The management of subacute bacterial endocarditis superimposed on rheumatic heart disease in the immediate pre-penicillin era: the case of Pasquale Imperato.

Subacute bacterial endocarditis (SBE) was invariably a fatal disease in the pre-penicillin era. The availability of sulfonamide antibiotics beginning in the mid-1930s raised hopes that they would be effective in SBE. Unfortunately, except in rare instances, they were not. This paper reviews the clinical experience with sulfonamides in the pre-penicillin period in treating patients with SBE. It presents in detail the case of Pasquale Imperato, who died from the disease at the age of 72 years on 30 November 1942. In so doing, it focuses on the medical management measures then available to treat patients with SBE and on the inevitable course of the illness once it began. Also discussed is the relationship of acute rheumatic fever and its sequela, rheumatic heart disease, to predisposing people to SBE and possible genetic factors. The well-known case of Alfred S. Reinhart, a Harvard Medical School student who died from SBE in 1931 and who kept a detailed chronicle of his disease, is also discussed and contrasted with Pasquale Imperato's case.

OTC tamsulosin for benign prostatic hyperplasia.

Earlier this year, tamsulosin, an alpha blocker previously only available on prescription, became available for sale by pharmacists as a treatment for functional symptoms of benign prostatic hyperplasia (BPH) in men aged 45-75 years (Flomax Relief MR - Boehringer Ingelheim). A television advert for the over-the-counter (OTC) product claims that it is a "simple and effective" treatment that can relieve symptoms within 1 week, allowing the user to "take control of your annoying pee problems".¹ Here we review the evidence on tamsulosin and assess whether its availability as an OTC product confers worthwhile advantages.

Fosamprenavir (GW433908)/ritonavir in HIV-infected patients: efficacy and safety results from the Spanish Expanded Access Program.

INTRODUCTION: The use of protease inhibitors (PI) has led to a decrease in HIV-1-related mortality and morbidity. The objective of this study was to collect safety data on treatment with fosamprenavir/ritonavir (FPV/r) 700/100mg BID in HIV-infected patients through an expanded access program. PATIENTS AND METHODS: Prospective, multicenter, noncomparative study in HIV-1 infected adults, for whom a regimen containing FPV/r 700/100mg BID was appropriate. RESULTS: A total of 678 patients were included in the intention-to-treat (ITT) and safety population. The on-treatment (OT) population contained 587 patients: 76% male, 98% Caucasian, and median age 41 years. Median CD4 cell count was 351 cells/microL, HIV-RNA was 3 log copies/mL, and 49% of patients were in CDC class C. After 24 weeks of treatment, serum viral load decreased a median of 1.3 log copies/mL and 73% of patients had <400 copies/mL (P<.0001 vs. baseline); 48-week results were similar. CD4 cell count increased a median of 49 and 62 cells/microL at 24 and 48 weeks, respectively. Adverse events (AEs) associated with the study medication occurred in 21% of patients. CONCLUSIONS: Ritonavir-boosted fosamprenavir as part of antiretroviral therapy is a potent, safe treatment in real-life clinical circumstances.

Are N-of-1 trials an economically viable option to improve access to selected high cost medications? The Australian experience.

OBJECTIVE: To explore the economic viability of N-of-1 trials for improving access to selected high cost medications in Australia. METHODS: Cost and effectiveness estimates were derived from two N-of-1 trials conducted by The University of Queensland from 2003 to 2005-celecoxib versus sustained-release paracetamol for osteoarthritis in a general practice setting and gabapentin versus placebo for chronic neuropathic pain in a hospital setting. Effectiveness was determined by the proportion of responders to each medication. The costs of trials were offset against the savings generated by subsequent changes in prescribing. Decision analysis models with semi-Markov processes were used to compare different scenarios of N-of-1 trials versus usual care. RESULTS: The fixed cost of performing N-of-1 trials was approximately AUS$23,000 for each trial and the variable cost was approximately AUS$1300 per participant. Clinical outcomes favored celecoxib over paracetamol in 17% of participants and gabapentin over placebo in 24% of participants. Modeling these results showed that the cost-offsets from efficient use of medications were less than the cost of running a trial; however, the incremental costs per quality-adjusted life-year gained were AUS$6,896 and AUS$29,550 for the gabapentin/placebo and celecoxib/paracetamol trials, respectively, over a 5-year horizon. Key factors affecting the viability were the time horizon modeled, the variable cost per participant, the probability of response to the intervention medication, and rates of use in nonresponders and the usual care alternative. CONCLUSIONS: The N-of-1 strategy offers a realistic and viable option for increasing access to selected high cost medications where the medications are used for the symptomatic treatment of chronic disease, have rapid onset of action, and clinical response is unpredictable without a trial.

Prezista (darunavir, TMC-114) approved; may be important treatment advance.

A major new antiretroviral has been approved, for patients resistant to more than one protease inhibitor. There is no information yet on risk/benefit compared to standard treatments for first-line use. Tibotec, which developed the drug and is now part of Johnson & Johnson, showed price restraint and avoided setting a new record high price, which other companies have done.

[Drug of the month. Rosuvastatin (Crestor)]. / Le médicament du mois. Rosuvastatine (Crestor).

