G. Dennis Johnston

Clinical pharmacologic observations on atenolol, a beta‐adrenoceptor blocker

The effects of oral and intravenous administration of atenolol were studied in healthy volunteers. The oral administration of aseries of single doses of atenolol reduced an exercise tachycardia. After a 200‐mg dose, the effect on an exercise tachycardia was maximal at 3 hr and declined linearly with time at a rate of approximately 10% per 24 hr. The peak plasma atenolol concentration occurred at 3 hr and thereafter declined exponentially with time with an elimination half‐life of 6.36 ± 0.55 hr: 43 ± 3.9% of the dose was excreted in the urine within 72 hr. There was a correlation between the reduction in an exercise tachycardia and the logarithm of the corresponding plasma concentration. The intravenous administration of atenolol reduced exercise tachycardia with a signi(icant correlation between effect and plasma concentration. After 50 mg intravenously, 100% of the dose was recoveredfrom the urine, ami the clearance was 97.3 ml/min. Comparison of AUCo→x after oral and intravenous administration of 50 mg showed the bioavailability to be 63% after oral drug. Repeated oral administration of atenolol 200 mg daily either as a single dose or in divided 12 hourly doses for 8 days maintained reduction of an exercise tachycardia of at least 24% during the period of drug administration. The plasma elimination half‐life, area under the plasma concentration‐time curve, and peak plasma concentration after 200 mg atenolol were not changed by chronic dosing for 8 days.

Functional consequences of endothelial nitric oxide synthase uncoupling in congestive cardiac failure.

Background—Impaired endothelium-mediated vasodilatation (EMVD) in congestive cardiac failure (CCF) has been linked to decreased nitric oxide (NO) bioavailability because of its interaction with vascular superoxide (O2·−), derived predominantly from NAD(P)H-dependent oxidases. When uncoupled from essential cofactors, endothelial nitric oxide synthase (eNOS) produces O2·−. We studied the functional consequences of eNOS uncoupling in relation to EMVD in patients with CCF. Methods and Results—We employed the platelet as a compartmentalized ex-vivo model to examine O2·− and NO production. When eNOS is functioning normally, incorporation of N&ohgr;-Nitro-l-Arginine methyl ester (L-NAME, 1 mmol/L), results in increased O2·− detection, as inhibition of NO production prevents NO scavenging of O2·−. This was observed in controls and 9 of the CCF patients, in whom O2·− detection increased by 63% and 101%, respectively. In the remaining 9 CCF patients, incorporation of L-NAME reduced O2·− production by 39%, indicating O2·− production by eNOS uncoupling. Detection of platelet-derived NO was significantly greater in eNOS-coupled platelets compared with the uncoupled group (2.8±1.4 versus 0.9±0.4 pmol/108 platelets, P =0.04). Endothelium-dependent and -independent vasodilator responses to acetylcholine and sodium nitroprusside recorded using venous occlusion plethysmography were significantly impaired in patients exhibiting eNOS uncoupling. Conclusions—This study provides first evidence that platelet eNOS can become uncoupled in human CCF. Impaired endothelium-dependent and -independent vasodilator responses and diminished platelet-derived NO production occurred in association with enzyme uncoupling.

Impaired Vasoconstriction to Endothelin 1 in Patients With NIDDM

Microvascular disease is an important cause of morbidity in diabetes. There is evidence that impaired autoregulation of blood flow is involved in the pathogenesis of diabetic microangiopathy. The vascular endothelium plays a central role in the regulation of vascular tone. Endothelin (ET)-1 is a potent endothelium-derived vasoconstrictor substance that contributes to basal vascular tone. Impaired vasoconstriction in response to endogenous ET could result in hyperperfusion and subsequent microvascular damage. The purpose of our study was to determine whether vascular responses to locally administered ET-1 are impaired in NIDDM. Nine patients with NIDDM and 12 control subjects underwent cannulation of the nondominant brachial artery. Forearm blood flow (FBF) was measured at baseline and during the drug infusion using strain-gauge venous occlusion plethysmography. ET-1 (5 pmol/min) was infused for 60 min at a rate of 1 ml/min. FBF was measured during the first 5 min of the infusion and at 5-min intervals thereafter. Results were expressed as change in FBF from baseline (ml.100 ml−1 · min−1) and were analyzed using repeated measures analysis of variance and Dunnetts test of multiple comparisons. Control subjects showed a gradual onset of vasoconstriction in response to ET-1, which reached maximum at 35 min (1.1 ml.100 ml−1 · min−1; P < 0.01). There was no reduction in FBF in response to ET-1 in the diabetic group. The differences between the diabetic and control groups were significant (P < 0.03). In conclusion, ET-1 infused locally at 5 pmol/min does not cause vasoconstriction in patients with NIDDM.

