New treatment for infertility due to congenital absence of vas deferens.
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Biomedical subjects
Publications and source records attributed to S Silber.
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There is increasing evidence that constant nitrate plasma levels, as induced by at least three-times-daily ingestions of isosorbide dinitrate in sustained-release form, lead to an attenuation or even complete loss of the anti-ischemic effects (nitrate tolerance). Therefore, the dependence of tolerance development on dosage intervals according to once-daily and twice-daily ingestions was assessed. Tablets of isosorbide dinitrate (80 mg) in sustained-release form were administered once-daily at 8 A.M. (dosage interval 24 hours) or twice-daily at 8 A.M. and 8 P.M. (dosage interval 12 hours), as well as at 8 A.M. and 2 P.M., respectively (maximal dosage interval 18 hours). A total of 34 patients with angiographically proven coronary artery disease, a history of stable, exercise-dependent angina pectoris, and a reproducible, exercise-induced ST-segment depression of at least 0.15 mV (1.5 mm), who initially showed a response to 80 mg of isosorbide dinitrate, were enrolled. The anti-ischemic effects of isosorbide dinitrate on exercise-induced ischemia were objectively determined by the measurement of exercise-induced ST-segment depression before as well as two, six, and 12 hours after the ingestion at the first and the 15th day of the studies. Since the dosage interval of 12 hours resulted in constant plasma levels, the initially beneficial anti-ischemic effects of isosorbide dinitrate were considerably attenuated after two weeks of treatment. In contrast, the once-daily regimen with its intermittent peaks and valleys of nitrate plasma levels showed identical anti-ischemic effects at the 15th day as compared with the first day. Ingestions at 8 A.M. and 2 P.M. also circumvented the development of nitrate tolerance, however, combined with an even more pronounced anti-ischemic effect after 12 hours as compared with the once-daily regimen. Thus, the circumvention of nitrate tolerance requires a daily "nitrate-poor" interval. The best compromise between a maximal possible anti-ischemic effect and the circumvention of tolerance development was found for the "eccentric" dosage regimen in which the tablets were ingested in the morning and early afternoon.
There is increasing evidence that relatively constant plasma nitrate concentrations induced by 3-times-daily administration of isosorbide dinitrate can lead to an attenuation or even complete loss of the drug's anti-ischaemic effects (nitrate tolerance). We therefore assessed the dependence of nitrate tolerance development from the haemodynamic and anti-ischaemic effects of a slow-release tablet formulation of isosorbide dinitrate 80 mg, administered according to different daily dosage regimens in patients with angina. It was found that a once-daily regimen, with its consequent peak and trough plasma nitrate concentrations, is capable of protecting against exercise-induced myocardial ischaemia for about 12 hours with the circumvention of nitrate tolerance.
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Although nitrates are the basic treatment for patients with ischemic heart disease and numerous clinical studies have compared the anti-ischemic effects of different combinations with beta-blockers and/or calcium antagonists, no study is known on a controlled intraindividual comparison of the combination nitrate plus beta-blocker with the combination nitrate plus a heart rate-decreasing calcium-antagonist. Therefore we performed a randomized, double-blind and crossover study to compare the effects of 80 mg isosorbide dinitrate in slow-release form (ISDN, once-daily) plus 120 mg verapamil (t.i.d.) with those of 80 mg ISDN plus 80 mg propranolol (b.i.d.). After these two phases of 3 weeks' duration respectively, patients received the combination of all three drugs with the same dosages in a single-blind manner. In addition to the standard inclusion criteria, a pathological exercise-ECG even after ISDN was required as well as a left ventricular ejection fraction (EF) of greater than or equal to 35%. This protocol could be completed in 26 of the 30 enrolled patients. The combination ISDN plus verapamil proved to exert the same anti-ischemic effects as the combination ISDN plus propranolol. The triple therapy showed a further improvement of exercise induced ischemia without deterioration of the EF at rest or during exercise. Even though only this triple therapy led to an optimal anti-ischemic result in about one third of the patients, it should be initiated cautiously, since symptomatic bradycardia may occur.