Rosuvastatin (Crestor) has been recently launched in Belgium by AstraZeneca. This new statin is indicated for the treatment of primary hypercholesterolaemia or combined dyslipidaemia, when changes in dietary habits are insufficient. Direct comparative randomised clinical trials with other statins demonstrated that rosuvastatin exerts a more favourable impact on lipid profile. When compared on a mg basis to other statins, rosuvastatin is associated with a greater reduction in total and LDL cholesterol levels and a greater increase of HDL cholesterol concentration, with a similar decrease in triglyceride levels. At the usual dosage of 10 mg, rosuvastatin allowed to reduce LDL cholesterol below recommended target levels for at risk patients among almost 80% of treated individuals in phase III clinical trials. If necessary, the daily dosage may be increased to 20 mg, or up to 40 mg (maximal dose), mostly in case of severe familial hypercholesterolaemia. Safety profile is good and similar to that of other commercialised statins. Rosuvastatin is currently evaluated in an extensive programme of randomised clinical trials (Galaxy programme) in order to demonstrate its efficacy in both prevention of atherosclerosis and reduction of cardiovascular morbidity and mortality.

[COX-2 inhibitor non-steroidal anti-inflammatory drugs, myth or reality?]. / Les AINS anti-Cox-2 sélectifs, mythe ou réalité?

The discovery of two isoforms of cyclooxygenase, Cox-1 constitutive and Cox-2 inducible, has prompted the development of new molecules with high Cox-2 selectivity. These new NSAIDs belong to the coxib class and have theoretically a better digestive tolerability than classical NSAID have. In Belgium, rofecoxib ((Vioxx) and celecoxib (Celebrex) are commercialized. Rofecoxib is indicated in the symptomatic treatment of osteoarthritis (12.5 to 25 mg/d) and celecoxib is indicated in osteoarthritis (200 mg/d) and in rheumatoid arthritis (200 to 400 mg/d). Several studies have demonstrated their efficacy, similarly to classical NSAID as diclofenac (Voltaren), naproxen (Naprosyne), ibuprofen (Brufen) and their superiority compared to placebo. Their safety profile for gastrointestinal events is proven in patients without ulcer history compared to classical NSAID. However, the concomitant use of aspirin decreases the benefit as demonstrated for celecoxib at 400 mg/d but not investigated for rofecoxib. The selective inhibition of Cox-2 with no effect on Cox-1 favors cardiovascular events in patients at risk. Other side effects are similar to classical NSAID. Thus Cox-2 inhibitors NSAID are interesting molecules for their sparing gastrointestinal activity. They must be used with caution in patients with ulcer history, in the elderly and in patients requiring aspirin for cardiovascular prophylaxis.

An assessment of antimicrobial consumption in food producing animals in Kenya.

Antimicrobial agents are useful for control of bacterial infections in food animals and man. Their prudent use in these animals is important to control any possible development and transfer of resistance between animals and man. The objective of this study was to generate quantitative information to evaluate antimicrobial usage patterns by animal species, route of administration, antimicrobial class and type of use from 1995 to 1999 in Kenya. Theses data are essential for risk analysis and planning and can be helpful in interpreting resistance surveillance data, and evaluating the effectiveness of prudent use efforts and antimicrobial resistance mitigation strategies. Data on quantities of active substance classes were collected from the official records of the Pharmacy and Poisons Board of the Ministry of Health and analysed in MS Excel 2000 program. The mean antimicrobial consumption for the 5-year period was 14 594 +/- 1457 kg per year. This was distributed in the various antimicrobial classes as follows: 7975 kg (54.65%) of tetracyclines, 3103.96 kg (21.27%) of sulfonamides and 954.5 kg (6.56%) of aminoglycosides, 905 kg (6.20%) of beta-lactams, 94 kg (0.64%) of quinolones, 35 kg (0.24%) of macrolides and 24 kg (0.16%) of others (tiamulin). Mean consumption per year among the various food animals was: 10 989 +/- 357 kg in large animals (cattle, sheep, pigs and goats), 2906 +/- 127 kg in poultry alone and 699 +/- 427 kg in both large animals and poultry. These quantities represented 56.56% (8255 kg) consumption per year for parenteral use, 41.79% (6098 kg) for oral use and 1.65% (241 kg) for topical use (intramammary and eye ointments) in cattle. With respect to intended use in food producing animals, the mean consumption per year was: 13 178 kg (90.30%) for therapeutic use (ST), 4 kg (0.03%) for prophylactic treatment (PT) and 1411 +/- 246 kg (9.67%) was used both for therapeutic and prophylactic purposes (GPT). The study confirmed that antimicrobials are not used for growth promotion in Kenya. There was no specific trend in the quantities of active antimicrobial classes. This study has revealed that the tetracyclines, sulfonamides and trimethoprim, nitrofurans aminoglycosides, beta-lactams and the quinolones are the most commonly used drugs in food-producing animals in Kenya. Tetracyclines contributed approximately 55% of the total consumption, and there was an increasing trend in the consumption of quinolones from 1998.

Amprenavir (Agenerase) now available in expanded access.

AIDS: Patients whose current treatment uses a protease inhibitor and has failed can participate in an expanded access program for amprenavir (Agenerase), a new protease inhibitor (PI) from Glaxo Wellcome and Vertex Pharmaceuticals, Inc. Several protocols are described, along with some of the participation criteria. Contact information is provided.^ieng

Expanded access.

AIDS: Amprenavir, abacavir, and adefovir are available at no cost during their final approval phase by the FDA. Eligibility requirements for receiving the drugs and contact information are provided.^ieng