抗HIV药物的筛选评价方法

随着对艾滋病致病机制的深入研究，越来越多新的抗艾滋病病毒（HIV）药物进入临床试验，但大量抗HW药物的应用也导致了耐药性问题的出现。因此，建立高通量快速的抗HW药物筛选平台对研究新的抗HW药物非常重要。本文综述了目前抗HIV药物研究中常用的体外和体内筛选模型，重点阐述了体外以病毒复制特异性功能活动或特定结构作为靶点的筛选系统及其评价方法。     

艾滋病治疗药物的研究进展

作者全面系统地阐述了近年来抗艾滋病新药的研发策略和研究进展,并根据药物作用靶点分别介绍了新上市的抗艾滋病药物的作用机制和结构特点,如第二代HIV-1逆转录酶抑制剂和HIV-1蛋白酶抑制剂,以及全新作用机制的HIV-1进入抑制剂和HIV-1整合酶抑制剂,并对今后抗艾滋病药物的发展方向进行了展望。     

抗艾滋病药物设计新策略:多靶点及多价态结合配体

HIV是艾滋病(AIDS)的主要病原体,由于目前临床药物严重的耐药性问题以及长期应用的毒副作用,研发高效抗耐药的抗艾滋病药物及全新疗法是当前药物化学领域的研究热点。近年来,多靶点和多价态结合药物越来越受到研究者的关注,并且成为合理设计抗艾滋病药物的新途径。本文结合具体实例综述了合理设计多靶点及多价态抗艾滋病药物的新进展,并对目前存在的问题和研究趋势进行了总结和展望,为发现新一代抗HIV药物提供重要信息。     

常用抗病毒药物的临床应用

抗病毒药物是病毒性感染治疗的主要药物，近年来，随着抗逆转录病毒药物开发，治疗其他病毒感染的药物也得到了发展。本文对临床常用的抗病毒药物(不包括艾滋病和病毒性肝炎)的药理、临床、毒副反应等进行了综述，并对临床常见病毒性感染的治疗方案以及抗病毒药物发展情况做简略介绍。     

Timing of carcinogenicity studies and predictability of genotoxicity for tumorigenicity in anti-HIV drug development

The timing of carcinogenicity studies in parallel with the clinical development of anti-human immunodeficiency virus (HIV) drugs has been flexible for most cases in the past. This includes postponement of the initiation of the studies and submission of final audited reports to the US Food and Drug Administration (FDA) for a new drug application (NDA) approval. We address this regulatory practice for anti-HIV drugs for which, in the past, there had been no effective treatment. We also examine the correlation of genotoxicity data with carcinogenicity data for the varied subclasses of anti-HIV drugs. We suggest that this regulatory policy regarding the timing of carcinogenicity testing does not compromise the safety standards of FDA's drug evaluation and the approval process. The policy does facilitate availability of these agents to meet the medical needs of the target population. Our analysis on the profile of carcinogenicity findings of anti-HIV drugs shows trends of class effects. Additionally, both carcinogenicity and genotoxicity data show significant correlations, which provide useful insights into issues involving these 2 important areas of toxicological investigations.     

Antiepileptic drug therapy in the twenty first century

In the last 25 years, particularly the last decade, there have been many advances relating to all aspects of epilepsy i.e. pathophysiology, diagnosis, pharmacotherapy and surgical interventions. Noteworthy has been the progress in terms of understanding of the established antiepileptic drugs (AEDs) and introduction of several newer agents developed rationally, on the basis of now available information on the biochemical changes in the epileptic brain. Data is accumulating regarding the use of newer agents but they still need to stand the test of time. Many of the newer AEDs may offer a better tolerability because of favorable pharmacokinetic characteristics and minimal drug interactions. However, serious adverse events have been associated with felbamate and lamotrigine already and for other newer agents reliable and accurate data needs to be generated.     

Potential use of rapamycin in HIV infection

The strong need for the development of alternative anti-HIV agents is primarily due to the emergence of strain-resistant viruses, the need for sustained adherence to complex treatment regimens and the toxicity of currently used antiviral drugs. This review analyzes proof of concept studies indicating that the immunomodulatory drug rapamycin (RAPA) possesses anti-HIV properties both in vitro and in vivo that qualifies it as a potential new anti-HIV drug. It represents a literature review of published studies that evaluated the in vitro and in vivo activity of RAPA in HIV. RAPA represses HIV-1 replication in vitro through different mechanisms including, but not limited, to down regulation of CCR5. In addition RAPA synergistically enhances the anti-HIV activity of entry inhibitors such as vicriviroc, aplaviroc and enfuvirtide in vitro. RAPA also inhibits HIV-1 infection in human peripheral blood leucocytes-SCID reconstituted mice. In addition, a prospective nonrandomized trial of HIV patient series receiving RAPA monotherapy after liver transplantation indicated significantly better control of HIV and hepatitis C virus (HCV) replication among patients taking RAPA monotherapy. Taken together, the evidence presented in this review suggests that RAPA may be a useful drug that should be evaluated for the prevention and treatment of HIV-1 infection.     

