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Biomedical subjects

E Grossman

Publications and source records attributed to E Grossman.

At least 55 records · Page 3Linked to original sources
PubMed2000

The effect of renin-angiotensin axis inhibition on early atherogenesis in LDL-receptor-deficient mice.

OBJECTIVE: The renin-angiotensin system may play a role in the development of atherosclerosis. Nevertheless, different results from studies attempting to attenuate the process by inhibiting the converting enzyme were equivocal, and in those who succeeded, blood pressure was lowered and/or the lipid profile was improved in addition to the inhibition of the renin-angiotensin axis. The aim of this study is to investigate the effect of low doses of fosinopril, a converting enzyme inhibitor, on the development of atherosclerosis in LDL-receptor-deficient mice. METHODS: Three groups of 15 mice were fed a high-fat, high-cholesterol western diet. The three study groups received either distilled water (control group), or water supplemented with fosinopril 0.01 mg/kg/day (low-dose group) or with 0.1 mg/kg/day (high-dose group). Plasma aldosterone levels and lipid profiles were measured at the beginning and at the end of the study. After 10 weeks, the mice were sacrificed and the extent of atherosclerosis was assessed at the aortic sinus. RESULTS: Plasma aldosterone levels did not change in the control group, but decreased significantly in both treated groups from 74.7 to 39.3 ng/ml in the low-dose group (p < 0.003) and from 70.7 to 33.6 ng/ml in the high-dose group (p < 0.001). The lipid profile at the end of the study showed significantly lower levels of cholesterol and triglycerides in the high-dose group as compared to the low-dose group (p < 0.05). There was no difference between the three groups regarding the area of atherosclerosis at the aortic sinus: 157,000 +/- 34,000, 130,000 +/- 58,000 and 145,000 +/- 26,000 microm(2) in the control, low-dose and high-dose groups, respectively. CONCLUSION: Inhibition of the renin-angiotensin-aldosterone axis by itself does not prevent the development of early atherosclerosis in LDL-receptor-deficient mice.

Aldosterone↗
PubMed2000

Results in 95 hemorrhagic stroke patients included in CLASS, a controlled trial of clomethiazole versus placebo in acute stroke patients.

BACKGROUND AND PURPOSE: Clomethiazole is a neuroprotective drug that enhances gamma-aminobutyrate type A (GABA(A)) receptor activity. Its efficacy and safety were tested in the CLomethiazole Acute Stroke Study (CLASS). The protocol allowed a CT scan to be done after randomization but within 7 days of stroke onset to minimize delays before start of treatment. Ninety-five of the 1360 patients randomized were diagnosed as having intracranial hemorrhage rather than ischemic stroke. Safety results for clomethiazole compared with placebo in this group are reported. METHODS: The study included patients with a clinical diagnosis of acute hemispheric cerebral infarction. Treatment was a 24-hour intravenous infusion of 75 mg/kg clomethiazole or placebo. Patients with intracranial hemorrhage discovered on a postrandomization CT were withdrawn from study treatment if treatment was ongoing, and all patients were followed up to 90 days. RESULTS: Ninety-four patients received treatment, 47 in each group. The hemorrhage was classified as intracerebral in 89 patients (94%). Mortality at 90 days was 19.1% in the clomethiazole group and 23.4% in the placebo group. Sedation was the most common adverse event, occurring at a higher incidence in clomethiazole-treated patients (clomethiazole 53%, placebo 17%), followed by rhinitis and coughing. The incidence and pattern of serious adverse events was similar between the treatment groups. The percentage of patients reaching relative functional independence on the Barthel Index (score >/=60) at 90 days was 59.6% in the clomethiazole group and 53.2% in the placebo group. CONCLUSIONS: Clomethiazole appears safe to administer to hemorrhagic stroke patients compared with placebo. These results would obviate the need for a CT scan before therapy is initiated in acute stroke. The safety of clomethiazole in hemorrhagic stroke patients will be further evaluated in a prospective study that is under way in North America.

Acute Disease↗
PubMed2000

Brain areas involved in perception of biological motion.

