Cidofovir is a nucleotide analogue which inhibits viral DNA polymerase and is effective against human cytomegalovirus (CMV) infection. It is phosphorylated to its active form by cellular enzymes. With the long intracellular half-life of its metabolites, cidofovir can be administered weekly during induction and every other week during maintenance therapy. Viral resistance has not been documented in patients treated with cidofovir to date, but has developed in vitro. Immediate cidofovir therapy delayed progression of CMV retinitis compared with deferred treatment in patients with AIDS. Cidofovir also delayed the progression of CMV retinitis relapsing after previous treatment. To avoid nephrotoxicity, probenecid and intravenous saline hydration must be administered with each dose of cidofovir.

Atorvastatin is a synthetic HMG-CoA reductase inhibitor which lowers plasma cholesterol levels by inhibiting endogenous cholesterol synthesis. It also reduces triglyceride levels through an as yet unproven mechanism. Dose-dependent reductions in total cholesterol, low density lipoprotein (LDL)-cholesterol and triglyceride levels have been observed with atorvastatin in patients with hypercholesterolaemia and in patients with hypertriglyceridaemia. In large trials involving patients with hypercholesterolaemia, atorvastatin produced greater reductions in total cholesterol, LDL-cholesterol, apolipoprotein B and triglyceride levels than lovastatin, pravastatin and simvastatin. In patients with primary hypercholesterolaemia, the combination of atorvastatin and colestipol tended to produce larger reductions in LDL-cholesterol levels and smaller reductions in triglyceride levels than atorvastatin monotherapy. Although atorvastatin induced smaller reductions in triglyceride levels and more modest increases in high density lipoprotein (HDL)-cholesterol levels than either fenofibrate or nicotinic acid in patients with combined hyperlipidaemia, it produced larger reductions in total cholesterol and LDL-cholesterol. As with other HMG-CoA reductase inhibitors, the most frequently reported adverse events associated with atorvastatin are gastrointestinal effects. In comparative trials, atorvastatin had a similar adverse event profile to that of other HMG-CoA reductase inhibitors. Clinical data with atorvastatin are limited at present. However, with its ability to markedly reduce LDL-cholesterol levels, atorvastatin is likely to join other members of its class as a first-line agent for the treatment of patients with hypercholesterolaemia, if changes in lipid levels with atorvastatin convert to reductions in CHD mortality and morbidity. Atorvastatin may be particularly suitable for patients with heterozygous or homozygous familial hypercholesterolaemia because of the marked reductions in LDL-cholesterol experienced with the drug. Additionally, because of its triglyceride-lowering properties, atorvastatin appears to have the potential to become an appropriate treatment for patients with combined hyperlipidaemia or hypertriglyceridaemia.

Ritonavir is a protease inhibitor with an HIV-1 resistance profile similar to that of indinavir, but different from that of saquinavir. Ritonavir has good oral bioavailability, and may increase the bioavailability of other protease inhibitors including saquinavir, nelfinavir, indinavir and VX-478. Clinically significant drug interactions have been predicted between ritonavir and a range of medications. In patients with HIV-1 infection, ritonavir markedly reduced viral load within 2 weeks of treatment onset and also increased CD4+ cell counts. In a large placebo-controlled trial in patients with advanced HIV infection, the addition of ritonavir to existing therapy reduced the risk of mortality by 43% and clinical progression by 56% after 6.1 months. Triple therapy with ritonavir plus zidovudine, in combination with lamivudine or zalcitabine, reduced HIV viraemia to below detectable levels in most patients with acute, and some patients with advanced HIV infection in 2 small trials. Early results suggest combination therapy with ritonavir and saquinavir increases CD4+ cell counts and decreases HIV RNA levels in patients with previously untreated HIV infection.

