Disposition, metabolism, and toxicity of methyl tertiary butyl ether, an oxygenate for reformulated gasoline.

Studies of the toxicology of methyl tertiary butyl ether (MTBE) were reviewed as a possible information base for evaluating the health effects of evaporative emissions from reformulated gasoline (RFG). The major metabolites of the oxidative demethylation of MTBE in vivo were methanol and tertiary butyl alcohol (TBA), whereas formaldehyde and TBA were the principal products of hepatic microsomal oxidation by cytochrome P-450. Pharmacokinetic studies in rats treated with intragastric MTBE in corn oil gave an initial disposition T1/2 for MTBE of 0.32 h. The decline in the serum drug versus time curve for MTBE in rats was accompanied by a progressive increase in serum methanol concentrations to levels more than 50-200 times those of the parent compound. Repeated exposure of MTBE vapor by inhalation in rats resulted in dose-dependent increases in MTBE in the blood, brain, and adipose tissue compartments. Blood concentrations of TBA were also dose dependent and provided an estimate of the total amount of MTBE distributed to peripheral drug metabolizing compartments. Perirenal fat/blood MTBE concentration ratios ranged from 9.7 to 11.6 after 15 wk of intermittent exposure. During an oxyfuels program in Fairbanks, AK, blood levels of occupationally exposed workers were 0.2-31.5 microgram/L MTBE and 1.6 to 72.2 microgram/L TBA with a mean TBA:MTBE blood concentration ratio of 4.2. In patients who received MTBE by percutaneous, transhepatic puncture for the dissolution of cholesterol gallstones, concentrations of MTBE in fat tissue reached 60 and 300 microgram/g at a treatment time when mean blood MTBE was less than 20 microgram/ml. The results of laboratory and clinical studies indicate that metabolites of MTBE may contribute to the nephropathy, neoplasms, and other pathological changes associated with repeated exposure to MTBE in experimental animals. It is concluded that such studies can provide a well-defined database for quantitative safety comparisons and health risk-benefit analyses of MTBE and other oxygenates in RFG.

A computer-based, problem-solving system of instruction in clinical pharmacology.

Advances in microcomputer technology provide new ways of incorporating PBL procedures in clinical pharmacology courses. Developments in graphics-user interfaces and analog/digital systems that display physiologic information directly on the monitor enable the computer to serve as a learning resource as laboratory classes did in the past. A model HyperCard-driven program describes four problem-oriented laboratory exercises that require interpretation and analysis of ECGs. The exercises that involve reading ECGs that were obtained before and after the onset of drug-induced changes in conduction and rhythm are designed to reinforce problem-solving skills in basic electrocardiography and give students a better understanding of the electrophysiologic basis for managing cardiac arrhythmias in clinical practice. For evaluating new programs in medical education, Schmidt describes three conditions that facilitate successful learning; (1) opportunity to use previously acquired knowledge in understanding new information, (2) applicability to future practice, and (3) ability to elaborate on the new information by interaction with other students. Advances that incorporate microcomputer technology and problem-solving learning would receive high scores by such criteria and are recommended by those who are developing courses in clinical pharmacology for medical students and others in the allied health sciences.

Changing patterns of ischaemic heart disease mortality in New Jersey 1968-1982, and the relationship with urbanization.

Geographical variations in the declining rates of ischaemic heart disease (IHD) mortality may provide clues about various environmental risk factors responsible as a mass influence on the population IHD rate. The rate of IHD decline in 18 of 21 NJ counties was 2 to 45% less than the USA national rate of decline. The overall decline of IHD mortality in New Jersey (NJ) counties lagged significantly (p less than 0.05 to p less than 0.0003) behind the national trend. Age-adjusted mortality rate (AAMR) for IHD in NJ's 21 counties were 4% to 56% higher than the US rates. The IHD mortality rate of 14 of 21 NJ, counties and the entire state were significantly (p less than 0.005 to p less than 0.000001) above the US rate. Highly urbanized, industrialized, and densely populated NJ counties had the highest IHD rates. In these highly urbanized, industrialized and overcrowded NJ counties the AAMR for IHD was significantly higher and the IHD decline was significantly lower than that in the US. There was a significant (p less than 0.02 to p less than 0.00001) inverse association between annual per capita income and IHD rates. These data suggest that a high degree of urbanization, extensive industrialization, high population density and low socioeconomic status were acting as mass influences on the NJ population IHD rate.

A decade of developments in diuretic drug therapy.

