Clopidogrel: new preparation. An alternative to aspirin

(1) Clopidogrel, an antiplatelet drug chemically similar to ticlopidine, is marketed in France for secondary prevention of thrombotic complications in patients with a history of myocardial infarction, ischaemic stroke or peripheral arterial disease. (2) Marketing authorisation was based mainly on the CAPRIE trial, a study that involved 19,815 patients. In this trial of secondary cardiovascular prevention, clopidogrel was slightly more effective than aspirin (325 mg/day) according to a statistical analysis of a combined end point (ischaemic stroke, or myocardial infarction, or death of vascular causes). The difference was more marked in the subgroup of patients with obstructive arterial disease of the lower limbs. (3) Clopidogrel was well tolerated in this trial. The only adverse effects more frequent on clopidogrel than on aspirin were rash and diarrhoea. (4) Clopidogrel showed no haematological toxicity, an adverse effect that restricts the use of ticlopidine. (5) The lack of long-term follow-up in real clinical settings prevents any meaningful estimation of the safety profile or of the risk of drug interactions.     

Transdermal fentanyl: new preparation. An alternative to morphine

(1) Fentanyl, an opiate agonist, was previously available in injectable form for use in anaesthesia. The new patch form is indicated for the treatment of chronic cancer pain. (2) The clinical assessment mainly involved non comparative trials showing good analgesic efficacy on chronic pain. (3) Given the long time-lag before the effect of fentanyl is felt, a short-acting analgesic should be given when the first patch is applied. Once adequate relief has been achieved the patch can be used alone to treat chronic pain. It must be replaced every three days. (4) Fentanyl patches have similar adverse effects to opiate agonists, i.e. gastrointestinal and neuropsychological disorders. However, the adverse effects of morphine and fentanyl are not always identical in a given patient. (5) Fentanyl patches carry a risk of misuse by opiate addicts and of acute intoxication.     

Levonorgestrel intrauterine device: new preparation. An alternative

(1) Mirena degrees is a contraceptive intrauterine device delivering levonorgestrel. (2) Its assessment is based on two prospective randomised multicenter trials comparing it to a copper device. (3) It is not known whether it is any more difficult to insert than other devices. (4) Efficacy, in terms of absolute protection and risk of extrauterine pregnancy, appears to be very good, at least equal to that of copper devices. (5) Women were less subject to menorrhagia than were women using a copper device. (6) In clinical trials up to a third of women had amenorrhoea. Some women had spotting during the first three months, and other adverse effects (e.g. acne, headache and mastodynia) were more frequent than among women using copper devices.     

Oxcarbazepine: new preparation. An alternative to carbamazepine in partial epilepsy

(1) The reference treatment for partial epilepsy in adults and children is carbamazepine. (2) Oxcarbazepine is available in the European Union for the treatment of partial epilepsy in adults and children aged over 6 years, alone or in combination with other antiepileptic drugs. (3) The clinical file on oxcarbazepine monotherapy of recent-onset generalised or partial epilepsy mainly contains data from one trial versus carbamazepine, two trials versus phenytoin, and one trial versus valproate sodium. In these trials, 52-60% of patients had no seizures on oxcarbazepine, a proportion not significantly different from that obtained with the comparators. Oxcarbazepine may, in fact, be slightly less effective than carbamazepine. (4) For refractory partial epilepsy (especially forms refractory to carbamazepine), oxcarbazepine is more effective than a placebo, when combined with the inadequately effective treatment, as shown in two trials. Two dose-finding studies show that 2 400 mg/day oxcarbazepine is more effective than 300 mg/day. (5) In trials comparing single-drug treatments there were fewer withdrawals for adverse events among patients on oxcarbazepine than among those on carbamazepine or phenytoin. Compared with carbamazepine, the risk of cutaneous hypersensitivity reactions seems to be lower with oxcarbazepine, while the risk of hyponatraemia is higher. This risk of hyponatraemia necessitates laboratory monitoring. (6) The risk of clinically significant interactions appears to be lower on oxcarbazepine than on carbamazepine, and is limited mainly to combined contraceptives (contraceptive inefficacy) and phenytoin. (7) In practice, carbamazepine remains the reference treatment for partial epilepsy, but oxcarbazepine is one of several second-line options, either alone or in combination with other antiepileptics.     

HIV protease inhibitors as new treatment options for Kaposi's sarcoma.

