Active safety monitoring of newly marketed medications in a distributed data network: application of a semi-automated monitoring system

We developed a semi-automated active monitoring system that uses sequential matched-cohort analyses to assess drug safety across a distributed network of longitudinal electronic health-care data. In a retrospective analysis, we show that the system would have identified cerivastatin-induced rhabdomyolysis. In this study, we evaluated whether the system would generate alerts for three drug-outcome pairs: rosuvastatin and rhabdomyolysis (known null association), rosuvastatin and diabetes mellitus, and telithromycin and hepatotoxicity (two examples for which alerting would be questionable). Over >5 years of monitoring, rate differences (RDs) in comparisons of rosuvastatin with atorvastatin were -0.1 cases of rhabdomyolysis per 1,000 person-years (95% confidence interval (CI): -0.4, 0.1) and -2.2 diabetes cases per 1,000 person-years (95% CI: -6.0, 1.6). The RD for hepatotoxicity comparing telithromycin with azithromycin was 0.3 cases per 1,000 person-years (95% CI: -0.5, 1.0). In a setting in which false positivity is a major concern, the system did not generate alerts for the three drug-outcome pairs.     

Novel drugs for Parkinson's disease

Treatment options in PD have expanded remarkably in the past several years. Three new drugs were approved for use in the United States just within the 9 months preceding the preparation of this article. Several new compounds are in the pipeline. Nevertheless, the unmet needs of PD patients are readily apparent in any busy clinical practice. These needs can be posed as three deceivingly simple questions: 1. When and how should L-dopa be started? Despite the fact that L-dopa remains the mainstay of PD therapy after 30 years' time, lacking is a fundamental understanding of proper usage and avoidance of long-term complications. 2. What can be done about cognitive decline and dementia in PD? The current answer is nothing. Efforts are just beginning to fill this large void in knowledge and provide adequate treatment for this disabling problem. 3. How can PD be prevented? This question cannot be answered because the cause of PD remains uncertain. The dearth of substantive information available on this topic is evidenced in this article. The bulk of text appears under the heading Symptomatic Treatments, whereas only a few speculative comments can be offered under the heading Preventive Treatments. The paramount need for expanded resources and dedicated efforts to identify the causes and devise preventions must be met if advances in the treatment of PD are to be made in the twenty-first century.     

口服药样品一览表在精神科安全用药管理中的应用

目的探讨口服药样品一览表在精神科用药安全管理中的效果。方法对制作和应用口服药样品一览表前后精神科安全用药管理情况进行对比。结果制作和应用口服药样品一览表后护士每次用于查对药物的时间明显减少(P0.01);护士查对药物的准确性明显提高(P0.01);病人的满意度提高(P0.05);药物因无法辨别丢弃明显减少(P0.01)。结论该方法对提高护士的工作效率、增加病人满意度、避免药物浪费、减少用药差错有重要意义。     

Novel drugs for oral anticoagulation pharmacotherapy

Long-term anticoagulation with warfarin is the mainstay of treatment in patients with diseases with high thromboembolic potential, such as atrial fibrillation. However, warfarin therapy carries a number of inherent limitations, including slow onset and offset of action, interindividual variability, food and drug interactions, lack of selectivity and a narrow therapeutic window. Recently developed oral anticoagulants that selectively block key factors in the coagulation cascade, with no need for monitoring or dose adjustment, have the potential to replace warfarin in clinical practice. The safety and efficacy of these agents in patients with atrial fibrillation, venous thromboembolisms and acute coronary syndromes have been the object of numerous recent large-scale clinical investigations. This article provides an overview of the evidence currently available on the use of novel, orally available, selective anticoagulants in patients at risk for thromboembolic events.     

Novel dry electrodes for ECG monitoring

The development, fabrication and characterization of two novel dry bioelectrodes--conductive and capacitive ones--for biopotential monitoring are presented. The new electrodes have the potential to improve the applicability of dry electrodes in ambulant recording of ECG by reducing motion artifacts as well as the contact impedance to the skin. Furthermore, a passive filter network is integrated into the new electrodes to suppress slow offset fluctuation of the ECG signal caused e.g. by motions like breathing or changes in the electrode-skin interface properties. Compared to standard gel electrodes these new electrodes exhibit equivalent and superior contact impedances and biosignals. The integrated filter network effectively suppresses fluctuating offset potentials.     

Evaluation of thiazolidinedione derivative drugs for safety]

The first thiazolidinedione derivative drug for diabetes, troglitazone, was found to cause fatal hepatotoxicity, although it was judged as safe during the clinical trial. Subsequently, pioglitazone has been clinically used both in Japan and U.S. and has had no fatal cases but caused heart failure. Therefore, careful follow up observation is necessary in these drugs by checking liver function tests and cardiac function.     

Current status of therapeutic drug monitoring for immunosuppressive drugs

Therapeutic drug monitoring(TDM) is advocate to provide information about the adequacy of a dosing regimen or likelihood of toxicity associated with drug. Such situations include large intra- and inter-individual variabilities in pharmacokinetics; correlation between drug concentrations and toxicity or between concentrations and efficacy; narrow therapeutic interval, meaning toxic symptoms close to concentration with full therapeutic effect; and absence of appropriate parameter to recognize pharmacological effect. Current clinical immunosuppressive regimens consist of combinations of drugs, to allow a reduction in the individual drug doses as a means widening the therapeutic interval and reduction the likelihood of individual drug toxicity. With the recent introduction of new immunosuppressive drugs, there is an unprecedented interest in TDM for immunosuppressive drugs. In this review I discuss the current status of pharmacokinetic monitoring for cyclosporine, tacrolimus and mycophenolate mofetil.     

