bluuebunny/crossref_metadata_2025 huggingface dataset:
Cardiopulmonary effects of diazepam
Authors: Rao S. , Sherbaniuk R. W. , Prasad K. , Lee S. J. K. , Sproule B. J.
Published: January 2016

Eighteen patients with appreciable obstructive lung disease and 18 patients without measurable mechanical lung impairment were given intravenous diazepam to permit endoscopy. Doses of diazepam required for comparable level of anesthesia were used. There was an increase in the heart rate, and there were decreases in the blood pressure, stroke volume, left ventricular stroke work, and cardiac output in patients with normal pulmonary function. Total peripheral resistance was elevated after 15 minutes. In patients with obstructive lung disease, diazepam produced insignificant changes in heart rate, diastolic blood pressure, and total peripheral resistance. Left ventricular stroke work, stroke volume, and systolic blood pressure were markedly reduced. There was a depression in alveolar ventilation, associated with an increase ill the arterial carbon dioxide tension and a decrease in pH. The only significant differences in the effects of diazepam on cardiopulmonary function were in diastolic blood pressure and left ventricular stroke work, which were more affected in the control subjects than in the patients. O2 saturation was affected more in the patients than in the control subjects.
Clearance and metabolism of mepivacaine in the human neonate
Authors: Meffin P. , Long G. J. , Thomas J.
Published: January 2016

The metabolism of mepivacaine in the human neonate and adult has been examined. Three types of metabolic reaction are involved in the adult: N‐demethylation to produce 2′,6′‐pipecoloxylidide, aromatic hydroxylations to produce 2′,6′‐pipecoloxylidide‐4′‐hydroxy‐1‐methyl and 2′,6′‐pipecoloxylidide‐3′‐hydroxy‐1‐methyl, both of which undergo glucuronide conjugation. More than 99 per cent of each phenol is excreted as a glucuronide. Excretion of mepivacaine is influenced by urinary pH, 10 per cent of the dose being excreted by subiects with acidified urine and 5 per cent by subjects with fluctuating urinary pH. Urine passed in the first 30 hours of life of neonates whose mothers had received mepivacaine during labor was examined for mepivacaine and metabolites. The results show that there is considerable net transfer of mepivacaine to the fetus as indicated by the urinary excretion of mepivacaine and metabolites. Aromatic hydroxylation does not occur, or if it does it is so inefficient as to be of no clinical significance. The position with N‐demethylation is not so clear as the data does not provide adequate evidence on which to make a clear decision. Even though the neonate either has a very limited capacity to metabolize mepivacaine or is incapable of doing so, it is still able to eliminate the drug. Approximately 90 per cent of the total amount of mepivacaine found in the urine of neonates was excreted in the first 24 hoors after delivery.
Effect of oral contraceptives on the thromboelastogram
Authors: Fisch Irwin R. , Freedman Shanna H. , Pellegrin Frederick A.
Published: January 2016

Thromboelastography, a method for studying clot kinetics and firmness, was performed on 1,133 women. Analysis of thromboelastographic parameters associated with contraceptive drug use revealed no differences between never and post users. Current users had shorter clotting times (R, K) and firmer clots (larger Ma), though very few subjects demonstrated extreme thromboelastographic hypercoagulability. These changes were not related to a specific brand, component, or dose of the contraceptive dmg. Longitudinal study is needed to determine whether these minor alterations in the thromboelastogram have clinical significance.
Effect of halofenate on serum uric acid
Authors: Aronow Wilbert S. , Harding Phillip R. , Khursheed Mohammed , Vangrow Jack S. , Papageorge's Nicholas P.
Published: January 2016

