bluuebunny/crossref_metadata_2025 huggingface dataset:
The hypnotic effects of codeine and secobarbital and their interaction in man
Authors: Bellville J. Weldon , Forrest William H. , Shroff Phyllis , Brown Byron W.
Published: January 2016

Codeine and secobarbital and a combination of the two were studied as nighttime hypnotics. There was a positive dose effect between 60 and 180 mg. of secobarbital, but increasing the dose of codeine from 30 to 90 mg. appeared to show a stimulant effect on onset and duration of sleep. Taken together, codeine plus secobarbital were more effective than was secobarbital alone. Analysis indicated that this interaction represented synergism.
Electrophysiologic basis of use of a polarizing solution in the treatment of myocardial infarction
Authors: Prasad Kailash , Callaghan John C.
Published: January 2016

The effects of glucose, glucose and insulin, and glucose, insulin, and KCl on the action potential duration, etJective refractory period, and rate of rise of 0 phase of action potential of the human papillary muscles, obtained from patients undergoing correctice open‐heart surgery, preincubated in nonoxygenated Krebs‐Ringer solution with or without glucose, were investigated. Nonoxygenated glucose‐free solution produced a marked shortening of the action potential duration and effective refractory period and a moderate decrease in the rate of rise of 0 phase of action potential of the papillary muscles. Glucose or glucose and insulin together brought back the shortened action potential duration arui effective refractory period produced by nonoxygenated glucose‐free solutions to near controllevels while glucose and insulin with KCl was less etJective. Potassium chloride alone produced a further decrease in the action potential duration and effective refractory period and rate of rise of 0 phase of action potential. Although glucose was able only partially to restote the decrease in the rate of rise of 0 phase of action potential produced by nonoxygenated glucose‐free solution, glucose and insulin together increased the rate of rise of 0 phase of action potential to well abooe the controllevel. On the other hand, glucose, insulin, and KCl together produced a further decrease in the rate of rise of o phase of action potential in such anoxic muscles. Glucose or glucose and insulin were superior to glucose, insulin, and KCl together in reversing the effect of anoxia and substrate free solution on the transmembrane potential of papillary muscles. It is therefore suggested that glucose or glucose and insulin should be better than glucose, insulin, and KCl in the treatment of acute myocardial infarction.
The metabolism of L‐3–0‐methyldopa, aprecursor of dopa in man
Authors: Kuruma I. , Bartholini G. , Tissot R. , Pletscher A.
Published: January 2016

L‐2‐14C‐3‐methoxy, 4‐hydroxyphenylalanine (L‐14C‐O‐methyldopa) has a biological half‐life of approximately 15 hours in human blood. 3‐Methoxy, 4‐hydroxyphenyllactic acid, homovanillic acid, and 3,4‐dihydroxyphenylacetic acid are metabolites found in the blood. The urinary excretion of radioactivity is slow and only a small proportion of excreted radioactivity represents unchanged O‐methyldopa. The same metabolites are found as in the blood as weU as small amounts of dopa, dopamine, and 3‐methoxytyramine. It is concluded that in man part of the L‐O‐methyldopa undergoes demethylation to dopa, which is further metabolized to dopamine and phenolcarboxylic acids.
Analgesie activity of oral and intramuscular profadol
Authors: Pearson John W. , Lasagna Louis , Laird Robert D.
Published: January 2016

A double‐blind clinical trial was conducted in 188 postpartum patients, comparing single oral doses of profadol, 50 mg. and 100 mg. base, with codeine, 60 mg., and placebo. Only the pain relief afforded by 100 mg. profadol was statistically significantly different from placebo. Intramuscular profadol was studied in a series of “opeo” and double‐blind clinical trials performed in patients with postoperative pain. The analgesie equivalent of 10 mg. of morphine was between 20 and 40 mg. of profadol base. The highest doses of profadol studied were 120 and 160 mg.; these provided outstanding relief of pain. Since the drug is a racemie mixture, studies of the isomere would be of inierest.
Decrease of tetracycline absorption in man by sodium bicarbonate
Authors: Barr William H. , Adir Joseph , Garrettson Lorne
Published: January 2016

Chelation is usually considered to be the mechanism responsible for the decreased absorption of tetracycline in the presence of antacids containing polyvalent cations such as Ca++, Mg++, or Al+++. The present study shows that tetracycline absorption can also be reduced to a similar extent by sodium bicarbonate, an antaCid which contains no polyvalent cations and cannot form chelates with tetracycline. In a crossover study, 8 fasting subjects received a 250 mg. commercial tetracycline hydrochloride capsule and 200 ml. of water with or without 2.0 Gm. of sodium bicarbonate. Each subject receiving sodium bicarbonate showed a significant decrease in absorption. An average reduction in absorption of 50 per cent was observed as determined by the cumulative amount of unchanged tetracycline appearing in the urine at 48 hours (Qu∞). The mean Qu∞ was 114.1 ± 27.0 mg. for tetracycline alone and 52.5 ± 14.0 mg. when given with sodium bicarbonate. When tetracycline was dissolved prior to administration, no differences in Qu∞ were observed with or without concomitant administration of 2.0 Gm. of sodium bicarbonate, indicating that the dissolution rate step is involved in the decreased absorption of tetracycline capsules. These results are consistent with a mechanism of absorption requiring a low gastric pH for complete dissolution of tetracycline and suggest that any substance or condition which significantly increases gastric pH may decrease dissoltltion and, hence, absorption of tetracycline
Impairment of drug metabolism by disulfiram in man
Authors: Vesell Elliot S. , Passananti G. Thomas , Lee Cynthia H.
Published: January 2016

