Int J Clin Pharm Th
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Int J Clin Pharm Th · Dec 1999
ReviewAlternative strategies in drug development: clinical pharmacological aspects.
Due to the continuous increase in time and cost of drug development and the considerable amount of resources required by the traditional approach, companies can no longer afford to continue to late phase 3 with drugs which are unlikely to be therapeutically effective. The future challenge must be for the pharmaceutical industry to slash its research and development costs by achieving a significant cut in the attrition rate for drugs entering preclinical and clinical development, and to reduce the development time and to increase the probability of success in later clinical trials by streamlining the development processes. In the 100 years to 1995, the pharmaceutical industry worked on about 500 targets with a limited number of compounds, whereas now, using new technologies like genomics, high throughput screening and combinatorial chemistry, drug companies will see an explosion in the number of targets and leads it can explore. ⋯ The more thorough and profound studies have been carried out during this exploratory stage of development, the earlier a decision can be made on the continuation or discontinuation of further development, thus saving development time and money and assessing and considerably reducing the risk for the patients and increasing the success-rate of the project in the later confirmatory effectiveness trial. Taking responsibility as the link between research and development gives clinical pharmacology a major opportunity to assume a pivotal role in research and development of new drugs. To reach this goal, clinical pharmacology must be fully integrated in the whole process from the candidate selection to its approval.
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Int J Clin Pharm Th · Mar 1999
Review Comparative StudySt. John's wort: a new alternative for depression?
The primary purpose of this article is to review the existing literature concerning the therapeutic uses, adverse effects, and possible drug interactions of St. John's wort (Hypericum perforatum) as compared to other antidepressant medications. ⋯ From the existing literature, St. John's wort appears to be a safe and effective alternative in the treatment of depression. Tricylic antidepressants and monoamine oxidase inhibitors can produce serious cardiac side-effects, such as tachycardia and postural hypotension, and many unwanted anticholinergic side-effects, including dry mouth and constipation. St. John's wort has proven to be free of any cardiac, as well as anticholinergic, side-effects normally seen with antidepressant medications. Based upon limited studies, St. John's wort appears to be an acceptable alternative to traditional antidepressant therapy, although trials on a larger scale are warranted in this area. Hypericum is available to the lay public as an over-the-counter preparation and may be misused if not fully understood.
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This review evaluates the effect of obesity on the various isozymes of the cytochrome P450 enzyme system. ⋯ The effect of obesity on CYP450 appears to be isozyme-specific with the activity of cytochrome P450 3A4 decreasing and that of cytochrome P450 2E1 increasing. The effect of obesity on the cytochrome P450 1A2, 2C9, 2C19, and 2D6 isozymes is inconclusive.
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Int J Clin Pharm Th · Oct 1997
ReviewBasic concepts of pharmacokinetic/pharmacodynamic (PK/PD) modelling.
Pharmacokinetic (PK) and pharmacodynamic (PD) information from the scientific basis of modern pharmacotherapy. Pharmacokinetics describes the drug concentration-time courses in body fluids resulting from administration of a certain drug dose, pharmacodynamics the observed effect resulting from a certain drug concentration. The rationale for PK/PD-modelling is to link pharmacokinetics and pharmacodynamics in order to establish and evaluate dose-concentration-response relationships and subsequently describe and predict the effect-time courses resulting from a drug dose. ⋯ Four basic attributes may be used to characterize PK/PD-models: First, the link between measured concentration and the pharmacologic response mechanism that mediates the observed effect, direct vs. indirect link; second, the response mechanism that mediates the observed effect, direct vs. indirect response; third, the information used to establish the link between measured concentration and observed effect, hard vs. soft link; and fourth, the time dependency of the involved pharmacodynamic parameters, time-variant vs. time-invariant. In general, PK/PD-modelling based on the underlying physiological process should be preferred whenever possible. The expanded use of PK/PD-modelling is assumed to be highly beneficial for drug development as well as applied pharmacotherapy and will most likely improve the current state of applied therapeutics.
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A major goal of current pain research is to develop scientifically-based guidelines to optimize selection of analgesic drug doses and control pain. Numerous clinical studies have shown that the drug dose required to effectively alleviate pain is often highly variable, both between patients and between pain episodes in individual patients. This high variability makes it difficult to predict appropriate dosing regimens that will adequately control pain in the individual patient. ⋯ This review examines the available pharmacokinetic-pharmacodynamic (PK/PD) data for selected opioid and nonopioid analgesics. Even though most analgesics are used clinically in multiple doses, the majority of PK/PD studies conducted to date evaluate single dose effects. Further studies with multiple doses are required to evaluate the validity of PK/PD relationships defined from single dose studies.