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Furosemide increases the synthesis of two major renal eicosanoids, prostacyclin (PGI2) and thromboxane A2 (TXA2), by stimulating the release of arachidonic acid which in turn is metabolized to PGG2/PGH2, then to PGI2 and TXA2. PGI2 may mediate, in part, the early increment in plasma renin activity (PRA) after furosemide. We hypothesized that thromboxane synthetase inhibition should direct prostaglandin endoperoxide metabolism toward PGI2, thereby enhancing the effects of furosemide on renin release. Furosemide (2.0 mg . kg-1 i.v.) was injected into Sprague-Dawley rats pretreated either with vehicle or with U-63,557A (a thromboxane synthetase inhibitor, 2 mg/kg-1 followed by 2 mg/kg-1 X hr-1). Urinary 6ketoPGF1 alpha and thromboxane B2 (TXB2), reflecting renal synthesis of PGI2 and TXA2, as well as PRA and serum TXB2, were measured. Serum TXB2 was reduced by 96% after U-63,557A. U-63,557A did not affect the basal PRA. Furosemide increased PRA in both vehicle and U63,557A treated rats. However, the PRA-increment at 10, 20 and 40 min following furosemide administration was greater in U-63,557A-treated rats than in vehicle-treated rats and urine 6ketoPGF1 alpha excretion rates were increased. These effects of thromboxane synthesis inhibition are consistent with a redirection of renal PG synthesis toward PGI2 and further suggest that such redirection can be physiologically relevant.

A survey of 'steady-state' serum levels of anticonvulsant drugs from 221 epileptic patients at a university hospital was conducted. Serum concentrations of phenobarbital, primidone, and diphenylhydantoin were determined by a gas chromatographic method. Sixty-five percent (130) of the patients receiving diphenylhydantoin had levels below the therapeutic range of 10-20mug/ml. Subtherapeutic levels appear to be due to inadequate dosage adjustment. Only 25% (33) of the patients receiving phenobarbital had levels below the therapeutic range. Serum levels of diphenylhydantoin or phenobarbital could not be predicted from dosage. Most patients received two or more drugs. Over 10% of the patients had potentially toxic levels of anticonvulsant drugs. High levels of diphenylhydantoin were easily recognized clinically but high levels of phenobarbital were not.

We had previously shown that the early increment in plasma renin activity occurring within ten minutes of intravenous furosemide is accompanied by an increase in urine 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha) the hydrolysis product of prostacyclin. Renal prostacyclin and thromboxane A2 synthesis are apparently limited to the cortex. To assess whether indomethacin would inhibit renal cortical eicosanoid synthesis and whether such reduction correlated with reduced early renin release, we assessed responses to intravenous furosemide (0.5 mg/kg) before and after indomethacin (150 mg/day for seven days) in ten normal male volunteers. Indomethacin did not change blood pressure but increased weight slightly (79.7 +/- 2.5 kg to 80.4 +/- 2.4 kg, p less than 0.05). Serum thromboxane B2 (TXB2), a measure of platelet thromboxane A2 production, was profoundly depressed (142 +/- 29 ng/ml to 4.8 +/- 1.6 ng/ml, p less than 0.001). Neither diuresis nor natriuresis were changed by indomethacin but potassium excretion was reduced (33 +/- 4 mmol/4 hr to 27 +/- 3 mmol/4 hr, p less than 0.05). Basal as well as furosemide stimulated plasma renin activity (at 10, 30 and 240 minutes) was reduced, as well as the transient increase in excretion rates of 6-keto-PGF1 alpha and TXB2. We conclude that the reduction in furosemide stimulated renin release by indomethacin is due to renal cyclo-oxygenase inhibition which is reflected in decreased excretion rates of hydrolysis products of renal eicosanoids.

Renal functional abnormalities, occurring before overt renal disease and possibly due to abnormal vascular control mechanisms, have been described in diabetes mellitus. We used intravenous (i.v.) furosemide, which stimulates renal prostaglandin (PG) synthesis and renin release, to compare these vasoactive systems in 14 diabetic and 23 normal control subjects. Using urine thromboxane B2 (TXB2) as an index of renal synthesis of the vasoconstrictor prostanoid TXA2, and urine 6keto-PGF1 alpha for the vasodilator PGI2, we found evidence of increased renal TXA2 synthesis in diabetic subjects in response to furosemide. The increased TXA2 synthesis did not occur at the expense of PGI2 synthesis, as urine 6keto-PGF1 alpha was not reduced. Increased TXB2 excretion in diabetic subjects was particularly marked in the first 10 min after i.v. furosemide. During this time, diabetic males excreted 31 +/- 6 ng of TXB2 compared with 10 +/- 1 ng for normal males (P less than 0.05), while diabetic females excreted 15 +/- 3 ng compared with 7 +/- 1 ng for normal females (P less than 0.05). Also, 6keto-PGF1 alpha excretion at 10 min was increased in diabetic subjects: males, 29 +/- 3 ng versus 19 +/- 3 (P less than 0.05); females, 33 +/- 8 versus 16 +/- 3 (P less than 0.05). The ratio of TXB2 to 6keto-PGF1 alpha tended to be higher in diabetic males.(ABSTRACT TRUNCATED AT 250 WORDS)