Disulfiram was administered for either 4 or 10 days to young, otherwise nonmedicated normal volunteers. In all subjects disulfiram prolonged the antipyrine half‐life and reduced urinary vanilmandelic acid (VMA) excretion; after disulfiram was discontinued, antipyrine half‐lives and VMA excretion returned toward normal. These results suggest the possibility of toxicity from dmg accumulation when certain other therapeutic agents are administered simultaneously with disulfiram. Such toxicity from diphenylhydantoin or warfarin has been reported in isolated case studies of patients receiving disulfiram. Since disulfiram administration alters catecholamine metabolism, patients receiving disulfiram should not be expected to exhibit normal parameters of catecholamine turnover. Effects of disulfiram on antipyrine and catecholamine metabolism reveal that disulfiram is not a selective inhibitor of aldehyde dehydrogenase but exerts several discrete inhibitory actions which should be recognized during its administration.
Diazoxide and renal function in man
Authors: Johnson Brian F.
Published: January 2016

In 14 patients with hypertension, 4 mg. at diazoxide per kilogram of body weight iniected intravenously caused an 18 per cent reduction in mean blood pressure, 18 per cent reduction in para‐aminohippurate (PAH) clearance, 27 per cent reduction in inulin clearance, and 50 per cent reduction in uric acid clearance. Marked reduction in urinary sodium, potassium, and chloride excretion occurred. Whereas all of these effects were immediate in onset and sustained, free water clearance fell progressively in over half the subiects and became negative in 7 during the second hour after iniection. There was no correlation between antinatriuresis and change in renal hemodynamics, blood pressure, or tree water clearance. In 6 patients with hypertension, 2 mg. of diazoxide per kilogram injected intravenously caused no change in blood pressure or clearances of inulin or PAH. However, uric acid clearance fell 23 per cent, and clear reductions in urinary electrolyte excretion occurred. In 2 subiects, free water clearance fell progressively and became negative 1.5 to 2.5 hours after iniection. On a constant diet, 300 mg. of diazoxide daily by mouth caused weight gain and sodium retention with minimal change in blood pressure or creatinine clearance. This dosage did not alter free water clearance during sustained water diuresis. The acute antihypertensive effect of diazoxide is associated with reduced renal blood flow and glomerular filtration rate (GFR). Antinatriuresis can occur without change in blood pressure or GRF and is probably caused by a direct tubular action of diazoxide. Frequent marked reduction in free water clearance suggests stimulation of pituitary release of antidiuretic hormone. Diazoxide also suppresses tubular uric acid excretion.
Ampicillin and kanamycin concentrations in joint fluid
Authors: Baciocco Eugene A. , lles Robert L.
Published: January 2016

Joint fluid and blood serum concentrations of ampicillin and kanamycin were measured in patients with traumatic joint effusions. The joint fluid concentrations of ampicillin averaged 1.80 μg per milliliter approximately 2 hours after the last 500 mg. oral dose. Joint fluid concentrations of kanamycin averaged 16 μg per milliliter within 2 hours after the last dose of 15 mg. per kilogram of body weight. At 2 hours, levels of both antibiotics were approximately the same in joint fluid and blood serum. No correlation could be made between patient's age or appearance of synOVial fluid and antibiotic levels. There was an in!;erse relationship between ampicillin joint fluid levels and patient weight. Joint fluid concentrations of the antibiotics were adequate for inhibiting or killing many common pathogens of infected joints.
Blockade of intravenous amphetamine euphoria in man
Authors: Jônsson Lars-Erik , Änggård Erik , Gunne Lars-M
Published: January 2016

In subjects who abuse amphetamine, the euphoric effect of 200 mg. of D,L‐amphetamine intravenously was reduced or abolished by oral pretreatment with α‐methyl‐p‐tyrosine (α‐MT) 2.0 to 4.0 Gm. The blockade of the amphetamine‐induced euphoria lasted for about 24 hours. After one week of daily administration of α‐MT, there was a reduction of the antiamphetamine effect. Three days after withdrawal, the renewed administration of α‐MT again caused a high degree of blockade of amphetamine‐induced euphoria.
Early human studies of a new carbonic anhydrase inhibitor (NSD 3004) with anticonvulsant properties
Authors: Lund Jergen , Pedersen Holger E. , Olsen P. Zander , Hvidberg Eigill F.
Published: January 2016

NSD 3004 is a nondiuretic carbonic anhydrase inhibitor which has shown anticonvulsant properties in animal experiments. The studies reported here with volunteers and patients confirmed the strong binding to carbonic anhydrase in human erythrocytes and an extremely long half‐life in these. The half‐life in plasma from 8 volunteers was 28 ± 4 hours (mean ± standard deviation) and the steady‐state concentration in plasma was 5.7 ± 1.3 µg per milliliter (mean ± standard deviation) on 200 mg. daily. About 10 per cent of the dose was excreted unchanged in the urine and about 20 per cent ay a conjugate. Low values of PCO2 and standard bicarbonate in arterial blood and of total CO2 in venous blood were seen during a two week medication. No other deviations were found in the clinical parameters. Electroencephalography including automatic period analysis revealed no changes related to NSD 3004 medication. Expected effects such as light paresthesias and slight dyspnea on exertion were observed in some volunteers and patients. NSD 3004 seemed to exhibit antiepileptic properties in human subjects; an extensive clinical evaluation is needed.
The efficacy of local anesthetics in blocking the sensations of itch, burning, and pain in normal and “sunburned” skin
Authors: Dalili Hamid , Adriani John
Published: January 2016

