bluuebunny/crossref_metadata_2025 huggingface dataset:
Normal cardiac output during beta blockade with timolol in hypertensive patients
Authors: Franciosa Joseph A. , Freis Edward D.
Published: January 2016

Data published by this laboratory indicated that the beta adrenergic blocking drugs timolol and propranolol exerted equivalent beta blocking and antihypertensive actions in patients with mild essential hypertension, but that whereas cardiac output fell acutely with both drugs, it returned to normal after 5 wk of treatment with timolol, but remained depressed after propranolol. This preliminary observation needed further confirmation in a larger series of patients. In this study, 11 patients with initial diastolic blood pressures between 90 and 125 mm Hg were given timolol for 5 wk, Hemodynamic measurements were made before and at the end of treatment. Mean heart rate fell from 76.8 to 64.3 bpm (p < 0.001), and blood pressure was reducedfrom 179.4/99 mm Hg to 167.4/93.3 mm Hg (p < 0.02). Cardiac output averaged 6.29 L/min before timolol, and fell to 5.95 L/min (NS) after treatment. Stroke volume increased significantly, while total peripheral resistance was unchanged. These results confirm our earlier observations that timolol is an effective beta adrenergic blocking drug with antihypertensive action that does not reduce cardiac output significantly when given chronically. This drug merits further evaluation in other cardiovascular disorders since it may have advantages over other beta adrenergic blocking drugs.
Respiratory effects of nefopam
Authors: Gasser J. Conrad , Bellville J. Weldon
Published: January 2016

Arespiratory study has been done to compare the respiratory effects of a potent new analgesic, nefopam, to morphine. Morphine was a potent respiratory depressant at therapeutic dosage while nefopam was not.
Interactions of levodopa with inhibitors of monoamine oxidase and L‐aromatic amino acid decarboxylase
Authors: Teychenne Paul F. , Calne Donald B. , Lewis Peter J. , Findley Leslie J.
Published: January 2016

Drug interactions between levodopa, tranylcypromine, and carbidopa have been studied in 4 patients with idiopathic parkinsonism. Pressor responses were induced by a combination of levodopa and tranylcypromine. These hypertensive reactions were inhibited by carbidopa, indicating that they are mediated at the periphery. Very small doses of levodopa induced an improvement in parkinsonism when patients were concomitantly taking carbidopa and tranylcypromine, but adverse reactions were prominent.
Triazolam in insomniac family practice patients
Authors: Rickels Karl , Gingrich Russell L. , Morris Richard J. , Rosenfeld Howard , Perloff Milton M. , Clark E. L. , Schilling Ann
Published: January 2016

Triazolam, 0.5 mg, a benzodiazepine with hypnotic properties, was compared to secobarbital, 100 mg, and placebo in a 1‐wk study conducted with 100 insomniac family practice patients. Considerable sensitivity to differential treatment effects was demonstrated for these family practice patients as well as for a research methodology that combines a crossover design, permitting preference ratings, with a between‐patient design. in almost all sleep parameters, assessed with a variety of subjective techniques, triazolam and secobarbital were shown to be significantly more effective than placebo. Triazolam was consistently and often significantly indicated to be a more effective hypnotic, particularly for reducing nocturnal awakening, than secobarbital. Analysis of self‐report emotional distress data revealed that present insomniac patients were slightly more emotionally symptomatic than other nonpsychiatric populations. Triazolam was followed by the greatest and secobarbital the least relief of emotional symptoms and triazolam emerged as an especially effective hypnotic for initially more depressed insomniac patients. Present findings suggest that type and degree of emotional symptomatology may affect the response of insomniac patients to hypnotics.
Effectiveness of hypnotic drugs with prolonged use: Flurazepam and pentobarbital
Authors: Kales Anthony , Kales Joyce D. , Bixler Edward O. , Scharf Martin B.
Published: January 2016

This study represents the first attempt to rigorously evaluate the effectiveness of hypnotic drugs under conditions of prolonged use. Flurazepam, 30 mg, and pentobarbital, 100 mg, were separately evaluated in identical 47‐night sleep laboratory drug evaluation studies on insomniac subjects, which included 4 weeks of drug administration. Flurazepam was found to be effective in inducing and maintaining sleep over all treatment conditions. With long‐term use, only a slight loss of effectiveness was suggested. Flurazepam also produced a moderate decrease in REM sleep and marked decrease in eye movement density and stage 4 sleep with short‐ and intermediate‐term use. While the decreases in both REM sleep and eye movement density lessened with long‐term use, stage 4 sleep remained markedly suppressed. No rebound was noted in any of these parameters after withdrawal. Pentobarbital was found to be effective in inducing and maintaining sleep only with short‐term drug administration. This strongly suggests that it is of limited value for insomniac patients who require nightly medication beyond short‐term use. Pentobarbital caused a minimal decrease in REM sleep with short‐ and intermediate‐term administration, and slight rebound following withdrawal. Stages 3 and 4 sleep were decreased with short‐term use and increased above baseline levels after withdrawal.
Pharmacokinetics of indomethacin
Authors: Alván Gunnar , Orme Michael , Bertilsson Leif , Ekstrand Roger , Palmér Lena
Published: January 2016

