bluuebunny/crossref_metadata_2025 huggingface dataset:
Pharmacokinetics of guanazole in man
Authors: Gerber Nicholas , Seibert Richard , Desiderio Dominic , Thompson Richard M. , Lane Montague
Published: January 2016

Guanazole, 3,5‐diamino‐1,2,4‐triazole, synthesized nearly a century ago, has recently been shown to have antitumor properties. In patients with cancer, intravenous doses ranging from 3.5 to 10 gm per square meter of body surface area have been used. It was found that the 15 minute plasma level declines to one‐half in 1 to 2 hours. After 4 to 6 hours the plasma half‐life is 5 to 10 hours. The drug is eliminated almost quantitatively in the urine in 24 hours. No metabolites could be detected in the perfusate or bile of the isolated perfused rat liver preparation, suggesting that the drug itself rather than a metabolite is responsible for the antitumor activity.
Intermittent guanazole therapy in adult acute leukemia
Authors: Hewlett James S. , Bodey Gerald P. , Coltman Charles A. , Freireich Emil J. , Haut Arthur B. , McCredie Kenneth B.
Published: January 2016

Guanazole is a specific inhibitor of DNA synthesis. It has shown marked schedule dependency in the treatment of L1210 leukemia. In a Phase II study guanazole was giveTi in an induction dose of 7.5 gm per square meter per day for 5 days by continuous intravenous infusion and repeated every 14 days. Twenty‐four leukemic patients received an adequate trial (3 or more courses). There were 4 complete remissions, 2 partial remissions, 4 hematologic responses, and 34 failures. Complete remissions occurred in 3 patients with acute myelogenous leukemia lasting 49 days in 1, and 2 patients were still in complete remission 451 and 230 days after treatment. One patient with chronic myelogenous leukemic blast transformation achieved a complete remission lasting 99 days. Myelosuppression was the maior toxic effect.
New ideas about drug labels
Authors: Hollister Leo E.
Published: January 2016

More than five years ago, an editorial in this JOURNAL found considerable fault with the so‐called package insert.1 It was asserted that the “stuffer” was not always current, that it was not a legal document, that it failed to make the risks of therapy calculable (largely by failing to indicate the relative frequency of adverse reactions), and that it was not compatible with generic equivalence, as the same chemie al substance from different drug houses often had inserts of different content. Some of these deficiencies were attributable to the fact that most package inserts evolved from a long and often arduous bargaining between the FDA and the manufaeturer. It was suggested that the proper name for the document, whatever form it might ultimately assurne, would be a label.
Respiratory effects of hydromorphone in man
Authors: Brown Colin R. , Forrest William H. , Hayden Johan , James Kenneth E.
Published: January 2016

The respiratory depressant efJeets of hydromorphone, a potent analgesie, were compared with morphine in a randomized double‐blind erossover study in human volunteers. Using a rebreathing technique, earbon dioxide response curves were plotted automatically with a speeial‐purpose analog computer. The respiratory depressant relative potency of hydromorphone to morphine over the total observation period was found to be 7.99 with lower and upper 95 per cent confidence limits of 5.44 and 10.69. Based on the displacement of the respiratory response curve, approximately 1.25 mg of hydromorphone is equivalent to 10 mg of morphine in our population of volunteers. For peak respiratorll depression, 0.95 mg of hydromorphone is equivalent to 10 mgoj morphine
Effects of orally administered delta‐9‐tetrahydrocannabinol in man
Authors: Hosko M. J. , Kochar M. S. , Wang R. I. H.
Published: January 2016

The etfects of Δ9‐tetrahydrocannabinol (Δ9‐THC) administered orally at 2 dose levels were studied in a group of 7 healthy young adult males. Each subiect was studied for 7 nights (2 drug, 5 placebo). Vital signs, subiective feelings, deep tendon reflexes, electrocardiogram, electroencephalogram, visual evoked responses, postural responses, time estimation and reaction time and sleep patterns were studied. At the doses studied, Δ9‐THC increased pulse rate, altered subjective feelings, and caused hyperreflexia and upset postural responses in the absence of visual cues. Some subjects also exhibited lowered oral temperature, changes in averaged visual evoked response, and alteration of sleep patterns.
Theophylline compounds end myasthenia gravis; I. In vitro studies
Authors: Jacobs Robert , Karczmar Alexander G. , Brumlik Joel
Published: January 2016

Intercostal nerve muscle preparations from 7 myasthenia gravis patients, 5 of whom were clinically refractory to anticholinesterase medication, were investigated to evaluate in vitro the efficacy of edrophonium, ephedrine, and aminophylline. Six of the 7 nerve‐muscle preparations demonstrated marked fatigue when orthodromic repetitive stimuli (3 per second for 2 seconds) were applied. Perfusion of the muscle with ephedrine caused marked facilitation of the overall twitch height in a train of stimuli with little or no effect on muscle fatigue. Aminophylline likewise markedly augmented twitch height and also demonstrated a significant anti‐fatigue effect. Analysis of the data obtained with edrophonium failed to demonstrate either a facilitatory effect or an anti‐fatigue effect.
Comparative pharmacokinetics of tobramycin and gentamicin
Authors: Regamey Claude , Gordon Ralph C. , Kirby William M. M.
Published: January 2016