The effect of halofenate on serum uric acid levels was evaluated in 48 people with hypertriglyceridemia in a 14 month double‐blind study. A 2 month control period began 1 month after starting dietary control. Twenty‐five patients were then given placebo, and 23 patients were given 2 halofenate tab lets of 500 mg each once daily for 48 weeks. The mean serum uric acid level during the 48 weeks of halofenate administration decreased 38%. The mean serum uric acid level during the 48 weeks of placebo administration decreased 3%. In comparison with placebo, halofenate caused a mean reduction in serum uric acid level of 35% (P < 0.01). Halofenate is especially of value in the treatment of patients with hyperuricemia and hypertriglyceridemia.
Effects of beta adrenergic blockade with sotalol in chronic anxiety
Authors: Tyrer Peter J. , Lader Maleolm H.
Published: January 2016

Psychiatrie outpatients with chronic anxiety of at least 6 months in duration were treated with sotalol (MJ 1999), a beta receptor‐blocking drug, and placebo for 2 weeks each in a crossover trial using double‐blind procedure. Ratings of anxiety and its bodily manifestations were made by therapist and patient after each treatment. Finger tremor was measured by power spectral analysis using a laboratory computer. Significant drug‐placebo ditferences were found for a number of clinical ratings, but for many of these there was discrepancy between patient and therapist. Reasons for this are discussed. Sotalol was also found to reduce the amount of tremor. It is suggested that sotalol has a place in the treatment of anxiety, particularly in patients with tremor as a maior symptom, but is unlikely to be etfective as a sole therapeutic agent.
Ether derivatives of a progestin and estrogen in monthly dosage
Authors: Danowski Thaddeus S. , Wilson H. Randolph , Vester John W. , Fisher Edwin R. , Khurana Ramesh C. , Nolan Sean , Stephan Thorsten , Sunder Joseph H.
Published: January 2016

The monthly ingestion of quingestanol acetate (2.5 mg) and quinestrol (2 mg) for 1 year by menopausal women was associated with increased numbers of superficial cells in Daginal smears and decreases in intermediate and parabasal cells. High serum FSH and LH levels were promptly returned to normal and remained normal. Serum triglyceride and T4 levels and plasma 11(OH) corticosteroids were consistently increased. Serum inorganic phosphorus and calcium levels decreased during the first month of treatment and remained decreased throughout the year. The calcium and phosphorus changes could reflect a protein‐anabolic effect with deposition of these ions in bone salts, but alternative explanations can be suggested. Serum solutes other than those already cited, serum enzymes, hematologic findings, electrocardiographic tracings, urinary steroids and creatinine, glucose tolerance and the associated serum insulin and growth hormone patterns, and a number of other routine laboratory procedures were not consistently affected by therapy with these dosages of quinestrol and quingestanol acetate. After 1 year of treatment urinary steroids and their responses to oral metyrapone were unchanged. Possible side etfects occurred in 3 of 18 patients: malaise, generalized pruritus, nausea, vomiting, and dizziness.
Pharmacokinetic study of a patient with diphenylhydantoin toxicity
Authors: Atkinson Arthur J. , Shaw John M.
Published: January 2016

Sequential determinations of plasma diphenylhydantoin (DPH) concentration in a patient with DPH toxicity have been used to study its dose‐dependent elimination kinetics. A pharmacokinetic model has been proposed for DPH that provides estimates of the apparent distribution volume, and characterizes the elimination of this drug in terms of a maximal excretory rate and apparent Michaelis‐Menten constant. This three‐parameter model has been used to illustrate a retrospective way of evaluating some possible causes of DPH toxicity in this patient.
Studies of the uricosuric action of the hypolipidemic drug halofenate
Authors: Ravenscroft Peter J. , Sands John M. , Emmerson Bryan T.
Published: January 2016

Six hyperuricemic patients, with a high incidence of hypertriglyceridemia, were placed on a purine‐free maintenance diet during a 2 week single‐blind study of the uricosuric activity of halofenate (MK‐185). In a single dose‐response study, halofenate, given in a dose of 1 gm orally, produced a uricosuric effect of 48 hours' duration and a peak response 6 to 8 hours after administration, with a significant fall in serum urate. In a 3 day trial of the drug, a progressive increase in urate excretion occurred with a further fall in serum urate. During the study, the mean triglyceride concentration fell by 26% and cholesterol by 15% of the pretreatment values.
Plasma renin response to lithium in psychiatric patients
Authors: Shopsin Baron , Sathananthan Gregory , Gershon Samuel
Published: January 2016