Plasma concentrations of indomethacin have been studied in 5 healthy volunteers after single and multiple doses (25 mg intravenously [iv], 25, 50, and 100 mg orally, 100 mg rectally, and 25 mg three times daily [tid]. In 8 other normal subjects and in 5 patients a 50‐mg oral dose of indomethacin was given and the indomethacin concentration was followed from 8 to 32 hr after dosing. All analyses were carried out using a new mass fragmentographic method. After oral and rectal doses the plasma decay of indomethacin was biphasic, and the data were interpreted according to a 2‐compartment open model. The half‐life of the β‐phase varied between 2.6 and 11.2 hr. The volume of distribution ranged from 0.34 to 1.57 L/kg and the plasma clearance from 0.044 to 0.109 L/kg/hr. There was no evidence of dose‐dependent elimination. Indomethacin was rapidly and well absorbed after oral dosing with peak plasma concentrations within 2 hr. Comparison with the area under the curve (AUC) after iv dosing indicated complete bioavailability. The AUC after rectal dosing indicated complete bioavailability, but the rate of absorption was slower than after oral administration. Indomethacin, 25 mg three times daily, was also given for 9 days to the same normal subjects; equilibrium concentrations obtained did not differ significantly (p < 0.1) from those predicted from single‐dose data in the 5 subjects.
Antipyrine metabolism in man: Influence of age, alcohol, caffeine, and smoking
Authors: Vestal Robert E. , Norris Arthur H. , Tobin Jordan D. , Cohen Bernice H. , Shock Nathan W. , Andres Reubin
Published: January 2016

Age has been shown to influence drug metabolism but effects of aging could be due to other variables that influence metabolism and differ with age. Plasma half‐life and metabolic clearance rate of antipyrine were studied in 307 healthy male subjects, aged 18 to 92. Half‐life was 16.5 % longer and metabolic clearance rate was 18.5% less in a group of the older than in the younger subjects. Alcohol consumption, caffeine consumption, and cigarette smoking all were lower in the older subjects. Both caffeine and cigarette use were positively correlated with the rate of antipyrine metabolism. Multiple regression analysis showed that the effect of smoking was partially responsible for the age differences in antipyrine metabolism. Smoking explained 12% of the variance in metabolic clearance rate and age explained 3%. Our results suggest that studies attempting to quantify the effects of aging on drug metabolism must also take into account other factors that differ with age.
Effects of ticlopidine, a new platelet aggregation inhibitor in man
Authors: Thebault Jean J. , Blatrix Charles E. , Blanchard Jean F. , Panak Edouard A.
Published: January 2016

Ticlopidine is a new platelet aggregation inhibitor. The effect of this drug was studied on 55 subjects, healthy volunteers and hospitalized patients. The action requires 24 to 48 hr to appear, and lasts more than 3 days. A dose‐effect relationship was studied with oral daily doses ranging from 250 to 1,000 mg during 1 wk; it showed a 50% inhibition on adenosine diphosphate (ADP )‐induced aggregation at 2 μM concentration on an oral daily dose of 450 mg. No action was found on collagen‐induced aggregation, and a mild effect was observed on platelet adhesiveness. Clinical tolerance was assessed in patients given ticlopidine in oral doses up to 500 mg /day during several weeks, showing no overt side effects and no change in the safety parameters.
Increased arachidonate in lipids after administration to man: Effects on prostaglandin biosynthesis
Authors: Seyberth Hannsjörg W. , Oelz Oswald , Kennedy Tom , Sweetman Brian J. , Danon Abraham , Frölich Jürgen C. , Heimberg Murray , Oates John A.
Published: January 2016

Ethyl arachidonate was administered orally to 4 healthy male volunteers in a dose of 6 gm daily for a 2 to 3 wk period after a 1O‐day control period. The increased intake of this precursor of the dienoic prostaglandins resulted in significant increases in the relative and absolute amount of arachidonate in plasma triglycerides, phospholipids, and cholesteryl esters. Similar changes in lipid composition were noted in platelets. The excretion of 7 α‐hydroxy‐5, 11‐diketotetranorprostane‐1 ,16‐dioic acid, the major urinary metabolite of E prostaglandins in man, was increased by an average of 47% in 3 of the 4 volunteers. Platelet reactivity was assessed by determining the threshold concentration of adenosine diphosphate (ADP) necessary to induce secondary, irreversible aggregation of platelet‐rich plasma. This threshold concentration dropped significantly in all volunteers (10% to 60% of control values). It is concluded that the biosynthesis and function of prostaglandins can be augmented in man by oral administration of an esterified precursor fatty acid.
A comparison of fenfluramine and amphetamine in man
Authors: Griffith John D. , Nutt John G. , Jasinski Donald R.
Published: January 2016

dl‐Fenfluramine hydrochloride (60, 120, 240 mg), d‐amphetamine sulfate (20, 40 mg), and placebo were compared in 8 postaddict volunteers, each dose given orally in random sequence at weekly intervals using a double‐blind crossover design, Fenfluramine had little effect on blood pressure and temperature, but caused a marked dilation of pupils, whereas amphetamine was a potent vasopressor and a weak mydriatic, While fenfluramine produced euphoria in some subjects, its overall effects were unpleasant, sedative, and qualitatively different from amphetamine, Three subjects given 240 mg of fenfluramine experienced brief but vivid hallucinogenic episodes characterized by olfactory, visual, and somatic hallucinations, abrupt polar changes in mood, time distortion, fleeting paranoia, and sexual ideation. These observations indicate that fenfluramine is a hallucinogenic agent with a pharmacologic profile in man that is not amphetamine‐like.
Duration of hydralazine action in hypertension
Authors: O'Malley K. , Segal J. L. , Israili Z. H. , Boles M. , McNay J. L. , Dayton P. G.
Published: January 2016