A reduced incidence and regression of Kaposi's sarcoma (KS) and other tumours has been reported in Acquired Immune Deficiency Syndrome (AIDS) patients treated with antiretroviral combination therapies containing Human Immunodeficiency Virus (HIV) protease inhibitors (PIs) such as indinavir or saquinavir. Indeed, evidence indicates that although PIs were designed to selectively inhibit the HIV protease activity, they can interfere with several cellular pathways and can inhibit tumour growth. In particular, our recent results indicate that doses of indinavir or saquinavir similar to those employed to treat AIDS patients can induce regression of experimental KS by directly blocking two fundamental steps of KS initiation and progression: new blood vessel formation (angiogenesis) and KS tumour cell invasion. This is because indinavir or saquinavir inhibit the activation of matrix metalloproteinase-2 (MMP-2), a basement membrane-degrading enzyme, which is required for the progression of most tumours. Based on these results, a multicentre clinical trial is now starting in Italy, which will assess PI effects on the progression of KS in HIV-uninfected individuals (classical KS).     

Targeting HIV protease: from peptidomimetics to non-peptide inhibitors

The identification of HIV-1 protease as a target for therapeutic intervention against AIDS, soon followed by the resolution of its three-dimensional structure, has had a major impact on drug-design methodologies. The possible HIV-1 protease inhibitors that have been synthesized number in the thousands and exhibit amazing chemical diversity, but only a few happen to be useful for human therapy. This review covers the development of some of these inhibitors, the reasons for this limited success, current therapeutic problems and challenges remaining ahead.     

Inorganic polyhedral metallacarborane inhibitors of HIV protease: a new approach to overcoming antiviral resistance

HIV protease (PR) is a prime target for rational anti-HIV drug design. We have previously identified icosahedral metallacarboranes as a novel class of nonpeptidic protease inhibitors. Now we show that substituted metallacarboranes are potent and specific competitive inhibitors of drug-resistant HIV PRs prepared either by site-directed mutagenesis or cloned from HIV-positive patients. Molecular modeling explains the inhibition profile of metallacarboranes by their unconventional binding mode.     

Resistance to HIV protease inhibitors: mechanisms and clinical consequences

HIV-1 protease is an aspartic protease composed by two identical monomers, 99 amino acids in length. Drug resistance is mainly mediated by structural changes in the substrate cleft that result in a reduction in drug binding affinity. Sequence analysis of drug resistance clones has shown mutations not only within the protease but also at several of the protease cleavage sites. Changes at more than 20 positions within the HIV-1 genome have been associated with PI resistance. The spectrum of mutations selected during therapy with indinavir, nelfinavir, saquinavir, ritonavir, amprenavir and atazanavir has been well characterized. Specific changes are characteristically linked to resistance to each of these compounds (i.e., D30N for nelfinavir, I50L for atazanavir or I50V for amprenavir). In contrast, for drugs such as lopinavir and tipranavir, which always are used boosted with low-dose ritonavir, combinations of multiple protease mutations rather than few specific changes seem to be necessary for causing significant drug resistance. Something similar happens when other PIs are equally boosted with ritonavir. Overall, when more than 5 protease resistance mutations are present, the response to any boosted-PI should be expected to be compromised.     

Prodrugs of HIV protease inhibitors

Despite the efficiency of the present polytherapies against AIDS, HIV replication continues indicating difficulties in drug adherence, drug-drug interactions, resistance issues, and the existence of reservoirs or sanctuaries for the virus. Moreover, most of the current FDA-approved HIV protease inhibitors (PIs) display disadvantageous physicochemical and pharmacological properties such as low water solubility, low oral bioavailability and/or low level of penetration into the HIV sanctuaries resulting from their in vivo binding to the plasma proteins and to the Multi-Drug-Resistant P-glycoprotein, their rapid metabolization and inactivation by the liver cytochrome P450 enzymes. To overcome these suboptimal pharmacokinetics, high daily doses must be ingested, which complicate patient adherence to the prescribed regimen and contribute to the appearance of serious long-term metabolic complications and to the decrease of the viral treatment outcome. Another attractive alternative aimed at improving the safety, pharmacokinetics, and therapeutic potency of the current PIs is to modify these PIs into pharmacologically inactive prodrugs which are converted in vivo into their parent active drug. The present review is dedicated to the different prodrug approaches, including the "lipophilic", "hydrophilic", "active transport" and "double-drug" prodrug strategies, which have been applied more particularly to the current HIV PIs used in clinic. Among the strategies explored up to now, the most successful one was the "hydrophilic" prodrug approach which has led to the discovery of fosamprenavir, a phosphate ester prodrug of amprenavir, which has reached phase III clinical trials. This success gives strong support for the search of PI prodrugs as a therapeutic alternative in addition to the development of new and well-tolerated PIs.     