Three hospitalized psychiatric patients with different diagnoses were monitored for plasma renin activity before and after subacute treatment with lithium carbonate. Plasma renin activity rose sharply after the first day on lithium and mean plasma renin values were elevated throughout the first week of treatment, returning to baseline levels during the second week. These changes occurred in all three subiects.
Pharmacokinetics of methotrexate
Authors: Huffman David H. , Wan Suk Han , Azarnoff Daniel L. , Hoogstraten Barth
Published: January 2016

The pharmacokinetics of SH‐methotrexate were studied in 22 patients with malignancies. Following the intravenous administration of 30 mg methotrexate (Mtx) per square meter, the plasma disappearance was triphasic with half‐lifes of 0.7.5 ± 0.11,3.49 ± 0 . .55, and 26.99 ± 4.44 hours, respectively. The urinary excretion of radioactivity paralleled the plasma data for most patients. A metabolite was found in urine that eluted before Mix when chromatographed on a diethylaminoethyl (DEAE) cellulose column. The excretion of this metabolite reached steady state and accounted for 20 (14 to 37) per cent of the radioactivity in urine after 30 hours. Our observation that Mtx has a long terminal half‐life may explain the high incidence of tOXicity in patients receiving chronic low‐dose Mtx therapy.
Antagonism by alpha methyltyrosine of the ethanol‐induced stimulation and euphoria in man
Authors: Ahlenius Sven , Carlsson Arvid , Engel Jörgen , Svensson Torgny , dersten Per Sö
Published: January 2016

The effect of α‐methyl‐p‐tyrosine (α‐MT) pretreatment on ethanol‐induced behavioral effects in man was studied using a crossover, double‐blind design. Two dose‐regimens of α‐MT were used (4 × 1 gm and 4 × 0.5 gm, respectively, given 26,18,10, and 2 hours before the ethanol intake) in two separate experiments in 10 male subiects. The ethanol was administered orally as hard liquor (43%, vol/vol) in a dose of 50 ml every tenth minute for 40 minutes. The degree of general intoxication and certain other behavioral variables were rated by 3 nonintoxicated observers and by the subiects themselves, using a graded scale. Some obiective performance tests were also used. Pretreatment with α‐MT caused a reduction of the ethanol‐induced stimulation and euphoria as indicated by a significant decrease in the observers' ratings of alertness, talkativeness, elation, and happiness. Fatigue was significantly increased. These observations were supported by the subiects' own general annotations and, in part, by their own ratings. α‐MT‐pretreatment per se caused marked fatigue with mild dysphoria and a feeling of discomfort. It is suggested that central catecholamines may be involved in ethanol‐induced stimulation and euphoria in man.
Keynote address
Authors: Hellman Louis M.
Published: January 2016

We are entering an age of intense consumerism. This is one of the many important social changes that are taking place. I suppose consumerism can be defined as public attitude demanding maximum benefit with absolute safety at the lowest cost. In the realm of drugs the attainment of that goal is, of course, impossible. Drugs taken by human beings are measured by the ratio of benefit to safety. No effective drug, even aspirin, is absolutely safe. The ratio of benefit to safety is difficult to ascertain, particularly when it comes to the effect on the fetus and offspring of drugs used during pregnancy. Dr. McCrory has said, “Any time a society limits the number of offspring, or at least offers the means of such limitation, there should be a guarantee that the children will be as perfect as possible.” It seems to me that the next 10 or 15 years offer a tremendous opportunity to develop techniques to perfect intrauterine diagnosis. Intrauterine diagnosis, the means of measuring the excellence of the product, the health of the baby, and its potential, are areas to which you should devote your attention.
The need for further data
Authors: Sereni Fabio
Published: January 2016