Satisfactory methods to determine the efficacy of topical anesthetics in relieving cutaneous itch, pricking, burning, and pain in unbroken skin have not been available. A technique with the use of an alternating current of low amperage and voltage that selectively induces these sensations without apparent in;ury to the skin is described. The efficacy of local anesthetics in obtunding itching and pricking induced experimentally and by exposure of the skin to ultraviolet light was evaluated. Studies in 150 volunteers indicate that salts of local anesthetics are ineffective in obtunding itching and burning in intact normal or ultraviolet burned skin; bases in concentrated solutions are effective.
Characteristics of prognosis and response to an imidazole carboxamide in malignant melanoma
Authors: Nathanson Larry , Wolter Janet , Horton John , Colsky Jacob , Shnider Bruce I. , Schilling Albert
Published: January 2016

In a prospective randomized study of 155 patients, dimethyltriazeno imidazole carboxamide, 2.0 or 4.5 mg. per kilogram given for 10 successive daily intravenous doses, resulted in ob;ective response in 28 per cent of 115 evaluable patients. The 2.0 mg. schedule produced a significantly greater rate and duration of response (p ≤ 0.05) than did the 4.5 mg. schedule. In half of the responding patients the response exceeded 6 months in duration. Urinary melanogens, detected by a qualitative test in 29 per cent of patients tested, suggested widespread disease but were not helpful in diagnosing clinically occult recurrent disease. Toxicity was somewhat greater on the 4.5 mg. regimen, but in general it was mild; there were no drug deaths. The drug, which has some interesting and unusual dose‐toxicity‐response relationships, appears to be the most effective chemotherapeutic agent for treatment of malignant melanoma.
Urinary excretion of methadone in man
Authors: Baselt Randall C. , Casarett Louis J.
Published: January 2016

The renal elimination of methadone and its mafor metabolite by subfects on a methadone maintenance program was studied quantitatively. The concentrations of unchanged drug and metabolite in random urine samples were dose dependent. Urinary excretion was found to constitute the mafor excretory pathway at daily doses in excess of 55 mg. Excretion of methadone was markedly enhanced by acidification of the urine, while the metabolite was less affected by changes in urine pH. A sex difference in the pattern of excretion of methadone and its metabolite was found; it may be related to the rate of biotransformation of the drug.
Serum organochlorine pesticides in mentally retarded patients on differing drug regimens
Authors: Watson Michael , Gabica Joe , Benson W. W.
Published: January 2016

Serum concentrations of p,p'DDT and its metabolite p,p'DDE were estimated by electron‐capture gas chromatography in a group of mentally retarded institutionalized patients receiving antiseizure and tranquilizing chemotherapy. Control patients not taking drugs tended to resemble the general population in terms of organochlorine residues, but drug takers showed greatly lowered levels of both p,p'DDE and p,p'DDT. The combination of phenobarbital and diphenylhydantoin seemed to be the most effective in depressing serum pesticides and remained so even in patients taking other drugs concurrently. P,P'DDE was found at detectable levels in all patients sampled, but the frequency of occurrence of p,p'DDT was considerably decreased among the drug takers. This was particularly true of patients receiving both phenobarbital and diphenylhydantoin concurrently. The possibility that the catabolism of p,p'DDT is induced preferentially to that of p,p'DDE by the phenobarbital‐diphenylhydantoin combination is discussed.
Plasma protein binding of diphenylhydantoin in patients with epilepsy; Agreement between the unbound fraction in plasma and the concentration in the cerebrospinal fluid
Authors: lund Lars , Berlin Anita , Lunde Per Knut M.
Published: January 2016

The plasma protein binding and the cerebrospinal fluid (CSF)‐plasma ratio of diphenyhydantoin (DPH) was determined in 8 patients with epilepsy treated only with DPH and in steady‐state conditions. The unbound fraction of DPH showed only minor interindividual differences and did not differ from the values in drug‐free volunteers. The CSF‐plasma ratio also varied very little interindividually and agreed well with the values of the unbound fraction. The discrepancy between our results and those of previous investigators is discussed.
Quantified human sleep after pentobarbital
Authors: Kay David C. , Jasinski Donald R. , Eisenstein Richard B. , Kelly Orville A.
Published: January 2016

Intramuscular doses of pentobarbital (75, 150, 300 mg. per 70 Kg.) and placebo were given to 8 male postaddict subjects at weekly intervals. After 4 adaptation nights, a crossover design with randomized block analysis of variance was used to demonstrate significant (p < 0.05) drug effect. Pentobarbital decreased rapid eye movement sleep (REMS) by decreasing the number and duration of REMS episodes and by delaying the onset of the first REMS episode, without measurably changing the period of the REMS cycle. Pentobarbital also decreased the prevalence of eye movements and of disruptions during REMS. Pentobarbital increased spindle (Stage 2) sleep and spindle burst incidence during Stage 2 sleep but had minimal effect on delta (Stages 3 and 4) sleep. Pentobarbital decreased muscle tension and body movements but had little effect on EEG measures of waking state. The combined reduction of REMS and increase of spindle sleep might be used as a standard effect with which to determine equivalent doses of barbiturates and similar hypnotics.
Altered plasma cortisol response in patients on methadone maintenance
Authors: Renault Pierre F. , Schuster Charles R. , Heinrich Richard L. , van der Kolk Bessel
Published: January 2016