These experiments use functional magnetic resonance imaging (fMRI) to reveal neural activity uniquely associated with perception of biological motion. We isolated brain areas activated during the viewing of point-light figures, then compared those areas to regions known to be involved in coherent-motion perception and kinetic-boundary perception. Coherent motion activated a region matching previous reports of human MT/MST complex located on the temporo-parieto-occipital junction. Kinetic boundaries activated a region posterior and adjacent to human MT previously identified as the kinetic-occipital (KO) region or the lateral-occipital (LO) complex. The pattern of activation during viewing of biological motion was located within a small region on the ventral bank of the occipital extent of the superior-temporal sulcus (STS). This region is located lateral and anterior to human MT/MST, and anterior to KO. Among our observers, we localized this region more frequently in the right hemisphere than in the left. This was true regardless of whether the point-light figures were presented in the right or left hemifield. A small region in the medial cerebellum was also active when observers viewed biological-motion sequences. Consistent with earlier neuroimaging and single-unit studies, this pattern of results points to the existence of neural mechanisms specialized for analysis of the kinematics defining biological motion.

Adult↗
PubMed2000

Plasma cell dyscrasia with polyneuropathy--POEMS syndrome presenting with vasculitic skin lesions and responding to combination chemotherapy.

We report a 61-year-old male patient who presented with severe sensorimotor neuropathy, leg edema and skin lesions with M-paraprotein and 50% plasma cells in the bone marrow. The POEMS (Crow-Fukase) syndrome was diagnosed and the skin lesions were compatible with vasculitis according to the histopathology. The patient was treated with aggressive combined chemotherapy, which induced improvement in both the clinical and laboratory parameters of his disease. To the best of our knowledge this is the first report of a vasculitic process underlying the skin changes in the POEMS syndrome. Our findings may shed light on the unknown pathogenesis of this syndrome and the successful results of treatment support the adoption of an aggressive therapeutic approach in symptomatic patients.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1999

Relation of early and one-year outcome after acute myocardial infarction to systemic arterial blood pressure on admission.

We evaluated whether elevated blood pressure (BP) levels with an acute myocardial infarction (AMI) affect the in-hospital course, short-term, and 1-year outcome. Data were derived from a nationwide survey of 2,212 consecutive patients with AMI. Patients were stratified into 3 groups according to admission BP levels: 1,320 patients had normal BP, 840 patients had high BP, and 52 patients had excessive BP. In-hospital (7 days) course, short-term (30 days), and 1-year outcome was compared between the groups. The 3 groups were similar with respect to age, but patients with excessive BP were more likely to be women and have a history of systemic hypertension and diabetes mellitus. The rate of thrombolytic therapy was similar among the 3 groups, but patients with excessively elevated BP were treated during hospitalization much more often with beta blockers, angiotensin-converting enzyme inhibitors, and diuretics. The incidence of stroke, transient ischemic attack, and bleeding complications were comparable in the 3 groups. In-hospital mortality was 5.0% , 4.0%, and 1.9% in the normal, high, and excessively elevated BP groups, respectively (p = 0.19). The short-term rehospitalization or mortality rate was similar among the 3 groups. The 1-year mortality rate was 12.3%, 14.1%, and 10.2% in the normal, high, and excessively elevated BP groups, respectively (p = 0.61). A multivariate logistic regression analysis yielded age, women, and Killip class > or = 2 as the only significant predictors of mortality during follow-up. Thus, with the current medical therapy, excessively elevated BP levels with AMI is not associated with a worse short-term or 1-year outcome.

Adrenergic beta-Antagonists↗
PubMed1999

Does diuretic therapy increase the risk of renal cell carcinoma?

Several studies have suggested that systemic hypertension as a disease or its therapy could increase the risk for malignancies. Diuretics reduce cardiovascular morbidity and mortality and constitute a cornerstone in the antihypertensive arsenal. To analyze the relation between diuretic therapy and the risk of malignancies, we conducted a comprehensive review of pertinent previous publications by searching the MEDLINE database for related articles in all languages published between January 1966 and April 1998. Within the past decade, we found 9 case control studies and 3 cohort studies in which the relation between diuretic use and renal cell carcinoma was examined. In the case control studies, the odds ratio of renal cell carcinoma occurring in patients treated with diuretics averaged 1.55 with a 95% confidence interval of 1.42 to 1.71 (p <0.00001) compared with nonusers of diuretics. In the 3 cohort studies of 1,226,229 patients, diuretic therapy was associated with a more than twofold risk of renal cell carcinoma when compared with patients not on diuretics. In 1 cohort study, and in the 7 case control studies in which the effects of gender were reported, women had a higher odds ratio (2.01, confidence interval 1.56 to 2.67) than men (1.69 confidence interval 1.34 to 2.13). Thus, cumulative evidence, possibly stronger in women than in men, suggests that the long-term use of diuretics may be associated with renal cell carcinoma. Although diuretics remain the best documented drug class to reduce morbidity and mortality in systemic hypertension, our data suggest a need for continued vigilance to assess the risk-benefit ratio of all drugs used for long-term therapy of cardiovascular disorders.

