Fluctuations of lipid and lipoprotein levels in hyperlipidemic postmenopausal women receiving hormone replacement therapy.

BACKGROUND: Fluctuations in lipid and lipoprotein levels are encountered quite often in hyperlipidemic patients. We examined the possibility that lipid and lipoprotein levels fluctuate due to the different effects of estrogen and progestogen in postmenopausal hyperlipidemic women receiving combined hormonal replacement therapy. METHODS: In an open-label study conducted during 3 consecutive hormonal cycles (3 months), levels of fasting total cholesterol, triglycerides, and low (LDLC)- and high-density lipoprotein cholesterol (HDLC) were determined in 36 postmenopausal hyperlipidemic women on day 13 of conjugated equine estrogen (1.25 mg/d) therapy and on day 25 after 12 days of receiving estrogen plus medroxyprogesterone acetate (5 mg/d). RESULTS: While receiving estrogen and combined therapies, means +/- SD total cholesterol levels increased from 6.50 +/- 0.97 mmol/L (251 +/- 37 mg/dL) to 6.88 +/- 1.42 mmol/L (266 +/- 54 mg/dL) (P<.001); LDLC levels, from 4.05 +/- 1.14 mmol/L (156 +/- 44 mg/dL) to 4.62 +/- 1.36 mmol/L (178 +/- 52 mg/dL) (P<.001). Mean +/- SD HDLC cholesterol levels decreased from 1.44 +/- 0.32 mmol/L (55 +/- 12 mg/dL) to 1.29 +/- 0.28 mmol/L (50 +/- 10 mg/dL) (P<.001); triglyceride levels, from 2.23 +/- 1.03 mmol/L (197 +/- 91 mg/dL) to 2.06 +/- 1.04 mmol/L (182 +/- 92 mg/dL) (P<.001). CONCLUSIONS: Hyperlipidemic postmenopausal women receiving combined sequential estrogen and progestogen replacement therapy demonstrate very significant fluctuations in their lipid and lipoprotein levels. These fluctuations depend on the hormonal phase, ie, estrogen alone or combined with progestogen.

Exercise-induced aortic flow parameters in early postmenopausal women and middle-aged men.

OBJECTIVE: Exercise Doppler echocardiography has been recognised as an accurate method for the assessment of left ventricular function in patients with coronary artery disease. Gender differences in aortic flow parameters during exercise have not been well established. The aims of this study were to compare basal ejection Doppler indexes in healthy early postmenopausal women with those of men, and to assess the effects of both isometric and dynamic exercises on these parameters. DESIGN: Intergroup comparison between early postmenopausal women and middle-aged men. SUBJECTS: Fifteen healthy women with a mean age of 55 (SD 5) years and 15 healthy men aged 52 (SD 4) were evaluated. SETTING: Women were recruited from a menopause clinic and men from a primary cardiovascular prevention program at a cardiac rehabilitation institute. INTERVENTIONS: Isometric exercise was performed with a 2-hand bar dynamometer, and dynamic exercise with a supine ergometer. Echo Doppler examination was performed at rest and at peak isometric and dynamic exercise with a pulsed Doppler transducer. RESULTS: Both types of exercise resulted in higher values of hemodynamic parameters in the women, with most figures reaching statistical significance. Most aortic flow parameters during rest and exercise were also significantly higher in the women. CONCLUSIONS: The unexpected higher values in hemodynamic and aortic flow parameters in early postmenopausal women as compared with middle aged men may shed light on a peculiar aspect of gender differences in cardiovascular function, perhaps specific to this age group and related to menopausal transition.

Comparative central nervous system effects and pharmacokinetics of neu-metoclopramide and metoclopramide in healthy volunteers.

