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1 The pharmacokinetic parameters of morphine were determined in a crossover fashion following 4 days pretreatment with cimetidine, 300 mg every 6 h, or placebo. 2 Cimetidine had no apparent effect on the mean morphine plasma clearance, volume of distribution, AUC or half-life (P greater than 0.05; power greater than 0.80). 3 Cimetidine had no apparent effect on the magnitude or duration of morphine induced miosis. 4 The absence of a demonstrable effect on the pharmacokinetics of a drug with a high extraction ratio such as morphine suggests that cimetidine did not significantly reduce hepatic blood flow in ambulant normal volunteers. [ABSTRACT FROM AUTHOR]

Competing Interests: Disclosures The author has no conflicts of interest to disclose.

Background/aims: To determine whether bezafibrates have adverse effects on renal function., Methods: (1) A 3-year retrospective survey of 526 patients who were on bezafibrate for a while and 614 controls following fluctuations of serum creatinine levels. (2) A prospective study on 33 patients with previous evidence of bezafibrate-induced elevation in serum creatinine. The patients were examined after 3 months on bezafibrate 400 mg/day and then after 3 months without bezafibrate. Eight patients repeated the tests after 3 months on bezafibrate 200 mg/day., Results: Retrospective: 295 bezafibrate-treated patients (56%) and 67 controls (11%) demonstrated fluctuations > or = 0.2 mg/dl in serum creatinine levels (p < 0.001); 113 patients (21%) and 16 controls (3%) showed fluctuations > or = 0.3 mg/dl (p < 0.001). Prospective: bezafibrate 400 mg/dl increased serum creatinine from 1.16 +/- 0.19 to 1.42 +/- 0.2 mg/dl (p < 0.001) and urea from 37 +/- 8 to 44 +/- 8 mg/dl (p < 0.001); creatinine clearance (Ccr) decreased from 104 +/- 23 to 82 +/- 27 ml/min (p < 0.001). CPK increased from 82 +/- 32 to 130 +/-58 mg/dl (p < 0.0001) and urinary myoglobin increased from 95.4 +/- 21 to 199 +/- 99 mg/dl (p < 0.0001). The 8 patients given bezafibrate 200 mg/dl experienced similar dose-dependent changes., Conclusions: Bezafibrate causes quiet common, dose-dependent and reversible changes in serum creatinine in patients with normal renal function, associated with a significant increase in serum CPK and urine myoglobin, suggestive of drug-induced mild subclinical skeletal muscle injury compromising renal function.

This review article discusses pharmacological approaches to optimizing myocardial metabolism during ischemia. Fatty acids are the main fuel for the healthy heart, with a lesser contribution coming from the oxidation of glucose and lactate. Myocardial ischaemia dramatically alters fuel metabolism, causing an accelerated rate of glucose conversion to lactate and a switch from lactate uptake by the heart to lactate production. This causes a dramatic disruption in cell homeostasis (e.g. lactate accumulation and a decrease in pH and ATP). Paradoxically, moderately ischemic tissue (approximately 50% of normal flow) continues to derive most of its energy (50-70%) from the oxidation of fatty acids despite a high rate of lactate production. This ischaemia-induced disruption in cardiac metabolism can be minimized by metabolic agents that reduce fatty acid oxidation and increase the combustion of glucose and lactate, resulting in clinical benefit to the ischemic patient. Agents that inhibit fatty acid beta-oxidation, such as ranolazine and trimetazidine, have proven to be effective in the treatment of stable angina. Treatment of acute myocardial infarction patients with an infusion of the glucose-insulin-potassium, which results in suppression of myocardial fatty acid oxidation and greater glucose combustion, has proven effective in reducing mortality. These metabolic therapies are free of direct hemodynamic or chronotropic effects, and thus are well positioned for use alongside traditional agents such as beta-adrenergic receptor antagonists or calcium channel antagonists.

Background: The majority of patients with Alzheimer's disease (AD) or vascular dementia display, in addition to cognitive impairment, various degrees of behavioral disturbances. As the use of cholinesterase inhibitors for the treatment of cognitive impairment in dementia becomes widespread, many of these patients will be treated concomitantly with cholinesterase inhibitors and with anti-psychotic drugs to ameliorate behavioral disturbances. Despite the widespread use of this combination in clinical practice, the safety and tolerability of such combination therapy has not been evaluated in controlled clinical trials. This pilot study examined the effects of addition of risperidone 0.5-2 mg/day to patients on rivastigmine 3-12 mg/day, and vice versa., Methods: 65 patients suffering from AD, 10 from vascular dementia, and 15 from both were randomized to open label rivastigmine and risperidone, alone or in combination, for 20 weeks. Adverse events caused by co-administration were assessed., Results: No clinically relevant adverse interactions were observed., Conclusions: These preliminary results indicate that rivastigmine and risperidone can be safely co-administered. Confirmation of these results in large clinical trials studies is warranted., (Copyright 2002 John Wiley & Sons, Ltd.)