Plasma cortisol response to cold exposure in 5 healthy male former heroin addicts maintained on stabilized doses of methadone ( 4 on 50 mg. and one on 80 mg.) for a minimum of 3 months was compared with that in 7 healthy male control subjects. In subjects on methadone (one hour after they had received their doses), there was no plasma cortisol increase following cold exposure for one hour at 0° C.; but when cold exposure was repeated on the following day (21 hours after methadone), plasma cortisol increased significantly in all. There was no response to either exposure at corresponding times in the control group. Mean increase after methadone was from 24 µg per cent to 33 p.g per cent. Corresponding control values were 20 and 40 µg per cent. We conclude that there is altered responsiveness to cold exposure toward the end of the duration of action of methadone in patients on methadone maintenance.
The rate of procaine hydrolysis in serum of normal subjects and diseased patients
Authors: Reidenberg Marcus M. , James Margaret , Dring L. Graham
Published: January 2016

The drug metabolism pathway of ester hydrolysis was studied by measuring the rate of procaine disappearance from unmodified serum samples incubated at 37° C. Serum pseudocholinesterase appears to be the enzyme catalyzing this hydrolysis. Healthy adults had a mean serum procaine half‐life of 0.66 ± 0.14 minutes. Sera from newborn infants (cord blood), adults with liver disease, and adults with impaired renal function hydrolyzed procaine more slowly than did sera from healthy adults. Mean half‐lifes for these groups were: 1.40 ± 0.5 minutes, 2.3 ± 0.9 minutes, and 1.40 ± 0.83 minutes, respectively. The degree of slowing of procaine hydrolysis in sera from patients with impaired renal function was proportional to the patients' blood urea nitrogen values. The mechanism for this slowed hydrolysis in sera from uremic patients is decreased levels of enzyme activity and not competitive enzyme inhibition by some substance in the serum.
Rapidly achieved plasma concentration plateaus, with observations on theophylline kinetics
Authors: Mitenko Paul A. , Ogilvie Richard I.
Published: January 2016

Many therapeutic agents can be applied more predictably and effectively if a constant plasma concentration is maintained. With the use of the two‐compartment open‐system model, a general and practical method of combining intravenous bolus and continuous infusion is described. The fastest approach to the plateau situation is shown to result from setting the maintenance infusion rate equal to β times the initial bolus, where β is the slower disposition constant. This procedure was verified in 3 normal subiects. Single bolus doses of theophylline were administered to study the pharmacokinetic behavior of this drug in each individual. This information was used to calculate the regimen required to reach a predetermined plateau concentration. The selected bolus and continuous infusion were given, and in each case resulted in constant plasma values within the first hour.
Metabolism of procainamide in rhesus monkey and man
Authors: Dreyfuss Jacques , Bigger J. Thomas , Cohen Allen I. , Schreiber Eric C.
Published: January 2016

Procainamide (1 Gm.) was administered orally to each of 2 cardiac patients and to 2 normal subjects. Total excretion of procainamide, its metabolites, or both in 6 hours was 19.2 and 48.8 per cent of the dose in the urine of the two patients and 57.1 and 79.5 per cent of the dose in 8 hours in the urine of the 2 normal subjects. Biologic half‐life in the plasma of 3 of the 4 human subjects ranged from 2.2 to 3.2 hours. Two metabolites were found in the pooled urine of the 4 subjects. The major metabolite has been identified as N‐acetylprocainamide; the other, as yet unidentified, has some alteration of the aromatic amino group. Procainamide•14C and N‐acetylprocainamide•14C were both administered orally at different times to 2 rhesus monkeys. Both were well absorbed; the biologic half‐life of each was about 2.5 hours. With both compounds, the radioactivity was excreted primarily in the urine (about 81 per cent of the dose) and, to a small extent, in the feces (about 6 per cent of the dose). After the administration of procainamide‐14C, the urine contained procainamide (1.7 per cent of the dose), N‐acetylprocainamide (67.6 per cent of the dose), and unidentified metabolite (3.8 per cent of the dose), and p‐acetamidobenzoic acid (2.7 per cent of the dose). After the administration of N‐acetylprocainamide‐14C, the urine contained N‐acetylprocainamide (1.7 per cent of the dose), N‐acetylprocainamide (67.6 per cent of the dose), an unidentified benzamide (5.2 per cent of the dose), and p‐acetamidobenzoic acid (3.8 per cent of the dose). Monkeys that received procainamide excreted much less unchanged drug in the urine (2.1 per cent) than did human subjects (63.6 per cent)
Pyridostigmine metabolism in man
Authors: Somani Satu M. , Roberts John B. , Wilson Andrew
Published: January 2016

Observations of myasthenic patients given oral pyridostigmine and 14C‐pyridostigmine by intramuscular injection were designed to determine the excretion in urine of unchanged pyridostigmine and its metabolites. Paper chromatography of urine revealed the presence of three metabolites in addition to pyridostigmine. The unchanged drug and its major metabolite were isolated from the urine of a patient given oral doses with the use of the combined techniques of ion‐exchange chromatography, electrophoresis, and paper chromatography. Pyridostigmine and 3‐hydroxy‐N“methyl pyridinium thus isolated were characterized by ultraviolet spectra and mass spectra and estimated by a reverse isotope‐dilution method. It is suggested that the problems of chronic overdosage with pyridostigmine are related to the possible accumulation of some of these substances in patients who are treated for prolonged periods with high doses of pyridostigmine.
Relation of hydralazine plasma concentration to dosage and hypotensive action
Authors: Zacest Rudolf , Weser Jan Koch
Published: January 2016