Metoclopramide, a drug used for the relief of nausea and emesis, is currently under development as a radio- and chemosensitizing agent. Its usefulness in high doses, however, is limited by its central nervous system side effects. Neu-metoclopramide (Neu-Sensamide), a novel, concentrated, phosphate-buffered, pH-adjusted (pH = 6.5-7.0) formulation of metoclopramide, has been shown to have an improved side-effect profile in animal studies. The present double-blind, four-way crossover study compared the central nervous system effects and pharmacokinetics of neu-metoclopramide (intravenously and intramuscularly at 1.8 mg/kg) with intravenous metoclopramide and intramuscular placebo in 19 healthy male volunteers. Eight participants withdrew from the study, one because of noncompliance and seven because of adverse events. A total of 28 central nervous system events were observed with intravenous metoclopramide administration, whereas 16, 15, and 6 such events were attributed to intravenous neu-metoclopramide, intramuscular neu-metoclopramide, and placebo, respectively. Extra-pyramidal effects occurred on 10 occasions: 7 after intravenous metoclopramide, 2 after intravenous neu-metoclopramide, and 1 after intramuscular neu-metoclopramide. No significant differences were observed in the pharmacokinetic profiles of the three formulations of metoclopramide. It may be speculated, therefore, that the molecular conformational changes inherent to neu-metoclopramide result in a reduced side-effect profile compared with conventional metoclopramide formulations.

Exercise echocardiography in postmenopausal hormone users with mild systemic hypertension.

Rest and exercise echocardiography (at dynamic and isometric exercise) were performed in 30 postmenopausal women (aged 54 +/- 4 years) with borderline to mild hypertension. They were then divided into 2 groups: 17 women who started oral hormone replacement therapy (0.625 mg/day conjugated estrogens or 2 mg/day estradiol) and a control group of 13 nonusers. After 6 to 9 months, a second echocardiography was performed in 26 women (4 withdrew). There were only a few changes in values obtained in the 12 controls at the end of follow-up compared with baseline. Primarily, these changes included a slight decrease in systolic blood pressure at rest and on exercise. Several significant morphologic and hemodynamic alterations appeared in 14 hormone users. Left ventricular cavity dimensions and mass became smaller: mean end-diastolic diameter decreased from 45.9 +/- 3 mm at baseline to 44.4 +/- 3 mm at study termination (p = 0.007). The corresponding values for end-systolic diameter were 25.8 +/- 4 mm and 23.9 +/- 4 mm (p = 0.006); for left atrium diameter, it was 34.5 +/- 4 mm and 32.5 +/- 4 mm (p = 0.001); for left ventricular wall width, it was 19.9 +/- 2 mm and 19.3 +/- 2 mm (p = 0.02); for left ventricular mass, it was 197 +/- 28 g and 179 +/- 32 g (p = 0.006). The resting aortic blood flow velocity and acceleration increased: 119 +/- 18 cm/s before therapy versus 129 +/- 23 cm/s while on hormone substitution (p = 0.04), and 13.6 +/- 3 m/s2 versus 16.5 +/- 4 m/s2 (p = 0.008), respectively. Mean rest to peak exercise systolic blood pressure difference became smaller after hormones: 39 +/- 19 mm Hg versus 28 +/- 13 mm Hg (p = 0.03) during dynamic exercise, and 43 +/- 22 mm Hg versus 25 +/- 13 mm Hg (p = 0.004) during isometric exercise. The above data probably indicate that with hormone replacement therapy, there is an improvement in cardiac function both at rest and during exercise.

Prescribing pattern of antihypertensive drugs in the community.

The selection of the most appropriate therapy for hypertension remains a controversial issue. Little information is available regarding the prescribing patterns of antihypertensives in the primary care setting in Israel. The use of antihypertensives in 200 patients of the Maccabi Health Fund was, therefore, examined from April to June 1994. Sixty-four per cent of patients received monotherapy and 36% combination therapy. The most commonly prescribed medication for monotherapy were angiotensin-converting enzyme (ACE) inhibitors (33.6%), followed by beta-blockers (28.1%) and calcium channel antagonists (26.6%). Diuretics were prescribed to 7.0% of the patients. Analysis of overall drug utilization showed that diuretics were used in 21.5% of patients, beta-blockers in 39.5%, calcium channel blockers in 46% and ACE inhibitors in 40% of patients. Despite the growing evidence of the benefits of diuretics and beta-blockers, our results show a low utilization of these agents in comparison to other countries. It may be speculated that the lack of national guidelines, the absence of utilization reviews by third party providers as well as differences in patient population and climate conditions may all contribute to the current prescribing habits of physicians in the Israeli community.

