Robert J. Weiss

Intracoronary fibrinolytic therapy in acute myocardial infarction. Report of a prospective randomized trial.

We performed a randomized trial comparing intracoronary administration of streptokinase versus dextrose placebo within six hours after the onset of symptoms of acute myocardial infarction in 40 patients. The base-line clinical, hemodynamic, and angiographic findings were similar in the control and streptokinase-treated groups. Reestablishment of flow occurred in 12 of 20 patients treated with streptokinase and in 2 of 20 given placebo (P less than 0.05). Left ventricular function, angiographic ejection fraction, and regional wall motion, measured before and immediately after intervention, and serial radionuclide ejection fractions, measured at treatment, at 12 days, and at 5 months, were compared according to type of treatment (streptokinase vs. placebo) and outcome of therapy (reperfusion vs. no reperfusion). No statistically significant differences between groups were found. Thus, although streptokinase was more effective than placebo in achieving reperfusion, we detected no improvement of left ventricular function as a result of reestablished coronary flow.

Combined enalapril and felodipine extended release (ER) for systemic hypertension

This multicenter, placebo-controlled, double-blind trial of factorial design evaluated the safety and efficacy of combination treatment with the angiotensin-converting enzyme inhibitor, enalapril, and the vascular selective calcium antagonist felodipine extended release (ER) in patients with essential hypertension. After a 4-week, single-blind placebo baseline period, 707 patients with sitting diastolic blood pressures (BPs) in the range of 95 to 115 mm Hg received placebo, enalapril (5 or 20 mg), felodipine ER (2.5, 5, or 10 mg), or their combinations for an 8-week double-blind treatment period. All doses of enalapril and felodipine ER had a statistically significant (p < 0.05) additive effect in reducing both systolic and diastolic BP. The trough to peak ratios for the combinations ranged from 0.63 (enalapril 5 mg-felodipine ER 2.5 mg) to 0.79 (enalapril 20 mg-felodipine ER 10 mg) and were consistent with effective BP control with 1 dose/day. Patients aged > or = 65 years demonstrated a greater reduction in diastolic BP. Combinations of enalapril-felodipine ER were associated with less drug-induced peripheral edema (4.1%) compared to felodipine ER monotherapy (10.8%). There were no serious drug-related adverse effects observed during the study. In this trial, the combination of enalapril and felodipine ER effectively lowered BP and was generally well tolerated with an excellent safety profile when used in the treatment of hypertension.

Beneficial effects of rosuvastatin alone and in combination with extended-release niacin in patients with a combined hyperlipidemia and low high-density lipoprotein cholesterol levels

Patients with combined hyperlipidemia and low high-density lipoprotein (HDL) cholesterol levels may benefit from combination therapy with a statin and niacin; therefore, we assessed the efficacy and safety of rosuvastatin and extended-release (ER) niacin alone and in combination in 270 patients with this atherogenic dyslipidemia. Men and women > or =18 years with fasting total cholesterol levels > or =200 mg/dl, triglycerides 200 to 800 mg/dl, apolipoprotein B > or cf=110 mg/dl, and HDL cholesterol <45 mg/dl were randomized to 1 of 4 treatments in this 24-week, open-label, multicenter trial: rosuvastatin 10 to 40 mg; ER niacin 0.5 to 2 g; rosuvastatin 40 mg/ER niacin 0.5 to 1 g; or rosuvastatin 10 mg/ER niacin 0.5 to 2 g. Percent changes from baseline in low-density lipoprotein (LDL) cholesterol, non-HDL cholesterol, and other lipid measurements at week 24 were determined by analysis of variance, with statistical testing performed separately between the rosuvastatin monotherapy group and each remaining treatment group. Daily doses of rosuvastatin 40 mg reduced LDL and non-HDL cholesterol significantly more than either ER niacin 2 g or rosuvastatin 10 mg/ER niacin 2 g (-48% vs -0.1% and -36% for LDL cholesterol and -49% vs -11% and -38% for non-HDL cholesterol, respectively; p <0.01 for all comparisons); no additional reduction in LDL or non-HDL cholesterol was observed with the combination of rosuvastatin 40 mg/ER niacin 1.0 g (-42% and -47%; p = NS). Triglyceride reductions ranged from -21% (ER niacin monotherapy) to -39% (rosuvastatin 40 mg/ER niacin 1 g), but no observed differences were statistically significant. Compared with rosuvastatin alone, rosuvastatin 10 mg/ER niacin 2 g produced significantly greater increases in HDL cholesterol (11% vs 24%, p <0.001) and apolipoprotein A-I (5% vs 11%, p <0.017). Similar increases in HDL cholesterol and apolipoprotein A-I were noted between the monotherapy groups. Over 24 weeks, rosuvastatin alone was better tolerated than either ER niacin alone or the combinations of rosuvastatin and ER niacin.