Furosemide causes both diuretic and non-diuretic changes in renal function. We compared responses to intravenous furosemide 0.5 mg.kg-1 in 38 subjects (30 males, 8 females) aged 18 to 30 with those in 14 subjects (9 males, 5 females) aged 50 and over. There were no consistent differences attributable to gender. Older persons showed greater natriuresis (47 percent in males and 26 percent in females) but their increment in plasma renin activity was markedly reduced. The urinary excretion of thromboxane B2 was elevated in older subjects (58 +/- 10 vs. 30 +/- 4 ng/4 h, p less than 0.05 for males; 48 +/- 7 vs. 29 +/- 4 ng/4 hr, p less than 0.05 for females) while that of 6-keto prostaglandin F1 alpha was not different. While differences in the diuretic response to furosemide may be due to pharmacokinetic differences, the non-diuretic response differences may reflect age related changes in renal prostaglandin synthesis.

In order to assess whether blood pressure reduction with atenolol or enalapril is associated with changes in renal prostaglandin (PG) synthesis, we studied the effects of 10 weeks therapy in 20 subjects with mild or moderate hypertension. After a four week placebo run-in period, subjects were randomized to receive either atenolol 50-100 mg/day or enalapril 5-20 mg/day for 10 weeks, then crossed over to the alternate active drug. Both drugs lowered blood pressure: placebo 147/97, atenolol 135/87, enalapril 132/87 (p less than 0.05, for both). Atenolol reduced resting heart rate but neither drug changed body weight, serum sodium or potassium or creatinine clearance. Intravenous furosemide was used as a standardized stimulus of renal PG synthesis. Neither drug changed the excretion rates of 6ketoPGF1 alpha or thromboxane B2 (hydrolysis products of PGI2 and thromboxane A2 respectively). Diuretic, kaliuretic, and natriuretic effects of furosemide were also not affected. Plasma renin activity was increased by enalapril but reduced slightly by atenolol. Subjects with more marked blood pressure reduction showed responses to furosemide no different than those with less effect. We conclude that blood pressure reduction with atenolol or enalapril does not change the response of renal eicosanoid synthesis to acute stimulation with furosemide.

A 1-year survey was conducted of all children with eye injuries seen in the Wills Eye Hospital emergency room to determine demographic, etiologic, and prophylactic factors. There were 810 children with ocular trauma. Childhood ocular injuries are frequent, often resulting in serious visual impairment. Many of these injuries are preventable.

Althesin in dose ranges of 40, 60 and 80 mul/Kg was administered to six healthy unpremedicated volunteers according to a balanced incomplete block design. Both subjective and objective changes resulting from the administration of the agent were studied and analyzed. In the dose ranges used, Althesin was found to have no deleterious effects on heart rate, respiratory rate or blood pressure and apnoea only occurred in one patient who had an end-expiratory CO2 level lower than normal, due to preanaesthetic hyperventilation. The onset of sleep is prolonged with Althesin at the injection rate of 1 ml/10 secs. The onset of anaesthesia is not influenced by the total dose, but the sleep time is directly proportional to the dose injected. Auditory evoked responses tended to lie on a curve which might indicate that with increasing dose the time to reappearance of these responses is not correspondingly prolonged. However, this last observation must be confirmed by studies on a larger scale.

Human urine was analyzed by mass spectrometry for the presence of prostaglandins. Prostaglandin E2 and F2alpha were detected in urine from females by selected ion monitoring of the prostaglandin E2-methylester-methoxime bis-acetate and the prostaglandin F2alpha-methyl ester-Tris-trimethylsilylether derivative. Additional evidence for the presence of prostaglandin F2alpha was obtained by isolating from female urine an amount of this prostaglandin sufficient to yield a complete mass spectrum. The methods utilized permitted quantitative analysis. The origin of urinary prostaglandin was determined by stimulating renal prostaglandin synthesis by arachidonic acid or angiotensin infusion. Arachidonic acid, the precursor of prostaglandin E2, when infused into one renal artery of a dog led to a significant increase in the excretion rate of this prostaglandin. Similarly, infusion of angiotensin II amide led to a significantly increased ipsilateral excretion rate of prostaglandin E2 and F2a in spite of a simultaneous decrease in the creatinine clearance. In man, i.v. infusion of angiotensin also led to an increased urinary eliminiation of prostaglandin E. These results show that urinary prostaglandins may originate from the kidney, indicating that renally synthesized prostaglandins diffuse or are excreted into the tubule. Thus, urinary prostaglandins are a reflection of renal prostaglandin synthesis and have potential as a tool to delineate renal prostaglandin physiology and pathology.