Our knowledge of the toxic effects of drugs on fetal tissues is still incomplete. We are in need particularly of additional comparative information on human and animal fetal tissues. Our future efforts should be directed toward the establishment of significant correlations for drug damage.
Changes in fetal steroid metabolism with age
Authors: Villee Dorothy B.
Published: January 2016

As gestation proceeds enzymes develop or are activated. Some of the enzymes catalyze steps in the synthesis of steroid hormones. The fetal adrenal gland has a distinct pattern of steroid metabolism that is due to the relative lack of 3β‐hydroxysteroid dehydrogenase and the very active sulfotransferases and 16α‐hydroxylases. This distinctive pattern is probably confined to the fetal zane af the fetal adrenal cortex. This zone develops during gestatian, passibly under the influence of chorianic and fetal pituitary gonadatrapins, and involutes after birth. The fetal adrenal gland, though unable to form pragesterone, metabalizes it to a variety of hydraxylated steraids. Very early in development only 16α‐hydraxylase and 17‐hydroxylase can be demonstrated in the fetal adrenal gland in vitro. By 7 to 8 weeks 21‐hydroxylase and desmalase are active in vitro, and thereafter 11‐hydraxylase becomes detectable. The cancentrations af steroids in adrenal tissue and fetal blood and urine suggest that there is a preponderance of cartisone aver cortisol and that the corticasterone/cortisol ratio is higher in perinatal life than that found in the child or adult. The activity of the sulfotransferases of the fetus explains the preponderance of sulfurylated steraids in fetal and newborn fluids. Depending on the sex of the fetus, andragen synthesis may rise just before differentiation af the gonaducts and external genitalia. The fetal testis at this period has numerous large Leydig cells, which may also be under the influence of charianic ganadotropin. There is no evidence of impaired 3β‐hydroxysteroid dehydrogenase in the fetal testis, and testasterone is a major product of steroid metabolism in vitro.
Hormonal effects on fetal development: A survey
Authors: Jost Alfred
Published: January 2016

Some possible interferences of drugs or hormones administered to the pregnant mother with endocrine processes involved in fetal development are surveyed. The sites and modalities of action are multifarious: (1) effects on uterine accommodation to fetal development; (2) direct effects of hormones or drugs on fetal endocrine glands or target organs, as far as they are transferred from mother to fetus; (3) indirect effects on the fetal glands mediated by changes in the maternal environment.
Research goals in developmental pharmacology
Authors: Mirkin Bernard L.
Published: January 2016

The biologic hazards of contemporary therapeutic practices must be comprehensively and rigorously evaluated at all stages of mammalian maturation. Our ability to reliably predict the effects of pharmacologically active molecules and to better understand the processes regulating drug disposition in developing organisms must be significantly enhanced. Initiation of a multifaceted program, at both the basic and applied levels, is essential if we are to advance pharmacologic therapy and avoid further iatrogenic catastraphes in this special population.
Inhibition by lithium of prostaglandin E1 and norepinephrine effects on cyclic adenosine monophosphate production in human platelets
Authors: Murphy Dennis L. , Donnelly Cynthia , Moskowitz Jay
Published: January 2016

Prostaglandin E1 (PGE1)‐stimulated cyclic adenosine monophosphate (AMP) production in human platelets is inhibited during treatment with lithium carbonate under ordinary clinical conditions. In acute experiments in vitro, greater concentrations of lithium chloride are required to produce a similar inhibition of PGE1‐stimulated cyclic AMP production. Antagonism by norepinephrine of the PGE1 stimulation effect on cyclic AMP production is also inhibited by lithium in vivo and in vitro. It is suggested that these and possibly other hormonal blocking effects of lithium may be relevant to its antimanic efficacy and to other clinical effects of this drug.
Effect of colestipol on gastrointestinal absorption of chlorothiazide in man
Authors: Kauffman Ralph E. , Azarnoff Daniel L.
Published: January 2016