Platelet alpha2 adrenoreceptors in chronic congestive heart failure

Patients with chronic congestive heart failure (CHF) are known to have elevated plasma concentrations of norepinephrine. Although this elevation of catecholamines in plasma may facilitate myocardial contractility, it may also be toxic to the myocardium in the long term. The alpha2 adrenoreceptor located on noradrenergic nerve terminals regulates neuronal norepinephrine release by feedback inhibition. This receptor is also located on human blood platelets. This study determines, the status of platelet alpha;! adrenoreceptors in 16 patients with CHF (class I and II in 7 and class Ill and IV in 9) and in 26 normal volunteers. Specific high-affinity binding of the alpha* agonist 3H-clonidine and the alpha* antagonist 3H-yohimbine was used to determine the number (B,,,) of alpha* receptors and the dissociation constant (Ku) for the 2 ligands. In the control population, the B,,, (in fmol/mg protein) for 3Hclonidine was 33 f 2 and for 3H-yohimbine was 165 f 12. There was a 25 % difference in the maximum number of specific binding sites for 3H-clonidine in the class III/IV group (B,,, 24 f 2, p X0.05) and a 43 % difference in the maximum number of specific binding sites for 3H-yohimbine (B,,, 94 f 9; p <0.005). There was a smaller but nonsignificant difference in the number of receptors on platelets from patients in the class I and II group. The Ku’s were similar in all 3 groups. These differences correlated well with the increases in plasma norepinephrine levels between the normal group (273.6 f 44.1 pg/ml) and the class III/IV group (1333.5 f 244.9, p <0.0005). This study supports the hypothesis that increased levels of circulating norepinephrine in CHF lead to a decrease in platelet alpha* adrenoreceptors. Further studies should be performed to determine whether pharmacologic stimulation of these receptors might lead to a decrease in the neuronal release of that norepinephrine which might be toxic to the myocardium. Monitoring of platelet alpha* adrenoreceptor number may provide a guide to therapy of CHF.

Foreign medical graduates and the medical underground.

Abstract A written questionnaire was distributed by the Educational Council for Foreign Medical Graduates to 4035 foreign medical graduates taking the January, 1973, examination in centers in the United States. Forty-eight per cent of the 3935 respondents were working in the health field at the time of the examination. In general, married males on permanent visas who entered the United States before 1970 had the highest rate of employment in the health field. Those working in the health field had a lower passing rate on the examination than those not working (15 vs. 26 per cent). The questionnaire was followed by telephone interviews of a sample of 850 respondents designed to obtain more detailed information about job duties. Seventy-three per cent of the 513 who reported working in the health field were involved in direct patient care, and 64 per cent of these were employed in hospitals. Analyses of specific job duties revealed large numbers functioning independently and in unsupervised settings. The res...

