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A practical and stereoselective synthesis of (+/,)- trans -4-benzyloctahydropyrrolo[3,4- b][1,4]oxazineJOURNAL OF HETEROCYCLIC CHEMISTRY, Issue 5 2010
Daniel P. Walker
trans -Octahydropyrrolo[3,4- b][1,4]oxazine is an important heterocycle within the pharmaceutical industry for the preparation of biologically active analogs, including the phase III drug, finafloxacin. A practical synthesis of the title compound (2) is described in eight steps and ca. 10% overall yield. The key synthetic step is the formation of the pyrrolo[3,4- b][1,4]oxazine core 20via a one pot double N -alkylation of the corresponding bis-tosylate 18 with 4-nitrobenzenesulfonamide. Subsequent removal of the nosyl group occurred under mild conditions. J. Heterocyclic Chem., (2010). [source]
Biowaiver monographs for immediate release solid oral dosage forms: ethambutol dihydrochloride,,JOURNAL OF PHARMACEUTICAL SCIENCES, Issue 4 2008
Abstract Literature data relevant to the decision to allow a waiver of in vivo bioequivalence (BE) testing for the approval of immediate release (IR) solid oral dosage forms containing ethambutol dihydrochloride as the only active pharmaceutical ingredient (API) are reviewed. Ethambutol dihydrochloride is a Biopharmaceutics Classification System (BCS) Class III drug with permeability properties approaching the border between BCS Class I and III. BE problems of ethambutol formulations containing different excipients and different dosages forms have not been reported and hence the risk of bioinequivalence caused by excipients is low. Ethambutol has a narrow therapeutic index related to ocular toxicity. However, as long as the prescribers' information of the test product stipulates the need for regular monitoring of ocular toxicity, the additional patient risk is deemed acceptable. It is concluded that a biowaiver can be recommended for IR solid oral dosage forms provided that the test product (a) contains only excipients present in ethambutol IR solid oral drug products approved in ICH or associated countries, for instance as presented in this paper, (b) complies with the criteria for "very rapidly dissolving" and (c) has a prescribers' information indicating the need for testing the patient's vision prior to initiating ethambutol therapy and regularly during therapy. © 2007 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 97:1350,1360, 2008 [source]
The Mechanisms of Atrial FibrillationJOURNAL OF CARDIOVASCULAR ELECTROPHYSIOLOGY, Issue 2006
PENG-SHENG CHEN M.D.
In this article we have reviewed the mechanisms of atrial fibrillation (AF) with special emphasis on the thoracic veins. Based on a number of features, the thoracic veins are highly arrhythmogenic. The pulmonary vein (PV)-left atrial (LA) junction has discontinuous myocardial fibers separated by fibrotic tissues. The PV muscle sleeve is highly anisotropic. The vein of Marshall (VOM) in humans has multiple small muscle bundles separated by fibrosis and fat. Insulated muscle fibers can promote reentrant excitation, automaticity, and triggered activity. The PV muscle sleeves contain periodic acid-Schiff (PAS)-positive large pale cells that are morphologically reminiscent of Purkinje cells. These special cells could be the sources of focal discharge. Antiarrhythmic drugs have significant effects on PV muscle sleeves both at baseline and during AF. Both class I and III drugs have effects on wavefront traveling from PV to LA and from LA to PV. Separating the thoracic veins and the LA with ablation techniques also prevents PV-LA interaction. By reducing PV-LA interaction, pharmacological therapy and PV isolation reduce the activation rate in PV, intracellular calcium accumulation, and triggered activity. Therefore, thoracic vein isolation is an important technique in AF control. We conclude that thoracic veins are important in the generation and maintenance of AF. [source]
Effect of Chronic Amiodarone Therapy on Excitable Gap During Typical Human Atrial FlutterJOURNAL OF CARDIOVASCULAR ELECTROPHYSIOLOGY, Issue 12 2004
PHILIPPE MAURY M.D.
Introduction: Class I antiarrhythmic drugs increase duration of the excitable gap (EG) during typical atrial flutter whereas intravenous class III drugs decrease the EG. The effect of chronic oral amiodarone therapy on the EG is unknown. Methods and Results: EG was prospectively determined by introducing a premature stimulus and analyzing the response pattern during typical atrial flutter in 30 patients without antiarrhythmic drugs and in 20 patients under chronic oral amiodarone therapy. EG was calculated by the difference between the longest coupling interval leading to resetting and the effective atrial refractory period (EARP). A fully EG was defined by the portion of EG where the response curve of the return cycles was flat. A partially EG was defined by the portion of EG where the return cycle increases while coupling interval decreases. A resetting response curve was constructed by plotting the duration of the return cycle against the value of the coupling interval. Cycle length (CL; 222 ± 17 vs 267 ± 20 msec, P < 0.0001), EARP (128 ± 16 vs 152 ± 18 msec, P < 0.0001), and EG (54 ± 19 vs 70 ± 21 msec, P = 0.01) were significantly longer in patients taking amiodarone than in controls. Compared to CL, the relative part of the EARP (57 ± 7 vs 57 ± 6%, P = 0.96) and EG (24 ± 7 vs 26 ± 8%, P = 0.41) were comparable in both groups. The fully EG was larger in patients under chronic amiodarone therapy than in controls (39 ± 21 vs 26 ± 20 msec, P = 0.03). Neither duration of the partially EG (28 ± 15 vs 31 ± 15 msec, P = 0.42) nor slope of the ascending portion of the resetting response curve (1.15 ± 0.5 vs 1.13 ± 0.4 msec/msec, P = 0.71) differed between the two groups. Conclusion: EG in patients under chronic amiodarone therapy is significantly larger than in controls, mainly because of a longer fully EG. This observation may be explained by opposite effects on conduction velocity and refractoriness. [source]
The New European Medicines Agency Guideline on the Investigation of BioequivalenceBASIC AND CLINICAL PHARMACOLOGY & TOXICOLOGY, Issue 3 2010
José Augusto Guimarães Morais
Several new features have been added to this guideline, as well as changes aimed at improving the clarity of the guidance provided. The first issue to be addressed was to limit the scope of the guideline to bioequivalence studies for immediate release dosage forms with systemic action. Therefore, the guideline refers to bioequivalence alone. Moreover, the new definition of Generic Medicinal Product has been incorporated. Clearer guidance covering more specific cases is now given on sections such as: fed/fasting conditions, use of metabolite data, enantiomers and strength to be used in the bioequivalence study. Steady-state design is now restricted and other designs, such as parallel group design, replicate design and two-stage design, are now incorporated in a more explicit form. New practical guidance on Highly Variable Drug Products and Narrow Therapeutic Index Drugs has been incorporated. The possibility for a biowaiver based on the Biopharmaceutics Classification System is now more explicit for Class I drugs and can be extended to Class III drugs under restricted conditions. We are aware that the initial goal of providing a very specific and clear guidance on these issues has not been entirely achieved, mainly because it is almost impossible to cover all individual cases and predict every possible situation that may arise. Demonstration of bioequivalence will still require in many instances a case by case approach. [source]