New diuretics introduced into clinical medicine during the past decade include potent new loop diuretics such as bumetanide and piretanide, the uricosuric indanyloxyacetic acid derivative indacrinone, and a new generation of sulfamoyl diuretics such as indapamide and xipamide, which are recommended primarily for the treatment of hypertension. Pharmacokinetic studies of individual diuretics have demonstrated that the diuretic and natriuretic responses to the newer agents generally follow the plasma drug concentration-time curves and urinary drug excretion rates. Therapeutic monitoring can therefore be achieved in most patients with edema or hypertension by close clinical observation and laboratory analysis of plasma electrolyte and creatinine concentrations and urinary electrolyte excretion rates. Interest in the mechanisms involved in the renal and extrarenal vascular actions of the newer diuretics has led to a better understanding of how changes in venous compliance, peripheral vascular resistance, and renal blood flow distribution may contribute to the overall therapeutic response to these agents, especially in patients with severe congestive heart failure, renal insufficiency with low glomerular filtration rates, and hypertension with cardiorenal complications. Adverse reactions to modern diuretics, which are mainly an extension of their renal pharmacodynamic effects, have proved to be minimal, provided that the dosage is adjusted to meet but not exceed individual patient requirements. However, the long-term consequences of prolonged periods of diuretic-induced alterations in plasma potassium levels, and metabolic effects that include elevated blood lipids, are still under investigation.

Factors affecting plasma benzo[a]pyrene levels in environmental studies.

Benzo[a]pyrene (BaP) is a useful indicator of exposure to polycyclic aromatic hydrocarbons (PAHs), airborne carcinogenic compounds. Radioimmunoassay was used to test for plasma BaP differences in 61 subjects divided into three groups based on geographic-demographic locale: urban-industrial, urban-residential, and outer suburban. The results showed that the urban-industrial area participants had a significantly higher mean plasma BaP level than did the outer suburban subjects. The urban-residential subjects did not have a significantly different mean plasma benzo[a]pyrene level from either of the other two groups. Obesity, as measured by Quetelet's index, was found to have a significant correlation with BaP levels. These results indicate that radioimmunoassay of plasma for BaP may be used successfully to judge environmental exposure to PAHs, provided physiological considerations such as obesity are taken into account.

Cardiopulmonary toxicity of tetrachloroethylene.

Tetrachloroethylene (1,1,2,2-tetrachloroethene) is a widely used organic solvent capable of producing adverse renal, hepatic, and central nervous system effects. The cardiac effects of tetrachloroethylene, thus far unexplored, were studied in several species. To standardize the dosimetry, tetrachloroethylene was prepared for intravenous injection in solutions of Tween 80, which had no demonstrable cardiotoxicity. In rabbits under urethane and in cats and dogs under pentobarbital, tetrachloroethylene increased the vulnerability of the ventricles to epinephrine-induced extra-systoles, bigeminal rhythms, and tachycardia. The mean threshold doses of tetrachloroethylene were 10 mg/kg in rabbits, 24 mg/kg in cats, and 13 mg/kg in dogs. In rabbits this threshold dose for cardiac arrhythmias correspond to blood levels between 2.2 and 3.6 microgram/ml. Animals demonstrating a reflex bradycardia to vasopressor doses of epinephrine were relatively resistant to the arrhythmogenic action of tetrachloroethylene. Ventricular arrhythmias occurred in less than 30% of the animals after tetrachloroethylene alone. In cats higher doses of tetrachloroethylene (40 mg/kg) produced acute pulmonary edema. Tetrachloroethylene (30-40 mg/kg) decreased left intraventricular dP/dt (max) in dogs, without significantly increasing left intraventricular end-diastolic pressure, although there was a transient decrease in arterial blood pressure that accompanied the early phase of myocardial depression. These results are being used as the basis for studies of the chronic effects of tetrachloroethylene on cardiac performance.

Renal electrolyte excretion pattern in response to bumetanide in healthy volunteers.