The Effect of Importing Physicians — Return to a Pre-Flexnerian Standard

Abstract Increasing concern about the control of the quality of medical care raises the question of the dilution of the physical manpower pool with foreign medical graduates, who constituted 46 per cent of new licentiates in medicine in the United States in 1972. The use of the Educational Council for Foreign Medical Graduates examination as a minimal level of educational quality for graduates entering the United States from medical schools in developing countries and the increasing number of such graduates entering the United States each year from those countries have produced a dual standard. Medical schools in the United States established controls over the input and process of medical education after the Flexner Report in 1910. Such controls do not exist in many foreign medical schools. Recommendations are made for control of a minimal educational level for physicians entering the United States health-care system and implications of these recommendations are discussed. (N Engl J Med 290:1453–1458, 1974)

Noninvasive quantification of jeopardized myocardial mass in dogs using 2-dimensional echocardiography and thallium-201 tomography☆

The evaluation of jeopardized myocardial mass is important in defining the effect of interventions during myocardial infarction. To quantitate the in vivo mass at risk, 2-dimensional echocardiography (2-D echo) and thallium-201 single-photon emission computed tomography (SPECT) was performed in 10 closed-chest dogs after circumflex coronary artery occlusion. The 2-D images were manually digitized to compute left ventricular (LV) mass using a modified Simpsons rule algorithm. This measure of LV mass correlated well with the actual LV mass (r = 0.97). Perfused myocardial mass was estimated from thallium SPECT images 4 hours after occlusion using a region-growing algorithm. After the dogs were killed, the jeopardized mass was outlined using a dual perfusion staining technique using triphenyltetrazolium chloride and Evans blue dye. The actual perfused mass was well estimated by the thallium images (r = 0.96). The noninvasively determined mass at risk was calculated as: 2-D mass--thallium SPECT mass, and correlated well with the pathologically determined mass at risk (r = 0.91). Thus, the jeopardized mass may be determined noninvasively by using 2-D echo and thallium-201 tomography. This approach may provide further information regarding the effect of intervention therapy on jeopardized myocardium.

The relationship between nonfasting and fasting lipid measurements in patients with or without type 2 diabetes mellitus receiving treatment with 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors

BACKGROUND Studies have confirmed a lack of patient and physician adherence to the revised National Cholesterol Education Program (NCEP) Adult Treatment Panel III (ATP III) guidelines. These guidelines state that lipid panels should be obtained while the patient is in the fasting state. However, this restriction may limit the ordering of these tests and thus decrease the number of patients on drug therapy and the number treated until goal cholesterol levels are reached. Evidence shows that testing in the nonfasting state may not be clinically or significantly different from testing in the fasting state in identifying patients at risk for a future cardiovascular event. OBJECTIVES The purpose of this study was to determine whether a relationship exists between nonfasting and fasting lipid values in diabetic or nondiabetic patients that will permit the more ready identification of patients who require treatment to meet NCEP ATP III guidelines. A secondary goal was to determine whether diabetic patients who appear to have reached goal cholesterol levels in the fasting state meet those goals when the non-high-density lipoprotein cholesterol (HDL-C) levels are measured in the nonfasting state. METHODS This observational study was conducted at Androscoggin Cardiology Associates (Auburn, Maine). Patients with hyperlipidemia receiving statin therapy whose doses had not changed for > or =2 months were enrolled. For all patients, nonfasting and fasting lipid panels (total cholesterol, triglycerides [TGs], and HDL-C) were calculated, whereas low-density lipoprotein cholesterol (LDL-C)levels were measured directly. The direct LDL-C method was used to determine the variance of the calculated LDL-C from the actual value. RESULTS One hundred consecutive hyperlipidemic patients were tested. Patients included 70 men and 30 women, with a mean (SD) age of 66.2 (12.0) years(range, 24-93 years). Eighteen patients had type 2 diabetes mellitus (DM). Non-fasting TG, HDL-C, and LDL-C levels were able to identify almost all patients who did not meet ATP III guidelines in terms of cholesterol levels (95%, 100%, and 95%, respectively). No predictive differences were found, regardless of whether the patients had type 2 DM. For the total population, statistically significant differences were found between calculated nonfasting and fasting measurements for mean (SD)LDL-C levels (90.2 [24.8] mg/dL vs 99.7 [26.1] mg/dL, respectively; P < 0.001). The regression equation was fasting LDL-C = 22.7 + 0.854 x nonfasting LDL-C.A nonfasting LDL-C level >130 mg/dL predicted a fasting LDL-C level >100 mg/dL(95% CI, -12.79 to -6.24), and a nonfasting LDL-C level >130 mg/dL predicted cases of fasting LDL-C level >100 mg/dL (95% CI, -5.79 to -1.35). CONCLUSIONS In this study population, nonfasting TG, HDL-C, and LDL-C levels successfully identified almost all patients who did not meet ATP III guidelines for cholesterol levels. No clinically significant difference was found in diabetic or nondiabetic patients.