Stavudine is a nucleoside analogue which undergoes intracellular phosphorylation to its active metabolite, stavudine-5'-triphosphate. At clinically relevant concentrations, the active metabolite restricts HIV replication by inhibiting the inclusion of thymidine-5'-triphosphate into proviral DNA by HIV reverse transcriptase, and/or by causing DNA chain termination. Viral resistance to stavudine does not commonly develop during treatment. Where it has developed, up to a 12-fold increase in resistance has been observed in clinical isolates from patients treated with stavudine for long periods. Stavudine 40mg twice daily and zidovudine 200mg 3 times daily were compared in 822 patients at various stages of HIV infection who had previously received long term zidovudine therapy. Stavudine was superior for both primary and surrogate end-points including clinical progression, treatment failure, increase in CD4+ cell counts and bodyweight gain. In a larger study, stavudine 40mg twice daily provided greater benefit than stavudine 20mg twice daily in terms of weight gain, haematological findings and the number of hospitalisations in 11 784 patients intolerant of or resistant to, zidovudine and didanosine. Peripheral neuropathy is the major dose-limiting adverse event associated with stavudine therapy and occurred more frequently with stavudine than zidovudine. However, haematological adverse events were observed less frequently with stavudine than with zidovudine. Thus, stavudine is effective in alleviating signs and symptoms of HIV infection in patients intolerant of or no longer responding to, zidovudine or didanosine. It is also more effective than zidovudine in slowing disease progression in patients previously treated with zidovudine for long periods. The results of studies which will reveal the role of stavudine therapy in untreated patients and in combination with other anti-HIV agents are awaited with interest.

Carvedilol competitively blocks beta 1, beta 2 and alpha 1 receptors. The drug lacks sympathomimetic activity and has vasodilating properties that are exerted primarily through alpha 1-blockade. Animal models indicate that carvedilol confers protection against myocardial necrosis, arrhythmia and cell damage caused by oxidising free radicals, and the drug has no adverse effects on plasma lipid profiles. Recent data have confirmed the antihypertensive efficacy of carvedilol in patients with mild to moderate essential hypertension. Carvedilol has similar efficacy to other beta-blocking agents, calcium antagonists, ACE inhibitors and hydrochlorothiazide. Carvedilol also improves exercise tolerance and ischaemic symptoms in patients with stable angina pectoris. Significant reductions in serious cardiac events after acute myocardial infarction and in frequency and severity of ischaemic events in patients with unstable angina have also been demonstrated. Interest in the use of carvedilol in patients with congestive heart failure (CHF) has culminated in the publication of a cumulative analysis of data from 1094 patients with mild to severe CHF who participated in the US Carvedilol Heart Failure Study Program (4 trials). After a median follow-up of 6.5 months, a significant overall reduction in mortality relative to placebo (3.2 vs 7.8%) was revealed in patients who had received carvedilol 6.25 to 50 mg twice daily (plus diuretics and ACE inhibitors). All-cause mortality, risk of hospitalisation for cardiovascular reasons and hospitalisation costs were also reduced significantly (by 65, 28% and 62%, respectively) in these trials. In addition, the Australia and New Zealand Heart Failure Research Collaborative Group showed a 26% reduction in the combined risk of death or hospitalisation with carvedilol 12.5 to 50 mg/day relative to placebo after a mean 19-month follow-up period in 415 patients with CHF (relative risk 0.74). Adverse events with carvedilol appear to be less frequent than with other beta-blocking agents, are dosage-related and are usually seen early in therapy. Events most commonly reported are related to the vasodilating (postural hypotension, dizziness and headaches) and the beta-blocking (dyspnoea, bronchospasm, bradycardia, malaise and asthenia) properties of the drug. Carvedilol appears to date to have little effect on the incidence of worsening heart failure. Concomitant administration of carvedilol with some medications requires monitoring. Carvedilol is therefore likely to have a beneficial role in the management of controlled CHF, but further clinical studies are required to show the place of beta-adrenoceptor blocking therapy in general in this indication, and the position of carvedilol relative to other similar agents. Carvedilol is also confirmed as effective in the management of mild to moderate hypertension and ischaemic heart disease.