA position on this recommendation was unclear and an analysis of industry practices since the ICH recommendation was made in 1997 has shown that the 9-month guideline is not widely applied. Recent clarification by the FDA will probably result in a continued but limited use of this alternative. An industry view on the future of chronic toxicology testing in rodents and non-rodents is presented. [source] Effects of lipid-lowering pharmaceuticals bezafibrate and clofibric acid on lipid metabolism in fathead minnow (Pimephales promelas),ENVIRONMENTAL TOXICOLOGY & CHEMISTRY, Issue 12 2009Anna Weston Abstract The lipid-lowering agents bezafibrate and clofibric acid, which occur at concentrations up to 3.1 and 1.6 ,L, respectively, are among the most frequently found human pharmaceuticals in the aquatic environment. In contrast to knowledge about their environmental occurrence, little is known about their effects in the environment. The aim of the present study was to analyze effects of these lipid-lowering agents in fish by focusing on their modes of action, lipid metabolism. Fathead minnows were exposed in aquaria to measured concentrations of 0.1, 1.27, 10.18, 101.56, and 106.7 mg/L bezafibrate and to 1.07, 10.75, and 108.91 mg/L clofibric acid for 14 and 21 d, respectively. After exposure, fish liver was analyzed for expression of peroxisome proliferator-activated receptor , (PPAR,) by quantitative polymerase chain reaction (PCR), and the PPAR-regulated enzyme fatty acyl-coenzyme-A oxidase (FAO) involved in fatty acid oxidation. Bezafibrate had no effect, either on PPAR, expression or on FAO activity, at all concentrations. In contrast, clofibric acid induced FAO activity in male fathead minnows at 108.91 mg/L. No increase in expression of PPAR, messenger ribonucleic acid was observed. Egg production was apparently decreased after 21 d of exposure to 108.91 mg/L clofibric acid. The present study demonstrates that bezafibrate has very little or no effect on PPAR, expression and FAO activity, but clofibric acid affects FAO activity. [source] Neuropharmaceuticals in the environment: Mianserin-induced neuroendocrine disruption in zebrafish (Danio rerio) using cDNA microarraysENVIRONMENTAL TOXICOLOGY & CHEMISTRY, Issue 10 2006Karlijn van der Ven Abstract Because of their environmental occurrence and high biological activity, human pharmaceuticals have received increasing attention from environmental and health agencies. A major bottleneck in their risk assessment is the lack of relevant and specific effect data. We developed an approach using gene expression analysis in quantifying adverse effects of neuroendocrine pharmaceuticals in the environment. We studied effects of mianserin on zebrafish (Danio rerio) gene expression using a brain-specific, custom microarray, with real-time polymerase chain reaction as confirmation. After exposure (0, 25, and 250 ,g/L) for 2, 4, and 14 d, RNA was extracted from brain tissue and used for microarray hybridization. In parallel, we investigated the impact of exposure on egg production, fertilization, and hatching. After 2 d of exposure, microarray analysis showed a clear effect of mianserin on important neuroendocrine-related genes (e.g., aromatase and estrogen receptor), indicating that antidepressants can modulate neuroendocrine processes. This initial neuroendocrine effect was followed by a "late gene expression effect" on neuronal plasticity, supporting the current concept regarding the mode of action for antidepressants in mammals. Clear adverse effects on egg viability were seen after 14 d of exposure at the highest concentration tested. Based on the specific molecular impact and the effects on reproduction, we conclude that further investigation of the adverse effects on the brain-liver-gonad axis is needed for a correct ecological risk assessment of antidepressants. [source] Environmental risk assessment of human pharmaceuticals in the European Union: A case study with the ,-blocker atenololINTEGRATED ENVIRONMENTAL ASSESSMENT AND MANAGEMENT, Issue S1 2010Anette Küster Abstract ,-Adrenergic receptor blockers (,-blockers) are applied to treat high blood pressure, ischemic heart disease, and heart rhythm disturbances. Due to their widespread use and limited human metabolism, ,-blockers are widely detected in sewage effluents and surface waters. ,-Adrenergic receptors have been characterized in fish and other aquatic animals, so it can be expected that physiological processes regulated by these receptors in wild animals may be affected by the presence of ,-blockers. Because ecotoxicological data on ,-blockers are scarce, it was decided to choose the ,-blocker atenolol as a case study pharmaceutical within the project ERAPharm. A starting point for the assessment of potential environmental risks was the European guideline on the environmental risk assessment of medicinal products for human use. In Phase I of the risk assessment, the initial predicted environmental concentration (PEC) of atenolol in surface water (500,ng L,1) exceeded the action limit of 10,ng L,1. Thus, a Phase II risk assessment was conducted showing acceptable risks for surface water, for groundwater, and for aquatic microorganisms. Furthermore, atenolol showed a low potential for bioaccumulation as indicated by its low lipophilicity (log KOW,=,0.16), a low potential for exposure of the terrestrial compartment via sludge (log KOC,=,2.17), and a low affinity for sorption to the sediment. Thus, the risk assessment according to Phase II-Tier A did not reveal any unacceptable risk for atenolol. Beyond the requirements of the guideline, additional data on effects and fate were generated within ERAPharm. A 2-generation reproduction test with the waterflea Daphnia magna resulted in the most sensitive no-observed-effect concentration (NOEC) of 1.8,mg L,1. However, even with this NOEC, a risk quotient of 0.003 was calculated, which is still well below the risk threshold limit of 1. Additional studies confirm the outcome of the environmental risk assessment according to EMEA/CHMP (2006). However, atenolol should not be considered as representative for other ,-blockers, such as metoprolol, oxprenolol, and propranolol, some of which show significantly different physicochemical characteristics and varying toxicological profiles in mammalian studies. Integr Environ Assess Manag 2010;6:514,523. © 2009 SETAC [source] Controlled drug delivery: therapeutic and pharmacological aspectsJOURNAL OF INTERNAL MEDICINE, Issue 5 2000J. Urquhart Abstract. Urquhart J (Department of Epidemiology, Pharmaco-epidemiology Group, Maastricht University, Maastricht, the Netherlands). Controlled drug delivery: therapeutic and pharmacological aspects (Internal Medicine in the 21st Century). J Intern Med 2000; 248: 357,376. Concerted work to develop human pharmaceuticals based on rate-controlled drug delivery systems began in 1970. Today there are over three dozen such products, plus a few for veterinary use. In addition, osmotic minipumps have been extensively used since 1978, resulting in over 6000 publications in the pharmacological, endocrinological and physiological literature. Rate-controlled delivery provides for drug entry into the bloodstream continuously at either a constant or a modulated rate. By this means, one avoids the usual peak and trough pattern of drug concentrations in plasma, with its echoing peak and trough pattern of drug actions, during the interval between successive doses. In contrast to the happenstance release kinetics of rapid-release dosage forms, rate-controlled delivery systems can be designed to provide specific temporal patterns of drug concentration in plasma, for the purpose of optimizing the selectivity of drug action, the interval between successive administerings of drug and the likelihood that the next administering will occur at the proper time. [source] | ||||||||||