The effect of fusion inhibitors on the phase behaviour of N-methylated dioleoylphosphatidylethanolamine.

The effects of two fusion inhibitors on the lipid polymorphism of N-methylated dioleoylphosphatidylethanolamine were studied using temperature-resolved, small-angle X-ray diffraction. The inhibitory role of the tri-peptide carbobenzoxy-D-phenylalanine-L-phenylalanine-glycine and the lipid 1-lauroyl-2-hydroxy-sn-glycero-3-phosphocholine in the fusion pathway was studied, using the non-lamellar phase behaviour of the lipid as a model. We used p15EK, the N-terminal region of gp41 from feline leukaemia virus as promoter of membrane fusion, and measured the structural parameters of each observed lipid phase as a function of temperature. The fusion inhibitors were found to impede the expression of negative curvature of lipid monolayers even in the presence of fusion peptide. The results of this study are interpreted in relation to models of the membrane fusion mechanism.

Consensus Management of Gastrointestinal Events Associated with Delayed-Release Dimethyl Fumarate: A Delphi Study.

INTRODUCTION: Delayed-release dimethyl fumarate (DMF, also known as gastro-resistant DMF) is indicated for the treatment of patients with relapsing multiple sclerosis. Gastrointestinal (GI) adverse events (AEs) occur with DMF therapy. METHODS: We used a Delphi process to reach consensus among North American clinicians on effective real-world management strategies for GI AEs associated with DMF. Clinicians were asked to complete two rounds of questionnaires developed by a steering committee; consensus in round 2 was attained if ≥70% of respondents agreed on a particular strategy. RESULTS: Consensus was reached on several strategies to manage GI AEs, including administering DMF with food, slow titration, dose reduction, and use of symptomatic therapies. CONCLUSION: These consensus strategies provide clinicians with information on real-world approaches used to address the tolerability of DMF in patients with multiple sclerosis. FUNDING: Biogen.

Cefditoren pivoxil.

Cefditoren pivoxil is an orally absorbed prodrug that is rapidly hydrolysed by intestinal esterases to the microbiologically active cephalosporin cefditoren. Cefditoren has a broad spectrum of activity against Gram-positive and Gram-negative bacteria, including common respiratory and skin pathogens. Cefditoren has shown excellent in vitro activity against the Gram-positive pathogens penicillin-susceptible and -intermediate Streptococcus pneumoniae, S. pyogenes and methicillin-susceptible Staphylococcus aureus. Cefditoren was inactive against methicillin-resistant S. aureus. Of the important Gram-negative pathogens, cefditoren had potent antibacterial effects against beta-lactamase-positive and -negative Haemophilus influenzae, H. parainfluenzae and beta-lactamase-positive and -negative Moraxella catarrhalis. Cefditoren does not have antibacterial activity against Pseudomonas aeruginosa or atypical respiratory pathogens and has only variable activity against anaerobes. In healthy volunteers, single doses of cefditoren pivoxil 200 and 400mg achieved maximal plasma concentrations of 2.6 to 3.1 mg/L and 3.8 to 4.6 mg/L, respectively. Cefditoren penetrates rapidly into bronchopulmonary and tonsillar tissue as well as inflammatory and noninflammatory blister fluid. In two, randomised, double-blind trials involving patients with acute exacerbations of chronic bronchitis (AECB), cefditoren 200 and 400mg twice daily for 10 days produced clinical cure rates of 88 to 89% within 48 hours of treatment completion. Clinical cure rates in patients with AECB were similar to those of either clarithromycin 500mg twice daily or cefuroxime axetil 250mg twice daily. In patients with streptococcal pharyngitis, a 10-day course of cefditoren pivoxil 200mg twice daily produced clinical cure rates of 94% at 4 to 7 days after treatment, which were similar to those observed for phenoxymethylpenicillin potassium 250 mg four times daily. In uncomplicated skin and skin structure infections, a 10-day course of cefditoren pivoxil 200 or 400mg twice daily produced the same clinical cure rate of 89% within 48 hours of treatment completion. These cefditoren pivoxil dosage regimens were as effective as a 10-day course of either cefadroxil 500 mg twice daily or cefuroxime axetil 250mg twice daily in treating uncomplicated skin and skin structure infections, including those caused by S. aureus and S. pyogenes. The most common adverse events associated with therapeutic doses of cefditoren pivoxil are diarrhoea, nausea, headache, abdominal pain and vaginal candidiasis.