The relationships between dosage, plasma concentration, and hypotensive action of hydralazine were examined in 20 patients with essential hypertension. Plasma hydralazine was assayed with a method which allowed measurement of concentrations as low as 0.05 µg per milliliter. The relation between dose and plasma level of hydralazine varied fourfold among patients but remained constant in individual subjects over several weeks. Acetylation phenotype, as determined by sulfamethazine acetylation rate, was an important determinant of the plasma level of hydralazine. The ratio of plasma concentration to daily dose of hydralazine averaged 1.7 times higher in slow acetylators than in fast acetylators. Plasma concentrations of hydralazine were also increased in patients with impaired renal function. The dose of hydralazine required for satisfactory blood pressure reduction was 58 per cent higher in fast acetylators than in slow acetylators. ln both phenotypes, the plasma concentration of hydralazine correlated well with the magnitude of its hypotensive effect. Determinations of plasma levels during the therapeutic use of hydralazine may be useful guides to effective and safe dosage.
Peripheral aromatic l‐amino acids decarboxylase inhibitor in parkinsonism. II. Effect on metabolism of l‐2‐14C‐dopa
Authors: Bianchine J. R. , Messiha F. S. , Hsu T. H.
Published: January 2016

The effects of MK‐486, an inhibitor of peripheral aromatic l‐amino acids decarboxylase, on certain urinary metabolites derived from orally administered l‐2‐14C‐dopa were studied in 3 patients with Parkinson's disease. Each patient received, after an overnight fast, 50 p.c of l‐2‐14C‐dopa (100 mg.). Urine and blood were collected serially and assayed for dopa and its major metabolites. This metabolic profile was compared with that obtained after the same dose of l‐2‐14C‐dopa but following pretreatment with MK‐486 (100 mg. in a single dose and 100 mg. given 3 times a day for 7 consecutive days). Plasma and urine specimens were subjected to ion‐exchange resin and alumina chromatography in order to separate dopa and its major metabolites prior to quantitative determinations. Plasma radioactivity half‐life increased from base line of 3 to 15 hours following pretreatment with MK‐486 in a single dose or after one week of therapy. Further, peak plasma dopa fraction radioactivity was increased threefold. Prior to MK‐486 treatment, 43 per cent and 81 per cent of total radioactivity administered were excreted at 2 and 8 hours, respectively. Following MK‐486 pretreatment (100 mg., single dose), only 13 per cent and 37 per cent of administered radioactivity were excreted at these same intervals. Similarly, a single dose of MK‐486 decreased dopamine from base‐line values of 2.6 and 7 mg. to 0.7 and 2.2 mg. at 2 and 8 hours, respectively. Similar trends for radioactivity and dopamine excretion followed multiple dose pretreatment with MK‐486. Homovanillic acid excretion was also decreased by MK‐486. However, MK‐486 did not markedly alter urinary epinephrine and vanilmandelic acid from base line. Pretreatment with MK‐486 reduced radioactivity found in catecholamine fraction by 70 to 80 per cent over the entire 48 hour period studied. Pretreatment with MK‐486 for a period of one week resulted in less inhibition of O‐methylated acid metabolite fraction than that which followed a single dose of MK‐486.
Hyperkalemia after triamterene in diabetic patients
Authors: Walker Barry R. , Capuzzi David M. , Alexander Fred , Familiar Robert G. , Hoppe Robert C.
Published: January 2016

Eleven patients with maturity‐onset diabetes mellitus and 6 normal subjects were studied to determine whether they would develop abnormal serum potassium or glucose levels in response to triamterene, to an acute glucose load, or to an acute glucose load during triamterene therapy. The response in each case depended on the presence of diabetes and the degree of glucose intolerance before triamterene. The normal subjects and mild diabetic patients showed no change in pattern of response to glucose load after triamterene, while the moderate diabetic patients displayed certain metabolic changes under the same experimental conditions. Triamterene caused a minor, reversible increase in serum potassium in all subjects but an increase in fasting blood sugar only in the moderate diabetic patients. In all groups there was a decline in creatinine clearance after 7 days on triamtercne. In addition, the moderate diabetic patients developed hyperkalemia during an intravenous glucose tolerance test while on triamterene therapy. Only one of the moderate diabetic patients developed hyperkalemia during an oral glucose tolerance test. Possible mechanisms for these effects are discussed and the use of triamterene in diabetes mellitus is assessed.
Metabolism of ethylmorphine and aniline in human fetal liver
Authors: Anders Rane , Else Ackermann
Published: January 2016

The oxidative demethylation of ethylmorphine and the hydroxylation of aniline were studied in different centrifugal fractions of the human fetal liver. The rates of metabolism of ethylmorphine and aniline per milligram of protein in the microsomal fraction were 35 and 40 per cent, respectively, of the corresponding values in human adult liver microsomes. The metabolic activity in the different centrifugal fractions, expressed as per cent of total, corresponded to the activities of microsomal marker enzymes in the same fractions (see the preceding paper in this issue). The rate of demethylation of ethylmorphine per gram of human fetal liver was somewhat lower than that in human adult liver, while the rate of aniline hydroxylation was greater. The apparent Km value for ethylmorphine demethylation was 1 to 2 · 10‐5M. Both metabolic pathways appear to be nicotinamide adenine dinucleotide phosphate reduced (NADPH) dependent and CO sensitive.
Effect of lithium on plasma cortisol and adrenal response to adrenocorticotropin in man
Authors: Halmi Katherine A. , Noyes Russell , Millard Sara A.
Published: January 2016