HIV蛋白酶抑制剂与细胞凋亡

HIV感染人体后造成大量CD4 + T淋巴细胞的凋亡 ,从而破坏免疫系统 ,使机体无法抵抗病毒的入侵 ,导致免疫缺陷。目前的药物靶点都针对病毒本身 ,无法清除体内储存病毒的感染细胞 ,而HIV蛋白酶抑制剂治疗HIV/AIDS患者后可以减少HIV感染引起的细胞凋亡 ,帮助机体恢复免疫功能 ,并且这种作用与其抑制病毒的作用是相独立的 ,这提示了可以通过免疫重建的策略来治疗AIDS。本文综述了HIV蛋白酶抑制剂的研究和发展概况 ,其作用特点以及对细胞凋亡的影响。明确HIV蛋白酶抑制剂与细胞凋亡的关系 ,可以启发新的思路从细胞着手 ,通过恢复机体的免疫能力来对抗病毒 ,从根本上治疗AIDS。     

A risk-benefit assessment of HIV protease inhibitors.

The use of triple regimens, often called highly active antiretroviral therapy (HAART), generally involving 2 nucleoside analogues and an HIV protease inhibitor, have been endorsed as the standard of care for persons with HIV initiating therapy by a number of sets of international guidelines. The widespread availability of protease inhibitor-containing regimens has been associated with a dramatic drop in the incidence of new AIDS events and mortality throughout the developed world. Use of HAART regimens, particularly in treatment-na?ve individuals, is also associated with dramatic reductions in HIV RNA load, rises in CD4+ cell numbers and improvements in some aspects of immune function. However, protease inhibitor therapy is associated with a range of adverse effects, which varies between agents, and regimens frequently involve inconvenient administration schedules and disruption to patient's lives. Thus, the undoubted benefits of antiretroviral therapy come at some cost in terms of both physical and psychological morbidity to the recipient. In assessing an individual for therapy, consideration of the risk of disease events and the benefit of therapy in reducing or preventing these events must be weighed against the potential of therapy to cause morbidity. Using these criteria, we suggest that an individual with a 3 year risk of disease progression of less than 10% (based on CD4+ cell count and HIV RNA load) is more likely to a experience a morbidity if treated with HAART than if left untreated and monitored. For individuals with higher risks of HIV progression the risk versus benefit of initiating therapy may, in many cases, still be in favour of no therapy and continued observation. This will vary depending on the individuals risks (such as family and past medical history) and on the choice of agents in the regimen, some regimens having greater risks than others.     

Determining and overcoming resistance to HIV protease inhibitors

HIV protease represents a major target for development of antiviral therapeutics. The introduction of HIV protease (PR) inhibitors (PIs) to clinical practice and the application of highly active antiretroviral therapy resulted in decreased mortality and prolonged life expectancy of HIV-positive patients. However, the high polymorphism of HIV leads to rapid selection of viral variants resistant towards the inhibitors. Such resistant PR variants have developed in HIV-positive patients after treatment with any of the eight PIs approved for clinical use. In this review we overview (i) the methods for the identification and assessment of viral resistance in HIV positive patients, and (ii) the approaches medicinal chemists take to overcome it. Rational antiviral therapy brings about the need for quantitative assessment of the level of drug resistance development in the course of the treatment. At present, two main approaches are taken: in genotypic assays the viral sequences are PCR amplified, sequenced and changes in the viral gene sequence known to be associated with reduced drug sensitivity are identified, while phenotypic assays test the ability of a virus to grow in the presence of a drug or combination of drugs. The advantages and drawbacks of these methods, as well as their relevance for the therapy are discussed. We also review the efforts to design second-generation PIs, capable of potently inhibiting multi-resistant HIV-1 PR species, using structure-assisted design of the compounds targeted to the active site, as well as alternative approaches with compounds binding to other domains of the PR molecule.     

Antileishmanial activity of HIV protease inhibitors

The proteasomes of some protozoa are possible targets for chemotherapy. Leishmaniasis is a major health problem in human immunodeficiency virus (HIV) co-infected subjects. Two HIV protease inhibitors (PI), indinavir and saquinavir, have been shown to block proteasome functions; we therefore investigated their effects on the growth of two Leishmania spp. (Leishmania major and Leishmania infantum). After 24 h of treatment, both drugs exhibited a dose-dependent antileishmanial activity, with 50% lethal dose (LD50) values of, respectively, 8.3 microM and 7 microM on L. major; minor activity was observed on L. infantum. These results add new in vitro insights into the wide-spectrum efficacy of PI and suggest studying their action on amastigote forms of leishmania within macrophages in order to validate their potential contribution against opportunistic infections in treated seropositive patients.