Novel drugs and treatment strategies for HIV-1

XIX International Conference of the International AIDS Society

Washington DC, USA, 22–27 July 2012

Exploring new approaches in the development of HIV-1 therapeutics is an important component in a multifaceted approach to combating global HIV-1/AIDS-related mortality. This meeting report describes novel concepts of three eminent investigators speaking at a session of the XIX International Conference of the International AIDS Society. This conference attracted approximately 24,000 delegates comprising patients, scientists, clinicians and other key stakeholders. Herein, three putative targets of novel therapy are described: initial CD8-positive T-cell responses to HIV-1 infection, integration of HIV-1 provirus and removal of proviral DNA from host cells.     

Pharmacokinetics-pharmacodynamics of antifungal drugs. Consequences for therapeutic drug monitoring

Despite pharmacokinetic-pharmacodynamic relationships were clearly evidenced for antifungal drugs by the use of experimental models, few target plasma concentrations could be determined from studies performed in patients. The main causes explaining this lack of data are reviewed and the possible use in humans of the parameters obtained from animal models is discussed.     

Novel treatment strategies and drugs in development for cryptosporidiosis

Introduction: Cryptosporidium is a protozoan pathogen that can cause diarrheal disease in healthy and immunosuppressed individuals, worldwide. Recent studies have highlighted the impact of cryptosporidiosis on children in resource-limited countries. Nitazoxanide is the only Food and Drug Administration approved treatment, but it is not consistently effective therapy for cryptosporidiosis in the most vulnerable populations.

Areas covered: This review focused on recent published studies evaluating novel drugs and new compounds for the treatment of cryptosporidiosis.

Expert commentary: Combinations of approved drugs have demonstrated some activity. Broad screens have demonstrated activity against Cryptosporidium for a number of available drugs, including statins and clofazimine, and the latter has advanced into clinical trials. Cryptosporidium calcium-dependent protein kinase 1 (CDPK1) has been identified as an attractive target for treatment, and bumped kinase inhibitors have been developed which inhibit CDPK1 and are active against Cryptosporidium growth both in vitro and in vivo. Inhibition of Plasmodium lipid kinase PI(4)K8 of Cryptosporidium by KDU731 greatly reduced oocyst shedding and improved diarrhea in calves with limited effects on the human PI(4)K. Another novel potent inhibitor MMV665917 was efficacious in mouse models with cidal activity against Cryptosporidium. Additional compounds have proved active in vitro. So far, only clofazimine has entered human trials.     

Novel computerized psychometric tests as primary screening tools for the diagnosis of minimal hepatic encephalopathy

Minimal hepatic encephalopathy (MHE) is a critical neurocognitive complication of decompensated liver cirrhosis and portosystemic shunting, which results in a wide range of cognitive deficits including impairments in working attention, psychomotor speed, and executive function. Current guidelines have recommended paper-and-pencil psychometric tests for the diagnosis of MHE. Most high-risk cirrhotic patients are required to be examined; however, paper-and-pencil psychometric tests are neither convenient nor rapid to perform in the clinic. Recently, novel computerized psychometric tests, including the inhibitory control test, EncephalApp Stroop App, and critical flicker frequency, have been proven to be rapid, effective, and convenient methods for screening MHE in clinical practice and for identifying high-risk cirrhotic patients for further validation using rigid neuropsychometric examinations. However, diagnostic accuracy of these tests is influenced by educational background, age, and cultural differences. This review summarizes clinical evidence of the application of novel computerized psychometric tests for screening MHE.     

Cardiovascular safety of non-steroidal anti-inflammatory drugs revisited

Non-steroidal anti-inflammatory drugs (NSAIDs) have been widely used to treat inflammatory pain for decades. More recently, newer NSAIDs were developed to target the inducible isoform of cyclooxygenase (COX), COX-2, with the aim of reducing gastrointestinal toxicity. While the COX-2 selective inhibitors were effective in reducing pain and gastrointestinal harm, they soon were associated with an increased risk of adverse cardiovascular events. Initially, the view emerged that selective inhibition of COX-2, and sparing of COX-1, was responsible for the increased cardiovascular harm observed. However, as more data from different human populations has become available this view has begun to be challenged. This review examines the current understanding of the role of prostaglandins and COX-1 and COX-2, particularly in platelets, the vasculature, and the kidney together with an overview of the cardiovascular and renal safety of both traditional NSAIDs and COX-2 selective inhibitors. Available data from active comparator randomized controlled trials, including the data from the PRECISION trial investigating the long term cardiovascular safety of patients exclusively with elevated baseline cardiovascular risk, are presented. The data, when considered holistically, support the idea that all NSAIDs carry some level of cardiovascular risk, be they traditional NSAIDs or COX-2 selective agents. There is also some evidence of heterogeneity of effect with NSAIDs particularly in relation to effects on blood pressure, with no clear demarcation based on the degree of COX-2 selectivity.