In male volunteers the circadian variation of serum cortisol was smaller while the men were receiving lithium (serum levels 0.60 to 0.86 mEq. per liter) than when they were given placebo. The difference was due to lower morning serum cortisol levels. In another group of volunteers, secretion of adrenocorticotropin (ACTH), hence of cortisol, was completely suppressed with dexamethasone while the men were receiving placebo and again during a perior of lithium medication. When synthetic ACTH was injected after dexamethasone, the rise in serum cortisol was the same in men on placebo and on lithium. It is suggested that the blunting of the circadian fluctuation of serum cortisolleve/s by lithium is due to alte1'ed secretion of ACTH rather than diminished responsiveness of the adrenal cortex to tmpic hormone.
Absorption and excretion of clindamycin‐2‐phosphate in children after intramuscular injection
Authors: Kauffman Ralph E. , Shoeman Don W. , Wan Suk Han , Azarnoff Daniel L.
Published: January 2016

The absorption and excretion of intramuscular clindamycin‐2‐PO4 was studied in 12 children aged 2 months to 11 years. The t1/2 of serum clindamycin activity following doses of 150 mg. per square meter and 117 mg. per square meter were 3.4 hours and 2.4 hours, respectively. The higher dose provided adequate serum antibiotic activity for 8 hours, whereas the lower dose did not. 1nfants and children exhibited more rapid absorption, higher peak levels, more rapid elimination, and greater urinary excretion of clindamycin than preViously reported in adults.
Pharmacokinetics and biotransformation of chlorpropamide in man
Authors: Taylor James A.
Published: January 2016

Chlorpropamide (CPA) pharmacokinetics were determined in 6 normal adult volunteers after a single oral 250 mg. dose. Drug absorption half‐lifes varied from 0.1 to 1.5 hours with a calculated mean of 0.5 hour. Half‐life for drug in plasma ranged from 25 to 42 hours with a calculated mean of 33 hours while the half‐life estimated from urinary excretion data averaged 36 hours. In addition to drug, p‐chlorobenzenesulfonylurea (CBSU),2‐hydroxy‐CPA (2‐OH‐CPA), and 3‐hydroxy‐CPA (3‐OH‐CPA) were recovered from urine of 4 diabetic subjects receiving 250 to 500 mg. of CPA daily. Approximately 2 per cent of daily dose was recovered from urine as p‐chlorobenzenesulfonamide (CBSA), a degradation product of CBSU, and a similar amount was excreted as 3‐OH‐CPA. Drug, CBSU, and 2‐OH‐CPA excretion quantitated in 24 hour urine samples of these diabetic subjects by high‐pressure liquid chromatography, averaged 18,21, and 55 per cent of dose, respectively. Two hours after CPA administration, unchanged drug accounted for 95 per cent of total drug and metabolite concentrations in plasma indicating that CBSU and 2‐OH‐CPA have significantly shorter elimination half‐lifes than unchanged drug.
Discussion
Authors: Moraczewski Albert
Published: January 2016

I will divide my discussion under two major headings: (1) A person is not and cannot be merely a means to an end regardless how worthy that end may be. (2) The review committee has the function of helping to ensure the optimal use of resources by the local scientific community.
Physiologic factors in selecting human volunteers for drug studies
Authors: Azarnoff Daniel L.
Published: January 2016

The wisdom of routine testing of drugs in healthy volunteers is questioned on 2 counts: scientific validity and the dubious ethical practice of giving normal individuals drugs that are not for their benefit and may be harmful to them. The metabolism of drugs is so changed by numerous diseases that any transfer of results from healthy volunteers to patients may be dangerously misleading. Drug interactions also modify results and must be evaluated in both normal and patient subjects. Agreed that early experiments with normal volunteers may be justified in some instances, rigid criteria should be dropped in favor of guidelines to be applied with careful consideration of both scientific and ethical factors.
Prediction of therapeutic uses of psychotherapeutic drugs from experiences with normal volunteers
Authors: Hollister Leo E.
Published: January 2016

One of the great paradoxes with psychotherapeutic drugs is that we are caught in a circular trap. We know the pharmacologic properties of sedatives and stimulants so well that we can identify some of these (largely those that are nontherapeutic) in normal subjects and make reasonably good predictions about drugs of this type. Antipsychotic and tricylic antidepressants have novel clinical actions unlike any we had before. Both types of drugs were discovered fortuitously in the clinic so that their pharmacologic properties were correlated retrospectively with their therapeutic effects. To make matters worse, pharmacologic effects of these drugs in most animals and human beings have little apparent relevance to the clinical disorders they are supposed to treat. Knowing these correlations, we can devise screening batteries to detect many other drugs similar to those that we now have, but none that are truly different. Until we have better human or animal models for the disorders in question or a better hypothctic basis for constructing drugs to treat these disorders, we may be stymied. It does not seem likely that one can predict these effects in any useful or innovative way fram the study of such drugs in normal, asymptomatic human subjects.
Discussion
Authors: Martz B. L.
Published: January 2016

