William J. Louis

Atrial Fibrillation After Coronary Artery Bypass Grafting Is Associated With Sympathetic Activation

BACKGROUND We prospectively investigated the role of sympathetic activation in the etiology of atrial fibrillation following coronary artery bypass grafting. METHODS Continuous ambulatory monitoring was performed for 80 hours in 131 patients after coronary artery bypass grafting. Right atrial plasma norepinephrine levels were assessed preoperatively and every 4 hours for 48 hours postoperatively. RESULTS Of the 131 patients, 50% (65) had development of atrial fibrillation and 36% (47) required treatment. Onset of atrial fibrillation was preceded by a significant increase in sinus rate and atrial ectopic activity. On multivariate logistic regression, elevated mean postoperative norepinephrine levels (5.78 +/- 2.83 versus 3.57 +/- 1.31 nmol/L; p < 0.0001), increased age (68.9 +/- 5.7 versus 63.8 +/- 8.7 years; p = 0.02), and decreased postoperative magnesium levels (0.79 +/- 0.09 versus 0.83 +/- 0.10 mmol/L; p = 0.02) were independently associated with the occurrence of atrial fibrillation. CONCLUSIONS Elevated norepinephrine levels suggest that sympathetic activation may be important in the pathogenesis of atrial fibrillation after coronary artery bypass grafting, and this underlines the importance of beta-adrenoceptor blockade as prophylaxis.

Plasma Norepinephrine Levels in Essential Hypertension

Abstract In 31 patients with essential hypertension there was a close relation between resting diastolic blood pressure and basal plasma norepinephrine concentrations (r = 0.741, p < 0.001). After ...

Paired associate performance in the early detection of DAT.

Subjects underwent longitudinal neuropsychological assessment in order to retrospectively determine which measures of cognitive function best predicted later development of dementia of the Alzheimer type (DAT). Three groups of subjects were studied: normal controls, patients with early DAT, and questionable dementia subjects (QD). All subjects were assessed using a battery of standard neuropsychological measures and two subtests from the Cambridge Neuropsychological Test Automated Battery (CANTAB), paired associate learning and delayed matching to sample. A structured interview was also used to elicit a profile of the subjects daily functioning. Subjects were assessed every 6 months for 2 years. At the 6 month assessment, almost half of the QD group exhibited significant deterioration in scores on the computerized paired associate learning subtest, while maintaining their scores on standard measures. At the conclusion of the study, all of this QD subgroup fulfilled the NINCDS-ADRDA criteria for probable DAT pertaining to significant cognitive and functional deterioration. Performance on the C

Omeprazole: A Study of Its Inhibition of Gastric pH and Oral Pharmacokinetics After Morning or Evening Dosage

Pharmacodynamic and pharmacokinetic studies of omeprazole, a new gastric antisecretory agent, were undertaken in 8 healthy subjects. The drug was administered orally as an encapsulated enteric-coated granulate (40 mg daily at 9 am or 9 pm for 5 days), and its effect on the integrated 24-h gastric pH was determined, together with its apparent bioavailability. The pretreatment 24-h median pH was 1.9 (interquartile range 1.4-2.9). After 5 days of treatment, the median pH had risen to 5.0 (3.7-6.0) (p less than 0.01) with morning dosage and 4.5 (3.0-5.6) (p less than 0.01) with evening dosage. This corresponded to a greater than 99% reduction in 24-h median hydrogen ion activity, with morning dosage having a greater effect (from 9 am to 8 pm) (p less than 0.01) than evening dosage. The relative bioavailability of omeprazole increased twofold from day 1 to day 5 of treatment with morning dosage (p less than 0.02) and threefold with evening dosage (p less than 0.02), suggesting that increased absorption of this acid-labile drug occurs with increasing inhibition of acid secretion. We conclude that this formulation of omeprazole presently being used in clinical trials is a highly potent antisecretory agent in humans, although its optimal effect may not be observed for several days.