Comparison of alpha2 adrenoreceptors on arterial smooth muscle and brain homogenates from spontaneously hypertensive and wistar-kyoto normotensive rats

Alpha 2 adrenoreceptors are located on vascular smooth muscle of the rat tail artery. In the present study this receptor was studied in spontaneously hypertensive (SHR) and Wistar-Kyoto (WKY) rats. Adrenergic agonists were used to produce isometric contractions of helically-cut tail artery strips from SHR and WKY. Clonidine and guanabenz, alpha 2 agonists, were more potent in the SHR than in the WKY (e.g. clonidine: EC50 SHR = 3.5 +/- 0.6 X 10(-8) M; EC50 WKY = 17.0 +/- 0.2 X 10(-8) M; P less than 0.0005). There was no difference in potency between the alpha 1 agonists, phenylephrine and methoxamine. Yohimbine, an alpha 2 antagonist, was more potent in inhibiting the clonidine-induced contraction in the SHR (pA2 = 7.66 versus 7.14). To determine the number of alpha 2 adrenoreceptors, the specific binding of 3H-clonidine to homogenates of tail artery and of five brain areas was also measured. The maximum number of high-affinity sites on the tail artery was threefold greater in SHR than in WKY (31 +/- 5 versus 11 +/- 3 fmol/mg protein, P less than 0.0005). No differences in the number or affinity of alpha 2 receptor sites was found in the hypothalamus, hippocampus, locus coeruleus or parietal cortex of the two strains of rat. There was a difference in the amygdala (SHR: 163 +/- 16 versus WKY: 108 +/- 14, P less than 0.05). The larger number of alpha 2 adrenoreceptors on the vascular smooth muscle in SHR may provide an explanation for the supersensitivity of SHR to adrenergic agonists.

Altered platelet alpha2-adrenoceptors in patients with angina pectoris

The alpha2-adrenoceptor located on noradrenergic neurons regulates the release of norepinephrine by negative feedback. This receptor is also located on human blood platelets, and the number of these receptors is correlated with the plasma norepinephrine content. The purpose of this study was to determine the status of platelet alpha2-adrenoceptors in patients with symptomatic and asymptomatic coronary artery disease. It was hypothesized that patients with symptomatic coronary disease might have a decrease in alpha2-adrenoceptor number that might be related to increased neuronal norepinephrine release. Specific, high-affinity binding of the alpha2-agonist, 3H-clonidine, and the alpha2-antagonist, 3H-yohimbine, to isolated platelet membranes was used to determine the maximal number of binding sites (in fmol/mg protein ± standard error of the mean) and the dissociation constant (in nM) of the alpha2-receptors. In normal subjects, the number of binding sites for 3H-clonidine was 32 ± 2 and the dissociation constant was 5.5 ± 0.6 (n = 26); the maximal number of binding sites for 3H-yohimbine was 165 ±12 and the dissociation constant was 4.0 ± 0.5 (n = 16). In patients with symptomatic coronary artery disease, there was a 38% decrease in 3H-clonidine binding (number of binding sites = 20 ± 3; dissociation constant = 6.6 ± 1.2; n = 9; p The affinity constants and plasma norepinephrine concentrations did not differ among the three groups. If similar changes in receptor number occur on nerve terminals, this may represent a primary abnormality that permits enhanced release of norepinephrine or a secondary down regulation of receptor number in response to increased synaptic levels of norepinephrine.