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Molecular Weight: 314.37

Valdecoxib is a second-generation COX-2 inhibitor, developed as a follow-up to celecoxib for the oral once-daily treatment of osteoarthritis, adult rheumatoid arthritis and menstrual pain. The first step for the preparation of valdecoxib is the conversion of deoxybenzoin to Its corresponding oxime. Deprotonation of this oxime with butyl lithium followed by condensation with ethyl acetate gave the corresponding isoxazoline, which, after treatment with chlorosulfonic acid and reaction with aqueous ammonia afforded valdecoxib. Valdecoxib is approximately 28,000-fold more selective against human recombinant COX-2 than human recombinant COX-1. In an ex vivo human whole blood assay, the IC50 values against COX-2 and COX-1 were respectively 0.89 nM and 25.4 |iM. In animal models, valdecoxib possesses excellent oral activity as an antiinflammatory. In rats, valdecoxib potently inhibited carrageenan footpad edema and adjuvant-induced arthritis. In the rat carrageenan air pouch model of Inflammation, valdecoxib showed an efficient inhibition of prostaglandin production. In pharmacokinetic studies, valdecoxib has a rapid onset of action (tmax = 2.25 h) and a prolonged duration of action (ti/2 = 8 h).

Valdecoxib is a substrate of CYP3A4 but no metabolism interference was seen with commonly used synthetic narcotics, alfentanil and fentanyl. Clinical studies have shown that valdecoxib is as effective as naproxen in treating osteoarthritis, rheumatoid arthritis and dysmenorrhoea. The efficacy of valdecoxib was also demonstrated in managing postoperative pain (oral and orthopedic surgery) with effective analgesia and time to rescue medication superior to those obtained with rofecoxib. Several clinical trials showed that valdecoxib has a better upper gastrointestinal safety profile compared to naproxen, ibuprofen or diclofenac and does not affect platelet function. Less abdominal pain, dyspepsia and constipation were observed with valdecoxib than with naproxen. Valdecoxib is contraindicated in patients with a history of allergic reactions to sulfonamides due to reported anaphylactic and skin reactions.

Voriconazole (Antifungal) (159-163)

Country of Origin : UK Originator: Pfizer

First Introduction : US Introduced by: Pfizer Trade Name : Vfend CAS Registry No.: 137234-62-9 Molecular Weight: 349.32

Voriconazole was introduced in the US for the treatment of acute invasive aspergillosis, candidosis and other emerging fungal infections seen in immuno compromised patients. It can be synthesized in 3 steps by reaction of readily available 6-(1-bromoethyl)-4-chloro-5-fluoropyrimidine with 1-(2,4-difluorophenyl)-2-(1,2,4-triazol-1-yl) ethanone in the presence of zinc metal. The resulting racemic mixture was submitted to a reductive dechlorination step followed by resolution with (R)-camphorsulfonic acid. Voriconazole is structurally related to fluconazole (Pfizer, diflucan®) and acts by inhibiting the cytochrome P450-dependant enzyme 14a-sterol demethylase of ergosterol synthesis (thereby resulting in the formation of a cell membrane with abnormal characteristics and accumulation of toxic sterol intermediates). Voriconazole was more active than itraconazole and fluconazole against Cryptococcus neoformans and a variety of Candidas species such as C. albicans, C. glabrata C. krusei. It also exhibits similar or superior activity compared to amphotericin B and itraconazole against filamentous fungi such as Aspergillus, an important pathogen which is not susceptible to fluconazole. In clinical trials, voriconazole was effective in the treatment of neutropenic patients with acute invasive aspergillosis, non-neutropenic patients with chronic invasive aspergillosis and HIV patients with oropharyngeal candidiasis. Voriconazole Is available as oral or intravenous formulations. Following oral administration, absorption is rapid and the bioavailability is greater than 80%. Voriconazole exhibits non linear pharmacokinetics, a large volume of distribution (2 L/Kg) and a relatively short half-life (6 h). It was extensively metabolized via hepatic cytochrome P450 and has a drug interactions potential similar to itraconazole. Voriconazole was generally well tolerated, the most common treatment-related adverse events were transient visual disturbances.

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