Current clinical pharmacology最新文献

Background: Metformin is sometimes used as an alternative to insulin in gestational diabetes mellitus (GDM). It is also used to achieve ovulation in polycystic ovary syndrome (PCOS). Pre-natal exposure to metformin results from its continuation after a successful ovulation in women with PCOS, its maintenance in women with pre-gestational diabetes or the installation of metformin in GDM. Little is known about the potential consequences of metformin exposure on pregnancy outcomes and offspring development. The aim of this review is to summarize the metformin effects on pregnancy outcomes and offspring development. Gaps in the available evidence and unanswered questions are also discussed.

Methods: A comprehensive literature search was carried out to identify eligible studies from MEDLINE/PubMed, EMBASE and SCIELO databases through 1995 first semester.

Results: Several factors limit the effect of metformin on embryos. In contrast, placental transport of metformin is effective allowing for a higher fetal exposure; the impact of this finding remains unclear. It seems that the interruption of metformin after a pregnancy diagnosis in women with PCOS is not associated with a higher miscarriage risk and it continuation does not seem to impair the maternal metabolic prognosis or prevent emerging GDM.

Conclusions: It seems to have no sense to prolong the use of metformin after a pregnancy diagnosis in women with PCOS. Patients with GDM may be treated with metformin under on judicious basis, and a careful attachment to clinical guidelines and regulations is recommended. The long-term effects of pre-natal exposure to metformin on the offspring remain uncertain.

Background: muscarinic acetylcholine receptors (mAChRs) have attracted interest as targets for therapeutic interventions in different illnesses like Alzheimer´s disease, viral infections and different tumors. Regarding the latter, many authors have studied each subtype of mAChRs, which seem to be involved in the progression of distinct types of malignancies.

Methods: We carefully revised research literature focused on mAChRs expression and signaling as well as in their involvement in cancer progression and treatment. The characteristics of screened papers were described using the mentioned conceptual framework.

Results: Muscarinic antagonists and agonists have been assayed for the treatment of tumors established in lung, brain and breast with beneficial effects. We described an up-regulation of mAChRs in mammary tumors and the lack of expression in non-tumorigenic breast cells and normal mammary tissues. We and others demonstrated that muscarinic agonists can trigger anti-tumor actions in a dose-dependent manner on tumors originated in different organs like brain or breast. At pharmacological concentrations, they exert similar effects to traditional chemotherapeutic agents. Metronomic chemotherapy refers to the administration of anti-cancer drugs at low doses with short intervals among them, and it is a different regimen applied in cancer treatment reducing malignant growth and angiogenesis, and very low incidence of adverse effects.

Conclusion: The usage of subthreshold concentrations of muscarinic agonists combined with conventional chemotherapeutic agents could be a promising tool for breast cancer therapy.

Hypertension and kidney disease often coexist, further increasing the risk of future cardiovascular events. Treatment of hypertensive adults with an angiotensin converting enzyme inhibitor in case of concomitant kidney disease may slow disease progression. The third-generation liphophilic angiotensin converting enzyme inhibitor zofenopril, administered alone or combined with a thiazide diuretic, has proved to be effective in lowering blood pressure in hypertensive patients and to reduce the risk of fatal and non-fatal events in post-acute myocardial infarction and heart failure. In almost three-hundred hypertensive patients with kidney impairment zofenopril administered for 12 weeks showed a similar blood pressure-lowering effect irrespective of the stage of the disease, with larger effects in combination with a thiazide diuretic, particularly in patients with slightly or moderately impaired kidney function. In animal models, zofenopril produced a significant and long-lasting inhibition of kidney angiotensin converting enzyme inhibitor and prevented kidney morphological and functional alterations following kidney ischemia-reperfusion injury. Treatment of hypertensive patients for 18 weeks with a combination of zofenopril 30 mg and hydrochlorothiazide 12.5 mg resulted in a reduction in albumin creatinine ratio of 8.4 mg/g (49.6% reduction from baseline values) and no changes in glomerular filtration rate, variations in line with those obtained in the control group treated with a combination of irbesartan 150 mg and hydrochlorothiazide 12.5 mg. Thus, some preliminary evidence exists to support that relatively long-term treatment with the angiotensin converting enzyme inhibitor zofenopril alone or combined with hydrochlorothiazide is effective in controlling blood pressure and may confer some kidney protection due to ACE inhibition properties.

Aim: Multiple drug intolerance syndrome (MDIS) is a unique clinical entity distinct from other drug hypersensitivity syndromes. The aim of this review was to critically appraise the various aspects of MDIS.

Methods: A review was conducted to search for the causes, mechanism, clinical features, and management of MDIS.

Results: The most common cause of MDIS is antibiotics followed by non-steroidal antiinflammatory drugs (NSAIDs). Although some non-specific immunological mechanisms are involved, the immunological tests for MDIS are negative. Rashes, gastrointestinal reflux, headache, cough, muscle ache, fever, dermatitis, hypertension, and psychiatric symptoms are the usual manifestations. Treatment is mostly symptomatic with the withdrawal of the offending drug. Drug rechallenges and desensitization may be required for the management of this syndrome.

Conclusion: MDIS occurs by a nonimmune mechanism which requires a prompt withdrawal of the offending drug(s), and in some cases may require drug re-challenge and desensitization.

Background: Knowledge of drugs safety collected during the pre-marketing phase is inevitably limited because the randomized clinical trials (RCTs) are rarely designed to evaluate safety. The small and selective groups of enrolled individuals and the limited duration of trials may hamper the ability to characterize fully the safety profiles of drugs. Additionally, information about rare adverse drug reactions (ADRs) in special groups is often incomplete or not available for most of the drugs commonly used in the daily clinical practice. In the paediatric setting several highimpact safety issues have emerged. Hence, in recent years, there has been a call for improved post-marketing pharmacoepidemiological studies, in which cohorts of patients are monitored for sufficient time in order to determine the precise risk-benefit ratio.

Objective: In this review, we discuss the current available strategies enhancing the post-marketing monitoring activities of the drugs in the paediatric setting and define criteria whereby they can provide valuable information to improve the management of therapy in daily clinical practice including both safety and efficacy aspects. The strategies we cover include the signal detection using international pharmacovigilance and/or healthcare databases, the promotion of active surveillance initiatives which can generate complete, informative data sets for the signal detection and systematic review/meta-analysis.

Conclusion: Together, these methods provide a comprehensive picture of causality and risk improving the management of therapy in a paediatric setting and they should be considered as a unique tool to be integrated with post-marketing activities.