- THERAPY FOR COMPLICATIONS OF DIABETES
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A method for enhancing glycemic control and/or insulin sensitivity in a human subject having diabetic nephropathy and/or metabolic syndrome comprises administering to the subject a selective endothelin A (ETA) receptor antagonist in a glycemic control and/or insulin sensitivity enhancing effective amount. A method for treating a complex of comorbidities in an elderly diabetic human subject comprises administering to the subject a selective ETA receptor antagonist in combination or as adjunctive therapy with at least one additional agent that is (i) other than a selective ETA receptor antagonist and (ii) effective in treatment of diabetes and/or at least one of said comorbidities other than hypertension. A therapeutic combination useful in such a method comprises a selective ETA receptor antagonist and at least one antidiabetic, anti-obesity or antidyslipidemic agent other than a selective ETA receptor antagonist.
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- ANTIHYPERTENSIVE THERAPY
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A new use of darusentan is provided in preparation of a pharmaceutical composition for lowering blood pressure in a patient exhibiting resistance to a baseline antihypertensive therapy with one or more drugs. The composition comprises darusentan in an amount providing a therapeutically effective daily dose; wherein (a) the composition is orally deliverable and/or (b) the daily dose of darusentan is effective to provide a reduction of at least about 3 mmHg in one or more blood pressure parameters selected from trough sitting systolic, trough sitting diastolic, 24-hour ambulatory systolic, 24-hour ambulatory diastolic, maximum diurnal systolic and maximum diurnal diastolic blood pressures. Further provided is a new use of darusentan in preparation of a pharmaceutical composition for lowering blood pressure in a patient exhibiting resistance to a baseline antihypertensive therapy, wherein the composition is administered adjunctively with at least one diuretic and at least one antihypertensive drug selected from ACE inhibitors, angiotensin II receptor blockers, beta-adrenergic receptor blockers and calcium channel blockers.
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- AN IMPROVED PROCESS FOR THE MANUFACTURE OF ISRADIPINE.
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The present invention relates to an improved method for the manufacture of Isradipine, 4-(4-Benzofurazanyl)-1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylic acid methyl 1-methylethyl ester. which, involves reacting 2,1,3-benzoxadiazole-4-carboxaldehyde with methyl acetoacetate in the presence of acetic acid and piperidine in diisopropyl ether. To obtain the product 2-acetyl-3-benzofurazan-4-yl-acrylic acid methyl ester which is then reacted with isopropyl-?-aminocrotonate in ethanol at 25 to 35°C to obtain the product.
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Page/Page column 7-9
(2008/06/13)
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- Enantioselective retention of 4-aryl-1,4-dihydropyridine calcium-channel blockers on human serum albumin and α1-acid glycoprotein HPLC columns: Relationships with different scales of lipophilicity
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The enantioselective retention of eight 4-aryl-1,4-dihydropyridine (DHP) calcium-channel blockers on HPLC stationary phases supporting human serum albumin (HSA) or α1-acid glycoprotein (AGP) was investigated. All chiral neutral DHPs were resolved on the AGP column, whereas, on the HSA column, only isradipine showed a split chromatographic peak. Analyses performed on AGP with eluents containing dimethyloctylamine (DMOA) as thc displacer demonstrated that the protein has at least two binding sites for DHPs. The first family of binding sites is enantioselective, binds exclusively to the (R)-forms, and presumably interacts competitively with DMOA. The second family of binding sites appears to be non-enantioselective and is affected by a cooperative interaction with DMOA. For the selected set of DHPs, the lipophilicity scale in octan-1-ol/H2O (log P) was not collinear with log k(w)(IAM) values obtained with immobilized artificial membranes (IAM-HPLC) due to the inclusion of both neutral and basic congeners. Only for the neutral DHPs did log k(w)(IAM) behave as a better descriptor than log P for retention date on HSA and AGP. In fact, the behavior of the basic DHPs amlodipine and nicardipine on both proteins correlated better with the octan- 1-ol/H2O log P values. We, therefore, infer that the amphipathic nature of the IAM phase only mimics the interaction of non-ionizable compounds with serum proteins. In contrast, the IAM-HPLC retention data of protonated bases encode additional interaction mechanisms that are specific for phospholipids and not involved in ligand-protein interactions.
- Barbato, Francesco,Quaglia, Fabiana,Quercia, Maria Tiziana,La Rotonda, Maria Immacolata
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p. 767 - 776
(2007/10/03)
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