The effect of colestipol on gastrointestinal absorption of chlorothiazide was studied in 10 adult patients. A 58% decrease in 24 hour cumulative urinary excretion of chiorothiazide was observed when the drug was ingested simultaneously with colestipol. A decrease of 54% was observed when the two drugs were administered one hour apart. The in vitro binding of chlorothiazide to colestipol is pH‐dependent, with 64% of the drug bound to the resin at pH 6.9 as opposed to 9% bound at pH 1.0. This implies that the in vivo binding of the drug takes place primarily in the small intestine.
Training in clinical pharmacology
Authors: Lasagna Louis
Published: January 2016

Clinical pharmacology is only one of many disciplines whose jugular vein has just been slashed by the myopic budgetary decisions of the Nixon administration. The belief that military spending is more crucial to our nation's survival than support of science or the handicapped or the poor is one that strikes many of us as a philosophy of despair.
Studies on the metabolism in man of oxisuran, a differential immunosuppressive drug
Authors: Crew Malcolm C. , Vesell Elliot S. , Passananti G. Thomas , Gala Rosemarie L. , Di Carlo Frederick J.
Published: January 2016

Two groups of normal human volunteers received 14C‐labeled oxisuran orally in doses of 0.5 gm or 1.0 gm. The compound reached peak plasma levels in 1 to 2 hours, indicating rapid absorption from the gastrointestinal tract. Oxisuran and its metabolites were excreted almost completely by the kidney. Oxisuran, two isomeric oxisuran alcohols, and oxisuran alcohol sulfone were identified in plasma and urine. The plasma half‐lifes were approximately 1.2 hours for oxisuran, 15 hours for the oxisuran alcohols, and 60 hours for oxisuran alcohol sulfone. Urinary half‐lifes of these maior metabolites were almost identical to their plasma half‐lifes. Low levels of unidentified polar and nonpolar metabolites were found in plasma and urine, and their half‐lifes was estimated. A model of oxisuran metabolism in man was developed trom these pharmacodynamic studies.
Hydralazine elimination in man
Authors: Reidenberg Marcus M. , Drayer Dennis , DeMarco Ann L. , Bello Carmen T.
Published: January 2016

The metabolism of hydralazine has been studied in a series of experiments. The hydralazine plasma half‐life values in volunteers ranged from 2.2 to 7.8 hours in rapid acetylators and from 2.0 to 5.8 hours in slow acetylators. Plasma concentrations following intravenous administration were similar in slow and rapid acetylators, indicating similar volumes of distribution of hydralazine. Plasma concentrations of hydralaZine following oral administration were lower in rapid acetylators than in slow acetylators, indicating a difference in gut wall and liver “first pass” metabolism since it has been shown by Lesser and associates7 that the molecule is well absorbed. Patients with impaired renal function had higher plasma concentrations of hydralaZine at various times after an oral dose than those with normal renal function. The metabolism of hydralaZine includes nonenzymatic degradation to phthalazine at a rate of 0.07 p.g per milliliter per hour in plasma at 37° C. Phthalazine may be subsequently enzymatically metabolized as well as excreted. There is metabolism by the intestinal wall or liver during absorption or “first pass” that is related to genetic acetylator phenotype. There is further biotransformation as well as excretion of the acetylated metabolite. This “first pass” acetylation by the intestinal wall and liver represents a true detoxication mechanism for inactivating orally administered hydralazine. There is also an elimination process that is unrelated to acetylator phenotype.
Plasma disappearance of transplacentally transferred diphenylhydantoin in the newborn studied by mass fragmentography
Authors: Rane Anders , Garle Mats , Borgå Olof , Sjöqvist Folke
Published: January 2016