Terbinafine: a review of its use in onychomycosis in adults.

UNLABELLED: Terbinafine, an orally and topically active antimycotic agent, inhibits the biosynthesis of the principal sterol in fungi, ergosterol, at the level of squalene epoxidase. Squalene epoxidase inhibition results in ergosterol-depleted fungal cell membranes (fungistatic effect) and the toxic accumulation of intracellular squalene (fungicidal effect). Terbinafine has demonstrated excellent fungicidal activity against the dermatophytes and variable activity against yeasts and non-dermatophyte molds in vitro. Following oral administration, terbinafine is rapidly absorbed and widely distributed to body tissues including the poorly perfused nail matrix. Nail terbinafine concentrations are detected within 1 week after starting therapy and persist for at least 30 weeks after the completion of treatment. Randomized, double-blind trials showed oral terbinafine 250 mg/day for 12 or 16 weeks was more efficacious than itraconazole, fluconazole and griseofulvin in dermatophyte onychomycosis of the toenails. In particular, at 72 weeks' follow-up, the multicenter, multinational, L.I.ON. (Lamisil vs Itraconazole in ONychomycosis) study found that mycologic cure rates (76 vs 38% of patients after 12 weeks' treatment; 81 vs 49% of recipients after 16 weeks' therapy) and complete cure rates were approximately twice as high after terbinafine treatment than after itraconazole (3 or 4 cycles of 400 mg/day for 1 week repeated every 4 weeks) in patients with toenail mycosis. Furthermore, the L.I.ON. Icelandic Extension study demonstrated that terbinafine was more clinically effective than intermittent itraconazole to a statistically significant extent at 5-year follow-up. Terbinafine produced a superior complete cure rate (35 vs 14%), mycologic cure rate (46 vs 13%) and clinical cure rate (42 vs 18%) to that of itraconazole. The mycologic and clinical relapse rates were 23% and 21% in the terbinafine group, respectively, compared with 53% and 48% in the itraconazole group. In comparative clinical trials, oral terbinafine had a better tolerability profile than griseofulvin and a comparable profile to that of itraconazole or fluconazole. Post marketing surveillance confirmed terbinafine's good tolerability profile. Adverse events were experienced by 10.5% of terbinafine recipients, with gastrointestinal complaints being the most common. Unlike the azoles, terbinafine has a low potential for drug-drug interactions. Most pharmacoeconomic evaluations have shown that the greater clinical effectiveness of oral terbinafine in dermatophyte onychomycosis translates into a cost-effectiveness ratio superior to that of itraconazole, fluconazole and griseofulvin. CONCLUSION: Oral terbinafine has demonstrated greater effectiveness than itraconazole, fluconazole and griseofulvin in randomized trials involving patients with onychomycosis caused by dermatophytes. The drug is generally well tolerated and has a low potential for drug interactions. Therefore, terbinafine is the treatment of choice for dermatophyte onychomycosis.

Ezetimibe.

Ezetimibe, a synthetic 2-azetidinone, is the first of a new class of compounds that selectively inhibits the absorption of cholesterol and related plant sterols in the intestine. The drug, and its glucuronyl metabolite, are thought to inhibit a putative cholesterol transporter of enterocytes, located within the brush-border membrane of the small intestine. In large, randomized, placebo-controlled, 12-week trials, ezetimibe reduced levels of low density lipoprotein-cholesterol (LDL-C) by approximately 18%; triglyceride levels were reduced by approximately 6% in one trial but not another. Ezetimibe produced a modest increase in levels of high density lipoprotein-cholesterol. Moreover, reductions in LDL-C and triglyceride levels were greater in patients treated with ezetimibe coadministered with a statin (lovastatin, pravastatin, atorvastatin or simvastatin), than with either of those agents given alone. The coadministration of the lowest statin dose and ezetimibe produced similar LDL-C reductions to the administration of the highest statin dose alone. Ezetimibe also provided beneficial effects on plasma lipid levels when administered to patients with hypercholesterolemia already receiving a statin. Ezetimibe plus a statin reduced LDL-C levels more than the maximum statin dose alone in a trial in patients with homozygous familial hypercholesterolemia and was effective in a placebo-controlled trial in patients with homozygous sitosterolemia. The drug was well tolerated in clinical studies conducted to date. In large, randomized, double-blind trials, ezetimibe had a similar tolerability profile to that of placebo. Coadministration of ezetimibe and a statin did not increase the incidence of adverse events related to statin monotherapy.