Clearance of chylomicron remnants in normolipidaemic patients with coronary artery disease: case control study over three years.

OBJECTIVE: To test the hypothesis that subjects who clear chylomicron remnants slowly from plasma may be at higher risk of coronary artery disease than indicated by their fasting plasma lipid concentrations. DESIGN: Case control study over three years. SETTING: An 800 bed general municipal hospital. SUBJECTS: 85 normolipidaemic patients with coronary artery disease selected prospectively and matched with 85 normolipidaemic subjects with normal coronary arteries on angiography. INTERVENTIONS: All subjects were given a vitamin A fat loading test which specifically labels intestinal lipoproteins with retinyl palmitate. MAIN OUTCOME MEASURE: Postprandial lipoprotein metabolism. RESULTS: The area below the chylomicron remnant retinyl palmitate curve was significantly increased in the coronary artery disease group as compared with the controls (mean 23.4 (SD 15.0) v 15.3 (8.9) mumol/l.h; 95% confidence interval of difference 4.37 to 11.82). CONCLUSION: Normolipidaemic patients with coronary artery disease had significantly higher concentrations of chylomicron remnants in plasma than normolipidaemic subjects with normal coronary vessels. This may explain the mechanism underlying the susceptibility to atherosclerosis of coronary artery disease patients with normal fasting lipid values. As diet and drugs can ameliorate the accumulation of postprandial lipoproteins in plasma, the concentration of chylomicron remnants should be measured in patients at high risk of coronary artery disease.

Low-dose thiazides in the treatment of hypertension: benefits and risks in perspective.

Diuretics in low doses are very effective agents for controlling hypertension either where used alone or in combination. They have a marked cardioprotective effect, are the best tolerated of any anti-hypertensives and are at the same time the least expensive.

Comparisons of beta-adrenergic blocking properties of S- and R-timolol in humans.

In animals, the R-enantiomer of timolol causes a significant reduction in intraocular pressure but had only 1/80 the activity of the S-enantiomer at extraocular receptors. The beta 1- and beta 2-adrenoceptor blocking properties of orally administered R- and S-timolol were compared in a double-blind placebo controlled trial in two groups of healthy men. Each subject in group A (n = 6) received placebo, 1 and 3 mg S-timolol and 25 and 75 mg R-timolol in random order, group B (n = 5) received placebo, 0.5, and 1 mg S-timolol and 3 and 10 mg R-timolol. In both groups, R- and S-timolol comparably inhibited isoproterenol-induced increases in heart rate (P < .05), forearm blood flow (P < .05, except at 3 micrograms/minute of isoproterenol after the R-doses in group B), and finger tremor (P < .05) in comparison with placebo. The findings for the R-enantiomer in this study were unexpected based on the animal studies and previous studies that demonstrated marked differences in beta blocking effects of other beta-blockers in which the R-enantiomers were less inhibitory.

Distribution of ciprofloxacin in ascitic fluid following administration of a single oral dose of 750 milligrams.

The penetration of ciprofloxacin into the ascitic fluid of eight patients was studied. Serum and ascitic fluid samples were obtained before and at 1, 2, 3, 6, and 12 h following administration of a single oral dose of 750 mg. Peak levels (mean +/- standard deviation) were 4.0 +/- 0.7 micrograms/ml in serum and 2.6 +/- 0.6 micrograms/ml in ascitic fluid; the areas under the curve (0 to 12 h) were 29.1 +/- 6.5 micrograms.h/ml in serum and 20.7 +/- 5.0 micrograms.h/ml in ascitic fluid. The concentrations that were achieved are well above the MICs of ciprofloxacin for the members of the family Enterobacteriaceae that cause spontaneous bacterial peritonitis.