With the intention of studying the fate of transplacentally transferred diphenylhydantoin (DPH, phenytoin) in the newborn infant, a mass fragmentographic analytic method has been developed, in which deuterium‐labeled DPH is used as internal standard. The analytic procedure permits precise determinations of DPH in 100 µl plasma samples in concentrations down to 0.01 µg per milliliter. Seven newborn infants of epileptic mothers treated with DPH throughout the pregnancy were studied during the first 4 to 9 days of life. The rate of plasma disappearance of DPH in the newborn infants was of the same order of magnitude as previously reported in adults. The initial parts of the plasma concentration curves indicated zero‐order disappearance of DPH. Nursing did not seem to affect the rapid plasma level decline in the babies until extremely low concentrations (0.1 p.g per milliliter) were reached. The arr,wunts of unchanged drug excreted in the urine were inSignificant. It is therefore concluded that babies born by mothers treated chronically with DPH are able to metabolize this drug effectively immediately after birth.
Effects of mebutamate on the electroencephalographic sleep profile
Authors: Whitsett Thomas L. , Hoyt Harvey J. , Czerwinski Anthony W. , Clark Mervin L.
Published: January 2016

This study evaluated the effect of mebutamate (600 mg) on the electroencephalographic sleep profile in 10 healthy, noninsomniac normal males. Placebo was administered on nights 1–4, mebutamate on nights 5–7, and placebo on nights 8 and 9. The results demonstrated that mebutamate significantly altered the electroencephalographic sleep profile. REM sleep was significantly depressed but was not associated with rebound. A low‐amplitude, high‐frequency (18–28 cps) beta rhythm emerged with the administration of mebutamate. There was a significant increase in stages 2 and 4 sleep patterns, the latter being in the range of 100%.
Orthohydroxyhippuric (salicyluric) acid—its physiologic and clinical significance
Authors: Altschule Mark D. , Hegedus Zoltan L.
Published: January 2016

Orthohydroxybenzoic acid was given the name salicylic acid because it was made in 1838 from a product of willow bark (Salix alba). About fifty years later salicylates became established as useful in the treatment of rheumatic fever. In the interval orthohydroxyhippuric acid was discovered and was named salicyluric acid. The fact that ingesting benzoic acid led to the excretion of hippuric acid led Bertagnini10 in 1856 to look successfully for salicyluric acid in the urine after the ingestion of salicylate. For almost a hundred years thereafter orthohydroxyhippuric acid was thought of almost entirely as a metabolite of salicylate. A large amount of research was done on the formation and excretion of orthohydroxyhippuric acid in relation to salicylate therapy. Orthohydroxyhippuric acid also became important in the chemical industry, and much study has been devoted to its synthesis and its properties.12, 28
Plasma half‐life of phenylbutazone in patients with impaired liver function
Authors: Hvidberg Eigill F. , Andreasen Per Buch , Ranek Leo
Published: January 2016

In 6 patients with cirrhosis at the liver and 5 control patients, the serum concentrations of phenylbutazone (pbz) and a major metabolite, oxphenylbutazone (ox‐pbz), were followed for 16 days after oral administration of fixed doses of pbz for 4 days (600, 600,300,300 mg). Preliminary evidence is presented for a significant correlation between the apparent elimination rate constant of pbz (the plasma half‐life) and the galactose elimination capacity (r = 0.868, P < 0.05) in cirrhotic patients. The ratio between the peak concentrations at pbz and ox‐pbz in the two groups was not different.
Pharmacokinetics of orally administered furosemide
Authors: Michael R. Kelly , Ralph E. Cutler , Arden W. Forrey , Barbara M. Kimpel
Published: January 2016

Furosemide (80 mg) as tablets or aqueous solution was taken orally by normal subjects during a fast and postprandially. Comparative studies were obtained using intravenous furosemide and 35S‐furosemide. No significant differences were apparent between tablets and aqueous solution. During fasting, detectable drug levels appeared in the serum within 10 minutes, peaked (mean 2.2 μg/ml) between 60 and 70 minutes, and decreased to nearly undetectable levels between 3 and 4 hours after ingestion. The postprandial studies displayed delayed appearance and low‐peak serum concentrations (mean 1.0 μg/ml), with only a slight decrease in concentration at the end of 4 hours. However, the total amount of drug absorbed was similar, and about 60% of the drug was calculated to be absorbed during fasting. The 24‐hour excretion of 35S‐furosemide was between 30% and 50% of the administered dose. The diuresis observed in each study over a 12 hour period was not Significantly different between dosage forms as well as whether given during a fast or postprandially. Extracellular volume appeared to be the most critical factor in determining diuretic response. It is concluded that the availability of orally administered furosemide is similar regardless of the dosage form and meals, and that the diuretic response is similar to that to a comparable parenteral dose.
Plasma protein binding of diphenylhydantoin Effects of sex hormones, renal and hepatic disease
Authors: Hooper Wayne D. , Bochne Felix , Eadie Mervyn J. , Tyrer John H.
Published: January 2016