Oxidative stress and erythrocyte membrane fluidity in patients undergoing regular dialysis.

Oxidative damage due to free radical production is increased in uraemic patients and has been suggested as a possible factor contributing to the anaemia of chronic renal failure (CRF) and the pathogenesis of atherosclerosis. Oxidative stress was assessed in 40 patients with CRF maintained by either haemodialysis (HD) or continuous ambulatory peritoneal dialysis (CAPD) and in 18 healthy controls. Lipid peroxidation (assessed as malondialdehyde, MDA), total glutathione (TG), antioxidant enzyme (glutathione reductase (GSHRx), glutathione peroxidase (GSHPx) and superoxide dismutase (SOD)) activity and antioxidant associated trace metal (selenium, copper, zinc) levels were studied. Erythrocyte membrane fluidity was examined using the fluorescent probe 1,6 diphenyl-1,3,5-hexatriene (DPH). The results indicate increased levels of oxidative stress and altered erythrocyte membrane fluidity in patients treated with CAPD compared with controls and patients treated with HD. Only minor changes were observed in patients treated with HD. Altered free radical activity, oxidative stress and altered erythrocyte membrane fluidity observed in patients with CRF may contribute to the increase in vascular disease in such patients and to the anaemia of CRF.

Severity of overdose after restriction of paracetamol availability: retrospective study

Paracetamol overdose is the commonest cause of intentional self harm in the United Kingdom, accounting for approximately 70 000 cases per year.1 It is the commonest cause of acute liver failure,1 although this is rare in adults if doses of <12 g are ingested.2 To reduce this major health problem the government introduced legislation in September 1998 to limit the number of tablets in a single packet to 32 for packets sold in pharmacies and 16 in non-pharmacy outlets.3 This study assesses the impact of reduced availability of paracetamol on the number and severity of overdoses by comparing self poisoning cases in two periods of six months before and after the change to smaller packets. Patients presenting with acute self poisoning to five general hospitals in the Belfast area during the months …

Effect of dietary fish oil supplementation on peroxidation of serum lipids in patients with non-insulin dependent diabetes mellitus.

Lipid peroxidation may be important in the development of cardiovascular disease, a common cause of mortality and morbidity in non-insulin dependent diabetes mellitus (NIDDM). We assessed the degree of lipid peroxidation by measuring plasma malondialdehyde, as thiobarbituric acid reacting substances (TBARS), in 23 non-insulin diabetic patients. Plasma levels of standardised alpha-tocopherol (vitamin E), lipid content of whole plasma and lipoprotein fractions, glycosylated haemoglobin, glycosylated low density lipoprotein (LDL) and fasting blood glucose were also measured. On completion of the baseline studies patients randomly received either fish oil or matching olive oil capsules in a double blind crossover fashion for 6 weeks followed by a 6 week washout period and a final 6 week treatment phase. Studies, identical to the initial baseline studies, were performed at the end of the of the active treatment periods at 6 and 18 weeks. Treatment with olive oil did not change levels of TBARS, vitamin E or indices of glycaemic control compared with baseline. Total cholesterol and triglyceride (TG) content of plasma and lipoprotein fractions were not significantly altered. Treatment with fish oil resulted in elevation of TBARS (P < 0.001) and reduction of vitamin E (P < 0.01) compared with baseline and olive oil treatment. Plasma cholesterol was unchanged. A reduction in plasma TG compared with baseline occurred but failed to reach significance (P =0.07). Changes in apo B containing lipoproteins induced by fish oil failed to reach significance. No significant changes were observed in concentration or composition of high density lipoprotein (HDL). Fish oil treatment showed no change in glycaemic control as assessed by glycosylated haemoglobin and LDL although a rise in fasting blood glucose just failed to reach significance (P = 0.06). Lipid peroxidation in NIDDM can be exacerbated by dietary fish oil. This potentially adverse reaction may limit the therapeutic use of fish oils in such patients.

Vasoconstriction to endogenous endothelin-1 is impaired in patients with Type II diabetes mellitus

Endothelin-1 has potent vasoconstrictor and vasopressor actions contributing to basal vascular tone and maintenance of blood pressure acting predominantly through endothelin-A receptors. Endothelin antagonists may be of value in the treatment of hypertension and heart failure. However, the role of endothelin-1 in the regulation of vascular tone and the potential benefits of endothelin antagonists in non-insulin-dependent diabetes mellitus (Type II diabetes) are less clear. Vasoconstriction to exogenous endothelin-1 is impaired in Type II diabetes. The purpose of this study was to determine whether vasoconstriction to endogenous endothelin-1 acting through the endothelin-A receptor is impaired in Type II diabetes. In ten patients with Type II diabetes and nine controls the endothelin-A receptor antagonist BQ123 was infused intra-arterially at 100 nmol/min for 60 min followed by normal saline for 30 min. Forearm blood flow was measured using venous occlusion plethysmography. Control subjects showed gradual onset of vasodilation in response to BQ123 (P < 0.001). Diabetic subjects, however, showed no significant response (P > 0.05). There was a significant difference between the diabetic and control groups (P < 0.05). Blockade of the endothelin-A receptor is associated with impaired vasodilation in Type II diabetes indicating vasoconstriction to endogenous endothelin-1 mediated by the endothelin-A receptor is impaired.