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The purpose of this study was to investigate whether the anti-ischemic effects of a single 80-mg tablet of isosorbide dinitrate in sustained-release form are attenuated after 2 weeks of twice-daily administration. In order to follow a double-blind protocol with respect to the 12-h interval, we also evaluated, in randomized order, another group of patients receiving the tablets once daily. Parameters for assessment of the anti-ischemic effects were changes in exercise-induced ST-segment depression and the simultaneously recorded left ventricular ejection fraction, as determined by radionuclide ventriculography. The ST-segment depression was measured completely blind; the left ventricular ejection fraction was calculated automatically with a clinically validated software. In the group that received the tablets once daily (n = 10) none of the patients showed any signs of attenuation of the beneficial anti-ischemic effects. However, seven of the 12 patients who received the tablets twice daily demonstrated significant attenuation. Thus, based on analysis of the presently available studies, in order to guarantee maintenance of the anti-ischemic benefits, a once-daily high dose of ISDN in sustained-release form (80 mg or even higher) is recommended.
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While the technetium-99m-pyrophosphate scintigram enables diagnostic proof of acute myocardial infarction, its use in the evaluation of the extent of infarction has not been clearly established. This study, in 30 patients with acute myocardial infarction was, thus, undertaken to assess the relationship between the findings of the technetium-99m-pyrophosphate scintigram, with respect to infarct area and uptake pattern, the infarct size, as determined from the total CK an CK-MB curves, and the mortality. The scintigraphically determined infarct areas ranged between 1.7 and 29.3 cm2; the 20.2 plus or minus 6.0 cm2 average for anterior wall infarction (n=18, range 7.4 to 29.3 cm2) was significantly greater (p smaller than 0.005) than the 8.3 plus or minus 5.3 cm2 average for inferior infarction (n=12, range 1.7 to 15.8 cm2). Correlation coefficients between the scintigraphically and enzymatically determined infarct sizes for the entire patient population ranged from 0.71 to 0.80. Anterior infarctions correlated more closely (0.66 to 0.84) than inferior infarctions (0.46 to 0.66). The technetium-99m-pyrophosphate uptake pattern was focal in 20 patients and ring-shaped (doughnut) in ten. Infarcts with focal uptake patterns were significantly smaller than those displaying a doughnut pattern (12.2 plus or minus 6.4 vs. 24 plus or minus 4.0 cm2, p smaller than 0.005). The infarct weight calculated from the CK-MC curve with application of individually determined disappearance rate for those infarcts displaying a focal uptake pattern was 34 plus or minus 29 grams while that associated with a doughnut uptake pattern was significantly greater at 86 plus or minus 25 grams (p smaller than 0.005). During the 18 -month observation period there were six deaths; the average scintigraphic infarct area of 22.8 plus or minus 3.6 cm2 in those who died was significantly greater (p smaller than 0.005) than that of the 13.8 plus or minus 8.2 cm2 of the survivors. Of the non-survivors, five had a doughnut uptake pattern and one displayed focal uptake. In the 24 survivors, a focal uptake pattern was found in 19 and a doughnut pattern in five. Conversely, 19 of the 20 patients with a focal uptake pattern survived while only five of the ten patients with a doughnut pattern were alive after 18 months. Thus, comparison with the enzymatically determined infarct weight as well as the mortality indicate that the technetium-99m-pyrophosphate scintigram yields clinically relevant data with regard to infarct size. Since no patient with an infarct area of less than 17 cm2 died within the 18-month observation period, designation of scintigraphically determined infarct size as small (smaller than 17 cm2) and large (larger than 17 cm2) was enabled. The corresponding cut-off point between large and small infarctions as determined enzymatically has been designated at 65 grams. Accordingly, agreement was found in 70% (14 of 20 patients) with scintigraphically small infarcts and in 80% (8 of 10 patients) with scintigraphically large infarcts...
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