First report of an intravenous and oral glycoprotein IIb/IIIa inhibitor (RPR 109891) in patients with recent acute coronary syndromes: results of the TIMI 15A and 15B trials.

BACKGROUND: RPR 109891 is a modified tetrapeptide glycoprotein IIb/IIIa inhibitor available in intravenous and oral formulations. Two phase II dose-ranging studies were performed to investigate pharmacodynamics and safety in acute coronary syndromes. METHODS: The Thrombolysis In Myocardial Infarction (TIMI) 15A trial was a randomized, open-label, study of RPR 109891 administered intravenously for 24 to 96 hours in 91 patients. TIMI 15B was a randomized, double-blind comparison of intravenous RPR 109891 plus 4 weeks of oral RPR 109891 (n = 142) compared with placebo (n = 50). RESULTS: Intravenous RPR 109891 exhibited a dose-response inhibition of platelet aggregation; mean inhibition after a bolus ranged from 53% to 92%, and at steady state 49% to 98%. Oral RPR 109891 demonstrated less platelet inhibition (peaks, range 48% to 59%; troughs, range 18% to 39%). Mean glycoprotein IIb/IIIa receptor occupancy and platelet inhibition were highly correlated (r = 0.82, 95% confidence interval 0.74-0.88). There were trends for increased major hemorrhage (10% vs 6%, P =.57), thrombocytopenia <90,000 cells/mm(3) (13% vs 4%, P =.11), and profound thrombocytopenia <20, 000 (3.5% vs 0%, P =.33) with intravenous plus oral RPR 109891 compared with placebo. In 3 of 5 cases of profound thrombocytopenia, RPR 109891 had been interrupted because of bypass surgery, and a precipitous fall in platelet count occurred after the first postoperative oral dose. CONCLUSIONS: Intravenous RPR 109891 is a potent, predictable, dose-related platelet inhibitor. Oral RPR 109891 (

Comparison of the degree of hemodynamic tolerance during intravenous infusion of nitroglycerin versus nicorandil in patients with congestive heart failure.

BACKGROUND: Continuous exposure to organic nitrates is associated with substantial tachyphylaxis. This study compares the development of tolerance during continuous intravenous treatment with nitroglycerin versus nicorandil over a 24-hour period. METHODS AND RESULTS: Twenty patients with congestive heart failure and pulmonary capillary wedge pressure (PCWP) > or = 18 mm Hg were randomly assigned to nitroglycerin or nicorandil in a double-blind, crossover study. Doses were titrated to obtain a reduction of PCWP of at least 30% and then maintained. The mean pretreatment PCWP for nitroglycerin was 25.4 +/- 6.7 mm Hg, decreasing to 19.0 +/- 6.8 mm Hg at 24 hours. The values for nicorandil were 24.3 +/- 6.3 mm Hg and 15.6 +/- 4.5 mm Hg, respectively. Between-treatment difference was significant (p < 0.01). The difference between the minimal PCWP value and the 24-hour PCWP value for nitroglycerin was 5.1 mm Hg vs 1.4 mm Hg for nicorandil (p < 0.005). The mean systemic vascular resistance was 1418 +/- 355 dynes.sec.cm-5 before nitroglycerin infusion, decreasing to 1312 +/- 353 dynes.sec.cm-5 at 24 hours. Corresponding values for nicorandil were 1420 +/- 366 dynes.sec.cm-5 and 967 +/- 274 dynes.sec.cm-5. Between-treatment difference was significant (p = 0.005). Tachyphylaxis developed in 12 (60%) patients during nitroglycerin infusion versus three patients (15%) during nicorandil infusion. CONCLUSION: This study demonstrates that intravenous nicorandil administration results in significantly less hemodynamic tolerance over a 24-hour period compared with nitroglycerin. This finding may represent a clinical advantage for nicorandil in the short-term treatment of patients with congestive heart failure.

[Abnormalities of the skeletal muscle in hypertrophic cardiomyopathy. Spectroscopy using phosphorus-31 nuclear magnetic resonance]. / Anomalies du muscle squelettique dans la myocardiopathie hypertrophique. Une étude par spectroscopie RMN-31P.

There have been several reports of electromyographic and histological changes of striated skeletal muscle, especially of the type I oxidative fibres, in hypertrophic cardiomyopathy. In order to determine whether these anomalies also cause metabolic changes, a P-31 magnetic resonance spectroscopic study was undertaken at rest and on exercise in 5 pauci-symptomatic patients and 10 control subjects. The 5 patients had primary hypertrophic cardiomyopathy without alteration of systolic function or signs of congestive cardiac failure (Stages I or II). There were no clinical signs of myopathy. None of the patients were receiving betablocker therapy at the time of investigation. No significant difference was observed at rest. Intracellular acidosis was particularly pronounced in 2 of the 5 patients at the peak of exercise. In addition, the phosphocreatine recovery time (T1/2) was longer in the patient group (3.4 +/- 1.7 vs 1.6 +/- 0.9 mn; p less than 0.01) suggesting a mitochondrial metabolic oxidation abnormality. These results suggest that some patients with primary hypertrophic cardiomyopathy have abnormalities of mitochondrial oxidation in their striated skeletal muscle which can be demonstrated by P-31 magnetic resonance spectroscopy. This would suggest a global abnormality of striated muscle which, at a more advanced stage of the disease, could account for decreased effort tolerance in these patients.