Blood and urine concentrations of a new aminoglycoside, tobramycin, were compared with those of gentamicin after intravenous and intramuscular administration in healthy adult volunteers. Serum concentrations for the two antibiotics were the same after an intravenous infusion of 100 mg for the first haur (about 4.75 p.g per milliliter), during the steady state attained by infusing 30 mg per hour for the next 2 haurs (about 3.85 p.g per milliliter), and during the elimination phase after the antibiotics were stopped. After a single intramuscular injection of 100 mg, the blood level curves were equal and the peak concentrations at 20 to 45 minutes were the same as those obtained after intravenous infusion of the same dose for 1 hour. Between 80% and 90% of each of the two antibiotics was recovered in the urine within 24 hours. Plasma clearance was not significantly higher than renal clearance, and glomerular filtration seemed to be the main pathway of elimination. The two aminoglycosides had an apparent volume of distribution of about 30% total body weight. Each had a half‐life of 2 hours.
Naproxen: A novel approach to dose‐flnding efficacy trials in rheumatoid arthritis
Authors: Lussier André , Segre Eugene J. , Multz Carter V. , MacCannell Keith L. , Alexander Stanley J. , Howard D. L. G. , Boost Gerhard , Varady John , Strauss Wolfgang
Published: January 2016

Because of the unpredictable course of rheumatoid arthritis, a special protocol was devised for a clinical trial of naproxen, a new, nonsteroidal, anti‐inflammatory agent, in 117 patients. Trial design included an open titration phase, permitting individualization of dose and minimizing positive placebo reactions, and a subsequent double‐blind phase during which patients took either naproxen, in the previously established dose, or placebo. Naproxen proved effective in the symptomatic treatment of rheumatoid arthritis at a dose range of 400 to 500 mg a day. At these doses, naproxen was well tolerated and produced no significant gastrointestinal irritation. Extensive laboratory evaluation uncovered no changes suggestive of drug toxicity. Our findings confirm that this is a powerful and efficient trial design that should be considered in the early evaluation of new drugs for the treatment of rheumatoid arthritis.
Pharmacology of fusaric acid in man
Authors: Matta Raymond J. , Wooten G. Frederick
Published: January 2016

Fusaric acid (5‐butylpicolinic acid) is shown to be an effective, partially reversible inhibitor of human plasma dopamine‐β‐hydroxylase (DBH), clinically reducing mean arterial blood pressure, in a dose range of 300 to 600 mg per day. Maximum inhibition of plasma DBH activity occurs 2.5 hours after oral administration. The biological half‐life of fusaric acid in blood is approximately 12 hours. A fusaric acid concentration of 23 ng per milliliter produces 50% inhibition of plasma DBH activity in vitro. It is suggested that the degree of plasma DBH inhibition by fusaric acid may be used for estimates of fusaric acid blood levels.
Comparative drug elimination capacity in man‐glutethimide, amobarbital, antipyrine, and sulfinpyrazone
Authors: Kadar D. , Inaba T. , Endrenyi L. , Johnson G. E. , Kalow W.
Published: January 2016

The apparent elimination half‐lifes were determined for 4 drugs that undergo hydroxylation in men. Glutethimide (500 mg), amobarbital sodium (130 mg), antipyrine (1.0 gm), and sulfinpyrazone (400 mg) were each taken orally by 10 healthy men at weekly intervals. When the half‐lifes in these 10 individuals were compared, positive correlations were found among 3 out of 4 drugs: glutethimide‐amobarbital (r 0.69, p < 0.05), glutethimide‐sulfinpyrazone (r 0.64, p < 0.05), and amobarbital‐sulfinpyrazone (r 0.87, p < 0.01). If these data are generally valid, it would mean, for example, that one could, from the sulfinpyrazone half‐life in a given subject, predict the amobarbital half‐life of the same individual within about ± 7 hours (30% of average half‐life, while the interindividual differences could be 300%). Antipyrine half‐life was not correlated with the half‐life of any of the other 3 drugs. The urinary levels of 6β‐hydroxycortisol were also determined in the same sub;ects and compared with the half‐lifes of the 4 drugs. The correlation coefficients taken singly were not statistically significant, but they were all negative and collectively seem to indicate an expected trend.
Metabolic patterns and clinical response to levodopa therapy in Parkinson's disease
Authors: Messiha F. S. , Knopp W.
Published: January 2016

Longitudinal double‐blind case studies of two parkinsonian patients simultaneously treated with equal doses of levodopa are reported. The patients were alternately treated with placebo and levodopa in crossover design after an initial period of treatment with trihexyphenidyl. The metabolic fate of orally ingested levodopa was determined by measuring the urinary excretion of dopa and some of its maior metabolites. Neurological and clinical measurements were made on days of 24 hour urine collection. Intersubiect differences were noted in the excretion profiles of dopa and metabolites studied as well as in clinical response to gradually increasing dosage buildup of levodopa. The maior portion of ingested levodopa was recovered in urine in the form of the acidic metabolites DOPAC and HV A, with urinary HV A exceeding that of DOPAC. Prolonged treatment with levodopa resulted in increased DOPAC excretion relative to HVA. Ingestion of levodopa at 5 gm per day decreased mean 5‐HIAA excretion from placebo value by apprOXimately 50 %. Less than 1 % of levodopa dose was recovered in urine during a 24 hour period. Concomitantly, dopamine and norepinephrine excretion increased by approximately 10 and 100 fold from placebo phase, respectively. Trihexyphenidyl administration did not affect excretion of catecholamines or those metabolites that were studied.
Human plasma and urine quinine levels following tablets, capsules, and intravenous infusion
Authors: Hall Anthony P. , Czerwinski Anthony W. , Madonia Eugene C. , Evensen Kenneth L.
Published: January 2016