Dr. Blackwell's survey provides a comprehensive consensus of current strategy in drug evaluation as it relates to the introduction of a new drug into man for the first time. The results provide a useful pattern for comparing what we are doing with the practices of others. Although the respondents were asked not to be influenced by present regulatory requirements, one can probably assume that the replies were significantly influenced by the current regulatory posture and, in all probability, by the circumstances in which thc investigator works and the strategy and approaches he is currently employing.
The changing profile and conditions surrounding clinical research in prisons
Authors: Estelle W. J.
Published: January 2016

It is a distinct pleasure to be allowed to share with you some of my thoughts, as a prison warden, about research involving inmate volunteers.
The drug defaulter
Authors: Blackwell Barry
Published: January 2016

There have been over 50 studies on patients who fail to take their medications “as directed.” The patients in these studies usually required chronic maintenance therapy for conditions including tuberculosis, schizophrenia, anemia, rheumatoid arthritis, and other diseases seen in general practice. Attention has also been paid to the special problems posed by geriatric patients and by children who depend for medication on their parents.
Treatment of arrhythmias with tolamidol
Authors: Aronow Wilbert S. , Harding Phillip R. , Nelson William H. , Vangrow Jack S. , Johnson Lucien L. , Khursheed Mohammed
Published: January 2016

Tolamidol (UK‐6558‐01), a beta adrenergic blocking agent with less myocardial depressant effect than propranolol, was given intrauenously to 30 patientl with cardiac arrhythmias. It abolished or greatly reduced digitalis‐induced arrhythmias in 5 of 5 patients, the arrhythmias being frequent premature ventricular beats, ventricular tachycardia, frequent premature atrial beats, and paroxysmal atrial tachycardia with 2:1 atrioventricular block. Paroxysmal atrial tachycardia, atrial fibrillation and a rapid ventricular rate, paroxysmal atrial flutter, and frequent premature atrial beats, were abolished or improved in many instances. Tolamidol was useful in treating digitalis‐induced arrhythmias and supraventriculiar arrhythmias, but was not very effective in treating frequent premature ventricular beats, not digitalis induced.
Intravenous triamterene in the treatment of acute digitalis intoxication
Authors: Weber Donald John
Published: January 2016

It was recently found that the “potassium‐sparing” diuretic triamterene, given prophylactically, increases tolerance to digitalis intoxication. This study demonstrated that triamterene is also of therapeutic value in dogs acutely intoxicated with ouabain. Not only was the digitalis‐induced myocardial potassium efflux reversed, but also the efflux of magnesium was reversed. In the doses employed the clinical benefit was definite but not always permanent. Triamterene also seemed to stop the ouabain‐induced hypementilation and retching. A significant technical problem was the poor solubility and relatively low pH of the drug for intravenous administration. Triamterene has theoretic advantages over intravenous potassium chloride, as it affects membrane Na‐K dependent ATPase and may favorably influence the Ki/Ko ratio. The implications in man are clear.
Enhancement of warfarin‐induced hypoprothrombinemia by triclofos
Authors: Sellers Edward M. , Lang Mary , Koch-Weser Jan , Colman Robert W.
Published: January 2016

Daily administration of hypnotic doses of triclofos (trichloroethyl sodium phosphate) significantly prolonged prothrombin time in 7 volunteers chronically anticoagulated with warfarin. Mean sensitivity to warfarin (prothrombin time prolongation/cumulative 72 hour warfarin dose) increased by 49 per cent during the first week of triclofos therapy. Plasma concentrations of factors II and X fell within 9 hours of a single dose of triclofos. A metabolite of triclofos, trichloroacetic acid, accumulated in plasma to 80 µg per milliliter during one week of triclofos administration. The displacement of warfarin from human albumin by trichloroacetic acid can account for the potentiation of warfarin action by triclofos.
Effect of glucagon on heart muscle contractility
Authors: Hammer Jan , Sriussadaporn Sujint , Freis Edward D.
Published: January 2016

Because of the increased clinical application of beta adrenergic drugs, a study was undertaken to determine in the intact beating heart in situ whether glucagon applied directly will overcome the negative inotropic effect at such blockade. The local inotropic effects of glucagon, dopamine, norepinephrine; and isoproterenol were assessed in the intact heart. A side branch of the left descending coronary artery was cannulated with a fine polyethylene catheter without interfering with blood flow in the main branch. A strain gauge was sutured in the myocardium distal to the catheter in order to detect changes in contractility induced by the local injection of the various compounds. As a control, a second gauge was sutured to the myocardium in an area of left ventricle not perfused by the descending branch. Each drug injected into the descending branch resulted in an inotropic effect isolated to the area perfused. FollOWing reserpinization, confirmed by failure to respond to tyramine, positive responses to all of the above agents injected locally were unaltered in all dogs. However, in both reserpinized and unreserpinized dogs propranolol given locally completely blocked the inotropic responses to dopamine, norepinephrine, and isoproterenol without altering the contractile response to glucagon even when the latter was given immediately following propranolol. These results further demonstrate the Tationale for using glucagon as an inotropic agent in patients who have been treated with beta adrenergic blocking agents.
Identification of glycinexylidide in patients treated with intravenous lidocaine
Authors: Strong John M. , Parker Michele , Atkinson Arthur J.
Published: January 2016

