Biomedical subjects

A P Lea

Publications and source records attributed to A P Lea.

8 recordsLinked to original sources

PubMed1997

Atorvastatin. A review of its pharmacology and therapeutic potential in the management of hyperlipidaemias.

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.

Anticholesteremic Agents↗

PubMed1997

Carvedilol. A reappraisal of its pharmacological properties and therapeutic use in cardiovascular disorders.

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.

Adrenergic beta-Antagonists↗

PubMed1997

Azithromycin. A pharmacoeconomic review of its use as a single-dose regimen in the treatment of uncomplicated urogenital Chlamydia trachomatis infections in women.

In women, Chlamydia trachomatis infection often occurs in the urethra or cervix, with up to 70% of infections associated with few or no symptoms. Inadequate treatment may lead to infection of the upper genital tract and subsequent pelvic inflammatory disease (PID) in 10 to 40% of patients. PID causes an increased relative risk of ectopic pregnancy of 2.5 to 7.9 and PID may also lead to tubal infertility in about 17% of patients. 60% of infants born of mothers with C. trachomatis infection may become infected, leading to conjunctivitis in 23% and pneumonia in 21%. All of these sequelae of C. trachomatis infection may require in- or outpatient treatment. With > 4 million infections estimated to occur each year in the US, C. trachomatis is one of the most common and costly of the sexually transmitted pathogens. Treatment options for uncomplicated C. trachomatis infections in nonpregnant women include single-dose azithromycin 1000 mg or doxycycline 100 mg twice daily for 7 days orally. In clinical trials, the bacteriological cure rate of single dose azithromycin 1000 mg (95 to 100%) was similar to that of oral doxycycline 200 mg/day for 7 days (88 to 100%) in nonpregnant women. Azithromycin was at least as well tolerated as doxycycline and was associated with mainly mild gastrointestinal adverse effects including diarrhoea, nausea and abdominal pain. Pharmacoeconomic analyses have sought to determine if the 2.7- to 12-fold higher acquisition costs of azithromycin in comparison with doxycycline are offset by its simple single-dose regimen which is likely to aid patient compliance and so optimise drug efficacy. All analyses were retrospective cost-effectiveness decision-tree models and mainly considered direct costs. All models incorporated an estimate of noncompliance with doxycycline and its influence on efficacy. For the treatment of confirmed C. trachomatis infection, azithromycin saved around $US1200 per major outcome avoided (1993 values; third-party payer perspective in the US) or US$3502 per case of PID avoided (1993 values; US healthcare system perspective) compared with doxycycline. If infection was treated empirically, azithromycin was more costly than doxycycline by $US792 (1993 values), but the result was sensitive to changes of some parameters of the model. Azithromycin was more costly than doxycycline from the perspective of a public health clinic which paid for the treatment of initial infection and acute sequelae only. Thus, pharmacoeconomic data from the US support the use of azithromycin in the treatment of nonpregnant women with confirmed C. trachomatis urogenital infections from the perspective of the healthcare system or third-party payer; however, from the perspective of a public clinic, doxycycline is the less costly option. Decreases in doxycycline compliance or azithromycin acquisition cost are factors that favour azithromycin.

Anti-Bacterial Agents↗

PubMed1996

Intracavernous alprostadil. A review of its pharmacodynamic and pharmacokinetic properties and therapeutic potential in erectile dysfunction.

Intracavernous alprostadil (synthetic prostaglandin E1) is a vasodilating agent which acts by relaxing the smooth muscles of the corpus cavernosum and by increasing the diameter of cavernous arteries; this leads to erection. Following intracavernous administration, alprostadil is either locally metabolised or rapidly cleared from the penis into the systemic circulation where it is extensively metabolised by the lungs. Studies suggest that long term use of intracavernous alprostadil may increase penile blood flow, although the clinical relevance of this is not currently known. In men with erectile dysfunction (ED), short term trials have shown that intracavernous alprostadil is superior or equal, in inducing erections, to other intracavernous agents such as papaverine, the combination of papaverine plus phentolamine, linsidomine and topical nitroglycerin (glyceryl trinitrate). Intracavernous alprostadil induced erections in around 70% of patients with ED of various origins in short term studies. 49 to 84% of patients accept the offer of joining self-injection programmes and 13 to 60% of these patients withdraw from such programmes for a variety of reasons. At therapeutic doses, intracavernous alprostadil is well tolerated. The most common adverse event of transient penile pain occurred in around one-third of patients and in 11% of injections, causing 3 to 5% of patients to withdraw from self-injection programmes. Potentially serious adverse events such as priapism and fibrosis occurred in 4 and 8% of patients. Overall, available data suggest that the efficacy of intracavernous alprostadil is superior or equal to that of other erectogenic agents which are in use. Furthermore, the drug is well tolerated especially with regard to serious adverse events. Thus, although further research is necessary to confirm its use in combination with other agents, alprostadil appears likely to become the intracavernous agent of choice for the management of erectile dysfunction.

Alprostadil↗

PubMed1996

Stavudine: a review of its pharmacodynamic and pharmacokinetic properties and clinical potential in 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.

Animals↗

PubMed1996

Cidofovir.

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.

Animals↗

PubMed1996

Ritonavir.

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.

Administration, Oral↗

PubMed1994

Minimal spectral contrast of formant peaks for vowel recognition as a function of spectral slope.

In four experiments we investigated whether listeners can locate the formants of vowels not only from peaks, but also from spectral "shoulders"--features that give rise to zero crossings in the third, but not the first, differential of the excitation pattern--as hypothesized by Assmann and Summerfield (1989). Stimuli were steady-state approximations to the vowels [a, i, e, u, o] created by summing the first 45 harmonics of a fundamental of 100 Hz. Thirty-nine harmonics had equal amplitudes; the other 6 formed three pairs that were raised in level to define three "formants." An adaptive psychophysical procedure determined the minimal difference in level between the 6 harmonics and the remaining 39 at which the vowels were identifiably different from one another. These thresholds were measured through simulated communication channels, giving overall slopes of the excitation patterns of the five vowels that ranged from -1 dB/erb to + 2 dB/erb. Excitation patterns of the threshold stimuli were computed, and the locations of formants were estimated from zero crossings in the first and third differentials. With the more steeply sloping communication channels, some formants of some vowels were represented as shoulders rather than peaks, confirming the predictions of Assmann and Summerfield's models. We discuss the limitations of the excitation pattern model and the related issue of whether the location of formants can be computed from spectral shoulders in auditory analysis.

Adult↗