The effect on blood pressure of giving hydralazine orally, 300 mg per day divided into 2, 3, and 4 doses, was studied in 4 hypertensive patients. There was no significant difference in average mean arterial pressure for the 3 regimens. Fluctuations of mean arterial pressure with time were not significantly different for the regimens as indicated by coefficient of variation. The mean coefficient of variation for the 2 days prior to initiation of hydralazine dosing was 4.0% ± 0.3 (SEM) and for the 3 dosing regimens ranged from 4.1% to 4.8%. Heart rate was used as an index of vasodilator‐induced increase in sympathetic tone and therefore as a measure of possible side effects. Fluctuations in heart rate were small and were not associated with symptoms. After discontinuation of hydralazine, the time for blood pressure to return halfway between initial placebo value and end treatment value varied from 30 to 140 hr. A tracer dose of hydralazine‐ 14C HCI was administered intravenously to the patients. The urinary excretion of 14C showed a multiexponential pattern of elimination with a previously undescribed prolonged terminal phase. Under the conditions of the present study, a daily dose of 300 mg of hydralazine was as effective and free of side effects given in 2 as in 4 divided doses.
Phenytoin and phenobarbital concentrations in saliva and plasma measured by radioimmunoassay
Authors: Cook C. E. , Amerson Ellen , Poole W. Kenneth , Lesser Philip , O'Tuama Lorcan
Published: January 2016

Saliva and plasma levels of phenytoin (DPH) and phenobarbital (PB) in a series of epileptic patients were compared by means of a radioimmunoassay (RIA) that required only 10 µ11 of saliva or plasma. There was an excellent linear relation (r = 0.98) between the logarithms of the concentrations of DPH in the two fluids. The ratio saliva/plasma was remarkably constant at 0.10 and was unaffected by varying levels of PB. The ratio was close to the fraction of DPH reported unbound in plasma at 37°. PB plasma and saliva levels were also closely related (r = 0.98 for logarithm of plasma and saliva levels). This relation was nonlinear [plasma concentration = 4.43 × (salivary concentration)0.86], but could be approximated by the ratio plasma/saliva = 3.4. The simplicity of sample collection and the sensitivity of the RIA procedure suggest that clinical monitoring of these anticonvulsant levels may be carried out by RIA on saliva samples.
Renal clearance of canrenoate in normal man
Authors: Hofmann Lorenz M. , Polk Rothwell C. , Maibach Howard I.
Published: January 2016

Potassium canrenoate was administered intravenously, twice at a 9‐hr interval, to 3 apparently healthy male volunteers. No consistent changes in endogenous creatinine or PAH clearances were observed for 6 hr after the initial 200‐mg dose of this aldosterone antagonist. The clearance of canrenone (the major γ‐lactone metabolite) exceeded by 70% the simultaneous clearance of creatinine from the second through the sixth hour. The excretion of canrenone amounted to 6.8 mg (3.4%) of the dose during the 6‐hr clearance study, but was nearly absent (0.2 mg) during the ensuing 6‐ to 9‐hr period. The cumulative excretion of the glucuronide conjugate of canrenone amounted to 4.6 and 2.8 mg (2.3% and 1.4%) of the dose during these respective periods. A sustained retention of K was observed in 1 subject. Otherwise, as was anticipated in the absence of hyperaldosteronism, urinary electrolyte levels were essentially unchanged. Circulating aldosterone and plasma renin activity levels were essentially unaltered.
Serial serum digoxin concentrations and quantitative electrocardiographic changes
Authors: Joubert Pieter , Kroening Bruce , Weintraub Michael
Published: January 2016

Four elderly female patients in sinus rhythm and with mild congestive cardiac failure were treated with digoxin and studied over a 6‐month period. There were significant linear correlations between serum digoxin concentrations and several quantitative electrocardiographic (ECG) parameters. T‐wave amplitude was the most important ECG variable. ECG changes reverted to baseline values when digoxin was discontinued. These findings suggest that quantitative ECG changes are potentially useful in clinical and research situations involving digitalis glycosides.
Superior bioavailability of digoxin solution in capsules
Authors: Mallis George I. , Schmidt Donald H. , Lindenbaum John
Published: January 2016

The bioavailability of various formulations of digoxin was assessed after single and multiple doses in a series of crossover studies in human volunteers. Digoxin tablets that were 97% dissolved in 1 hr in vitro were not significantly better absorbed than tablets with a dissolution rate of 78%. A solution given in capsule form had greater bioavailability than tablets of 97% dissolution rate; serum and urinary glycoside levels after 0.4 mg doses of the encapsulated solution were similar to those attained after 0.5 mg doses of tablets with dissolution rates of 78% and 97%. The bioavailability of the solution in capsule form exceeded that of equal doses of the same solution given as a liquid or that of a standard elixir. No increase in gastrointestinal or cardiac toxicity was detected. Inter‐ and intrasubject variation in bioavailability was not decreased. Above a certain level, dissolution rate is no longer the limiting factor in digoxin absorption. The mechanism of the enhanced bioavailability of concentrated liquid digoxin in capsule form remains to be determined. Such a preparation deserves further consideration as a possible replacement for digoxin tablets.
Assay of aspirin and naproxen analgesia
Authors: Mahler Donald L. , Forrest William H. , Brown Colin R. , Shroff Phyllis F. , Gordon H. Earl , Brown Byron W. , James Kenneth E.
Published: January 2016

To establish the relative potency ofnaproxen and aspirinfor oral analgesia, a 4‐point, noncrossover bioassay with placebo control was undertaken with 197 patients. Subjective‐response methods were used to determine two measures of postoperative analgesia over aperiod of 6 hr. With reasonable confidence for an oral analgesic assay, we found 220 mg of naproxen to be equivalent to 600 mg of aspirin for pain relief and 330 mg of naproxen to be equivalent to 600 mg of aspirin for decreased pain intensity.
Evaluation of lorazepam and pentobarbital as surgical premedicants
Authors: Conner James T. , Parson Narendra , Katz Ronald L. , Wapner Susan , Bellville J. Weldon
Published: January 2016