Glycinexylidide (GX) has been identified in the urine of 8 patients treated with intravenous infusions of lidocaine. The concentration of GX ranged from 1.0 to 2.7 Ilg per milliliter in the plasma of 3 of these patients. This di‐desethylated product of lidocaine metabolism, like the mono‐desethylated metabolite, monoethylglycinexylidide (MEGX) also has local anesthetic activity. Both compounds may contribute to central nervous system (CNS) toxicity in some patients treated with lidocaine.
Effects of heat and exercise on the elimination of pralidoxime in man
Authors: Swartz Richard D. , Sidell Frederick R.
Published: January 2016

Pralidoxime chloride, used clinically to reactivate cholinesterase in organophosphate poisoning, is rapidly eliminated by the kidney. In these studies, heat and exercise stress significantly decreased the renal excretion of both pralidoxime and p‐aminohippurate (PAR) in man. Pharmacokinetic data suggest that the over‐all drug removal from plasma is also affected by changes in tissue distribution of these drugs: With stress conditions there is a marked increase in volumes of drug distribution. Furthermore, decreased total recovery of drugs in the urine under heat and exercise conditions implicate tissue metabolism as a factor of heretofore undetermined significance in the over‐all elimination of both pralidoxime and PAR.
Practolol in patients with angina pectoris
Authors: Alderman Edwin L. , Davis R.O. , Friedman Joel P. , Graham Anthony F. , Matlof Harvey J. , Harrison Donald C.
Published: January 2016

Eight patients were given practolol in a double‐blind, randomized study comparing doses of 200, 400, and 800 mg per day against placebo. Double‐blind periods were preceded by a 12 week single‐blind run‐in period. Data obtained from 21 double‐blind periods showed a significant reduction in heart rate at all dose levels and a reduction in blood pressure at the maximal dosage. Improved treadmill exercise tolerance after practolol administration was demonstrated, in association with suppression of exercise‐induced tachycardia. Improvement in exercise performance was observed with practolol doses of 200 mg per day. Clinical improvement could be detected at the 800 mg per day dosage in individual patients.
Drug interactions with guanethidine
Authors: Ober Karl F. , Wang Richard I. H.
Published: January 2016

The effect of a single oral dose of tripelennamine, 100 mg., methyldopa, 500 mg., d‐amphetamine, 10 mg., amitriptyline, 50 mg., or prochlorperazine, 25 mg., on the blood pressures of hypertensive patients treated chronically with guanethidine was measured half‐hourly for 8 hours. D‐amphetamine antagonized the antihypertensive effect of guanethidine in the lying systolic blood pressure, while the orthostatic hypotension persisted. The effect of d‐amphetamine seems to be due to the direct stimulation of vasoconstrictor receptors. Tripelennamine, amitriptyline and prochlorperazine had no demonstrable short‐term effect on the guanethidine action. Methyldopa potentiated guanethidine in the standing diastolic blood pressure.
Hydrochlorothiazide therapy in nephrolithiasis Effect on the urinary activity product and formation product of brushite
Authors: Pak Charles Y. C.
Published: January 2016

The effect of hydrochlorothiazide on the formation of renal stones containing calcium was evaluated by the quantitative assessment of the propensity of urine for the nucleation of brushite (nidus of calcium stones). In 6 patients with renal stones, the urinary activity product ratio (APR) and the formation product ratio (FPR) of brushite were measured before, during, and following treatment with hydrochlorothiazide (50 mg twice a day orally) for from 5 days to 1 month. The urinary APR (the state of saturation with respect to brushite) decreased in the majority of cases primarily as the result of a fall in urinary calcium. The urinary FPR (lowest state of supersaturation at which nucleation is initiated) usually increased, probably as a result of a rise in urinary pyrophosphate. Both changes reduced the propensity for the formation of the nidus of brushite, and may therefore account for the improvement reported after thiazide therapy in nephrolithiasis.
Effect of coadministration of aluminum and magnesium hydroxides on absorption of anticoagulants in man
Authors: Ambre J. J. , Fischer L. J.
Published: January 2016

Bishydraxycaumarin (BHC) and wmjarin plasma levels were measured in narmal humans to' determine whether caadministratiall with antacids altered the gastraintestinal absarptian af the anticaagulants. Milk af magnesia, aluminum hydraxide gel, or water (control) was administered at the same time as a single 300 mg. aral dase af BHC and again 3 haurs later to valunteer subjects. Each af 6 subjects received all 3 combinations in a controlled sequence. Administration af magnesium hydraxide with BHC on this schedule resulted in a 75 per cent increase ill mean peak plasma levels af BHC and a 50 per cent increase in the area under the plasma level curve compared to controls. Coadministration of aluminum hydraxide did not alter BHC plasma levels. Evidence is presented to suggest that chelate formation may be involved in the increased absorption of BHC when it was administered with magnesium hydroxide. III identical experiments using warfarin, it was found that the antacids had no effect on absorption. It is suggested that, in the selection of a coumarin anticoagulant for clinical use, consideration should be given to the predictability of absorption.
Bioavailability of potassium from a slow‐release tablet
Authors: Ben‐Ishay Drori , Engelman Karl
Published: January 2016

The bioavailability of potassium (K) from orally administered 10 per cent potassium chloride (KCI) solution has been compared with that from a slow‐release KCl tablet (Slow‐K) in 10 normal subiects under metabolic balance conditions. After a single 40 mEq. KCl dose, urinary K increased sooner and to greater peak levels after the solution was administered. In both cases greater amounts of K appeared in the urine when administered in the fasting than in the postprandial state. In 4 days of administration there was no difference in the net increment in urine K produced by equivalent doses of either preparation. No significant toxicity was experienced with either preparation. The unpleasant taste of the KCI solution was noted by each subject.