Renal electrolyte excretion patterns were determined in nonedematous healthy volunteers following bumetanide and furosemide in two separate clinical studies. In study 1, intravenous bumetanide was administered to 24 subjects at four dose levels. In study 2, bumetanide (1 or 2 mg) or furosemide (40 or 80 mg) was administered in a single oral dose to 32 subjects assigned at random to one of the four treatment groups. In study 1, there was a significant dose-related increase in urine volume and sodium, potassium, and chloride excretion, with chloride exceeding sodium at all dose levels, and the Na+/K+ ratios after bumetanide were greater than 3:1. In study 2, the Na+/K+ ratio increased significantly after treatment in all four treatment groups. The relative Na+/K+ ratios showed higher natriuretic potency and lower kaliuretic potency for bumetanide than for furosemide, but the differences were not statistically significant. Additionally, all four treatment groups demonstrated elevation in titratable acidity, ammonia formation, and total acid excretion. There was a significant degree of positive correlation in the bumetanide-treated groups between Na+/K+ and the three variables. In the furosemide-treated groups, this positive correlation was statistically significant between the Na+/K+ ratio and ammonia and total acid secretion but not for titratable acidity. The results support the view that increased H+ formation after the administration of loop diuretics has a relative potassium-sparing effect.

Distribution of intracortical renal blood flow induced by bumetanide in the dog.

Experiments were performed in hydropenic, anesthetized dogs to investigate the effect of two dose levels of bumetanide on sodium excretion, urinary concentration, total renal blood flow and intracortical distribution of blood flow using the radioactive microsphere technique. Intravenous administration of bumetanide (0.025 mg/kg followed by 0.025 mg/min) did not alter blood flow within the kidney. A higher dose of bumetanide (0.1 mg/kg followed by 0.1 mg/min) significantly increased total renal blood flow and lowered renal vascular resistance. The rise in renal blood flow after bumetanide was due entirely to an increase in perfusion to the midcortical and juxtamedullary regions. A transient rise in plasma renin activity was measured only after the higher dose of bumetanide. Both doses of bumetanide increased sodium excretion and depressed solute free water reabsorption, although natriuresis was greater in response to the high dose. The results indicate that higher dose levels of bumetanide can increase total renal blood flow to the inner cortex. However, changes in renal blood flow were apparently not essential for the diuretic action of bumetanide because a significant natriuresis was observed in a setting where no change in intrarenal hemodynamics could be detected.

Comparison of bumetanide and hydrochlorothiazide on renal potassium and hydrogen ion excretion.

The purpose of this study was to compare the renal electrolyte excretion pattern of bumetanide with that of hydrochlorothiazide in dogs anesthetized with pentobarbital. In bumetanide-treated animals, mean sodium excretion rose to 12 per cent of the filtered load, while hydrochlorothiazide increased sodium excretion to 4 per cent of the filtered load. After bumetanide, urine pH fell from 6.1 to 5.1 and net hydrogenion excretion increased significantly. After hydrochlorothiazide, urinary pH went from 6.4 to 7.4, and there was no change in net hydrogen ion excretion. Potassium excretion rose to 106+/-22 muEq/min with bumetanide and to 99+/-17 muEq/min with hydrochlorothiazide. These changes in electrolyte excretion occurred despite lack of changes in arterial blood gases, arterial blood pressure, and glomerular filtration rate. In addition, bumetanide did not exert an inhibitory effect on potassium excretion under conditions of potassium loading. It is concluded that bumetanide produces a higher urinary Na+:K+ ratio with a lower pH than hydrochlorothiazide and that renal potassium ion excretion in response to sulfamoyl diuretics is not solely dependent on the rate of sodium excretion.

Furosemide and plasma renin activity in essential hypertension.

Changes in arterial blood pressure, renal electrolyte excretion, and plasma renin activity in response to repeated doses of furosemide were measured in 12 patients with essential hypertension admitted to the medical service for electrolyte balance studies. Eighty and 120 mg/day furosemide in divided doses for 5 to 10 days produced a prompt increase in renal sodium excretion. Urinary Na/K concentration ratios, which were elevated during peak natriuresis, returned to control levels following the initial diuretic response. In 2 patients with high initial levels of plasma renin activity, arterial blood pressure was not reduced by furosemide, and more potent antihypertensive agents were required to control the blood pressure. In the remaining patients, furosemide produced a significant decrease in systolic and diastolic blood pressure. There was a general upward shift of plasma renin levels in terms of 24-hour renal sodium excretion in those who demonstrated an antihypertensive response to the drug. However, the average increase in plasma renin activity after repeated doses of furosemide was not statistically significant and no correlation was demonstrated between the level of plasma renin activity after furosemide and the blood pressure lowering effect of the drug.

Cardiovascular drug interactions.

Drug interactions may be responsible for certain changes in therapeutic response and toxicity of cardiac drugs. Interactions occur at the sites of drug absorption and elimination as well as at the receptor sites in the pacemaker cells, specialized conducting tissue, and myocardium. Studies of the kinetics of cardiac drugs are being applied clinically in an effort to reduce the danger of adverse drug interactions in heart patients.