Lorazepam. a new benzodiazepine. was compared with a standard surgical premedicant. pentobarbital. In a double‐blind study in 128 patients. lorazepam. 2 and 4 mg. and pentobarbital. 50 and 100 mg. were given intravenously in a randomized sequence. Significant differences were noted; lorazepam was found to provide greater sedation. lack of recall, and greater antianxiety effect than pentobarbital. No significant adverse effects were noted following either drug. Vital signs remained stable.
Disposition kinetics of quinidine
Authors: Ueda Clarence T. , Hirschfeld David S. , Scheinman Melvin M. , Rowland Maleolm , Williamson Blake J. , Dzindzio Barry S.
Published: January 2016

The disposition kinetics of quinidine in 12 hospitalized patients in whom oral quinidine therapy was to be initiated is described. Quinidine in doses of 2.6 to 5.2 mg/kg base were injused intravenously over 22 min. Plasma sampies were collected during and postinfusion for 24 hr and analyzed by a specijic and sensitive assay procedure. In the 12 hr after administration, postinfusion plasma quinidine concentration decay was described by a biexponential equation. Attempts to include the 24‐hr data point in the fitting procedures resulted in poorer agreements between the theoretical and experimental curves. A 2‐compartment open model is proposed to describe the disposition of quinidine. The volume of the central pool (Vc) and steady‐state volume of distribution (Vdss) were 0.91 ± 0.11 L/kg and 3.03 ± 0.25 L/kg, respectively, and indicate that quinidine distribution is predominantly extravascular. Quinidine distribution was quite rapid (t½α = 7.19 ± 0.70 min), while the apparent elimination half‐life (t½ß) was considerably longer, 6.33 ± 0.47 hr. Total body plasma clearance ranged from 1.49 to 7.15 ml/min/kg (mean 4.70) and is primarily associated with nonrenal mechanisms of drug elimination. Urine specimens collected for 48 hr indicated that 17% of the dose is excreted intact and that urinary excretion was essentially complete within 24 hr. Renal clearance (Clr) was 0.80 ± 0.18 ml/min/kg. The study demonstrated that there is substantial interpatient variability with respect to quinidine disposition.
Ethosuximide dosage regimens
Authors: Buchanan Robert A. , Kinkel Arlyn W. , Turner Janeth L. , Heffelfinger J. C.
Published: January 2016

A study was conducted in 9 children with petit mal epilepsy to compare the plasma levels of ethosuximide after divided daily administration with those after single daily administration. The children received their previously established dose in divided doses for 4 wk, in single morning doses for 4 wk, and again in divided doses for 4 wk. None of the children suffered petit mal seizures during the study. Three had grand mal seizures but the frequency did not differ between the dosage regimens. Plasma levels during the single‐dose period peaked more rapidly and fell more quickly than during the other periods, but mean levels remained in the therapeutic range. The mean half‐life of the drug in these children was 29 hr. For reasons not understood, plasma levels generally were lower in the second divided dose period than in the other two periods. No adverse experiences were reported during the study. The data indicate that ethosuximide is clinically effective when given in a single daily dose. This regimen offers advantages in convenience and possibly in patient compliance.
Duration of cardiac effects of timolol and propranolol
Authors: Achong Michael R. , Piafsky Kenneth M. , Ogilvie Richard I.
Published: January 2016

The duration of the cardiac effects of single intravenous doses of the ß‐antagonists, timolol and propranolol, was compared in 6 healthy male subjects. Timolol and propranolol were given in doses of 1 mg and 10 mg, respectively, and at specified times after their administration, ß‐blockade was assessed by the reduction of maximal exercise‐induced tachycardia and by the inhibition of the chronotropic and inotropic effects of isoproterenol. Inotropic effects were measured by changes in the pre‐ejection period of left ventricular systole obtained from systolic time intervals. There was no statistically significant difference in the timolol and propranolol time‐courses of ß‐blockade. The change in exercise‐tachycardia was maximal 5 min after ß‐antagonist infusion but dissipated rapidly so that no statistically significant change was observed 9 hr later. The chronotropic and inotropic effects of isoproterenol were almost completely antagonized for 1 V2 hr after ß‐antagonist infusion, and significant ß‐blockade could be demonstrated 9 hr later. There was no difference in the time‐course of the negative chronotropic and inotropic effects of either ß‐antagonist.
Hypnotic efficacy of lorazepam and flurazepam
Authors: Wang Richard I. H. , Stockdale Susan L. , Hieb Elizabeth
Published: January 2016

In a double‐blind crossover study involving 15 insomniac subjects, the hypnotic efficacy of lorazepam, 2 and 4 mg, was compared with flurazepam, 15 and 30 mg, and placebo. Five subjective measures were used: onset, length, and depth of sleep, number of times awakened, and satisfaction with the hypnotic. Lorazepam in 2‐ and 4‐mg doses was comparable in hypnotic efficacy to flurazepam, 30 mg, according to most parameters of measurement. Side effects were minor, although relatively numerous at the 4‐mg doses.
Thyroid hormone‐like effects without thyrotoxicosis during one year's therapy with NA‐DT3 for hypercholesterolemia
Authors: Danowski T. S. , Stephan T. , Nolan S. , Ahmad U. , Wingert J. P. , Bowman D. H. , Sunder J. H. , Fisher E. R.
Published: January 2016