Using a crossover design, 12 healthy male volunteers received 3 forms of quinine in 3 day courses in random sequence at weekly intervals. Enteric‐coated tablets and gelatin capsules of quinine sulfate (540 mg base) were given orally every 8 hours for 3 days (1.62 gm base daily), and quinine dihydrochloride (490 mg base) was given as a continuous intravenous infusion every 8 hours for 3 days (1.47 gm base daily). Drug‐related toxicity included headache, tinnitus, and liver dysfunction. Form‐related toxicities were nausea, abdominal pain, and diarrhea with oral administration and ephemeral thrombophlebitis at the needle site with intravenous administration in 2 of 12 infusions. The plasma quinine levels were maximal at 72 hours with mean levels of 5.3,3.7, and 4.1 mg per liter for infusions, capsules, and tablets, respectively. Quinine by infusion resulted in significantly higher plasma levels than oral quinine. The plasma quinine concentrations during administration of capsules and tablets were not significantly different. Recovery of quinine in the urine was 18%, 14%, and 10% for intravenous, capsule, and tablet forms, respectively.
Welcome
Authors: Apgar Virginia
Published: January 2016

The Program Committee has worked for more than a year to assemble the program —this array of talent on a very important subject. The Greater New York Chapter of the March of Dimes is delighted to bring this conference to you.
Active products of fetal drug metabolism
Authors: Gillette James R. , Menard Raymond H. , Stripp Bitten
Published: January 2016

Theoretical relationships between the activities of placental and fetal enzymes and their ability to perturb the steady‐state tissue levels of drugs have been calculated. Although the calculations suggest that the activities of the enzymes that metabolize desipramine and 3,4‐benzpyrene in human placentas and fetuses may be high enough to decrease the steady‐state concentrations of these substances, the rates of metabolism of most drugs are probably too slow to affect the fetal levels of most lipid‐soluble compounds. It is also probable that the rate of bromobenzene metabolism by cytochrome P‐450 enzymes in fetal liver is too slow to cause liver necrosis caused by this toxicant. Nevertheless, it is possible that enzymes that catalyze the reduction of nitro compounds, such as nitrofurazone, to hydroxylamino derivatives may mediate various drug toxicities in fetuses.
Effects of hormones on development of fetal enzymes
Authors: Greengard Olga
Published: January 2016

The adaptation of newborn mammals to extrauterine life is conditioned, to a large extent, by the maturity that their biochemical functions have attained during prenatal tissue differentiation. We concentrated on studying the development of enzyme systems in rat liver during late fetal and neonatal life; this was combined with the morphometry of cell types and of subcellular organelles. A cluster of enzymes that emerge during late fetal life and attain their adult concentrations at term has been distinguished from another cluster that makes its appearance immediately after birth. Different hormones (e.g., thyroxine, glucagon, and glucocorticoids), the secretion of which is the natural stimulus for the expression of specific groups of genes, have been identified. With the administration of these hormones to fetuses it is possible to evoke the synthesis of chosen enzymes before the scheduled time and to produce newborn mammals (delivered at term or prematurely) with precociously mature enzyme profiles. The potential medical application of the numerous experimental means by which we can now manipulate the course of enzymic differentiation remains to be evaluated.
Failed and flawed drugs: A frozen resource
Authors: Modell Walter
Published: January 2016

Clinical phannacology may be a young discipline, but it is nonetheless difficult to say something new about it. In general, it is easier to complain than explain, declaim, or proclaim, and, since I have a well‐entrenched highly personal concern over any obstacle to the continued growth of clinical phannacology, I have decided to share it with you. I will therefore say a few selected words about a valuable resource for clinical pharmacologists which is being withheld from them, that of “Failed and Flawed Drugs.” Whether you find any wisdom in my remarks or are provoked by them remains to be seen. At the moment I feel all alone.
The renal handling of diphenylhydantoin and 5‐(p‐hydroxyphenyl)‐5‐phenylhydantoin
Authors: Bochner Felix , Hooper Wayne D. , Sutherland John M. , Eadie Mervyn J. , Tyrer John H.
Published: January 2016

The renal clearances of diphenylhydantoin (DPH) and its maior metabolite, 5‐(p‐hydroxyphenyl)‐5‐phenylhydantoin (HPPH) have been measured in groups of 16 and 14 ambulant epileptic patients, respectively. All patients had normal renal function (creatinine clearances, 83 to 148 ml per minute), and were taking oral diphenylhydantoin sodium in doses of 300 to 500 mg per day. DPH clearance (3 to 23 ml per minute, depending on urine flow rate) was considerably less than that expected for inulin, and it seems probable that DPH undergoes net resorption in its passage through the kidney. HPPH clearance (76 to 420 ml per minute depending on urine flow rate) exceeded expected inulin clearance if urine flow rates were sufficiently high, allowing the Stlggestion that net secretion of HPPH occurs during its passage through the nephron. Although the clearances of both compounds increase with urine flow rate, it is concluded that neither oliguria nor polyuria would be likely to greatly influence plasma DPH concentration in the short term, making dosage adiustment in these two circumstances unnecessary, at least as a matter of urgency.
Metabolism of salicylazosulfapyridine in healthy subjects and in patients with ulcerative colitis; Effects of colectomy and of phenobarbital
Authors: Schrôder Hasse , Lewkonia Raymond M. , Price Evans David A.
Published: January 2016