Carcinoma, Renal Cell↗
PubMed1999

Carcinogenicity of cardiovascular drugs.

Antihypertensive treatment may promote cancer through unknown mechanisms. Early retrospective studies implicated reserpine in breast cancer, but the drug was later absolved by prospective analyses. Data from case-controlled studies and several cohort studies suggested an association between the use of a diuretic and the occurrence of renal cell cancer. Several prospective studies showed that treatment with atenolol may increase mortality from malignancy. However, other studies that analyzed data from several thousand patients could not confirm this association. In two prospective studies, angiotensin-converting enzyme (ACE) inhibitors were associated with increased mortality from malignancy, but a few case-controlled studies showed no association between use of ACE inhibitors and malignancy. In addition, a recent retrospective study showed that long-term use of ACE inhibitors had a protective effect against malignancy. In some studies, calcium antagonists were implicated in increasing the risk for cancer; however, two large case-controlled studies and the combined data from nine observational studies showed a similar risk for malignancy among users and nonusers of a calcium antagonist. Ongoing long-term prospective studies will tell us more about the carcinogenicity of cardiovascular drugs.

Adrenergic beta-Antagonists↗
PubMed1999

Homocysteine levels in hypertensive patients with a history of cardiac or cerebral atherothrombotic events.

Hypertension is one of the most important risk factors for cardiovascular morbidity and mortality. Recently it has been suggested that the amino acid homocysteine contributes to this process. This study evaluates whether elevated plasma levels of homocysteine in hypertensive patients are associated with increased risk for cardiovascular events. Fifty hypertensive patients with a documented history of cerebral or cardiac events were age and gender matched to 50 hypertensive patients with no evidence of any cerebral or cardiac event. Demographic details, duration of hypertension, presence of other risk factors, and use of antihypertensive medications were recorded for each patient. Plasma levels of homocysteine were measured by high-performance liquid chromatography technology. The two groups had similar demographic parameters, with a mean age of 64.6 +/- 9.4 years. Patients with cardiovascular events were more likely to be past smokers and to have been treated with calcium antagonists, aspirin, and nitrates. Homocysteine levels were 12.1 +/- 5.8 micromol/L in those with documented cardiovascular disease and 11.1 +/- 4.7 micromol/L in those without (P = NS). Levels of plasma homocysteine were higher in those with hypercholesterolemia (P = .03) and in smokers, and tended to be lower in those who used beta-blockers, angiotensin converting enzyme (ACE) inhibitors, diuretics, and nitrates. Thus, hyperhomocysteinemia is not a feature of hypertensive patients with atherothrombotic events and there is no support for additive or synergistic effects between these two independent risk factors.

Aged↗
PubMed1999

Beta-blockers and diuretics: to use or not to use.