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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)

Sulindac, a nonsteroidal anti-inflammatory agent, is converted to a bioactive sulfide metabolite via reversible reduction of its sulfoxide moiety. To test whether DMSO can inhibit conversion of sulindac to its active form, eight healthy men received, in a randomized, crossover manner, 400 mg of sulindac, orally, either alone or 60 min after an oral dose of DMSO (30 ml, 70% solution). After the drug combination, mean plasma concentrations of the sulfide metabolite were significantly lower than in controls at 1.5, 2, 3, 4, and 8 hr after sulindac administration. The mean area under the plasma sulfide concentration-time curve for 0 to 12 hr was 30% (range 7% to 56%) lower after DMSO treatment. This study suggests that DMSO can inhibit metabolism of other sulfoxides in man and may antagonize the therapeutic efficacy of sulindac.

Bucindolol is a newly developed, nonselective beta-adrenergic blocking agent with intrinsic sympathomimetic activity and direct vasodilator properties. In 14 patients with mild to moderate essential hypertension, the effects of bucindolol, hydrochlorothiazide and their combination on blood pressure (BP), heart rate (HR) and parameters of the renin-aldosterone system were compared with those after placebo. Bucindolol's antihypertensive effect was evident within the first hour after drug administration, maximal at 2 to 3 hours, and lasted for as long as 12 hours. Compared with placebo values (108 +/- 5 mm Hg), both bucindolol (97 +/- 9 mm Hg) and hydrochlorothiazide (99 +/- 10 mm Hg) alone significantly and comparably reduced the 12-hour averaged standing diastolic BP, with the combination resulting in approximately additive effects (91 +/- 9 mm Hg). Although bucindolol alone did not affect HR, it attenuated the hydrochlorothiazide-induced increase in HR. There was a tendency for bucindolol to decrease plasma renin activity. Except for transient postural hypotension in 2 patients, bucindolol was well tolerated.

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.

We compared the effect of two commonly prescribed nonsteroidal anti-inflammatory drugs, ibuprofen and sulindac, and placebo on intravenous furosemide-induced natriuresis and renin stimulation in 11 healthy male volunteers, consuming a 100 mEq sodium, 80 mEq potassium diet. Chronic (6-day) therapy with each agent was followed by a 1-week washout period. There were no significant treatment-related differences in either urine volume or sodium excretion for any of the designated collection periods or for the cumulative value for the 4 h after furosemide administration. Similarly, differences among groups were not observed for creatinine clearance, urinary potassium and urinary chloride excretion. Mean basal plasma renin activity levels prior to furosemide administration on day 6 were significantly lower in the presence of ibuprofen (1.5 +/- 2.0 ng/ml/h;p less than 0.01) and sulindac (2,3 +/- 0.9 ng/ml/h; p less than 0.05), compared with placebo (3.3 +/- 1.1 ng/ml/h); the difference between the two NSAIDs was also significant (p less than 0.05). Mean plasma renin activity levels in the 4 h after furosemide increased significantly at all time points in comparison to basal values, but were significantly less for ibuprofen and sulindac groups in the first hour. Our data suggest that the natriuresis following intravenous furosemide in men consuming a normal sodium intake is not prostaglandin-dependent. Furthermore, the observation that sulindac suppressed basal and stimulated plasma renin activity levels, albeit to a lesser extent than ibuprofen, questions the claim that sulindac "spares' the kidney and compels further evaluation of this issue.

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.

Indacrinone is an investigational loop-acting diuretic. To evaluate the natriuretic and uricosuric effects of varying ratios of its enantiomers, 10 healthy men, on a controlled Na+ (100 mEq) and K+ (80 mEq) diet, participated in a double-blind, randomized, balanced incomplete block, multiple-dose (one week) study of a fixed daily dose (10 mg) of (-) enantiomer combined with increasing doses (40, 90 and 140 mg) of (+) enantiomer versus 50 mg hydrochlorothiazide and placebo. On day 1, mean 24-h urinary Na+ increased (p less than 0.01) comparably (approximately 285 mEq) after each enantiomer combination and hydrochlorothiazide; however, the enantiomer combinations had marked uricosuric and hypouricemic effects that were enhanced with increased (+) enantiomer doses. By day 7, while enantiomer combinations and hydrochlorothiazide demonstrated comparable natriuretic activity, mean serum uric acid levels (mg/dl), in comparison to placebo, were increased (p less than 0.05) with hydrochlorothiazide but progressively decreased with increases in (+) enantiomer. Thus varying the ratio [(+, uricosuric): (-, natriuretic)] of the enantiomers of indacrinone caused natriuresis similar to hydrochlorothiazide, but had an opposite effect on serum uric acid.