The metabolism of salicylazosulfapyridine in steady state was studied in 26 healthy volunteers, in 19 colitis patients (17 of whom had ulcerative colitis and 2 Crohn's disease), and in 10 subjects in whom the colon had been removed (ileostomized subjects). This study provides evidence that the site of reductive cleavage of the azo linkage of salicylazosulfapyridine in man is the colon. Subjects with an intact colon excreted 60.5% ± 4.3% of the dose in the urine as sulfapyridine metabolites (which are formed after azo link cleavage), while ileostomized sub;ects excreted 7.1% ± 6.8% of the dose of sulfapyridine metabolites. The metabolic pattern of sulfapyridine in healthy volunteers was in the main similar to that in colitis patients. The serum concentrations of the various metabolites were measured in colitis patients and in ileostomized subjects. The levels of salicylazosulfapyridine on a dose of 2 gm daily were similar in the two groups with a median of about 5 µg per milliliter. The serum concentration of total sulfapyridine ranged from 17 to 40 µg per milliliter in colitis patients and from 0 to 8 µg per milliliter in ileostomized subjects. Phenobarbital sodium, 50 mg nightly, was taken for 5 to 7 nights. In subjects with an intact colon phenobarbital depressed the urinary excretion of salicylazosulfapyridine by 18%, either by induction of a hepatic azo reductase or by enhancement of the biliary excretion of the drug. The proportions in urine of O‐glucuronidized sulfapyridine were increased by 10%, at the cost of acetylation of sulfapyridine. Phenobarbital had no detectable effects on the metabolic pattern of salicylazosulfapyridine in ileostomized subjects.
Quantitative determination of carbamazepine in plasma by mass fragmentography
Authors: Palmér Lena , Bertilsson Leif , Coliste Per , Rawlins Michael
Published: January 2016

A specific and sensitive method for the quantitative determination of carbamazepine in plasma by combined gas chromatography‐mass spectrometry (mass fragmentography) has been developed. 10,11‐Dihydrocarbamazepine was synthesized and used as an internal standard. With this method only one extraction step is needed and derivatization is unnecessary. Eighty to one hundred analyses can be performed per day. The standard deviation of the method is ± 0.08 above, and ± 0.02 p.g per milliliter below 1 µg carbamazepine per milliliter plasma, respectively. Concentrations of carbamazepine can be accurately determined down to 50 ng per milliliter using 0.5 ml of plasma for analysis. In a pilot volunteer study two subjects each received a single oral dose of 200 mg carbamazepine, and the plasma level of the drug was followed for 7 days. The half‐lifes (35 and 37 hours) and volumes of distribution (1.3 L per kilogram in both) were similar in both.
Intravenous clonidine in hypertensive patients
Authors: Mroczek William J. , Davidov Michael , Finnerty Frank A.
Published: January 2016

Clonidine (Catapres), a new imidazoline derivative with antihypertensive properties, was administered parenterally to 20 hypertensive patients. Thirteen patients with stable hypertension received clonidine electively. After a brief pressor phase, the patients with stable hypertension had a good antihypertensive response (a 17% average reduction in mean arterial pressure from 139 ± 11 to 115 ± 12 mm Hg). In 7 patients with accelerated hypertension who received clonidine intravenously, the pressor phase was of greater magnitude, lasted for a longer period of time, and was not associated with an antihypertensive response. It is concluded that transferring drug‐response data from patients with stable hypertension to those in an accelerated phase and vice versa may give erroneous impressions. Since the major need for a parenteral antihypertensive drug is for the therapy of hypertensive crises, the usefulness of intravenous clonidine appears limited.
Pharmacokinetic studies on minocycline in man
Authors: Macdonald Hugh , Kelly Robert G. , Allen E. Stewart , Noble John F. , Kanegis Leon A.
Published: January 2016

Minocycline, a new member of the tetracycline series, has been reported to have a high level of activity against tetracycline‐sensitive organisms and significant activity against tetracycline‐resistant staphylococci. Results presented show that in man it has a biologic half‐life apprOXimately that of doxycycline but appreciably longer than that of other tetracyclines. It appears to be more rapidly absorbed than doxycycline, demethylchlortetracycline, and methacycline. Evidence indicates that with minocycline, like doxycycline, but unlike other tetracycline antibiotics, absorption following oral administration is essentially complete. Lower values for renal clearance are found for minocycline than for the other tetracyclines studied. Of the minocycline recovered, a higher percentage was excreted in the feces and biologic transformation was greater than with the other tetracyclines. Minocycline has greater lipophilic properties than other tetracyclines, which may account for the highly favorable ratios of tissue to serum concentrations.
XXIII. The role of randomization in sampling, testing, allocation, and credulous idolatry (Part 2)
Authors: Feinstein Alvan R.
Published: January 2016

The previous paper13 in this series was concerned with the advantages and pitfalls of using a randomization process in sampling from a parent population. By depending on chance alone, the randomized selection removes any element of human choice in the sample, and allows the results to be interpreted with inferences based on statistical probability. These statistical inferences are particularly useful when the parent population is being sampled to estimate the value of an unknown parameter, such as the mean of a selected variable. From the results found in the random sample, the investigator can demarcate a zone of values, called a “confidence interval,” and can have a specified “confidence level” for the probability that the true value of the parameter lies within the demarcated zone. The main pitfall of random sampling is that it does not indicate the reliability of the particular sample that was selected in the research. The randomization process provides no safeguards against the 5% of chance occasions in which a 95% confidence interval will be erroneous because the “luck of the draw” produced a substantially distorted sample.
Mebutamate as a hypnotic: Clinical trial and statistical considerations
Authors: Morgan John P. , Wardell William , Lasagna Louis , Mazzullo John M. , Weintraub Michael , Mudholkar Govind S. , Mietlowski William
Published: January 2016

