Diuretic agents and glucose reabsorption.

Acetazolamide, chlorothiazide, ethacrynic acid and furosemide were infused to glucose loaded dogs. Glucose reasorption was unchanged after acetazolamide and chlorothiazide. Ethacrynic acid depressed glucose reabsorption significantly. Furosemide caused a modest decrease in glucose reabsorption which was not significant when the control values were compared with the last three experimental values, but which was significant when all experimental values are analyzed. These diuretics most likely depress glucose reabsorption by acting on the proximal tubule, though a distal effect cannot be excluded.     

Effects of therapeutic doses of amiloride and hydrochlorothiazide on taste, saliva and salt intake in normotensive adults

Tentative evidence suggests that hydrochlorothiazide (HCTZ)and amiloride may alter salivary function, taste sensitivityand dietary intake. The effects of these diuretics on salivaryflow and composition, taste attributes (i.e. recognition thresholds,perceived intensity ratings and preference) as well as sodiumintake were further examined in 73 normotensive adults in adouble-blind, placebo-controlled, cross-over study. Followingrandom assignments to one of three groups [5 mg twice per dayof amiloride (n = 24), 50 mg/day of HCTZ (n = 24) or placebo(n = 25)], subjects took appropriate placebos for 2 weeks, activedrug for 8 weeks and placebo for 3 weeks. Relative to baselinevalues, amiloride treatment resulted in a significant 39% decreasein stimulated salivary sodium levels and a 28% decline in NaClrecognition thresholds. HCTZ significantly stimulated sodiumintake as the sodium/creatinine ratio was {small tilde}50% higherfollowing 4 weeks of drug use relative to baseline values. Subjectswere subjectively unaware of these changes. Potential mechanismsand clinical implications of these findings are considered.     

Prevention of atherosclerotic complications: controlled trial of ketanserin. Prevention of Atherosclerotic Complications with Ketanserin Trial Group.

STUDY OBJECTIVE--To determine whether ketanserin, an antagonist at the serotonin receptor, prevents important vascular events such as death, myocardial infarction, major stroke, and amputation of a leg in patients with claudication. DESIGN--Double blind, randomised, placebo controlled trial after a single blind run in period of placebo treatment for one month. SETTING--One hundred and forty seven outpatient clinics in 14 countries. PATIENTS--Total of 3899 patients over 40 years old who had had documented intermittent claudication for at least two months and in whom the ratio of systolic blood pressure in the ankle to that in the arm was less than or equal to 0.85 in both arteries of at least one foot. INTERVENTION--After the one month placebo run in period patients were randomly allocated to take 20 mg ketanserin three times daily for the first month and 40 mg three times daily thereafter or to take the same number of placebo tablets. Five months after the onset of the trial, on the recommendation of the ethical and safety committee, four patients stopped taking ketanserin and two stopped taking placebo because they had a corrected QT interval greater than 500 ms. Four months later the committee recommended that all patients taking diuretics should stop receiving trial treatment (167 of those taking ketanserin and 144 of those taking placebo). END POINT--The first primary event after randomisation. Primary events were definite myocardial infarction, major stroke, amputation above the ankle, excision of ischaemic viscera, and death due to other vascular causes. MEASUREMENTS and MAIN RESULTS--There were 136 study end points in the 1930 patients treated with ketanserin, who were followed up for 2063 patient years, and 132 study end points in the 1969 patients treated with placebo, who were followed up for 2129 patient years. A harmful interaction of ketanserin and potassium losing diuretics resulted in an increase in the number of deaths. After patients taking potassium losing diuretics or antiarrhythmic agents were excluded [corrected] a secondary analysis showed that there were 65 end points in 1514 patients taking ketanserin and 87 in 1557 patients taking placebo, a reduction of 23% in the number of study end points in those taking ketanserin. CONCLUSIONS--Ketanserin can prolong the corrected QT interval, and the combined use of ketanserin and potassium losing diuretics can be harmful. A secondary analysis suggested a protective effect of ketanserin against cardiovascular complications in patients with claudication.     