The effect on arterial pressure of incremental doses of norepinephrine (2 to 10 micrograms/min) and angiotensin II (50 to 800 ng/min) administered over 10 min periods was studied in sodium-replete hypertensive patients after crossover oral treatments with placebo, captopril 50 mg in a single dose, captopril 50 mg three times daily for one week and hydrochlorothiazide 50 mg daily for a week. Neither captopril nor hydrochlorothiazide affected the dose response to infusions of angiotensin II. In comparison to placebo responses, however, both single and multiple-dose captopril therapy, and hydrochlorothiazide attenuated the pressor responses to infusions of norepinephrine. Captopril significantly depressed angiotensin converting enzyme activity from pre-dose levels and angiotensin II infusions significantly elevated plasma aldosterone concentrations. These results confirm findings reported for single dose captopril in normotensive volunteers and indicate that attenuation of the vascular responsiveness to sympathetic stimulation may contribute to the antihypertensive effects of captopril and hydrochlorothiazide therapy.

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.

Although only recently introduced, angiotensin-converting enzyme inhibitors have been utilized to treat a wide variety of clinical disorders. Their uses to date, approved by the Food and Drug Administration, have been in the treatment of refractory hypertension and congestive heart failure. However, they have been evaluated with mixed results in numerous other conditions in which the renin-angiotensin-aldosterone system may play a role. Their current status in the treatment of hypertension, congestive heart failure, and these other conditions is reviewed.

Calcium-entry blockers have proven efficacy in a variety of cardiovascular disorders. The effects of these agents on ionic calcium fluxes and, thus, on smooth-muscle contraction suggest that several noncardiac conditions involving smooth-muscle dysfunction may be managed with calcium antagonists. Beneficial therapeutic results have been reported in various forms of hypertension and Raynaud's phenomenon. The results of preliminary studies in treating pulmonary hypertension, cerebral arterial spasm, migraine headache, esophageal motility disorders, and myometrial hypercontractile states are encouraging. Carefully designed, large-scale and long-term clinical trials are needed to establish the therapeutic value of calcium-entry blockers in these disorders.

In a retrospective study of 304 patients with acute transmural myocardial infarction admitted to the coronary care unit, 22 percent (67 patients) exhibited low voltage on their electrocardiograms within 72 hours of admission. The course of hospitalization of these patients was compared with an equal number of consecutive patients with transmural infarctions and normal electrocardiographic voltages. Among the patients with low voltage, there was a significantly higher incidence of previous infarction or present extensive infarction, congestive heart failure, and cardiogenic shock. This group of patients also demonstrated a markedly higher mortality. This study substantiates the clinical impression that acute myocardial infarction complicated by a low-voltage ECG implies a poor prognosis. It is speculated that this electrocardiographic pattern may reflect decreased ventricular performance as a result of widespread myocardial damage.

A prognostic profile for patients with acute myocardial infarction (AMI) treated in a coronary care unit has been constructed by applying a modified sequential statistical analysis. The profile represents a dynamic system which enables the physician to predict hospital prognosis simply and rapidly on the basis of daily changing clinical and laboratory parameters. The procedure was tested prospectively on a population of AMI patients and was found to be a reliable prognostic tool. Comparing this scale with that of popular prognostic indices, it was found that prediction was more accurate with this technique.

Single doses of norfloxacin (200, 400, 800, 1,200, and 1,600 mg) or placebo were administered orally at weekly intervals to 14 healthy male volunteers in a double-blind study. Norfloxacin was measured in serum and urine by high-pressure liquid chromatography with UV detection. The concentrations of this drug in serum peaked 1 to 2 h after each dose; the mean peak values for increasing doses were 0.75, 1.58, 2.41, 3.15, and 3.87 micrograms/ml. Mean area under the serum concentration-time curves for the first 12 h after each dose were 3.56, 6.26, 11.4, 16.1, and 19.7 micrograms . h/ml, respectively. The elimination half-life of norfloxacin was about 7 h and was similar for all doses. The concentrations of the drug in urine also peaked 1 to 2 h after dosage; mean peak values for increasing doses were 200, 478, 697, 992, and 1,045 micrograms/ml. Renal clearances approximated 285 ml/min. About 30% of each dose was excreted into urine as unmetabolized norfloxacin. Crystals of the drug were occasionally observed during microscopic examination of freshly voided urine collected after the 1,200- and 1,600-mg doses. Crystalluria was not encountered at lower doses.