A thyroid hormone analogue, sodium dextro‐triiodothyronine (NaDT3), at a dosage of 1 mg/day for 1 or 2 yr, decreased serum cholesterol levels about 30% in 26 hyperlipidemic adults. There were less sustained decreases in the serum phospholipids, and occasional lowering of the serum triglycerides, but no effects on body weight, blood pressure, or pulse rate. Changes recognized as variable concomitants of spontaneous or induced thyrotoxicosis, such as transient increases in fasting blood glucose, calcium, and globulin, persistent rises in alkaline phosphatase, and nonsustained decreases in hematocrit are consonant with the fact that Na‐DT3 exerts about one tenth of the thyroid hormone activity of LT3. These changes, however, appear to represent actions of iodinated amino acids apart from those effects that result in clinical thyrotoxicosis.
N‐acetylprocainamide levels in patients with end‐stage renal failure
Authors: Gibson Thomas P. , Matusik Edward J. , Briggs William A.
Published: January 2016

Serum concentrations of pro cain amide (PA) and N‐acetylprocainamide (NAPA) were measured by fluorometry in subjects with normal renal function (n = 4) and in patients with end‐stage renal failure (n = 3) after administration of 6.5 mg/kg of PA · HCI orally. Two subjects with normal renal function were rapid isonicotinic acid hydrazide (INH) acetylators and two were slow acetylators. The rapid acetylators had higher peak serum levels of NAPA (1.80 µg/ml) than the slow acetylators (0.40 µg/ml). Peak serum levels of PA were essentially identical in both. The half‐life (T½) of PA was shorter, 2.5 hr, in the rapid acetylators than in the slow, 4.1 hr. The slope of the terminal portion of the blood time curve for NAPA was steeper (−0.087) for slow acetylators than for rapid (−0.078). These apparent differences between rapid and slow acetylators are not conclusive in themselves but tend to support the differences in acetylation previously reported. In the absence of renal function, the serum levels of PA were higher and the T½ prolonged. The serum levels of NAP A rose slowly and reached peak levels of 2 to 3 µg/ml and declined only with hemodialysis. In 3 patients measurable levels of NAPA were still present 78 hr (0.62 µg/ml), 94 hr (0.36 µg/ml), and 124 hr (0.70 µg/ml) after the single oral dose of PA. Clearance of NAPA during clinical hemodialysis was 48 ± 10 cc/min compared to 75 ± 12 ml/min for PA.
Maternal and neonatal elimination of amobarbital after treatment of the mother with barbiturates during late pregnancy
Authors: Draffan G. H. , Dollery C. T. , Davies D. S. , Krauer B. , Williams F. M. , Clare R. A. , Trudinger B. J. , Darling M. , Sertel H. , Hawkins D. F.
Published: January 2016

Plasma half‐lives of amobarbital were determined in newborn children of 10 mothers who had been treated with barbiturates for hypertension in pregnancy for 6 to 42 days prior to delivery. Five mothers had received amobarbital, 200 mg daily, and 5, phenobarbital, 60 to 180 mg daily. Half‐lives in 7 of the babies ranged from 16.6 to 49.4 hr, comparable to those previously reported in babies of mothers who had received only a single dose of amobarbital. Thus there was no evidence of induction of amobarbital hydroxylation in these children. Two babies who had a greater than normal rise in serum bilirubin had longer half‐lives (86.1 and 117.7 hr). In 1 baby whose mother had membranous glomerulonephritis, plasma amobarbital concentration did not significantly change over the period of the study.
Kinetics of carbamazepine and its 10,11‐epoxide metabolite in children
Authors: Rane Anders , Höjer Bengt , Wilson John T.
Published: January 2016

The plasma steady‐state concentration of carbamazepine (CBZ) and its metabolite (carbamazepine‐10,11‐epoxide, CBZ‐epoxide) was assessed in 43 children (2–15 yr) on CBZ (Tegretol) treatment. Twenty of the children received combined treatment with other anticonvulsant drugs simultaneously. The plasma concentrations were in the same range as had been found in adult patients on corresponding doses. Only a weak correlation was noted between dose and plasma CBZ concentration in the group of children on single‐drug treatment, and there was no correlation in the group of children on combined drug regimen. Plasma levels of CBZ correlated with those of the metabolite. Children on combined treatment had lower CBZ concentration and, expressed as percent of the parent drug, the metabolite concentration was significantly higher than in children treated only with CBZ. In 2 children the plasma half‐life of CBZ was estimated and found to be slightly shorter than has previously been reported in adults. In evaluating the plasma level‐effect relationship of CBZ, the plasma concentration of the CBZ‐epoxide should be measured simultaneously because of its anticonvulsant effect and interindividual variability.
Acetaminophen elimination kinetics in neonates, children, and adults
Authors: Miller R. P. , Roberts R. J. , Fischer L. J.
Published: January 2016

The elimination of acetaminophen (AP AP) following an oral dose of 10 mg/kg in newborn infants, children, and adults was compared. Urinary excretion of unchanged AP AP, APAP‐suljate, and APAP‐glucuronide was complete within 30 hr at all ages. Higher percentages of the dose were excreted in the urine as APAP‐suljate in neonates (0–2 days old) and children (3–9 yr old) than in 12‐yr‐old children and adults. A pharmacokinetic analysis indicated that the higher rate of APAP‐suljate formation in younger age groups apparently compensated for a deficiency in glucuronide formation. No dramatic age‐related differences in the overall elimination rate constant for APAP were observed despite the quantitative changes in the metabolic pathways during early childhood.
Influence of cannabidiol on delta‐9‐tetrahydrocannabinol effects
Authors: Dalton William S. , Martz Robert , Lemberger Louis , Rodda Bruce E. , Forney Robert B.
Published: January 2016