Perhexiline maleate treatment for severe angina pectoris — correlations with pharmacokinetics

Perhexiline maleate, which causes inhibition of myocardial fatty acid catabolism with a concomitant increase in glucose utilization, is particularly useful in the management of patients with severe angina pectoris. While perhexiline exerts no significant negative inotropic or dromotropic effects, its short- and long-term use has hitherto been restricted because of complex pharmacokinetics and the eventual development, in many patients, of hepatitis and peripheral neuropathy. Correlations between perhexiline dose, plasma drug concentrations, efficacy and development of toxicity were examined prospectively in 3 groups of patients. The first group (n = 29) were patients in whom perhexiline was added to previously prescribed anti-anginal medication for short-term (pre-surgical or post-myocardial infarction) control of angina pectoris. Over a mean treatment period of 18 +/- 2 (SEM) days, 13 patients experienced a marked reduction in frequency and severity of attacks. No adverse effects occurred. A second group of patients (n = 19) were treated chronically with 50-400 mg/day of perhexiline, dosage being adjusted to minimize symptoms. Over a mean treatment period of 8.8 +/- 1.7 months, 5 patients became asymptomatic, while 9 developed evidence of hepatitis or neurotoxicity, with concomitant plasma perhexiline concentrations of 720-2680 ng/ml. Subsequently, a further group of similar patients (n = 22) were treated for 12.4 +/- 2.6 months, perhexiline dosage being adjusted to maintain plasma perhexiline concentrations below 600 ng/ml. Nine patients became asymptomatic, while none developed adverse effects. It is concluded that perhexiline is useful both as a short-term adjunct to anti-anginal therapy and in the long-term management of patients unsuitable for coronary artery bypass grafting. The risk of long-term toxicity can be reduced markedly by maintenance of plasma drug concentrations below 600 ng/ml without significantly compromising anti-anginal efficacy.

Fluorouracil therapy in patients with carcinoma of the large bowel: a pharmacokinetic comparison of various rates and routes of administration.

SummaryThe pharmacokinetics of fluorouracil after oral, intravenous and rectal administration were compared in 12 patients with colorectal cancers.Oral administration of 10 to 15mg/kg gave variable plasma levels (0 to 10.5μg/ml) and bioavailability (0 to 74%; mean 28%). Bioavailability increased markedly with increases in dose, suggesting saturation of the ‘frst pass’ hepatic metabolism of the drug. Differences in bioavailability could not be related to standard liver function tests or the presence of metastatic deposits i the liver.Plasma levels were not detectable after rectal administration in the 4 patients studied and were very low (0 to 8μg/ml) during high dose (20 to 30mg/kg/24h) slow intravenous infusion in 6 patients.These findings indicate that different dose schedules and routes of administration produce markedly different plasma levels. They suggest that the rate of degradation of fluorouracil by the liver is quite variable and may become saturated with increasing dose. For these reasons monitoring of plasma levels of the drug in individual patients may be useful.

Medial prefrontal cortical lesions modulate baroreflex sensitivity in the rat

Previous neuroanatomical studies in rats have demonstrated that the medial prefrontal cortex sends projections to the nucleus of the solitary tract which also receives the bulk of baroreceptor information from primary afferents within the IXth and Xth cranial nerves. The present study examines the influence of the prefrontal cortex on baroreceptor heart rate reflex in conscious rats. Baroreceptor reflex activity was examined in rats with bilateral excitotoxin (N-methyl-D-aspartate)-induced lesions of the medial prefrontal cortex and in control rats (artificial cerebrospinal fluid). Seventeen to eighteen days after lesioning, reflex heart rate responses were recorded following intravenous bolus doses of the pressor agent phenylephrine and the depressor agent sodium nitroprusside. Baroreceptor reflex parameters i.e., maximum and average baroreceptor reflex gain (or sensitivity): minimum and maximum heart rate plateaus; heart rate range; upper and lower reflex thresholds, were determined by sigmoidal computerized curve-fitting. Lesioning the medial prefrontal cortex did not affect resting mean arterial pressure and heart rate. However, the lesion reduced maximum and average baroreceptor reflex gain and produced a small reduction in lower reflex threshold. The other parameters were unaffected by the lesion. These observations suggest that although the medial prefrontal cortex does not exert a tonic influence on brainstem vasomotor neurons, there may be a descending excitatory projection from this brain region to medullary neurones involved in the baroreceptor reflex arc.