The present review scrutinizes the recommendations of many guidelines to use beta-blockers and diuretics as first-line therapy in hypertension. These recommendations were ostensibly based on multiple prospective randomized trials attesting to a reduction of morbidity and mortality with both beta-blockers and diuretics in monotherapy as well as in combination. Although diuretic-based therapy has been shown to prevent strokes (and, to a lesser extent, heart attacks, and cardiovascular and all-cause mortality), no such data are available for beta-blockers. To the contrary, a recent metaanalysis documented that although blood pressure was lowered significantly by beta-blockers, this drug class was ineffective in preventing coronary heart disease, and cardiovascular and all-cause mortality (odds ratio 1.01, 0.98, and 1.05, respectively). Patients who received a combination of beta-blockers and diuretics fared consistently worse than those taking diuretics alone. Although diuretics have an unparalleled track record of safety and efficacy, the recent findings suggesting that long-term use increased the risk for renal cell carcinoma (RCC) is of concern. Over the past decade, an association between RCC and diuretic therapy has been documented in nine case control studies (odds ratio 1.55, confidence interval [CI] 1.42-1.71). In three cohort studies, diuretic therapy was associated with a greater than twofold increased risk of RCC. The risk of RCC increased with cumulative diuretic doses. In the elderly, a low-dose diuretic probably remains a good choice for antihypertensive therapy; however, in middle-aged patients, particularly in women, diuretics should be avoided for the long-term treatment of hypertension. Sweeping recommendations for the use of beta-blockers and diuretics as preferred therapeutic strategies are inappropriate and a more sophisticated drug therapy regimen is often needed.

Adrenergic beta-Antagonists↗
PubMed1999

Renal effects of L-DOPA in heart failure.

We examined whether low-dose L-DOPA treatment induces natriuresis and diuresis in patients with congestive heart failure who have cardiac decompensation despite treatment with digoxin, a diuretic, and an angiotensin-converting enzyme inhibitor and who respond acutely to intravenously infused dopamine. In a randomized, double-blind, placebo-controlled crossover study, 11 patients with severe congestive heart failure received L-DOPA (0.10 g, p.o., t.i.d., for 1 day and then 0.25 g, p.o., t.i.d., for 2 days after a washout period of > or = 1 day), with assessments of plasma and urinary levels of catechols, urinary volume, and sodium content, and clinical and laboratory measures of improvement of congestive heart failure. L-DOPA elicited short-term, dose-related increases in urinary volume and sodium excretion. At the 0.10-g dose, L-DOPA increased plasma L-DOPA levels and urinary L-DOPA excretion by about fivefold, whereas at the 0.25-g dose, L-DOPA increased plasma and urinary L-DOPA by >50-fold. Twenty-four-hour urinary dopamine excretion increased by about fivefold after the low dose of L-DOPA and approximately 50-fold after the high dose. The results demonstrate that oral L-DOPA treatment can produce beneficial natriuretic and diuretic effects in selected patients with congestive heart failure. The bioavailability of oral L-DOPA appears to vary with the dose. These results support findings from previous studies about beneficial cardiac functional effects of L-DOPA in patients with refractory heart failure.

Administration, Oral↗
PubMed1999

A test of the "epinephrine hypothesis" in humans.

-According to the "epinephrine hypothesis," circulating epinephrine taken up by sympathetic nerves is coreleased with norepinephrine during sympathetic stimulation and binding of coreleased epinephrine to presynaptic beta-adrenoceptors augments exocytotic release of norepinephrine, contributing to high blood pressure. This study examined whether infusion of a physiologically active amount of epinephrine affects subsequent vascular responses and the estimated rate of entry of norepinephrine into regional venous plasma (norepinephrine spillover). Each of 3 experiments included intravenous infusion of 3H-norepinephrine, measurements of forearm vascular resistance, and intra-arterial infusion of epinephrine (3 ng/min per deciliter forearm volume). In experiment 1, subjects underwent lower body negative pressure (LBNP-25 mm Hg) before and after intra-arterial epinephrine; in experiment 2, LBNP and intra-arterial yohimbine before and after intra-arterial epinephrine; and in experiment 3, intravenous nitroprusside before and after intra-arterial epinephrine. In all subjects, intra-arterial epinephrine produced ipsilateral pallor and decreased forearm vascular resistance. Ipsilateral venous epinephrine increased by 10-fold. Epinephrine did not affect forearm vasoconstrictor responses to LBNP or vasodilator responses to intra-arterial yohimbine or intravenous nitroprusside; did not affect venous norepinephrine levels or norepinephrine spillover during LBNP, yohimbine, LBNP during yohimbine, or nitroprusside; and did not increase venous epinephrine levels during any of these manipulations. Loading of forearm sympathetic terminals with epinephrine therefore does not augment subsequent neurogenic vasoconstriction or norepinephrine release in the human forearm in response to sympathetic stimulation. The findings are inconsistent with the epinephrine hypothesis.

Adrenergic alpha-Antagonists↗