Diuretic effects on renal brush border membrane transport and metabolism

Previous studies have indicated that the thiazide diuretics exert effects on proximal electrolyte transport. To determine whether the locus of these effects is at the brush border membrane (BBM) and if renal metabolism is affected, adult female Sprague-Dawley rats were acutely treated with either 1 mg/kg metolazone, 20 mg/kg chlorothiazide followed by a 20 mg/kg/hr maintenance infusion, 10 mg/kg acetazolamide followed by a 10 mg/kg/hr maintenance infusion, or the vehicles only. Administration of these agents resulted in an approximately tenfold increase in sodium excretion. Neither urinary phosphate nor inulin excretion changed significantly in any group. Sodium dependent BBM vesicle phosphate transport was examined at 0.15, 0.5, and 1 and 120 minute incubation periods in the diuretic treated groups and their respective control groups. Decreased uptake was seen in all pre-equilibrium time points in rats treated with metolazone: 0.15 minutes: 221 +/- 24 pmoles/mg protein (pmol/mg prot) in control rats versus (vs) 185 +/- 23 pmoles/mg prot in metolazone-treated animals (P less than .05) ; 0.5 minutes: 463 +/- 54 vs 369 +/- 49 pmol/mg prot (P less than .005); 1 minute: 549 +/- 74 vs 460 +/- 61 pmol/mg prot (P less than .05); no significant difference in phosphate transport was noted at the two hour equilibrium time point. No significant differences in sodium dependent phosphate transport existed between chlorothiazide or acetazolamide treated rats and control animals. Substrate-stimulated renal gluconeogenesis did not differ between metolazone treated and control animals. We therefore conclude that metolazone inhibits phosphate transport through an effect on the BBM and does not affect renal gluconeogenesis in the rat.     

Antihypertensive efficacy of alpha-methyldopa,chlorothiazide and Supres-150 (alpha-methyldopa-chlorothiazide).

Twenty-two white men and two white women with uncomplicated essential hypertension participated in a randomized double-blind trial comparing placebo with alpha-methyldopa (750 mg/d orally) and chlorothiazide (450 mg/d orally), alone or in combination. There were no significant differences in blood pressures as measured with the patients lying down; however, with the patients standing the systolic, diastolic and mean arterial blood pressures were significantly lower (P < 0.05) after treatment with alpha-methyldopa or the combination product. The higher the blood pressure before treatment, the greater the fall with treatment. Adverse effects were infrequent.     

Response of the Infant Kidney to Diuretic Drugs

The diuretic response of normal infants, 6 to 47 days of age, to single doses of mercaptomerin, chlorothiazide, acetazolamide, triamterene and spironolactone was studied by following urinary electrolytes, pH and osmolality. Peak diuresis occured two to four hours after drug administration, and because of compensatory mechanisms little change in urinary excretion was found if only 24-hour urines were studied. Mercaptomerin increased sodium excretion seven-fold, compared to three- to four-fold increases for the other diuretics. Control urinary Na:K ratios averaged 0.68 in infants compared to 2.8 for adults, and mercaptomerin produced the largest increase in this ratio. Qualitatively the response to diuretics is the same in newborn in the ages studied as it is reported to be for adults; no immaturity of the infant kidney in this regard was demonstrated.     

Economic consequences of postinfarction prophylaxis with beta blockers: cost effectiveness of metoprolol.

Treatment with certain beta adrenoceptor blocking agents after myocardial infarction reduces mortality and the incidence of reinfarction. Data from a randomised placebo controlled study of the beta 1 selective blocker metoprolol given as secondary prophylaxis were therefore analysed for the possible cost effectiveness of extending this treatment to the general population of patients with myocardial infarction. Metoprolol 100 mg twice daily and matching placebo were given to 154 and 147 patients, respectively, for three years. During this period drug costs for the beta blocker, digitalis, and diuretics were analysed as well as costs of readmission for cardiac problems and indirect costs arising from sick leave or early retirement. Active treatment with metoprolol significantly reduced costs of readmission as well as indirect costs. The net effect per patient over the three years was a reduction of roughly kr 19,000 (1930 pounds). These results suggest that beta blocker treatment given as secondary prophylaxis after myocardial infarction is highly cost effective.     

Attenuation of hypotensive effect of propranolol and thiazide diuretics by indomethacin.