Mebutamate, an antihypertensive drug, has been reported to have hypnotic efficacy. We evaluated, by a questionnaire method, its efficacy in a geriatric, insomniac nursing home population. Two doses of mebutamate, 300 and 600 mg, were compared to 100 and 150 mg of secobarbital sodium and placebo, all administered randomly as identical tablets. Three cycles of test drugs were given and each nightly dose was alternated with the patient's own usual sleeping pill. Twenty‐two patients completed at least two consecutive cycles of the trial; 15 completed all three. A sleep index computed from “usual” sleeping pill nights and subjected to principal component analysis constituted the primary statistical evaluation. Supporting analyses used composite categories of questions called hypnotic power, global evaluation, and freedom from hangover. Mebutamate performed well and had little toxicity. In hypnotic power and global evaluation the mean effect of mebutamate, 600 mg and 300 mg, bracketed that of secobarbital, 150 mg. Statistical significance over placebo was reached for the higher doses of each active drug and the lower dose of mebutamate. No differences in freedom from hangover were noted.
Time for loss of innocence
Authors: Hollister Leo E.
Published: January 2016

Much of what we do as clinical phannacolo gists is under the scrutiny of politicians. Through laws or regulations many procedures in the study of drugs are being increasingly controlled. For the most part, we who are most affected have the least to say about it. Let me briefly discuss some examples.
Deoxythioguanosine and thioguanine
Authors: LePage G. A. , Gottlieb J. A.
Published: January 2016

Incorporation of 6‐thioguanine (TG) and β‐2'‐deoxythioguanosine (β‐TGdR) into the DNA and RNA of human bone marrow and tumors were measured. The ratio of incorporation into DNA vs that into RNA was taken as an indication of the extent to which β‐TGdR was a direct precursor for DNA synthesis without conversion to TG. Incorporation into DNA has been found to correlate with lethal effects of the cells. The data support the concept that β‐TGdR was superior to TG in obtaining incorporation into DNA and to a considerable extent was a direct DNA precursor. Clinical observation also indicates that β‐TGdR acts as a direct precursor of DNA. In 7 of 18 patients receiving β‐TGdR, skin toxicity was observed. In 38 patients receiving TG, no such skin toxicity was observed.
Tracer microspheres as a fecal marker in balance studies
Authors: Carmichael R. H. , Crabtree R. E. , Ridolfo A. S. , Fasola A. F. , Wolen R. L.
Published: January 2016

The use of radio labeled microspheres as fecal markers was investigated and compared in vivo to chromium sesquioxide and β‐sitosterol. They proved to be chemically inert, uniformly distributed in feces, and fully recoverable. The advantages over the other markers include minimal handling of specimen and direct measurement without complex analytic procedures.
Halofenate, serum lipids, and exercise performance in coronary heart disease
Authors: Aronow Wilbert S. , Vangrow Jack S. , Nelson William H. , Pagano James , Papageorge's Nicholas P. , Khurshee Mohammed , Harding Phillip R. , Khemka Mahaveer
Published: January 2016

We have already reported the effect on serum lipids and exercise performance of halofenate administered for 48 weeks to 48 patients with hypertriglyceridemia in a 14 month double‐blind study. Forty‐one of these patients received halofenate for an additional 48 weeks. In 21 patients with hypertriglyceridemia, halofenate significantly lowered the mean serum triglyceride level from the control period 21 % during the first 48 weeks of therapy and 27% during the second 48 weeks of therapy. In another 20 patients with hypertriglyceridemia, halofenate significantly lowered the mean serum triglyceride level from the control plus placebo period 26% during 48 weeks of therapy. Halofenate did not significantly affect mean serum cholesterol levels. Halofenate did not significantly affect the exercise performance until angina in 24 anginal patients or the resting or exercise electrocardiograms in 41 patients, including 28 with documented coronary heart disease. At the end of this 25 month study, 6 of 23 surviving anginal patients (26%) had no angina following exercise, and 14 of 23 surviving anginal patients (61 %) had no angina or at least a 25% increase in exercise time until angina, attributed to the natural history of coronary heart disease.
Effect of concurrent administration of aspirin and indomethacin on serum concentrations
Authors: Lindquist Bo , Jensen Karen Møiler , Johansson Henry , Hansen Tage
Published: January 2016

Because of a suggested interaction between salicylates and indomethacin, 6 healthy volunteers were given salicylate by mouth and indomethacin by rectum at different intervals. Serum concentrations were determined. The results show that the serum concentrations of salicylate and indomethacin are independent of their concurrent administration and presence in the serum.
Morphine metabolism in man: Effect of aspirin
Authors: Brunk S. Fred , Delle Margrieta , Wilson William R.
Published: January 2016

