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doi: 10.1002/cpt1974155443pmid: 4597226
This paper describes a new method of assigning patients to treatment and control groups to minimize differences between the groups, not only in the number of patients but in patient characteristics. Testing the method by computer simulations, using data on 40 patients with 15 variates each, demonstrates a four‐ to fivefold reduction of the probability of severe imbalance, relative to randomization. Minimization can maintain tight control of one variate, comparable to the currently acceptable experimental design of blocking, while reduCing the probability of severe imbalance in the other 14 variates by a factor of 3. It also compares favorably with accepted methods regarding susceptibility to experimenter bias. Therefore, it is suggested that minimization should replace randomization in assigning patients in clinical trials.
Koysooko, Renu; Ellis, Elliot F.; Levy, Gerhard
doi: 10.1002/cpt1974155454pmid: 4827461
The concentration of theophylline in the plasma and saliva of 7 normal adults receiving single oral doses of 200 mg theophylline per square meter of body surface area (BSA) was determined spectrophotometrically over 8 hours. There was an excellent linear relationship between theophylline concentrations in plasma and saliva, over a plasma concentration range of 4 to 14 µg per milliliter. Theophylline concentrations in the saliva were about 48% lower than in the plasma and are similar to the concentration of free (not protein‐bound) drug in the plasma. There is very little intersubiect and intrasubiect variation of theophylline blank values in plasma and saliva, in the recovery of theophylline from plasma and saliva, and in the proportionality factor that relates saliva to plasma concentrations of the drug. These observations suggest that theophylline determination in saliva may be a convenient, painless, and noninvasive method for routine monitoring of theophylline levels.
Gorodetzky, Charles W.; Angel, Charles R.; Beach, Douglas J.; Catlin, Don H.; Yeh, Shu-Yuan
doi: 10.1002/cpt1974155461pmid: 4827462
In evaluating methods of detecting drugs of abuse in biological fluids it is of special importance to determine the ability of detecting a drug or its metabolites in biological fluids. To evaluate several methods of detecting heroin use by urine analysis for morphine and its metabolites, single intravenous doses of 2.5 and 5 mg/70 kg heroin were administered a week apart in random order to 10 nontolerant subjects and their urine was collected for the week following. Along with pre‐drug control urines, each sample was coded, randomized, and analyzed under blind conditions by the following methods: (1) thin‐layer chromatography (TLC) with iodoplatinate preceded by each of 4 extraction procedures, organic solvent and ion exchange resin impregnated paper extraction both without and with prior acid hydrolysis; (2) the free radical assay technique (FRAT); (3) radioimmunoassay (RIA); and (4) the Technicon Autoanalyzer. There was a high probability of detection for the first 8 hours by all methods except the Technicon Autoanalyzer (which gave a low proportion of positives 8 hours after the 2.5 mg per 70 kg heroin dose); up to 16 hours with TLC procedures with hydrolysis and FRAT; and up to 32 to 48 hours with RIA.
Dasberg, Haim H.; van der Kleijn, Eppo; Guelen, Pieter J. R.; van Praag, Herman M.
doi: 10.1002/cpt1974155473pmid: 4827463
Fifteen nonpsychotic patients suffering from acute anxiety in a crisis situation, admitted for a short inpatient treatment, were treated orally with diazepam (Valium), 20 mg daily, for a period of at least 5 consecutive days. Measurements were made on 3 levels: (1) psychometric measurements, using rating scales, for the degree of improvement of a wide variety of anxiety symptoms, (2) pharmacochemical measurements of plasma levels of diazepam and its main active derivative N‐desmethyldiazepam, (3) clearance rates relative to body weight were calculated, (4) correlation between improvement ratings on the one hand and plasma concentrations and clearance ratings of both substances on the other hand. A control group consisted of 15 similar patients receiving placebo. The design was double‐blind and randomized. Our results suggest that the degree of the diazepam effect is directly proportional to plasma concentrations and reCiprocal clearance values of diazepam and N‐desmethyldiazepam. The minimal effective plasma concentration in the steady state is 400 ng per milliliter. The desmethyl metabolite has a slightly different action than diazepam, even a disturbing action on certain symptoms, with plasma levels of 300 ng per milliliter or more. Monitoring of diazepam treatment on the basis of plasma concentrations seems to be advisable.
doi: 10.1002/cpt1974155484pmid: 4827464
The effect of the β‐adrenergic receptor‐blocking drug, practolol, on plasma renin activity at rest and on the renin response to a graded isoproterenol (isoprenaline) infusion has been studied in man. Plasma renin activity at rest was not significantly changed by parenteral practolol. With isoproterenol, a dose of practolol that produced 50% to 60% reduction in the heart rate response to isoproterenol was without effect on the renin response. With chronic oral dosage of practolol, in 11 patients with essential hypertension, there was no significant change in plasma renin activity. The fall in blood pressure in these patients was unrelated to the pretreatment plasma renin level. Practolol, a “cardioselective” β‐adrenergic blocking drug, appears to lower blood pressure by a mechanism unrelated to inhibition of renin release.
Molnar, George W.; Read, Raymond C.; Wright, F. Elvis
doi: 10.1002/cpt1974155490pmid: 4827465
Oral propranolol doubled sweating during insulin‐induced hypoglycemia in 19 men. Two of 7 hypoglycemic patients studied with propranolol alone did not sweat, establishing that propranolol does not initiate sweating either by discharges from the hypothalamus or by direct action on sweat glands. Therefore, propranolol enhances hypoglycemic sweating by either blocking a beta adrenergic agent (perhaps epinephrine) that inhibits secretion or by potentiating the discharge of impulses by glucopenic neurones of the hypothalamus (possibly by competitive displacement of membrane calcium).
Carruthers, S. George; Kelly, John G.; McDevitt, Denis G.; Shanks, Robin G.
doi: 10.1002/cpt1974155497pmid: 4827466
Blood levels of practolol after oral and parenteral administration were determined in normal subjects, and the effects of each dose on the heart rate induced by strenuous exercise were measured. Oral practolol was rapidly absorbed and produced peak blood levels in 1 to 3 hours. Between 2 and 7 hours blood levels varied little more than twofold either within or between subjects. The half‐life of practolol in blood was 10 to 11 hours. Practolol100 mg was the minimum dose to produce near maximum blockade at 2 hours; maintenance of this effect for 24 hours reqUired 400 mg. Near maximum blockade was produced as long as a blood practolol level of 1.0 to 1.4 µg per milliliter was maintained. There was a correlation between the logarithm of the blood practolollevel and the percentage reduction of exercise heart rate. Practolol 40 mg and 80 mg intravenously initially achieved near maximum blockade associated with blood practolol levels above 1.0 p.g per milliliter. The effects and blood levels fluctuated during the first 7 hours. Intramuscular doses up to 40 mg failed to produce near maximum blockade; higher doses were precluded by pain at the injection site.
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