The effects of 100 mg indomethacin daily for three weeks on blood pressure and urinary excretion of prostaglandin F2 alpha were studied in a double-blind, placebo-controlled comparison of two groups of patients with essential hypertension, eight receiving propranolol and seven thiazide diuretics. Compared with placebo, adding indomethacin to the patients'' established antihypertensive treatment increased blood pressure by 14/5 Hg supine and 16/9 mm Hg erect in the patients receiving propranolol, and by 13/9 mm Hg supine and 16/9 mm Hg erect in the patients receiving thiazide diuretics (all p less than or equal to 0.05). The excretion of the major urinary metabolite of prostaglandin F2 alpha was reduced by 67% in the propranolol-treated patients and by 57% in those receiving a thiazide diuretic. Body weight increased by 0 . 8 kg (propranolol) and 1 . 1 kg (thiazide diuretic) when indomethacin was given, but there were no significant changes in creatinine clearance, urinary sodium excretion, or packed cell volume in either treatment group. These results suggest that products formed by the arachidonic acid cyclo-oxygenase contribute to the regulation of blood pressure during treatment with both propranolol and thiazide diuretics. Inhibition of the cyclo-oxygenase with indomethacin partially antagonises the hypotensive effect of these drugs.     

A Clinical Trial of Four Hypnotic Drugs

A clinical trial of four hypnotic drugs was carried out: Ro 4-5360, 10 mg. (Mogadon), methyprylon, 200 mg. (Noludar), Ro 4-5360, 5 mg. (Mogadon), secobarbital sodium, 100 mg. (Seconal), and a placebo. The study was on the usual double-blind basis, and all observations were made by a full-time nurse. Capsules were given at 10 p.m. for five successive nights, with two nights free from medication or observation. There were five such periods. The nurse carried out her observations right through the night, determining whether the patients were awake or asleep. Each of these drugs was statistically significantly different from the placebo, in terms of length of sleep. Differences between the individual drugs were not significant. The length of action of the various drugs appeared to be similar, with a somewhat longer period of activity for the Mogadon in both dosages. The major side effect was some drowsiness: this was more marked with Mogadon 10 mg. With the hypnotics, the patients had, on the average, about one hour more sleep than on the placebo.     

Long term propranolol treatment and changes in body weight after myocardial infarction.

OBJECTIVE--To determine the effect of long term propranolol treatment on body weight. DESIGN--Retrospective analysis of data from a placebo controlled randomised double blind clinical trial (the beta blocker heart attack trial). PATIENTS--3837 Men and women randomised 5-21 days after an acute myocardial infarction to treatment with placebo or propranolol for up to 40 months. Patients were followed up at annual visits. MAIN OUTCOME MEASURE--Changes in body weight. RESULTS--At the first annual visit patients treated with propranolol had gained more weight than those given placebo (mean weight gain 2.3 kg v 1.2 kg respectively, mean difference 1.2 kg (95% confidence interval 0.9 to 1.5]. These group differences remained at the second and third annual visits. The difference in weight gain could not be explained by discrepancies in the use of diuretics or in physical activity and was similar in patients of both sexes and of all ages. CONCLUSION--Long term beta blockade results in a sustained weight gain.     

A Double-Blind Randomized Placebo-Controlled Trial of Sibutramine

Sibutramine is a β-phenethylamine which blocks reuptake of norepinephrine and serotonin. In this clinical study, a group of 173 patients were randomized to treatment with sibutramine at doses of 1, 5, 10, 15, 20 or 30 mg/d and were compared with placebo in a 24-week double-blind trial. There was a dose-dependent reduction in body weight, with doses of 10, 15, 20 and 30 mg being significantly greater than placebo. Weight loss was still continuing in the highest three doses at the end of the study. When drugs were discontinued patients regained weight, as expected. Side effects were generally mild and were most evident in the group treated with the highest dose. These studies suggest that sibutramine may be a valuable new drug for treatment of obesity.     

Acetazolamide or dexamethasone use versus placebo to prevent acute mountain sickness on Mount Rainier.

Eighteen climbers actively ascended Mount Rainier (elevation 4,392 m) twice during a randomized, double-blind, concurrent, placebo-controlled, crossover trial comparing the use of acetazolamide, 250 mg, dexamethasone, 4 mg, and placebo every 8 hours as prophylaxis for acute mountain sickness. Each subject was randomly assigned to receive placebo during one ascent and one of the active medications during the other ascent. Assessment of acute mountain sickness was performed using the Environmental Symptoms Questionnaire and a clinical interview. At the summit or high point attained above base camp, the use of dexamethasone significantly reduced the incidence of acute mountain sickness and the severity of symptoms. Cerebral and respiratory symptom severity scores for subjects receiving dexamethasone (0.26 +/- 0.16 and 0.20 +/- 0.19, respectively) were significantly lower than similar scores for both acetazolamide (0.80 +/- 0.80 and 1.20 +/- 1.05; P = 0.25) and placebo (1.11 +/- 1.02 and 1.45 +/- 1.27; P = .025). Neither the use of dexamethasone nor that of acetazolamide measurably affected other physical or mental aspects. Compared with placebo, dexamethasone appears to be effective for prophylaxis of symptoms associated with acute mountain sickness accompanying rapid ascent. The precise role of dexamethasone for the prophylaxis of acute mountain sickness is not known, but it can be considered for persons without contraindications who are intolerant of acetazolamide, for whom acetazolamide is ineffective, or who must make forced, rapid ascent to high altitude for a short period of time with a guaranteed retreat route.     