Pneumococcal conjugate vaccine (Prevnar; PNCRM7): a review of its use in the prevention of Streptococcus pneumoniae infection.

UNLABELLED: PNCRM7 (Prevnar) is a pneumococcal vaccine containing seven capsular polysaccharide antigens from the bacterium Streptococcus pneumoniae, each of which is conjugated to diphtheria protein [cross-reactive material (CRM(197))]. CRM(197) is an inert but immunogenic variant of diphtheria toxoid that is also used as a carrier molecule in one Haemophilus influenzae type b conjugate vaccine. Unlike the 23-valent unconjugated pneumococcal vaccines, PNCRM7 elicits a T cell-dependent response and thus protects young children against pneumococcal disease. The immunogenicity of PNCRM7 has been demonstrated in both healthy children aged <2 years and older children in high-risk groups. Two randomized, double-blind trials conducted in the US demonstrated that all PNCRM7 serotypes were immunogenic in healthy infants and young children when compared with a control vaccine. A booster dose of PNCRM7 elicited an anamnestic response to all seven serotypes. Data from a large, randomized, double-blind study conducted in California (US) have confirmed the protective efficacy of PNCRM7 against invasive pneumococcal disease (e.g. bacteremia, meningitis) caused by serotypes included in the vaccine. The vaccine efficacy in the per-protocol analysis was 97.4% and its efficacy against invasive disease caused by any pneumococcal serotype in the intent-to-treat (ITT) analysis was 89.1%. Indeed, a postlicense surveillance study (n = 211,565) showed that the introduction and routine use of PNCRM7 was associated with a marked reduction in invasive pneumococcal disease in children <5 years of age. In addition, the US trial and another randomized, double-blind trial conducted in Finland, showed that PNCRM7 vaccine efficacy against all otitis media episodes was between 6 and 7%. PNCRM7 vaccine was generally well tolerated and had a similar local and systemic adverse events profile to other pediatric vaccines. The most common local adverse event associated with PNCRM7 administration was inflammation at the injection site, and the most common systemic adverse effect was febrile illness (> or =38 degrees C) that usually resolved without treatment. The limited available pharmacoeconomic data suggest that PNCRM7 could be cost effective depending, in part, on the manufacturer's list price of the vaccine. Results of the base case analysis in a US study showed a cost-effectiveness ratio for PNCRM7 of US dollars 80,000 per life-year saved from a societal perspective compared with US dollars 176,000 from a healthcare payer perspective, assuming a nondiscounted list price of US dollars 58 per dose (1997 costs). Concomitant administration of PNCRM7 vaccine with hepatitis B, oral polio, meningococcal oligosaccharide protein conjugate or H. influenzae type b vaccines did not affect the immunogenicity of these pediatric vaccines to a clinically relevant extent. CONCLUSION: PNCRM7 vaccine will be of great benefit to those societies that have active immunization programs implemented. In infants and vulnerable children throughout the world, PNCRM7 vaccine has the potential to reduce the mortality and morbidity rates associated with S. pneumoniae infections. In developed countries, the vaccine will be of particular benefit in preventing disabling infections but its impact in developing countries will be more pronounced with the potential to greatly reduce mortality.

Incidence and management of gynecomastia in men treated for prostate cancer.