The efficacy and safety of low-dose guanadrel sulfate were evaluated in 20 patients with essential hypertension based on seated diastolic blood pressures (SDBP) ranging from 95 to 115 mm Hg despite a trial dosage of hydrochlorothiazide 50 mg/d for up to five weeks. These patients had been resistant to, or intolerant of, one or more step-two antihypertensive drugs in the past (i.e., methyldopa, beta-adrenergic blocking agents, clonidine, or prazosin). The majority of patients demonstrated a satisfactory response (SDBP 95 mm Hg or reduction in SDBP of 10 mm Hg) to guanadrel. Nine patients responded at a low dosage, 10 to 20 mg/d and remained free from adverse effects throughout the study (up to 12 weeks of treatment). Of the remaining 11 patients titrated to higher dosages of guanadrel (30 to 60 mg/d), three had no discernible response while six developed adverse effects. The results of the study suggest that guanadrel has an acceptable benefit-to-risk ratio only when used in low dosages (10 to 30 mg/d) and may be successfully employed as step-two antihypertensive therapy in patients resistant to, or intolerant of, other step-two agents.

The purpose of the present report is to review the available pharmacokinetic information on amiodarone with an emphasis on our own experience in monitoring serum amiodarone concentrations. We have found that 400 mg should be the maximal maintenance dose; if that treatment fails, careful addition of other antiarrhythmic agents is preferable over an increase in amiodarone dosage. Serum concentrations below 2.5 mg/L will significantly improve amiodarone's benefit-to-risk ratio.

The relationship between morphine plasma concentration and pupil diameter was evaluated 2-10 h following intravenous administration of morphine sulfate (10 mg). Seven healthy male volunteers received 10 mg of morphine intravenously following pretreatment for 4 d with either cimetidine (300 mg po four times a day) or placebo in a single blind, balanced crossover study. Pupil diameters were measured directly from contact prints using calipers and a photographed millimeter scale. Cimetidine pretreatment had no significant effect on pupil size either before or after morphine administration or on morphine pharmacokinetics. The relationship between morphine plasma concentration (2-10 h postdose) and pupil diameter was evaluated from the pooled data from both morphine treatment periods by perpendicular least-square regression. In each individual, a strong relationship existed between morphine plasma concentrations and pupil diameter (r = -0.76 to -0.91; p less than 0.05). Weaker correlations for both pupil diameter (r = -0.65; p less than 0.0001) and the absolute change in pupil diameter from baseline (r = 0.72; p less than 0.0001) for the grouped data probably reflect intersubject variation in morphine sensitivity. Thus, the miotic response to an intravenous dose of morphine varies in proportion to morphine plasma concentration.

The intravenous administration of chlorpromazine in 12 patients with acute myocardial infarction and altered pump function was followed by a significant reduction in systemic vascular resistance (28.4%) and an increased cardiac index (23.0%). The drug also produced a significant decline in mean pulmonary capillary wedge pressure (38.2%), while the heart rate and mean stroke work index did not change significantly. Although the mean blood pressure decreased by 18.3%, the transymocardial pressure gradient was not affected. A significant reduction in the major determinants of myocardial oxygen consumption, such as arterial blood pressure and left ventricular wall tension, suggested a decrease in myocardial demand for oxygen. Improvement of left ventricular performance was associated with a sedative effect in most of the patients. Intravenous administration of chlorpromazine proved to be of benefit in patients with moderate to severe congestive heart failure and cardiogenic shock.

MK-521 is a new orally active, nonsulfhydryl angiotensin-converting enzyme (ACE) inhibitor. Single doses of 2.5, 5.0, 10.0, and 20.0 mg were administered to nine hypertensive patients alternating with placebo. All doses of MK-521 caused profound suppression of ACE activity for more than 24 h and decreased standing diastolic blood pressure for more than 12 h without changes in pulse rate. Although there was no further reduction in blood pressure with doses above 5.0 mg, the duration of action was prolonged for more than 24 h with the higher doses. Serum MK-521 concentrations increased with dosage, and ACE was inhibited maximally at concentrations above 10 ng/ml. In this initial study, MK-521 was well tolerated and proved to be a potent and long-acting antihypertensive agent.

The efficacy of captopril treatment was compared with that of propranolol in a single-blind crossover study in 14 patients with essential hypertension uncontrolled on diuretic alone. Both captopril (37.5 to 75 mg daily) and propranolol (60 to 120 mg daily), in combination with hydrochlorothiazide (50 mg daily), caused a significant fall in sitting systolic and diastolic blood pressure. Heart rate, plasma renin activity, and plasma aldosterone data were consistent with the effects of converting enzyme inhibition or beta blockade. Both drugs were well tolerated. Captopril appeared to be equivalent in efficacy and safety to propranolol when added to hydrochlorothiazide. It may be considered as an alternative step 2 antihypertensive agent, especially in patients experiencing unwanted effects on beta blockers.

Current evidence for the role of immune mechanisms in drug-induced liver disease is briefly surveyed. Cell-mediated immune reactions are frequently reported in the disease process, while humoral sensitization is poorly documented. The use and limitations of new diagnostic techniques in identifying drug hypersensitivity are discussed.