Targeting anti-HIV drugs to the CNS

The development of antiretroviral drugs over the past couple of decades has been commendable owing to the identification of several new targets within the overall HIV replication cycle. However, complete control over HIV/AIDS is yet to be achieved. This is because the current anti-HIV drugs, although effective in reducing plasma viral levels, cannot eradicate the virus completely from the body. This occurs because most anti-HIV drugs do not accumulate in certain cellular and anatomical reservoirs including the CNS. Insufficient delivery of anti-HIV drugs to the CNS is attributed to their low permeability across the BBB. Hence, low and sustained viral replication within the CNS continues even during prolonged antiretroviral drug therapy. Therefore, developing novel approaches that are targeted at enhancing the CNS delivery of anti-HIV drugs are required. In this review, we discuss the potential of nanocarriers and the role of cell-penetrating peptides in enhancing drug delivery to the CNS. Such drug delivery approaches could also lead to higher drug delivery to other cellular and anatomical reservoirs where the virus harbors than with conventional treatment, thus providing an effective therapy to eliminate the virus completely from the body.     

Risk of seizures associated with psychotropic medications: emphasis on new drugs and new findings

Psychotropic medications in the classes of antidepressants, antipsychotics and mood stabilisers have been recognised in the literature and clinical settings as having high epileptogenic potential. Among these three classes, clozapine, tricyclic antidepressants (TCAs) and lithium are agents that clinicians have historically recognised as precipitants of drug-induced seizures. There are few reports that review the epileptogenic risk of newer psychotropic agents; in this qualitative review, the authors provide an update on the most recently published reports on seizures associated with antidepressants, antipsychotics, mood stabilisers, anxiolytics and sedative-hypnotics. In general, the epileptogenic risks of the newer psychotropic agents appear to be quite low as long as dosing strategies are consistent with recommended guidelines. Whilst newer psychotropic medications appear to be safe in patients with epilepsy, few studies have specifically addressed this population. In addition, the potential for drug interactions between antiepileptic drugs and psychotropics may be substantial with certain agents. For example, many psychotropes are both substrates and inhibitors of cytochrome P450 (CYP450) isoenzymes, whilst many antiepileptic drugs are both substrates and inducers of CYP450 activity. Every attempt should be made to minimise potential interactions when these agents are concomitantly administered.     

Selection criteria for the clinical use of the newer antiepileptic drugs

In recent years, several new antiepileptic drugs (AEDs) have been licensed: felbamate, gabapentin, lamotrigine, levetiracetam, oxcarbazepine, tiagabine, topiramate, vigabatrin and zonisamide. These drugs have proven efficacy as add-on therapy in patients with difficult-to-treat partial epilepsy, as 20-50% of patients treated in add-on trials experienced a seizure reduction of >or=50%. Relatively few trials have been conducted to evaluate these drugs as monotherapy for patients with newly diagnosed epilepsy. In the monotherapy trials that have been conducted, the newer drugs were often as efficacious as conventional drugs, and their tolerability was often better. However, the methodology of these trials can be criticised. Because of the relative lack of robust data for the newer agents, the conventional drugs have thus far maintained their status as first-line monotherapy. However, when first-line monotherapy fails, an alternative drug has to be chosen from the available conventional and newer drugs. This article aims to give detailed background information on the newer AEDs in order to enable physicians to make a rational choice from the available drugs for individual patients. Data are provided for the different newer AEDs on mechanisms of action; efficacy in refractory partial epilepsy, newly diagnosed epilepsy in adults and generalised seizure types; adverse effects; pharmacokinetics; and use in special patient categories.     

Risk of seizures associated with psychotropic medications: emphasis on new drugs and new findings

Psychotropic medications in the classes of antidepressants, antipsychotics and mood stabilisers have been recognised in the literature and clinical settings as having high epileptogenic potential. Among these three classes, clozapine, tricyclic antidepressants (TCAs) and lithium are agents that clinicians have historically recognised as precipitants of drug-induced seizures. There are few reports that review the epileptogenic risk of newer psychotropic agents; in this qualitative review, the authors provide an update on the most recently published reports on seizures associated with antidepressants, antipsychotics, mood stabilisers, anxiolytics and sedative-hypnotics. In general, the epileptogenic risks of the newer psychotropic agents appear to be quite low as long as dosing strategies are consistent with recommended guidelines. Whilst newer psychotropic medications appear to be safe in patients with epilepsy, few studies have specifically addressed this population. In addition, the potential for drug interactions between antiepileptic drugs and psychotropics may be substantial with certain agents. For example, many psychotropes are both substrates and inhibitors of cytochrome P450 (CYP450) isoenzymes, whilst many antiepileptic drugs are both substrates and inducers of CYP450 activity. Every attempt should be made to minimise potential interactions when these agents are concomitantly administered.     