PURPOSE: Gynecomastia is a potentially treatment limiting adverse event in men receiving hormone therapy for prostate cancer. MATERIALS AND METHODS: In large, randomized, placebo controlled studies approximately 50% or more of patients with prostate cancer experienced gynecomastia due to multiple mechanisms. Although its severity was mostly reported as mild to moderate, gynecomastia was cited as the reason for most premature withdrawals from therapy. In patients with advanced forms of prostate cancer bilateral orchiectomy was associated with the lowest incidence of gynecomastia, followed by nonsteroidal antiandrogen therapy, diethylstilbestrol and estrogen in rank order. RESULTS: It is important that gynecomastia is well managed in patients with prostate cancer who want to proceed with hormone therapy. Patients should be assessed for the likely etiology of gynecomastia and preventive therapy or treatment for established gynecomastia should be instituted. Prophylactic radiotherapy has been shown to decrease the incidence of hormone induced gynecomastia by more than 50%. An alternative course of action, which may be more convenient for the patient, is the prophylactic use of tamoxifen. Tamoxifen may also mitigate or resolve gynecomastia during its early or proliferative phase. In severe long-standing gynecomastia surgery is warranted since medical therapies are less likely to succeed. Aromatase inhibitors and 4-hydroxytamoxifen are investigational. CONCLUSIONS: Gynecomastia is a significant problem in men undergoing hormonal therapy for prostate cancer. It requires prompt recognition, evaluation and management.

Clarithromycin extended-release tablet: a review of its use in the management of respiratory tract infections.

UNLABELLED: Clarithromycin is an orally active, advanced-generation macrolide that has been reformulated as an extended-release tablet (Biaxin) XL Filmtab allowing convenient once-daily administration. The reformulation is intended to improve patient compliance and the tolerability of the drug. Although maximum plasma clarithromycin concentrations are lower and reached later with the extended-release tablets than with the immediate-release tablets, the two formulations are bioequivalent with respect to the area under the plasma concentration-time curve. Bioequivalence is also achieved between the formulations for the microbiologically active metabolite, 14-hydroxy-clarithromycin. Two randomized trials in patients with acute exacerbations of chronic bronchitis (AECB) showed that a 7-day course of clarithromycin extended-release 1000 mg once daily produced clinical cure rates of 83% and 85% and bacteriologic cure rates of 86% and 92% at the test-of-cure study visit. Similar rates of cure were achieved with a 7-day course of twice-daily clarithromycin immediate-release and with a 10-day course of twice-daily amoxicillin/clavulanic acid.A 7-day course of clarithromycin extended-release 1000 mg once daily produced clinical and bacteriologic cure rates of 88% and 86%, respectively, in patients with community-acquired pneumonia (CAP). Similar cure rates were achieved in recipients of once-daily levofloxacin in the same trial. In patients with acute maxillary sinusitis, a 14-day course of either once-daily clarithromycin extended-release or twice-daily clarithromycin immediate-release produced statistically equivalent clinical cure rates of 85% and 79%, respectively. Both treatment groups achieved similar rates of radiographic success and resolution of sinusitis. Recent results indicate that clarithromycin extended-release 500 mg once daily for 5 days is also effective in the treatment of patients with streptococcal pharyngitis/tonsillitis and in the treatment of AECB. The most frequently reported drug-related events with clarithromycin extended-release were abnormal taste (7% incidence), diarrhea (6%) and nausea (3%). Most adverse drug reactions were of a mild and transient nature. In comparative clinical trials, clarithromycin extended-release had an improved gastrointestinal tolerability profile compared with the immediate-release formulation. In addition, clarithromycin extended-release was better tolerated than amoxicillin/clavulanic acid and as well tolerated as levofloxacin. Further studies are required to assess the cost-effectiveness ratio of clarithromycin relative to comparator antibacterial agents. CONCLUSION: Clarithromycin extended-release is an effective treatment for AECB, CAP, acute maxillary sinusitis, and pharyngitis (although not approved for the latter in the US), and is administered in a convenient dosage regimen that has the potential to encourage good compliance. The reformulation modulates clarithromycin absorption kinetics thereby improving tolerability. Therefore, clarithromycin extended-release provides a useful option for the treatment of specific respiratory tract infections.