To investigate whether chronic hydrochlorothiazide (HCTZ) therapy increases synthesis of tissue vasodilator prostaglandins (PG), we used intravenous furosemide as a standardized stimulus of renal PG synthesis before and after HCTZ dosing. Sixteen subjects with mild hypertension received placebo for 4 weeks, followed by HCTZ, 50 mg/day, and potassium chloride, 60 mmol/day, for 4 weeks. Nine subjects had decreased mean arterial pressure (-12.2 +/- 0.9 mm Hg) after HCTZ (responders), while seven others had no antihypertensive effect (nonresponders). Responders increased their excretion of the prostacyclin (PGI2) hydrolysis product 6-keto-PGF1 alpha in the first 10 minutes after furosemide, from 17.8 +/- 2.7 ng after placebo to 34.9 +/- 7.5 ng (P less than 0.05) after HCTZ, whereas nonresponders showed no such increase. These groups could not be distinguished on the basis of sex, age, or pretreatment plasma renin activity. After HCTZ dosing, responders showed evidence of increased action of PGI2 by increased plasma renin activity 10 minutes after furosemide (6.10 +/- 1.06 vs. 3.39 +/- 0.4 ng/ml/hr; P less than 0.05). Furthermore, creatinine clearance was maintained in responders (while decreasing slightly in nonresponders) despite lower blood pressure, a finding consistent with increased vasodilator effect. We conclude that an antihypertensive response to HCTZ is accompanied by an increase in renal PGI2 synthesis and action.

Timolol, like propranolol, is a nonselective beta-adrenergic blocker, but it is much less lipid soluble and is formulated as a single enantiomer rather than a racemic mixture. We examined the effects of such differences on bioavailability, systemic clearance, and pharmacologic response. Ten healthy subjects received placebo, 0.2 mg/kg IV propranolol, 3.2 mg/kg oral propranolol, 0.025 mg/kg IV timolol, and 0.4 mg/kg oral timolol in double-blind, randomized crossover fashion. Plasma concentrations of total drug were monitored up to 8 hr, while responses to submaximal exercise were measured at 0, 2, and 6 hr. Timolol had greater bioavailability (F = 0.61 +/- 0.06(SEM) and 0.32 +/- 0.04) and lower systemic clearance (463 +/- 74 ml kg-1 hr-1 and 1040 +/- 120 ml kg-1 hr-1) than propranolol. Half-lifes were of the same order (2.7 and 2.9 hr). There was a marginal correlation between areas under the intravenous and oral plasma concentration-time curves for timolol (r = 0.66, P = 0.054), but none for propranolol (r = 0.48, P NS). There were also correlations of the response (percent reduction in heart rate) to oral and intravenous timolol at 2 hr (r = 0.72, P less than 0.05) and 6 hr (r = 0.84, P less than 0.01) hr, but none between responses to oral and intravenous propranolol. Finally, the response to oral timolol was related to the area under its plasma concentration-time curve, whereas that to propranolol was not. We conclude that the physicochemical properties of timolol lead to greater bioavailability. Pharmacologic response to an oral dose of timolol, unlike that to propranolol, can be predicted from the response to an intravenous dose and reflects its plasma concentration.

In 1973 the division of continuing medical education of the University of Saskatchewan initiated a 3-year study to determine the effect of hospital-based education on the prescribing accuracy of physicians. This study was undertaken in response to an urgent need to develop more effective methods of continuing medical education and improved techniques of measuring their effectiveness. The educational program focused on common prescribing problems that had previously been defined by experts in the field. Problem frequency was determined by the monitoring of hospital records prior to institution of the educational program and at 3, 6 and 12 months after the program had concluded; this was found to be a satisfactory method of identifying educational needs and is considered to provide a measure of the quality of medical care. Fifteen physicians at three rural hospitals participated in the study. Seventeen physicians at two similar hospitals served as controls. The average problem frequency for topics selected at the study hospitals was reduced by 63% (the percentage of possible improvement), whereas at the control hospitals the frequency of the same problems declined by 32% over the same period. The results of this study provide evidence that an intensive, problem-based program on therapeutics can improve physician performance.