Experiments investigating the possible interaction of tetrahydrocannabinol (THC) and cannabidiol (CBD), two major components of marihuana, were conducted under controlled laboratory conditions in a double‐blind manner. In one study, 15 male volunteers were given placebo or 25 µg/kg of THC together with either placebo or 150 µg/kg of CBD by inhalation of the smoke of a single cigarette. All four treatments were assigned to each subject according to a series of Latin‐square designs. CBD significantly attenuated the subjective euphoria of THC. Psychomotor impairment due to THC was not significantly altered by the simultaneous administration of CBD, but a trend indicating a decrease in THC‐like effects was observed after the combination. When administered alone CBD was inactive for all the parameters measured. In a second study, 8 male subjects were given CBD (0 or 150 µg/kg) by smoke inhalation 30 min before THC (0 or 25 µg/kg) in a second cigarette. In contrast to the simultaneous administration of both drugs, CBD pretreatment did not alter the effects of THC on the parameters observed.
Marijuana and T Iymphocyte rosettes
Authors: Cushman P. , Khurana R.
Published: January 2016

The effect of marijuana smoking on sheep cell rosetting properties of both early (active) and total T lymphocytes was studied in vitro. Significantly fewer active rosettes were formed by T cells from a population of 35 who appeared to be chronic marijuana smokers than the 34 controls. The late, or cold‐enhanced rosettes formed by smokers and nonsmokers were similar, suggesting that similar numbers of rosette‐forming T cells were present in the peripheral blood of smokers. These data suggest that marijuana smoking may affect the function of a subpopulation of T lymphocytes, identified by their capacity to form early rosettes, possibly by affecting these cell membranes.
Metabolism of procainamide in normal and cardiac subjects
Authors: Giardina Eisa‐Grace V. , Dreyfuss Jacques , Bigger J. Thomas , Shaw James M. , Schreiber Eric C.
Published: January 2016

N‐Acetylprocainamide (NAPA) has been well documented as a metabolite of pro cain amide (PA) in man. The objective of the present study was to separate and quantify PA and its metabolites in man. Ten subjects (5 normal and 5 patients with heart disease) were given 40 µCi of PA−14C orally, and samples of blood, urine, and expired air were collected for 72 hr. Each subject received 500 to 1,000 mg of PA (7 to 13 mg/kg). During the 72 hr after dosing, 73% to 91% of the dose was excreted in urine. During the first 24 hr, 31% to 56% of the dose [48 ± 2.2 (mean ± SEM)] was PA; 7% to 24% (15 ± 1.8) of the dose was NAPA; 6% to 10% (7 ± 0.5) of the dose was an unknown metabolite (Rf = 0.0); and 2% to 4% (3 ± 0.2) of the dose was another unknown metabolite (Rf = 0.3). No radioactivity was detected in expired air. Less than 0.2% of the dose was accounted for as either p‐aminobenzoic acid or as p‐acetamidobenzoic acid. The maximum concentration of PA in plasma for all 10 subjects was 5.6 ± 0.9 µg/ml, 4.2 ± 0.3 µg/ml for the normal subjects and 7.1 ± 1.4 µg/ml for the patients. The T½ for the elimination of PA was 2.9 ± 0.5 hr for the normals and 5.5 ± 0.9 hr for patients. The maximum concentration of NAPA in plasma for all subjects was 2.8 ± 0.6 µg/ml, 1.6 ± 0.3 µg/ml for normal subjects and 4.1 ± 0.8 µg/ml for patients. In 2 patients, concentrations of NAPA (4.0 and 5.6 µg/ml) were as high or higher than those of PA.
Relationship of urinary metabolites of theophylline to serum theophylline levels
Authors: Jenne John W. , Nagasawa Herbert T. , Thompson Richard D.
Published: January 2016

Using high‐pressure liquid chromatography, we have quantitated the theophylline metabolites in the 24‐hr urines of 15 patients in a clinical ward who had been receiving 800 or 1,200 mg of aminophylline /24 hr in divided oral doses. Mean values for the theophylline‐derived urine products were as follows: unchanged theophylline, 7.7 ± 6.1%; 3‐methylxanthine, 36.2 ± 7.3%; 1,3‐dimethyluric acid, 39.6 ± 4.5%; and 1‐methyluric acid, 16.5 ± 3.3%. These data are consistent with those earlier reported for theophylline metabolism in man with other methodology. The fractional contents of urine products were variably related to trough serum theophylline levels, the latter determined by the Schack and Waxler method. There was a significant direct correlation between serum theophylline levels and the urine theophylline fraction, and a significant inverse correlation between serum theophylline and the urine 3‐methylxanthine fraction. Urinary 3‐methylxanthine and 1,3‐dimethyluric acid were inversely related, implicating competition for substrate. The urine content of 1,3‐dimethyluric acid and 1‐methyluric acid diverged as serum theophylline increased, suggesting that the former may give rise to the latter by a rate‐limiting demethylation reaction. The data suggest that the 1‐demethylation of theophylline to 3‐methylxanthine is the dominant reaction determining serum theophylline.
Antitussive activity of diphenhydramine in chronic cough
Authors: Lilienfield Lawrence S. , Rose John C. , Princiotto Joseph V.
Published: January 2016

A double‐blind crossover study was conducted to evaluate the antitussive effectiveness of diphenhydramine (DPH) in chronic coughs related to bronchitis, at doses of25 and 50 mg every 4 hr for four doses. Both 25− and 50‐mg doses caused a statistically and clinically significant reduction in frequency of coughs, compared to placebo. The most frequently reported side effect was drowsiness, principally at the 50‐mg dose level. There was little or no apparent correlation between antitussive effectiveness and incidence of drowsiness, however, suggesting that the two effects were pharmacologically unrelated.
Sodium salicylamide: Relative bioavailability and subjective effects
Authors: Fleckenstein Lawrence , Mundy Gregory R. , Horovit Richard A. , Mazzullo John M.
Published: January 2016