Morphine metabolism was studied in 12 normal subjects. Six were studied before and while receiving aspirin, 0.6 gm every 6 hours, and 6 were studied before and while receiving aspirin, 1.2 gm every 6 hours. The study was performed to determine whether aspirin decreases the conjugation of morphine with glucuronide. When aspirin and morphine were given together, plasma levels of free morphine were lowered slightly; after the high dosage of aspirin, the plasma levels of conjugated morphine were slightly higher than control. The urinary excretion of conjugated morphine was decreased by aspirin. Total radioactivity excreted in the urine was similar in all studies. These findings can best be explained by changes in renal clearance of free and conjugated morphine. The clearance of free morphine (organic calion system) tends to be either unchanged or increased by aspirin while the clearance of conjugated morphine (organic anion system) is decreased. These changes appear to be sufficient to explain the changes in plasma and urinary ffee and conjugated morphine levels. Aspirin, at these dosage levels, therefore, does not decrease the conjugation of morphine with glucuronide and does not affect N‐demethylation.
Disposition of propoxyphene and norpropoxyphene in man after a single oral dose
Authors: Verebely Karl , Inturrisi Charles E.
Published: January 2016

The disposition of propoxyphene and its major biotransformation product norpropoxyphene was studied in normal subjects following a single 130 mg oral dose. The concentration of propoxyphene and norpropoxyphene in samples of plasma and urine was determined by use of gas‐liquid chromatography. The peak plasma level of propoxyphene occurs at 2 hours followed by a rapid elimination with an average apparent half‐life of 3.0 hours (range 1.6 to 4.1 hours). The plasma level of norpropoxyphene renches a peak at 4 hours and slowly decays with an apporent half‐life of 16.8 hours (range 11.5 to 28.8 hours). For a given subject, the ratio of the concentration of propoxyphene over the norpropoxyphene in plasma at 4 hours after a 130 mg dose is well correlated with the apparent plasma half‐life of propoxyphene. This suggests that this single plasma sample may provide an indication of the rewtive rate of N‐demethylation in a population. The data indicate that individual ditJerences in absorption and biotransformation may be responsible for the substantial variation of the pklsma propoxyphene levels seen in subjects receiving the same dose.
Pharmacokinetics of cefazolin in normal and uremic subjects
Authors: Welling Peter G. , Craig William A. , Amidon Gordon L. , Kunin Calvin M.
Published: January 2016

The pharmacokinetics of the 7‐amino‐cephalosporanic acid derivative, cefazolin, has been studied in normal subjects and in uremic patients after single and multiple intramuscular doses. In most cases serum concentration and cumulative urinary excretion data were successfully fitted to equations appropriate to the pharmacokinetic one‐compartment open madel with first‐order absorption and elimination. In normal subjects cefazolin gave maximum serum concentrations of 30 to 50 fLg per milliliter 1 hour after a single 500 mg injection with a serum half‐life of about 2 hours. Higher serum levels were obtained after identical doses to uremic subjects, and serum half‐lives increased with decreasing renal function. The apparent distribution volume of cefazolin was slightly greater in uremic subjects and was proportional to the decrease in serum protein binding. Urine concentrations were higher in normal than in uremic subjects but were consistently above the minimum inhibitory concentrations (MIG) for most organisms in both groups. Pharmacokinetic parameters were little affected by multiple dosing in normal subjects, but there was some evidence of enzyme induction. Good linear correlations were obtained between the elimination rate constant, serum and renal clearance, and creatinine clearance, and also between the logarithms of the amount of drug eliminated unchanged and creatinine clearance. It is proposed that the observed relationships may be used for adjustment of dosage regimens in cases of renal failure.
Comparative study of the effects of metolazone and other diuretics on potassium excretion
Authors: Puschett Jules B. , Rastegar Asghar
Published: January 2016

The acute effects on potassium excretion of the new diuretic agent, metolazone, were compared to those of chlorothiazide, acetazolamide, furosemide, and ethacrynic acid. Metolazone was antikaliuretic when mildly natriuretic, nonkaliuretic when modestly natriuretic, and only minimally kaliuretic at the highest rates of sodium excretion obtained (apprOXimately 5% to 7% of filtered load). This action of the drug on potassium excretion was not obviated by superimposing its administration on steady‐state ethacrynic acid diuresis, but the provision of pharmacologic doses of mineralocorticoid did convert it to a frankly kaliuretic agent. In comparison to the other diuretics, metolazone showed the least tendency to induce urinary potassium loss, but ethacrynic acid was also nonkaliuretic at low levels of natriuresis. Both metolazone and ethacrynic acid were much less kaliuretic than the carbonic anhydrase inhibitors: acetazolamide, furosemide, and chlorothiazide.
Evaluation of albutoin as an antiepileptic drug
Authors: Cereghino James J. , Brock Joseph T. , Meter John C. Van , Penry J. Kiffin , Smith Lawrence D. , Fisher Pearl , Ellenberg Jonas
Published: January 2016

A double‐blind, controlled study of efficacy and bioavailability of the investigational antiepileptic drug albutoin was performed in a population of institutionalized patients whose seizures were not completely controlled by therapeutic dosages, as determined by serum levels, of combinations of currently available antiepileptic drugs. Albutoin did not appear to be as effective as diphenylhydantoin, primidone, or phenobarbital in controlling seizure frequency. Serum albutoin levels indicated the drug was poorly absorbed at dosages up to 1,200 mg per day. Nausea, anorexia, and weight loss were significant problems in over 10% of the patients receiving 1,200 mg of albutoin per day. Few controlled studies are available as models for evaluating the efficacy of antiepileptic drugs. With minor modifications, the double‐blind study design described could be used as a means of rapidly (21 days) evaluating drugs as antiepileptic agents.
Pharmacokinetics and pharmacodynamics of the enantiomers of warfarin in man
Authors: Breckenridge A. , Orme M. , Wesseling H. , Lewis R. J. , Gibbons R.
Published: January 2016

