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Doripenem is a parenteral carbapenem antibiotic launched last year in Japan for the treatment of bacterial respiratory and urinary tract infections. It is a 1p-methyl carbapenem derivative, and it is the fourth analog to be marketed in this series following the launch of meropenem, biapenem, and ertapenem in previous years. The introduction of a 1 p-methyl group to the carbapenem skeleton enhances metabolic stability to renal dehydropeptidase-1 (DHP-1) and leads to improved antibacterial potency. The mechanism of action is likely to involve covalent modification of peptidoglycan biosynthetic enzymes responsible for catalyzing the final transpeptidation step of cell wall biosynthesis. The chemical synthesis of doripenem involves the coupling of a commercially available 4-nitrobenzyl protected 1 p-me-thylcarbapenem enolphosphate intermediate with a protected version of 2-(sulf-amidomethyl)-4-mercaptopyrrolidine as the key step. The requisite pyrrolidine intermediate is prepared in six steps starting from trans-4-hydroxy-L-proline. In vitro, doripenem exhibits activity similar to that of imipenem against Grampositive pathogens, and to that of meropenem against Gram-negative pathogens. The key differentiator for doripenem is its superior activity against Pseudomonas aeruginosa (MIC90 = 3.13 mg/mL) as compared with meropenem and imipenem. Additionally, it possesses higher stability than imipenem or meropenem against mammalian dehydropeptidase I, and it is stable to most serine-based beta-lac-tamases. The route of administration of doripenem is either intravenous or intramuscular. It has low plasma protein binding (8.1%), and the primary route of elimination is renal. After single doses of doripenem 125-1000 mg in volunteers, Cmax values were 8.1-63.0 mg/mL, and AUC was 8.7-75.6 mg h/mL. The mean urinary recovery of doripenem over 24 h was 75%. It has a half-life of approximately 1 h in normal individuals, and this value increases substantially in subjects with renal disease. In a phase II study in 55 patients with chronic respiratory tract infections (RTIs), parenteral doripenem (250-1000 mg/day twice daily or three times daily, for 15 days) resulted in the achievement of clinical efficacy in 40/42 evaluable patients (95.2%). Bacteriological eradication occurred in 21/24 (87.5%) isolates. A 95% overall clinical efficacy rate was achieved in 42 patients with chronic bronchitis, infected bronchiectasis and secondary infection of chronic respiratory disease treated with doripenem 125 mg, 250 mg, or 500 mg twice, daily.
Japan Shinogi Japan Shinogi/
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Bacteriological eradication rate was 87.5%. The main adverse events associated with doripenem were drowsiness, headache, injection site reactions, and nausea. An inhaled formulation of doripenem is currently in development for the potential treatment of cystic fibrosis related infections.
Eberconazole is a new member of the azole class of antifungal agents, and it is indicated for the topical treatment of cutaneous fungal infections, including tinea corporis (ringworm of the body), tinea cruris (ringworm of the groin) and tinea pedis (athlete's foot) infections. Its mode of action is similar to that of other azole antifungals, namely inhibition of fungal lanosterol 14a-demethylase. Eberconazole exhibits good in vitro activity against a wide range of Candida species, including Candida. tropicalis, dermatophytes and Malassezia spp. yeasts. It shows good activity against Candida. Parapsilosis (MIC90 — 0.125 mg/mL), which is a relevant species in skin and nail disorders. In addition, eberconazole is effective against some of the highly triazole-resistant yeasts such as Candida. glabrata and Candida. krusei, as well as fluconazole-resistant Candida. albicans. However, eberconazole is less active than clotrimazole and ketoconazole against Candida. neoformans and a number of clinically relevant molds. Eberconazole is supplied as a 1% or 2% cream, and the topical application does not result in detectable serum, urine, or fecal levels. In a phase II study of 60 patients with tinea corporis and tinea cruris, treatment with topical eberconazole (1% or 2% cream), applied once or twice daily for 6 weeks, resulted in cure rates ranging from 73.3-93.3% at the end of therapy, and 66.7-100% six weeks post-therapy. In a phase III study of 157 patients with either cutaneous candidosis or dermatophyte skin infection, 1% eberconazole cream and 1% clotrimazole cream, both applied twice daily for 4 weeks, showed comparable overall effectiveness of 72% and 61%, respectively (p — 0.15). Eberconazole is synthesized in seven steps starting from 2-(carbomethoxy)benzyltriphenylphos-phonium bromide, via a Wittig reaction with 3,5-dichlorobenzaldehyde, followed by ester hydrolysis, double-bond reduction, and cyclization to produce a di-benzocycloheptenone intermediate. Subsequent reduction of this intermediate to the corresponding alcohol, followed by conversion to the chloride, and alkylation with imidazole gives eberconazole.
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