Characterization of sarcoplasmic reticulum in skinned heart muscle cultures.

The plasma membranes of rat heart muscle, grown in cell culture, were made permeable with saponin in a Ca-free solution. The cells were then supplied with a medium resembling the cytosol, and the adenosine triphosphate (ATP)-dependent Ca2+ sequestration was measured in the presence of oxalate. The nonmitochondrial component accounts for about 50% of the total Ca2+ uptake. The nonmitochondrial accumulation of Ca2+ within myocardial cells was found to be reversible by addition of the Ca2+ ionophore A23187. On the other hand, the Ca2+ antagonist D-600 (50 microM) had almost no effect on Ca2+ accumulation. Caffeine reduced Ca2+ accumulation in the skinned cardiomyocytes in a concentration-dependent manner. In addition, the anticalmodulin drug trifluoperazine (TFP) reduced Ca2+ accumulation in the skinned cells. Because of the analogy between nonmitochondrial ATP-dependent Ca2+ accumulation and the sarcoplasmic reticulum (SR) function with regard to the influence of various agents, it is assumed that we actually measure Ca2+ accumulation in the SR. The rate of Ca2+ accumulation into the SR measured during the development of the cardiomyocytes in culture shows an almost linear increase as a function of culture age. Amiodarone, a potent antiarrhythmic agent, and its metabolite, desethylamiodarone, inhibited Ca2+ accumulation into SR, which may explain their therapeutic effect.

Varied presentations of sporadic group A streptococcal bacteremia: clinical experience and attempt at classification.

The epidemiologic, clinical, and laboratory aspects of group A streptococcal bacteremia were studied in 33 patients seen at two urban hospitals in the Tel Aviv (Israel) area, over an 8-year period. Most patients (two-thirds) were female. Clinically significant bacteremia was observed in 26 patients, two of whom acquired their infection (puerperal sepsis) during hospitalization. A portal of entry, mainly cutaneous, was recognized in 61% of the patients, and a chronic underlying condition was observed in 69%. The case-fatality rate was 27%, with death occurring predominantly in patients admitted with shock or cryptogenic bacteremia. Our clinical experience and literature review show that the presentation of group A streptococcal bacteremia is diverse, with transient bacteremia of uncertain clinical significance on one end of the spectrum and overwhelming sepsis on the other. A practical classification of the various clinical forms of group A streptococcal bacteremia is proposed.

Effect of repeated doses of L-5-hydroxytryptophan and carbidopa on prolactin and aldosterone secretion in man.

To evaluate changes in serum prolactin and plasma and urine aldosterone after a serotonergic challenge, 8 healthy men (19 to 42 yr), taking dexamethasone (0.75 mg qid), received the serotonin precursor L-5-hydroxytryptophan (L5HTP; 100 mg qid) with the peripheral decarboxylase inhibitor carbidopa (C; 50 mq qid) or matching placebos in a randomized, crossover manner. Serum prolactin concentration increased in all subjects after L5HTP/C in comparison to placebo, mean (SD) prolactin (ng/ml) at 8 h after dosing was 19.8 +/- 6.3 after L5HTP/C and 12.0 +/- 3.1 after placebo (p less than 0.05). In contrast, in comparison to values on placebo, L5HTP/C had no apparent effect on mean plasma concentration at all observation times; mean (SD) aldosterone (ng/dl) at 8 h after dosing was 12.0 +/- 5.1 and 12.0 +/- 3.8 after placebo (NS). Mean (SD) urinary aldosterone (micrograms/24 h), Na+(mEq/24 h) and K+(mEq/24 h) excretion were 7.0 +/- 4.4, 49.3 +/- 30.6, 30.1 +/- 11.2, after L5HTP/C and 7.4 +/- 5.8, 59.7 +/- 23.9, 33.3 +/- 7.4 after placebo (NS). Under these study conditions, subacute serotonergic stimulation with oral L5HTP/C resulted in prolactin but not aldosterone release.