Combined use of nitroglycerin and N-acetylcysteine in the management of unstable angina pectoris.

The vasodilator effects of nitroglycerin (NTG) are mediated via activation of guanylate cyclase; this process is believed to require the availability of free sulfhydryl groups. Previous studies in man have shown that the sulfhydryl donor N-acetylcysteine (NAC) potentiates the systemic and coronary vasodilator effects of NTG. Furthermore, interaction of NTG and NAC may lead to the formation of S-nitroso-NAC, which strongly inhibits platelet aggregation. The effects of intravenous NTG combined with intravenous NAC (5 g 6 hourly) were compared with those of intravenous NTG alone in a double-blind trial in 46 patients with severe unstable angina pectoris unresponsive to conventional treatment, which included calcium antagonists and cutaneous nitrates in all but one patient. Treatment with NTG/NAC (24 patients) and that with NTG alone (22 patients) was associated with a similar frequency of episodes of chest pain and of increments in NTG infusion rate for pain control (10 vs 17; p = NS). The NTG/NAC group had a significantly lower incidence of acute myocardial infarction than the NTG/placebo group (three vs 10 patients; p = .013). Symptomatic hypotension occurred frequently in the NTG/NAC group (seven vs 0 patients; p = .006). Lactate-pyruvate ratios and venous NTG concentrations were not significantly affected by NAC. Subsequently, another 20 consecutive patients were treated with intravenous NTG and continuously infused NAC (10 g/day). Seven remained pain free during the first 24 hr of NTG infusion; 11 required increments in NTG infusion rate for pain control. Acute myocardial infarction occurred in one patient, while none developed symptomatic hypotension.(ABSTRACT TRUNCATED AT 250 WORDS)

Genealogy of the spontaneously hypertensive rat and Wistar-Kyoto rat strains : implications for studies of inherited hypertension

The spontaneously hypertensive rat (SHR) is the most commonly used animal model of hypertension. For many years, it has been widely accepted that the most appropriate control strain is the Wistar-Kyoto (WKY) rat to which SHR rats are genetically related. However, recent concerns have been raised about genetic differences between the various colonies of SHRs and, in particular, genetic differences between colonies of WKY rats. It has been further emphasized that the only way to establish that a genetic trait is an etiological factor in the development of hypertension is through studies of F2 backcrosses between SHR and WKY rats. The present article details the history of the SHR and WKY strains and demonstrates why there is high likelihood of genetic variability between rats of both strains from different colonies around the world. It suggests that the WKY strain is not the most suitable for backcross studies because of the incidence of spontaneous hypertension and the somewhat higher levels of blood pressure in these rats. A central reference strain is proposed using SHRs inbred at Kyoto University, where brother/sister inbreeding has continued for more than 80 generations.

Effects of pravastatin on cardiovascular reactivity to norepinephrine and angiotensin II in patients with hypercholesterolemia and systemic hypertension.

This study was conducted to examine the effects of short-term cholesterol reduction on cardiovascular reactivity in mildly hypertensive patients. Seven male and 7 female patients, aged 34 to 68 years, received pravastatin (40 mg/day) or matched placebo for 3 weeks in a randomized, double-blind, crossover study. Cardiovascular reactivity was assessed by measurement of blood pressure (BP) responses to incremental infusions of angiotensin II and norepinephrine, by cold pressor testing and isometric exercise. Compared with placebo, pravastatin caused significant reductions in plasma total and low-density lipoprotein cholesterol levels, which averaged 20% and 31%, respectively (both p < 0.0001), and in diastolic BP responses (expressed as the infusion rate required to raise BP by 20 mm Hg) to both angiotensin II (7.3 +/- 3.0 vs 9.7 +/- 4.7 ng/kg/min, p = 0.05) and norepinephrine (0.15 +/- 0.13 vs 0.38 +/- 0.33 micrograms/kg/min, p = 0.03). Systolic BP responses were similar with both treatments. Body weight, resting BP, and maximal BP responses to physical stressors were similar with each treatment.