The bioavailability of sodium salicylamide (NaSAM) in solution of salicylamide (SAM) tablets was compared in 6 healthy human volunteers. Bioavailability was assessed by plasma level determinations of nonmetabolized salicylamide (free SAM) and salicylamide plus conjugated metabolites (total SAM) for 3 hr following oral doses of 0.65, 1.30, 1.95, and 2.60 gm of salicylamide. The availability of NaSAM was found to be superior to SAM and dose‐dependent. Mean peak levels offree SAM and total SAM were higher and were reached earlier after NaSAM liquid than after SAM tablets. Significantly higher mean levels offree SAM were found at the 1.95 and 2.60 gm dose levels after NaSAM administration than after SAM. Mean total SAM concentration was significantly higher after NaSAM at all dosage levels. The sedative effects of salicylamide were assessed with a self‐scoring questionnaire. Sedation seemed to increase with increasing dose of both NaSAM and SAM. The sedative response occurred earlier after NaSAM than after SAM. Side effects were minor and transient in nature, occurred at the higher dosage levels, and were predominantly lightheadedness and dizziness. Because NaSAM produces higher drug levels and has a more rapid onset of subjective effects, we conclude that it represents a potentially superior dosage form.
XXXVI. The persistent biometric problems of the UGDP study
Authors: Feinstein Alvan R.
Published: January 2016

As a medical cause célébre of our era, the therapeutic trial conducted as the University Group Diabetes Program (UGDP) has been a fertile source of educational material. The study itself and the controversies it has engendered have produced issues that are now being avidly discussed not only for their clinical and statistical consequences, but also for their impact in such domains as law, ethics, health policy, legislation, press relations, and medical statesmanship. Although many editors and readers may be tired of hearing about the UGDP, it continues to warrant thorough attention and scrutiny because its wide‐ranging implications extend far beyond the immediate topic of pharmaceutical treatment for patients with diabetes mellitus.
Serum triiodothyronine levels in patients receiving L‐thyroxine
Authors: Kahn Amnon
Published: January 2016

Serum triiodothyronine (T3) and thyroxine (T4) levels were measured in 103 adult patients receiving sodium L‐thyroxine (Synthroid), 0.2 or 0.3 mg daily for at least 3 mo, as suppression or replacement therapy. All were judged to be clinically euthyroid at the time of the measurements. The mean ± SD T3 level during treatment was 130.3 ± 47.5 ng% and the mean T4 level was 11.0 ± 2.0 /μg%. In normal untreated euthyroid subjects, the meant T3 level was 115.4 ± 26.0 ng% and the mean T4 level was 8.0 ± 1.7/μ%. When sodium L‐thyroxine was added in vitro to the stored sera of 10 hypothyroid patients to produce serum T4 levels equivalent to those that the patients later showed in vivo while on therapy, the cross‐reaction was 0.85%. Thus at a mean T4 level of 11.0 /μg%, there was a mean T3 level of 93.5 ng% that could be attributed to the added thyroxine itself. This cross‐reaction was found to be due to contamination of the added sodium L‐thyroxine with T3 and not due to cross‐reactivity of the T3 antibody in the immunoassay system with T4. For 3 other brands of sodium L‐thyroxine, the T3 contamination of the added T4 was 0.75%, 0.55%, and 0.40%. When 6 hypothyroid patients were given 5/μg of L‐triiodothyronine (Cytomel) daily for 4 wk, there was no rise in serum T3 levels. When the same patients were switched to sodium L‐thyroxine, 0.2 mg daily, serum T3 levels rose from a mean ± SD of 60.0 ± 16.3 ng% to a mean of 130.0 ± 38.0 ng%. It would thus appear that in patients receiving sodium L‐throxine therapy, the resulting serum T3 levels are due to extrathryoidal conversion of the administered T4 to T3, and not to the T3 present in the L‐thyroxine administered.
Absorption, metabolism, and excretion of hydrochlorothiazide
Authors: Beermann Björn , Groschinsky‐Grind Margaretha , Rosén Anders
Published: January 2016

14C‐hydrochlorothiazide (hct) was administered orally (n = 4) and iv (n = 2) to healthy subjects. The gastrointestinal absorption ranged between 60% and 80%, most of it took place in the duodenum and the upper jejunum. The radioactivity was eliminated mainly in the urine, while no significant biliary excretion was observed. Chromatographic analysis of the urinary radioactivity demonstrated that >95% of the absorbed or injected 14C‐hct was excreted unchanged. The radioactivity in plasma during the first 10 hr after oral administration declined with a fast phase but the levels of label thereafter suggested a slow phase. The existence of such a phase was verified in 1 subject given 75 mg hct orally. His plasma levels of hct (determined with gas‐liquid chromatography) declined according to a 2‐compartment model, the half‐lives of the α− and β‐phases being 1.7 and 13.1 hr, respectively. Hct accumulated in the blood cells and the ratio between the radioactivity in cells and that in plasma averaged 3.5. The fate of a single dose of 14C‐hct in 2 hypertensive patients treated with the drug chronically was similar to that in the healthy subjects. A third patient, who had slightly elevated serum creatinine, eliminated hct more slowly than the others. Like the healthy subjects, the patients eliminated hct
Furosemide and bumetanide: A study of responses in normal English and German subjects
Authors: Branch Robert A. , Read Peter R. , Levine David , Elst Eric Vander , Shelton John , Rupp Werner , Ramsay Lawrence E.
Published: January 2016