Amiodarone in the management of cardiac arrhythmias: current concepts.

This article reviews current information on the clinical pharmacology, therapeutic utility, and adverse reactions of amiodarone, with emphasis on guidelines for its rational use.

Angiotensin-converting enzyme inhibitors.

There is convincing evidence that ACE inhibitors, alone or in combination with a diuretic, effectively lower blood pressure in patients with all grades of essential or renovascular hypertension and that they are of particular benefit as adjunctive therapy in patients with congestive heart failure. The hemodynamic, hormonal and clinical effects of the presently available ACE inhibitors, captopril and enalapril, are comparable and their side effect profiles are extremely favorable. One important difference between the two oral ACE inhibitors, however, is their pharmacokinetics; enalapril's action is slower to begin and is of longer duration. Compared with other agents, ACE inhibitors offer important advantages, among them an improved feeling of well being. It is, therefore, expected that ACE inhibitors will gain greater acceptance by patients and physicians in the future.

Amiodarone therapy: role of early and late electrophysiologic studies.

Forty-two patients with a history of symptomatic ventricular tachycardia or cardiac arrest underwent electrophysiologic testing at control and early in the course of amiodarone therapy (mean 12 +/- 7 days). Late electrophysiologic studies (mean 17 +/- 4 weeks) were repeated in 23 patients on a maintenance dose of 400 mg/day. At control study, all patients had inducible ventricular tachyarrhythmias (sustained ventricular tachycardia in 35, nonsustained ventricular tachycardia in 4, ventricular fibrillation in 3), while after amiodarone loading (1,200 mg daily) 4 (10.5%) of the 42 patients developed noninducible ventricular arrhythmias. At late study, an additional 6 (26%) of the 23 patients with inducible arrhythmias at early study developed noninducible arrhythmias. The cycle length of induced ventricular tachycardia increased from 275 +/- 61 ms at control study to 340 +/- 58 ms at early study (p = 0.001). A further increase in ventricular tachycardia cycle length was noted in patients who underwent both early and late study (341 +/- 38 versus 375 +/- 63 ms, p less than 0.05). The percent of induced tachycardias that were clinically tolerated increased as patients were treated longer with amiodarone (control = 22%, early = 34%, late = 53%, p less than 0.001). Of the 23 patients who had both early and late electrophysiologic studies and were followed up for a mean of 21.7 months (range 4 to 47), there were no recurrences among the 6 patients with noninducible arrhythmias, but there were five recurrences among the 17 patients with persistently inducible arrhythmias. None of the four patients with noninducible arrhythmias at early study had a recurrence. On the basis of these findings, it is concluded that: 1) The timing of programmed electrical stimulation will affect the results of the study in patients treated with oral amiodarone.(ABSTRACT TRUNCATED AT 250 WORDS)

Cancer family syndrome of Lynch.

This report describes a family in whom eight cancers (six colonic and two endometrial) occurred in seven relatives. The colonic cancer was diagnosed in five of the six affected patients at an unusually young age, had a predilection for the proximal colon, and was of the mucinous type in four patients. Polyposis was not found in any colon. The occurrence of cancer in this kindred is characteristic of the "cancer family syndrome" of Lynch.

Management of cardiac arrhythmias during pregnancy. Current concepts.