The rate of elimination, apparent volume of distribution, plasma clearance, and relative anticoagulant potency of the enantiomers of warfarin have been determined in man. In 9 subjects the plasma half‐life (T½) of R warfarin after a single oral dose of 0.5 mg/kg ranged from 19.9 to 69.S hours, and was significantly longer than that of S warfarin, which ranged from 18.0 to 34.1 hours. There was no significant difference in the apparent volume of distribution of the enantiomers, and thus the plasma clearance of R warfarin was significantly less than that of S warfarin. After multiple dosing to steady state, the plasma T% of R warfarin in 8 subjects ranged from 37.4 to 88.6 hours and was significantly longer than that of S warfarin, which ranged from 21.2 to 42.6 hours. The apparent volume of distribution of the enantiomers was the same, and thus the plasma clearance of R was again significantly less than that of S warfarin. The plasma T½ of R but not of S was significantly longer after multiple dosing than after a single dose. The ratio of the steady‐state plasma concentration of R to S warfarin was 3.80 : 1 in 4 patients with the same degree of anticoagulant control. The relative dose requirements of R to S warfarin were 1.5.9 : 1 in these sub;ects. S warfarin is a more potent anticoagulant than R warfarin in man.
Minimization: A new method of assigning patients to treatment and control groups
Authors: Taves Donald R.
Published: January 2016

This paper describes a new method of assigning patients to treatment and control groups to minimize differences between the groups, not only in the number of patients but in patient characteristics. Testing the method by computer simulations, using data on 40 patients with 15 variates each, demonstrates a four‐ to fivefold reduction of the probability of severe imbalance, relative to randomization. Minimization can maintain tight control of one variate, comparable to the currently acceptable experimental design of blocking, while reduCing the probability of severe imbalance in the other 14 variates by a factor of 3. It also compares favorably with accepted methods regarding susceptibility to experimenter bias. Therefore, it is suggested that minimization should replace randomization in assigning patients in clinical trials.
Blood levels of practolol after oral and parenteral administration and their relationship to exercise heart rate
Authors: Carruthers S. George , Kelly John G. , McDevitt Denis G. , Shanks Robin G.
Published: January 2016

Blood levels of practolol after oral and parenteral administration were determined in normal subjects, and the effects of each dose on the heart rate induced by strenuous exercise were measured. Oral practolol was rapidly absorbed and produced peak blood levels in 1 to 3 hours. Between 2 and 7 hours blood levels varied little more than twofold either within or between subjects. The half‐life of practolol in blood was 10 to 11 hours. Practolol100 mg was the minimum dose to produce near maximum blockade at 2 hours; maintenance of this effect for 24 hours reqUired 400 mg. Near maximum blockade was produced as long as a blood practolol level of 1.0 to 1.4 µg per milliliter was maintained. There was a correlation between the logarithm of the blood practolollevel and the percentage reduction of exercise heart rate. Practolol 40 mg and 80 mg intravenously initially achieved near maximum blockade associated with blood practolol levels above 1.0 p.g per milliliter. The effects and blood levels fluctuated during the first 7 hours. Intramuscular doses up to 40 mg failed to produce near maximum blockade; higher doses were precluded by pain at the injection site.
Methemoglobin formation in analgesic nephropathy
Authors: Gault M. H. , Shahidi N. T. , Barber V. E.
Published: January 2016

Three groups were investigated to determine whether methemoglobin formation is greater than normal in chronic phenacetin analgesic abusers. Group I (8 patients) was comprised of nonabusers with normal renal function; Group II (12 patients), of nonabusers with impaired renal function; Group III (9 patients), of abusers who had consumed phenacetin in combination with acetylsalicylic acid, caffeine, and codeine for 7 to 20 years, and had Similarly impaired renal function. Each subject was given 2 gm of phenacetin in a single dose, orally. Analysis of variance revealed significantly higher methemoglobin levels in Group III than in Groups I and II (p < 0.005). After cessation of analgesic abuse, there was a reduction in methemoglobin formation in 5 of 6 Group III patients. Continued heavy consumption of phenacetin may lead to increased production of the toxic metabolites that lead to methemoglobin formation.
Disopyramide in the prevention of recurrence of atrial fibrillation after electroconversion
Authors: Härtel G. , Louhija A. , Konttinen A.
Published: January 2016

The effect of a new antidysrhythmic drug, disopyramide, was tested in a double‐blind clinical trial in 52 patients undergoing electroconversion of atrial fibrillation. During a 3 month follow‐up, the number of patients remaining in sinus rhythm after successful electroconversion was higher (p < 0.05) in the disopyramide group (72%) than in the placebo group (30%).
Comparison of graded single intramuscular doses of morphine and pentobarbital in man
Authors: Martin William R. , Thompson William O. , Fraser Havelock F.
Published: January 2016