Maintenance digoxin after an episode of heart failure: placebo-controlled trial in outpatients.

The need for maintenance digoxin treatment was assessed in a double-blind, variable-dose, crossover comparison with placebo. Forty-six outpatients who had been prescribed the drug for heart failure were studied; 33 were in sinus rhythm and the remainder in atrial fibrillation. Mean serum digoxin concentrations in those with sinus rhythm averaged 1-33 nmol/l, but a lower concentration, averaging 0-97 nmol/l, was accepted in those with atrial fibrillation as six of them developed bradycardia. Sixteen of the 46 patients deteriorated on placebo, and eight completely recovered when digoxin was reintroduced; in the remainder additional diuretics were required temporarily. Spirometric values deteriorated on changing to placebo whether or not the patient showed clinical evidence of recurrence of heart failure. In a separate study of nine patients who showed no clinical evidence of deterioration on placebo, reintroduction of digoxin caused a shortening of left ventricular ejection time, which persisted for at least a month. This suggests that the inotropic response to digoxin is sustained during maintenance treatment.     

Comparative insecticidal power of three pyrethroids on netting

Adult mosquitoes, Anopheles gambiae Giles and Culex quinquefasciatus Say (Diptera: Culicidae), were exposed for 3 min to replicate samples of polyester netting cut from replicate bednets treated with pyrethroid insecticide formulations at the recommended concentration (alphacypermethrin SC at 40mg ai/m2; cyfluthrin EW at 50 mg ai/m2; deltamethrin WT at 25 mg ai/m2), or treated with only a quarter of those dosages. After 4 months domestic use of the bednets in Malawi, chemical assays showed that pyrethroid deposits on the netting were somewhat less than the target concentrations. Comparing the pyrethroid bioassay results with Anopheles at both treatment concentrations, deltamethrin gave significantly higher mortality (99.7-100%) than the other compounds (alphacypermethrin 94-96%, cyfluthrin 80-89%). Culex bioassay mortality was lower (alphacypermethrin 56-74%; cyfluthrin 63-65%; deltamethrin 50-81 %) and results with the three pyrethroid insecticides at their recommended doses did not differ significantly.     

A Novel Monoclonal Antibody Degrades the Thyrotropin Receptor Autoantibodies in Graves' Disease

ObjectiveAutoantibodies against the thyrotropin receptor (TSH-R-Ab) are key mediators for the pathogenesis of Graves' disease (GD). TSH-R-Ab degradation was evaluated using several immunoassays within an exploratory, controlled trial in patients with GD receiving a monoclonal antibody (mAb) targeting the neonatal crystallizable fragment receptor (FcRn).MethodsSerial measurements of TSH-R-Ab serum levels were performed using 3 different binding and cell-based assays in patients with GD either on medication or on placebo.ResultsIn contrast to the placebo group, in which no changes were observed, a 12-week mAb therapy led to an early and significant decrease (>60%) in the serum TSH-R-Ab levels in patients with thyroidal and extrathyroidal GD, as unanimously shown in all 3 assays. These marked changes were noted already at week 7 post baseline (P <.0001 for the binding immunoassay and for the luciferase (readout) bioassay). The 3 TSH-R-Ab binding and bioassays were highly correlated in the samples of both study groups (binding immunoassay vs luciferase bioassay, r =.91, P <.001, binding vs cyclic adenosine monophosphate (cAMP) bioassay, r = 0.86, P <.001, and luciferase vs cAMP bioassay, r = 0.71, P =.006). The serological results correlated with the course of the extrathyroidal clinical parameters of GD, that is, clinical activity score and proptosis.ConclusionTargeting the FcRn markedly reduces the disease-specific TSH-R-Ab in patients with GD. The novel and rapid TSH-R-Ab bioassay improves diagnosis and management of patients with GD.     