We have examined the differences in urinary excretion of water, sodium, potassium, chloride, urea, and creatinine produced by different dosage regimens offurosemide in normal volunteers. Three oral dosage regimens were compared: 20 mg daily, 20 mg twice daily, and 40 mg daily. Furosemide, 20 mg, did not produce a significant weight loss, diuresis, or natriuresis in 12 normal subjects. With 40 there was a significant weight loss, diuresis, natriuresis, and chloruresis over 24 hr. Comparison of the divided regimen with 40 mg daily revealed significantly greater sodium excretion, and chloride excretion with 20 mg twice daily. The divided dosage regimen produced a different pattern of diuresis with most of the sodium and water excretion occurring after the second dose. These differences in response to different regimens are predictable from pharmacokinetic considerations and may have clinical significance.

The objective was to characterize, by dynamic mechanical analysis (DMA), the polymeric materials used to restore teeth and, in particular, to assign a glass transition temperature, Tg. Generally, in DMA work, Tg is taken as the temperature at which the internal damping, i.e., tan delta, has a maximum value. However, in the present work it was shown that the classical method of assigning Tg corresponds more closely to an assignment based on changes in elastic modulus. On this basis, a bis-GMA copolymer and a proprietary dental composite, both polymerized by exposure to light, were assigned Tg values of -25 degrees C and +10 degrees C, respectively. The composite had an even lower value, Tg = -10 degrees C, after saturation with water. The value of Tg can be increased considerably by treatments which are known to increase the degree of polymerization, i.e., by heating or by gamma-irradiation. The present findings imply that composites made by photopolymerization may undergo marked changes in mechanical state (becoming glassy, leathery, and rubbery) in the oral cavity, due to changes in temperature from about 0 degree C to 50 degrees C. It is not known which of these states would give best service properties, such as wear resistance, but in any case variation of properties in service would appear to be undesirable.

As many as forty percent of Canadians over age sixty-five have blood pressure readings of 160/90 or higher. They are at greater risk for stroke, congestive heart failure, myocardial infarction and sudden death. Hypertension appears to be an exaggeration of the normal circulatory changes of aging--increased systemic vascular resistance and a slight decrease in cardiac output at rest and during exercise. The major trials of treatment for hypertension have included subsets of elderly hypertensives who have enjoyed about the same overall benefit from treatment as younger subjects. Two treatment trials specifically for elderly hypertensives also show that treating systolic-diastolic hypertension does more good than harm. Isolated systolic hypertension appears to be a risk factor of equal magnitude to systolic/diastolic hypertension. Although it is possible to treat isolated systolic hypertension, the definitive clinical trial comparing mortality and morbidity in treated and untreated groups is not yet published. Thiazides, while inexpensive and effective antihypertensives for the elderly, are relatively contraindicated in as many as half. Other classes of drugs, particularly calcium channel blockers, can be effective alternatives. Many, if not most, elderly hypertensives will be prescribed more than one type of antihypertensive in addition to other types of drugs. The possibility of drug interactions as well as the danger of overly rapid blood pressure reduction must be kept in mind.

Twenty family physicians in Saskatchewan participated in this randomized controlled study which examined the effects of relatively low-cost educational techniques on the office management of hypertension. We measured 1,538 episodes of care relating to the office management of hypertension by chart review, prior to, and at six and 12 months following education. The family physicians who participated in the education were found to perform the recommended behaviours significantly more often at six and 12 months post education than those physicians who did not have the education. Our findings indicate that carefully planned, inexpensive educational techniques can improve clinical behaviour in areas where there is identified educational need.

We studied the effects of a specific thromboxane (TX) synthetase inhibitor (U-63,557A) and a cyclooxygenase inhibitor on furosemide-induced renin release. Furosemide (2.0 mg X kg-1) was injected into Sprague-Dawley rats pretreated with indomethacin (10 mg X kg-1, i.v.), U-63,557A (1.0-32.0 mg X kg-1, i.v.), or vehicle (Na2CO3 0.03 M). Plasma renin activity was measured in blood samples collected 0, 10, 20, and 40 min after the injection of furosemide. Blood was also collected after the administration of vehicle, indomethacin, or U-63,557A for serum TXB2, a measure of platelet TXA2 synthesis. The results demonstrated that plasma renin activity rose with time following furosemide in the various groups of rats; indomethacin suppressed the furosemide-induced increments in plasma renin activity, while U-63,557A at doses of 4-8 mg X kg-1 augmented it. At doses below 4 mg X kg-1 or above 8 mg X kg-1, U-63,557A did not augment renin secretion. Indomethacin and U-63,557A reduced serum thromboxane by 81 and 90%, respectively. Thus, these experiments suggest that thromboxane synthetase inhibition, within a narrow dosage range, potentiates furosemide-induced renin release while cyclooxygenase inhibition suppresses it.