Effect of Methionine Supplementation on Endothelial Function, Plasma Homocysteine, and Lipid Peroxidation

BACKGROUND Acetaminophen (paracetamol) poisoning is a major source of morbidity and mortality. It has been proposed that methionine be incorporated into acetaminophen tablets routinely as a protective mechanism. Methionine has been shown to be effective in the treatment of acetaminophen toxicity and a combination preparation of acetaminophen and methionine may prevent toxicity. However, there has been some concern that chronic methionine supplementation may be associated with vascular disease. The aim of the study was to investigate if methionine supplementation causes changes in endothelial function, plasma homocysteine, or lipid peroxidation which may be associated with atherosclerosis. METHODS Sixteen healthy volunteers were studied. Forearm blood flow in response to local intra-arterial infusion of acetylcholine to assess endothelium-dependent vasodilatation and sodium nitroprusside to assess endothelium-independent vasodilatation was measured by venous occlusion plethysmography. Plasma homocysteine and lipid peroxidation, measured as thiobarbituric acid reactive substances, were measured using high-performance liquid chromatography. Forearm vascular responses, plasma homocysteine concentrations, and thiobarbituric acid reactive substances were measured at baseline and following methionine supplementation. RESULTS There was no significant difference in endothelial-dependent vascular responses after acute (methionine 250 mg orally, p > 0.05), 1 month of low-dose (methionine 250 mg daily, p > 0.05), or 1 week of high-dose (methionine 100 mg/kg daily, p > 0.05) methionine administration. There was no significant difference in plasma homocysteine concentrations after acute (p > 0.05) or 1 month of low-dose (p > 0.05) methionine administration. However, 1 week of high-dose methionine (100 mg/kg) administration daily significantly increased homocysteine concentrations (p < 0.0015). Thiobarbituric acid reactive substances were unchanged during the period of study (p > 0.05). CONCLUSIONS Methionine supplementation does not impair endothelial-dependent vascular responses in healthy volunteers. Although high-dose methionine administration causes elevation of plasma homocysteine concentrations, doses similar to those used in combination preparations with acetaminophen do not affect plasma homocysteine concentrations.

Digoxin after myocardial infarction. Does it have a role

As far back as 1912, Herrick recommended digitalis for the treatment of acute myocardial infarction because the haemodynamic features of this disease entity resembled those of heart failure (Herrick 1912). Since then there has been considerable controversy concerning the value and possible toxicity of the digitalis glycosides in this setting. Although there is little doubt that digoxin exerts an inotropic effect (Sonnenblick et al. 1966) which is maintained long term (Arnold et al. 1980), it has been difficult to document a beneficial clinical response in several subsets of patients with congestive heart failure. Digoxin has been shown to improve ventricular function as measured by specialised tests (Smith 1973; Weissler et al. 1968) but investigations of therapeutic efficacy have yielded different conclusions when patients with different degrees of congestive heart failure have been studied (Arnold et al. 1980; Captopril-Digoxin Multicentre Research Group 1988; Fleg et al. 1982;German and Austrian Xamoterol Study Group 1988; Johnston & McDevitt 1979; Lee et al. 1982; Taggart et al. 1983). Early clinical trials in which digitalis was administered to alternate patients after a myocardial infarction with and without complications suggested that digitalis was well tolerated (Askey 1951; Boyer 1955) and of clinical value (Gorlin 1962). Since then the bulk of evidence has suggested a small and clinically unimportant effect, except possibly in patients with severe cardiac dysfunction. In addition, there has been substantial concern recently that the digitalis glycosides might have a detrimental effect on the recently infarcted myocardium. These concerns have arisen because of observations made in animals following coronary artery ligation, which have shown an increased incidence of ventricular arrhythmias (Iesaka et al. 1983) and an extension of the area of infarction after digitalis administration (Braunwald et al. 1969; Maroko et al. 1970). Evidence for a deleterious effect of digitalis in humans has been more difficult to demonstrate (Muller et al. 1986). This review discusses the evidence for and against a significant haemodynamic and cardiotoxic effect of digitalis in the setting of acute myocardial infarction.