A proposed standardized bioassay for formulations of Bacillus thuringiensis based on the international unit

Since standardization of preparations of Bacillus thuringiensis containing the δ-endotoxin cannot be accomplished by spore count alone, a bioassay is needed. However, before a bioassay can enjoy widespread use, there must be a generally accepted bioassay procedure. A bioassay based on the international unit (IU) and using the cabbage looper, Trichoplusia ni, is proposed to fulfill this requirement. In this assay, the product is incorporated into an alfalfa meal-based diet, and 15–25 mg larvae are allowed to feed on the diet for 5 days. At the end of the test period, activity is measured by determining the LD₅₀ of the test material and comparing it with that of a standard preparation. Potency is then expressed as IU/mg.     

The Metabolism of the Volatile Amines: IV. The Role of Drugs in the Pathogenesis of Hepatic Encephalopathy

The effects of certain drugs on metabolism of ammonia by the liver and kidneys in dogs were investigated by a technique in which both hepatic inflow and outflow bloods could be repeatedly sampled in unanesthetized healthy animals. Specific representatives of the classes of the drugs studied included thiopental (barbiturates), morphine (opiates and analgesics), promazine (tranquillizers), and chlorothiazide (oral diuretics).The three drugs commonly used as sedatives were all found to impair the ability of the liver to metabolize ammonia. The diuretic, by contrast, increased the amount of ammonia put into the systemic system by the kidneys. Ethanol appeared to have little or no direct effect on ammonia metabolism.The possibility exists that the occurrence of acute hepatic encephalopathy in patients with severe liver disease may be avoided in many cases if these drugs are administered with proper care. Results also indicated that current concepts of the pharmacological action of sedatives, opiates and tranquillizers may require revision.     

Comparison of mosquito nets,proguanil hydrochloride,and placebo to prevent malaria.

One hundred and ninety students aged 6 to 18 at a boarding school 120 km west of Nairobi in the Rift Valley participated in a comparative trial of malaria prophylaxis. Treatment with a combination of amodiaquine 25 mg/kg over three days plus doxycycline 100 mg twice daily for five days cleared their blood of Plasmodium falciparum. They were then randomly divided into the following three groups matched for age and sex: one group slept under mosquito nets; one group received one or two tablets (100 mg each) of proguanil hydrochloride daily according to weight; one group received one or two placebo tablets daily which were the same size and colour as the proguanil tablets. Malaria was diagnosed when asexual P falciparum were seen on blood films and was treated with pyrimethamine-sulphadoxine. At the end of one school term 188 of the 190 students had completed the study. One new infection was found during 3893 days of follow up in the mosquito net group, eight new infections over 3667 days in the proguanil group, and 35 new infections over 3677 days in the placebo group, representing a reduction of 97.3% and 77.1% in attack rates for the mosquito net method and for treatment with proguanil respectively. Both provide effective protection from malaria.     

A comparative study of three hypnotics: methyprylon,glutethimide and chloral hydrate

A controlled study designed to evaluate the hypnotic potentiality of methyprylon (300 mg.), glutethimide (500 mg.) and chloral hydrate (1000 mg.) was carried out on 50 in-patients experiencing long-standing insomina. The patients ranged in age from 21 to 60 years, the sexes were equally represented and the clinical diagnoses were psychoneurosis, reactive depression, or anxiety reaction. An interesting feature of the experimental design allowed for the exclusion of placebo reactors before the initiation of the main trials. No difference in effectiveness of maintaining sleep could be established among the three hypnotic agents, indicating that at the usual levels of statistical significance, all three agents were equally effective as hypnotics. However, a significant trend (P = .05) was found for methyprylon (Noludar) to be the most effective and chloral hydrate to be the least effective of the three drugs in maintaining sleep. Methyprylon was found statistically (P = .05) to be the fastest sleep-inducing agent, whereas glutethimide (Doriden) proved to be the slowest of the three hypnotics with respect to sleep induction time.     

First Clinical Studies with Orlistat: A Short Review

Lipase inhibition, leading to decreased intestinal fat adbsorption can be used in the treatment of obesity. Orlistat, a lipase inhibitor, in a dose of 50 mg three times a day leads to a significant increase in weight loss compared to placebo in moderately obese people. These results are confirmed in a multiple-dose study using 10 mg, 60 mg and 120 mg Orlistat three times a day vs. placebo. The use of lipase inhibition has no significant influence on fasting levels of several hormonal systems, including thyroid hormones, catecholamines and IGF-I. The same is true for the responses of several gastrointestinal and pancreatic hormones after a liquid high-fat mixed meal. In general, Orlistat is tolerated very well, although a higher occurence of gastrointestinal side effects is seen.