A method is presented for the measurement of 6-mercaptopurine (6-MP) in serum. Serum samples containing the drug were treated with dithioerythritol and saturated with ammonium carbonate. 6-MP was then extracted from the serum with a mixture of isopropanol-ethyl acetate (1:1, v/v) containing 0.01% ethanethiol. The solvent was evaporated, the residue dissolved in dilute hydrocholoric acid, washed with chloroform, and extracted with ethyl acetate. 6-MP was derivatized with trimethylanilinium hydroxide and measured gas chromatographically. The sulfhydryl-protecting reagents, dithioerythritol and ethanethiol, were added to prevent the decomposition of 6-MP. The extraction and clean-up method recovered 78 +/- 2% (S.E.) of the 6-MP present. Tracer amounts of [8-14C]6-MP served as the internal standard during the extraction part of the method. Theophyline was used as the internal standard during the gas chromatographic analysis. The standard curve obtained from the gas chromatograph was linear between 0.5 and 20 mug/ml of 6-MP. Serum samples were stored in the freezer for two weeks without significant loss of drug. No interference was encountered from normal serum constituents or xanthines, such as caffeine or theophylline added to serum.

Rats drank solutions of narcotic analgesics as the only drinking fluid available in their cages. Relative to their daily water intake before the drug solutions were introduced, the rats drank more etonitazene solution, less methadone solution, and about the same volume of morphine, meperidine and levorphanol solution as water, although some rats would not drink the higher concentrations of morphine (1.0 mg/ml), levorphanol (1.0 mg/ml) and methadone (1.0 mg/ml). When naloxone (1.0 mg/kg) was administered after 12 days of drinking the drug solutions, the severity of the abstinence syndromes based on scoring of symptoms and on weight loss was morphine greater than or equal to etonitazine greater than levorphanol greater than meperidine greater than methadone. The animals showing the most severe syndrome after naloxone usually consumed more drug solution than usual during the next 24 hours, so that body weights were normal at the end of the 24-hour period. Nonprecipitated abstinence was also studied in these rats by replacing the drug solutions with water 3 to 5 days after the naloxone injection. Rats that had been drinking morphine, etonitazene and levorphanol lost weight for 2 or 3 days and then began to regain their lost weight. In contrast, rats which had been switched from methadone and meperidine solutions to water gained weight rapidly. Morphine and etonitazene drinkers which had been switched to water drank a lesser volume of water than they had been drinking of drug solution whereas some ex-methadone drinkers drank more water.

A randomized controlled study was conducted to determine if specifically designed continuing medical education in the fields of cardiovascular and cancer medicine could change doctor office behaviour significantly. Thirty-one volunteer family doctors from 25 offices participated. Six (three cardiovascular and three cancer) learning objectives were defined. Two educational formats were selected as the independent variables: (1) group interaction opportunities (face-to-face and teleconference); and (2) concisely written newsletters. Chart measures of doctor performance prior to and 6 and 12 months following education served as the dependent variables. The family doctors receiving education were found to perform the recommended behaviours significantly more than those who did not receive the education (P less than 0.05) at 6 months post-education. This difference was maintained at the 12-month post-educational period for one of the educational programmes offered. A carefully planned programme of continuing medical education will result in favourable changes in the office practice of volunteer doctors. These changes can persist for as long as 12 months. Adherence to several essential learning principles is required.

Gentamicin toxicity has been shown to be related to high concentrations in serum. Because there is a narrow range between its therapeutic and toxic levels, serial monitoring of gentamicin is the most reliable method of guiding therapy. Microbiological assays commonly in use do not afford the desired speed and accuracy, and results may be difficult to interpret in the presence of other antimicrobials. Hence, a rapid, sensitive, and highly specific radioimmunoassay for measurement of gentamicin in serum has been developed. Antibody to gentamicin was raised in rabbits by using a gentamicin-albumin conjugate. Tritiated gentamicin (specific activity 1.0 Ci/mM) competes with unlabeled gentamicin for binding sites on the antibody. Dextran-coated charcoal separates the unbound from antibody-bound gentamicin. Serum levels of gentamicin are determined by comparison with a standard curve. This method can detect concentrations as low as 0.01 mug/ml. Results of a 24-tube run can be obtained in 1 h, thus allowing modification of gentamicin dosage to advantage.