Section Review—Cardiovascular & Renal: Recent Developments in Antithrombotic Agents

During the past decade, many significant developments in the clinical management of thrombotic and vascular disorders have occurred. In particular, several newer approaches for the prophylactic and therapeutic management of such disorders as venous thrombosis, acute myocardial infarction and stroke have been introduced. This has only been possible due to the understanding of the molecular mechanisms involved in the thrombogenic process which plays a key role in the pathophysiology of thrombotic and vascular disorders. With the increased knowledge of the pathophysiology of thrombosis have come advances in drug treatment possibilities. Advances in biotechnology and separation techniques have contributed to the development of many newer antithrombotic, anticoagulant and thrombolytic drugs. Many new drugs and devices based on newer concepts are currently being tested in various clinical trials. Hirudin, hirulog, Gpllb/llla targeting antibodies and tissue factor pathway inhibitor (TFPI), are some examples. From these current developments, it can be appreciated that antithrombotic drugs represent a wide spectrum of natural, synthetic, semisynthetic and biotechnology produced agents with marked differences in chemical composition, physico-chemical properties, biochemical actions and pharmacologic effects. The use of physical means to treat thrombotic disorders and advanced means of drug delivery add to the expanding nature of treatment. The endogenous actions of the antithrombotic drugs are quite complex. It is no longer valid to assume that an antithrombotic drug must produce an anticoagulant action in blood, as do the classical heparin and oral anticoagulants. Many of these new drugs do not produce any alteration of currently measurable blood clotting parameters, yet they are effective therapeutic agents because of their interactions with the elements of the blood and the vasculature. Another perspective is that several of these agents require endogenous transformation to become active products. Therefore, it becomes important to rely on the pharmacodynamic actions of these agents rather than on other in vitro characteristics to assess potency or efficacy. Haematologic and vascular modulation play a key role in the mediation of the antithrombotic actions of these drugs involving red cells, white cells, platelets, endothelial cells and blood proteins. Thus, an optimal antithrombotic drug/approach will include the targeting of all possible sites involved in thrombogenesis. Polytherapeutic approaches utilising combinations of drugs may turn out to be the most effective in the management of thrombotic disorders.     

Current status of newer antiinfectives

In the era of multidrug resistance keen interest needs to be taken in developing newer antiinfective drugs and patents. We all are aware that not many such drugs are readily available and still less are in the pipeline, and thus, such patents are limited in number. This is an attempt to review some of the newer antiinfectives used as antibacterial, antifungal and antiparasitic agents. An attempt has been made here to review the lately added newer antiinfectives. However, there has not been much change in the antiparasitic drug development arena. But it is interesting to note that even much older antiparasitic formulations are still of much use and the reason for this is reviewed here. Among the antibacterial drugs ertapenem, gemifloxacin, tigecycline and daptamycin are discussed. Doripenem has not been included here, due to the paucity of randomized trials of the molecule; however, it appears to be a promising penem that is to get added to the list of available antibiotics. The antiparasitic and antifungal drugs have attracted major attention of the research scientists and clinicians because of the increasing incidence of parasitic and fungal infections in the immunocompromised patients, leading to added morbidity and mortality. In the present review, besides newer antibiotics, newer anti parasitic and antifungal drugs have also been discussed.     

艾滋病抗病毒治疗进展

抗HIV药物的研发和应用为临床控制疾病的进展发挥了重要的作用。回顾了临床常用的抗HIV药物的研发历史,综述了目前应用于临床的逆转录酶抑制剂、蛋白酶抑制剂、病毒入胞抑制剂和整合酶抑制剂及其新产品的作用和机制,以及对HIV治疗的新思路和药物预防策略。     

Advances in molecular targets and chemotherapy of tuberculosis

The need for newer, effective drugs with different modes of action against tuberculosis is great, despite the numerous drugs in clinical use and the development of Bacilli Calmette-Guerin (BCG) vaccine. Three major goals should be considered in the development of new antituberculosis drugs: 1) they should be fast acting to reduce the long duration of treatment, thereby avoiding drug toxicity; 2) they should be active against both sensitive and resistant strains of tubercle bacilli; and 3) they should possess significant activity against dormant bacilli, which represent the stage affecting one-third of the world's tuberculosis patients. This review provides an overview of important current drugs, novel targets for the development of antituberculosis agents and future drug candidates.