Cardiac arrhythmia is one of the most common reasons for cardiac consultation during pregnancy. Fortunately, malignant arrhythmias during the course of normal gestation are rare, and the relatively common complaint of palpitations is usually due to benign arrhythmias. However, in pregnant patients with organic heart disease, arrhythmias are often triggered by the haemodynamic burden of pregnancy and may be the first manifestation of the disease. In addition, rhythm abnormalities in patients with limited cardiac reserves may have significant haemodynamic consequences and can compromise fetal well-being. Any woman who presents with rhythm disorders during pregnancy should undergo a diagnostic evaluation to rule out an underlying disease, including cardiac, pulmonary, endocrine, or metabolic disease. Additionally, removal of precipitating factors, such as excessive ingestion of caffeine and/or alcohol, cigarette smoking, drug abuse or therapy with arrhythmogenic compounds, is indicated (as these measures are desirable in any pregnant woman). Antiarrhythmic drug therapy is indicated in such patients only in symptomatic or haemodynamically significant arrhythmias. In cases where organic heart disease or any other cause for arrhythmia is identified, the underlying disease should be treated first. Antiarrhythmic drug therapy is indicated when arrhythmias persist or as a prophylactic measure. In principle, the approach to drug therapy in pregnant patients is similar to that in non-pregnant patients. However, special consideration should be given to drug selection in order to avoid adverse effects to the fetus. Those antiarrhythmics that have been shown to be relatively safe during pregnancy include digoxin, quinidine, procainamide, some beta-blocking drugs and lignocaine (lidocaine). In addition to careful drug selection, the smallest effective dose should be used and the indication for antiarrhythmic therapy should be periodically reassessed during the course of pregnancy.

Lack of effect of multiple doses of cimetidine on estimated hepatic blood flow.

Conflicting data exists regarding the effect of the H2-receptor blocking agent cimetidine on hepatic blood flow (HBF). The variance in the results of these studies may be due in part to differences in the duration of cimetidine administration, the posture of the volunteers during their course of study, and the method used to estimate HBF. To assess the effects of chronic cimetidine (300 mg q.i.d. X 4 days) on estimated HBF while controlling posture (supine and standing), a double-blind, placebo-controlled, repeated measures study was performed in 9 healthy males. Indocyanine green (ICG) plasma clearance after an i.v. dose of 0.5 mg kg-1 was used to calculate HBF. ICG plasma concentrations were measured by HPLC. Compared to placebo treatment, cimetidine had no effect on mean (SD) estimated HBF (ml min-1 m-2) in either the supine (497 (64) vs 494 (80] or the standing (443 (117) vs 404 (89] posture. These data had a power greater than 0.8 to detect a treatment effect of 20 per cent. Standing produced a significant decrease in estimated HBF (496 (70) vs 424 (102); p less than 0.01). In contrast to previous reports, chronic cimetidine treatment had no apparent effect on hepatic blood flow.

Double-blind comparison of captopril and enalapril in mild to moderate hypertension.

To compare the antihypertensive and humoral effects of the angiotensin-converting enzyme inhibitors captopril and enalapril, 20 patients with essential hypertension, not receiving treatment for 2 weeks and consuming a prescribed sodium ion intake, were randomly assigned to two parallel, double-blind treatment groups with stratification based on race and untreated seated diastolic blood pressure. These groups received a placebo (day -1) followed by either captopril, 200 mg every 12 hours (n = 9), or enalapril maleate, 20 mg every 12 hours (n = 11), alone (days 1 to 14) and then with hydrochlorothiazide, 25 mg every 12 hours (days 16 to 28). Captopril and enalapril were coadministered alone (day 15) and with hydrochlorothiazide (day 29) to assess whether further decreases in blood pressure would occur. Captopril and enalapril alone caused comparable decreases (p less than 0.05) in the mean 12 hour time-averaged seated diastolic blood pressure from values on day -1 (placebo), on day 1 (11 and 9 mm Hg, respectively) and day 14 (8 and 7 mm Hg, respectively). The addition of hydrochlorothiazide further decreased (p less than 0.05) blood pressure in each group (7 and 8 mm Hg, respectively) from values on day 14. Combined use of captopril and enalapril did not result in further reduction. Coupled with the comparable changes observed in each treatment group in serum angiotensin-converting enzyme activity, plasma renin activity and plasma aldosterone concentration, these data support the view that captopril and enalapril have similar antihypertensive effects and mechanisms.