Diuretic responses to oral administration of 1 mg bumetanide and 40 mg furosemide were determined in double‐blind, crossover balanced trials in 10 normal English subjects and 6 normal German subjects. In each experiment the 0‐ 10 8‐hr urine volume and sodium excretion were significantly higher after bumetanide, potassium excretion did not differ, and the Na/K ratio, although higher after bumetanide, was not significantly different by analysis of variance. in German subjects the diuretic and natriuretic responses to both drugs were greater and the potassium excretion less than in English subjects. In the English, the pretreatment 24‐hr urinary NalK ratio correlated with the urinary Na/K ratio response to both drugs and with the potassium excretion after furosemide. The mean plasma uric acid before treatment correlated with the Na/K ratio and potassium excretion after furosemide. Aldosterone excretion did not correlate with response to either diuretic. The mean pretreatment 24‐hr log10 Na/K ratio in the two treatment periods of the English and German subjects correlated with the mean sodium excretion, potassium excretion, and log10 Na/K after the two diuretics, thus providing a partial explanation for intersubject and interstudy variation. Pretreatment log10 Na/K could also explain intrasubject variation, justifying its use as a covariate in covariance analysis. This demonstrated that at this dose ratio the urinary log10 Na/K ratio response to bumetanide was significantly higher than that to furosemide.
Session III. Patterns of drug utilization; Sources of information on drug usage in Sweden
Authors: Westerholm Barbro
Published: January 2016

Based on sales statistics, prescription habits and figures, interviews, and, in certain instances, on determinations of drug plasma levels, various aspects of drug usage in Sweden are examined. The working of the drug regulatory agency in Sweden is elucidated against the background of the above sources from which drug usage information is obtained.
How study of geographie epidemiology of disease can help in detection of adverse drug reactions
Authors: Stolley Paul D.
Published: January 2016

The geographie epidemiology of adverse drug reaetions ean often help in their recognition and in pinpointing the responsible drug. Sinee different eountries often introduee new drugs at varying periods of time and they aehieve varying degrees of popularity and use, this information may sometimes aid the epidemiologist in the seareh for the etiology of unwanted drug effeets. Some examples where geography helped unravel the story behind eertain adverse drug reaetions are presented.
Proposed procedural changes in new drug evaluation by the Food and Drug Administration
Authors: Walters Philip G.
Published: January 2016

Proposals for changes in the procedures for evaluating new drug applications by the Food and Drug Administration (FDA) are described. Under consideration are the following innovations. (1) The sponsor is to submit protocols at the time of applying for an 1ND and prior to initiating studies. Data are 10 be submitted at the end of each Phase (I, II, III) of investigation, rather than as now at the time offiling the New Drug Application (NDA). By this system it is hoped to identify early problems and to make recommendation to the sponsor for the next steps in the investigation. (2) To broaden the base on which the new drug is evaluated, it is proposed to make use of clinical data available from experts in other countries. Criteria of acceptability of evidential material from foreign clinical studies are essentially those that meet the standards imposed for United States investigations, e.g., training and experience qualifications of the investigator, adequacy offacilities for investigational studies, maintenance of detailed case reports, conduct of the studies in conformance with the declaration adopted by the World Medical Assembly (Helsinki 1964), and according to ethical considerations approved by a Review Committee.
Regulatory milieu in India
Authors: Sheth U. K.
Published: January 2016

The regulatory agency under the control of the Food and Drug Administration operating at both central and state levels in India is described. The Central Drug Controller operates under the Ministry of Health. Together with a panel of experts in an advisory capacity, a Drug Technical Advisory Board and its own staff of pharmacologists, chemists, and pharmacists, the Central Drug Controller, administers the introduction of new drugs, marketing and quality control, and drugs and cosmetics regulations. The State Drug Control Administration [unctions under the state Ministry of Health, working in close liaison with and under the supervisory control of the Central Drug Control Administration. The State Drug Controller enforces quality control during pharmaceutical manufacture, checks on quality control of marketed drugs, and enforces compliance witn Food and Drug regulations in the state. Prior to initiation of clinical trials, the sponsor is required to submit preclinical data and obtain permission for Phase I, II, and III trials, submitting data at each stage. Complete teratogenic data are to be submitted prior to receiving marketing permission. If clinical trials have been carried out in other countries, the available data of these trials should be submitted. The regulations for the introduction of new drugs in general follow the recommendations by WHO. Even if a drug has been marketed outside the country, the drug control authorities require limited clinical trials, particularly to determine the dosage and safety in the Indian population, because of lower body weight, nutritional status, and lower plasma protein values, the last being important as binding sites. Also unexpected toxicities may be revealed because of genetics and racial differences not noted in the country of the drug' sarigin. Monitoring of efficacy and of adverse reactions for at least 3 yr after marketing would be desirable, but is not done at present. The mechanics of collecting such data in India at present are not defined and are difficult.
Session VI. Patterns of education and training; Drug evaluation, educational system, and clinical pharmacologic training in a small country
Authors: Hvidberg Eigill F.
Published: January 2016

The need for clinical pharmacology as an integral part of medical training is emphasized. The lack of a formal system of educating candidates in this discipline in a small country with limited means of personnel and Junds has to be compensated Jor by close cooperation among practicing physicians, clinical pharmacologists in universities and some hospitals, industry technologists, and the personnel serving on national drug regulation committees. The system of drug regulation in Denmark and its tangential contribution to educating the younger clinical pharmacologists are described. The efficiency as well as the limitations of the system are assessed.