Prodrug Design, Synthesis and Pharmacokinetic Evaluation of (3′ R, 4′ R)-3-Hydroxymethyl-4-Methyl-3′,4′-Di-O-(S)-Camphanoyl-(+)-Cis-Khellactone.

Prodrug design, synthesis and pharmacokinetic evaluation of (3′ R, 4′ R)-3-hydroxymethyl-4-methyl-3′,4′-di-O-(S)-camphanoyl-(+)-cis-khellactone.

Acta Pharm Sin B. 2012 Apr 1; 2(2): 213-219
Guo H, Zhuang X, Qian K, Sun L, Wang X, Li H, Lee K, Xie L

3-Hydroxymethyl-4-methyl-DCK (3, HMDCK) was discovered previously as a potent HIV non-nucleoside reverse transcriptase inhibitor (NNRTIs) (EC50: 0.004 ?M, TI: 6225) with a novel mechanism of action. It exerts anti-HIV activity by inhibiting the production of HIV-1 double-stranded viral DNA from a single-stranded DNA intermediate, rather than blocking the generation of single-stranded DNA from a RNA template, which is the mechanism of action of current HIV-1 RT inhibitors. However, the insufficient metabolic stability of 3 limits its further clinical development. In the current study, a series of ester prodrugs of 3 was designed and synthesized to explore the new drug candidates as NNRTIs. The l-alanine ester prodrug 10 exhibited desirable pharmacokinetic properties in vitro and in vivo and showed improved oral bioavailability of 26% in rat, and would be a potential clinical candidate as a new anti-AIDS drug. HubMed – drug


Clinical Value of an Ambulatory-Based Antibiogram for Uropathogens in Children.

J Pediatric Infect Dis Soc. 2012 Dec; 1(4): 333-336
Dahle KW, Korgenski EK, Hersh AL, Srivastava R, Gesteland PH

Unnecessarily broad-spectrum antibiotic prescribing for ambulatory pediatric urinary tract infection may result from clinicians not having antibiograms specific to this population. Comparing an existing hospital-based with a proposed ambulatory uropathogen antibiogram for children in Utah, Escherichia coli accounted for a larger percentage and was more susceptible to narrower-spectrum antibiotics, demonstrating the potential need for ambulatory pediatric antibiograms. HubMed – drug


The 2′-Trifluoromethyl Analogue of Indomethacin Is a Potent and Selective COX-2 Inhibitor.

ACS Med Chem Lett. 2013 May 9; 4(5): 486-490
Blobaum AL, Uddin MJ, Felts AS, Crews BC, Rouzer CA, Marnett LJ

Indomethacin is a potent, time-dependent, nonselective inhibitor of the cyclooxygenase enzymes (COX-1 and COX-2). Deletion of the 2′-methyl group of indomethacin produces a weak, reversible COX inhibitor, leading us to explore functionality at that position. Here, we report that substitution of the 2′-methyl group of indomethacin with trifluoromethyl produces CF3-indomethacin, a tight-binding inhibitor with kinetic properties similar to those of indomethacin and unexpected COX-2 selectivity (IC50 mCOX-2 = 267 nM; IC50 oCOX-1 > 100 ?M). Studies with site-directed mutants reveal that COX-2 selectivity results from insertion of the CF3 group into a small hydrophobic pocket formed by Ala-527, Val-349, Ser-530, and Leu-531 and projection of the methoxy group toward a side pocket bordered by Val-523. CF3-indomethacin inhibited COX-2 activity in human head and neck squamous cell carcinoma cells and exhibited in vivo anti-inflammatory activity in the carrageenan-induced rat paw edema model with similar potency to that of indomethacin. HubMed – drug


Safety and Efficacy of Prehospital Diltiazem.

West J Emerg Med. 2013 May; 14(3): 296-300
Luk JH, Walsh B, Yasbin P

Introduction: Very few studies exist on the use of diltiazem in the prehospital setting. Some practitioners believe this medication is prone to causing hypotension in this setting. Our goals were to determine whether the prehospital administration of diltiazem induced hypotension and to evaluate the efficacy of the drug. Methods: Our two-tiered system is located in a suburban region of New Jersey with advanced life support (ALS) care provided by fly-car units. The ALS units do not transport patients, and all of them are hospital based. The ALS providers are employed by the hospital system. In New Jersey, all ALS care requires online medical control, including the administration of diltiazem. We retrospectively reviewed patient care records for those who were believed to be in rapid atrial fibrillation and were given diltiazem in a suburban emergeny medical services system over a 22-month period. We examined the differences between heart rate (HR) and blood pressure (BP) on the initial evaluation and on arrival to the emergency department (ED). A hypotensive response was defined as a final systolic BP (SBP) less than 90 mmHg and a drop in SBP of at least 10 mmHg. Diltiazem was considered effective if the ED HR was <100 beats per minute (bpm) or if it decreased ?20%. Results: During the study period, 26,979 patients were transported. Of these patients, 2,488 had a documented rhythm of atrial fibrillation or atrial flutter. Of the 320 patients who received diltiazem, 42 patient encounters were excluded for incomplete data, yielding 278 patients for analysis. The average initial SBP was 139 mmHg and the average diastolic BP was 84 mmHg. The average diltiazem dosage was 16.7 mg. Two patients became hypotensive. The average initial HR was 154 bpm. On arrival to the ED, 33% of the patients had an HR < 100 bpm and 69% had a drop in HR ? 20%. The overall efficacy of prehospital diltiazem was 73%. Conclusion: In the prehospital setting, diltiazem is associated with a very low rate of hypotension and appears to be effective in decreasing HR adequately. Prospective studies are needed to confirm these findings. HubMed – drug