Graded single intramuscular doses of morphine sulfate (8, 16, and 32 mg) and pentobarbital sodium (150, 200, and 250 mg) and a placebo were administered double blind to 12 nontolerant narcotic addicts. To assess the the magnitude and time course of subiective effects and associated signs, “single and chronic dose” opiate questionnaires were completed by subjects and observers. Objective measurements of drug effect were concurrently made, using photographs of the pupils and the duration of postrotational nystagmus. Overall, the questionnaires showed definite and different constellations of symptoms and signs for morphine and pentobarbital. Objective measurements were also different. Morphine induced a dose‐related decrease in pupillary diameter and an increase in the signs scratching, relaxed, coasting, talkativeness, and conjunctival injection and caused relaxation, talkativeness, and turning of the stomach. Pentobarbital induced a dose‐related increase in the duration of postrotational nystagmus and caused sleepiness and drunkenness. Both drugs induced euphoria.
Studies on digitalis; I. Renal excretion of digitoxin and its cardioactive metabolites
Authors: Storstein Liv
Published: January 2016

Simultaneous serum and urine measurements of digitoxin and its cardioactive metabolites were performed in patients with normal renal function, after a single intravenous dose (5 patients) and on maintenance therapy (22 patients). A modified 86Rb method was used for the measurement of digitoxin in serum and urine. After a single dose of digitoxin intravenously, the mean serum‐tissue equilibration half‐time (T/2) was 71 minutes, the mean serum elimination T/2 8.1 days, and urine concentration T/2,7.2 days. Only 2.8% of the dose was excreted as cardioactive metabolites during the first 24 hours and 15.8% after 8 days. Twenty‐two patients on maintenance dosage had a mean serum concentration of 20.6 ng per milliliter, urine concentration of 24.9 ng per milliliter, and the renal excretion of cardioactive substances during 24 hours was 32.9% of the daily dose. Digitoxin clearance was calculated to be 1 ml per minute. Diuretics did not alter the excretion of digitoxin. There was no significant correlation between urine flow and renal excretion of digitoxin. The results suggest that other cardioactive metabolites of digitoxin are present after single‐dose and maintenance therapy.
Pharmacokinetics of pivampicillin and ampicillin in man
Authors: Loo J. C. K. , Foltz E. L. , Wallick H. , Kwan K. C.
Published: January 2016

The absorption of orally administered pivampicillin, an ester that hydrolyzes to ampicillin in vivo, was studied in healthy males and compared to ampicillin administered intravenOusly, intramuscularly, and orally. Using intravenous ampicillin as the reference, pharmacokinetic analyses were performed on data of ampicillin concentrations in sera and urine. All doses were expressed as molar equivalents of anhydrous ampicillin. Following single oral doses of 500 mg, absorption of pivampicillin (P), ampicillin anhydrous (AA), and ampicillin trihydrate (AH) was estimated to be 82%, 53% and 49%, respectively. In a second panel, absorption was 89% after a 500 mg oral dose of pivampicillin and 85% after a 616 mg dose of ampicillin sodium solution administered intramuscularly. Orally, maximum absorption rates occurred in 1 hour; they were approximately 300, 150, and 120 mg per hour for P, AA and AH, respectively. Intramuscularly, peak absorption rates of 500 mg per hour were observed in 15 minutes; these high rates were maintained for a shorter period. There appears to be some diminution in pivampicillin absorption with increasing doses; the absorption increases in a ratio of 1:1.85:3.34 for doses of 250, 500, and 1,000 mg, respectively. Renal clearances and serum half‐lives for pivampicillin were the same as those for ampicillin.
Antianginal effects of chromonar A combined investigation
Authors: Bing Richard J. , Bender Sheldon R. , Dunn Marvin I. , Fry Gary A. , Fuller William M. , Liu S. C. K. , Miller Henry S. , Moses John W. , Ritzmann Leonard W. , Segal J. P. , Shugoll Gerald I. , Tillmanns Harald , Wallace Alexander
Published: January 2016

The antianginal effect of chromonar was investigated in patients with coronary artery disease. Results are presented from twelve clinical departments in North Atnerica, all of which followed an identical protocol and test procedure. The results from these institutions illustrate some definite effects of chromonar. Using the attack rate, nitroglycerin requirement, and exercise tolerance test, chromonar was followed by a reduction in the number of attacks and nitroglycerin reqUirements. There was some carryover when the sequence chromonar‐placebo was used in the crossover design. Side effects were minimal; laboratory data indicated no tOXicity. Clinical conditions associated with coronary artery disease, such as hypertenSion and heart failure, were without influence on the effect of the drug. The data point toward an interesting field of research since the mechanism of the beneficial effect of chromonar in angina is obscure.
Tolerance to pirprofen and preliminary efficacy trial in rheumatoid arthritis
Authors: Proctor Jack D. , Evans Eleanor F. , Campos Victor , Velandia Jorge , Pollack David , Wingfield William L. , Wasserman Albert J.
Published: January 2016

Pirprofen is an anti‐inflammatory drug derived from propionic acid. The compound inhibits the inflammatory response in the paw edema test, the cotton pellet granuloma test, and the adiuvant arthritis model in rats. Animal studies indicated a propensity to cause gastrointestinal ulcerations. Normal human subiects tolerated doses up to 600 mg per day. Occult fecal blood loss was rare. A preliminary efficacy study in 3 patients with definite, active rheumatoid arthritis showed apparent therapeutic benefit in doses of 200 to 400 mg daily. Pirprofen 400 mg per day was therapeutically eqUivalent to indomethacin 100 mg per day in 18 patients with definite, active rheumatoid arthritis in a double‐blind comparison. Adverse effects appeared to be more frequently abdominal in origin during pirprafen and more often central nervous system related during indomethacin. No serious manifestations of toxicity were noted in these studies.