The in vitro binding of diphenylhydantoin (DPH) to the protein in plasma from 97 volunteers has been studied using ultrafiltration at 37° C. The capacity of plasma protein to bind DPH did not differ significantly between pregnant women (11.6 ± 1.7% of total drug unbound), women taking oral contraceptives (9.9 ± 1.7% unbound), healthy males (10.6 ± 1.3% unbound), and healthy females (11.0 ± 3.2% unbound). However, in plasma trom patients with renal disease (15.8 ± 3.9% unbound), hepatic disease (15.9 ± 6.0%) or hepatorenal disease (15.6 ± 5.4%), the protein binding of DPH was significantly decreased. These changes in protein binding were found to correlate better with changes in albumin and bilirubin levels in plasma than with any of 13 other biochemical parameters examined.
XXVI. Medical ethics and the architecture of clinical research
Authors: Feinstein Alvan R.
Published: January 2016

Before World War II, most of the activities called medical research were performed in laboratories, upon materials that were animals, inanimate objects, or substances derived from living people. During the past few decades, the scope and volume of clinical investigation have enlarged so that intact living people have been increasingly involved as the “material” of the research. The use of living people as the investigated subjects has heightened interest in medical ethics and expanded it to include specific attention to issues in medical research. The attention was particularly spurred in the past few years after Beecher3 in the United States and Pappworth25 in the United Kingdom presented prominent indictments of various “unethical” activities in clinical investigation. These indictments helped arouse concern and stimulate the various new standards, committees, and legislation that have subsequently been proposed as prophylaxis for undesirable ethical phenomena.
Diuretic action of the narcotic antagonist oxilorphan
Authors: Nutt John G. , Jasinski Donald R.
Published: January 2016

The narcotic antagonists oXilorphan and d,l‐cyclazocine increased urinary output without affecting fluid intake in 10 subjects on ad libitum fluids. 1n 8 water‐deprived subjects oXilorphan increased urinary output and decreased urine osmolality without significantly altering blood pressure, creatinine clearance, electrolyte excretion, or solute excretion. Three of 4 water‐loaded subjects excreted a water load slightly more efficiently after the drug. Ten milligrams of naloxone had no diuretic effect itself and did not antagonize the diuretic effect of oxilorphan. Five units of vasopressin prevented the drug‐induced diuresis. These results suggest that the diuretic effect is an agonistic action of oXilorphan produced by inhibition of antidiuretic hormone (ADH) release.
Safety and efficacy of zinc sulfate in geriatric patients
Authors: Czerwinski Anthony W. , Clark Mervin L. , Serafetinides Eustace A. , Perrier Celia , Huber Wolfgang
Published: January 2016

Using a double‐blind design, 30 geriatric patients with the diagnosis of senile dementia were treated with zinc sulfate, 220 mg three times daily, or with an identical‐appearing placebo for 24 weeks. Diarrhea occurred in 6 of 16 zinc‐treated patients and in one of 14 placebo patients. In zinc‐treated patients, plasma zinc concentrations increased during the first 4 weeks of study and thereafter stabilized at approximately 150 µg/dl. Psychometric and behavioral evaluations did not demonstrate a statistically significant difference between placebo and zinc‐treated patients. Some behavioral tests did illdicate that zinc‐treated subjects deteriorated less rapidly thall concurrent placebo subjects.
Strategies of science in human affairs: How to assure the quality of scientific statements
Authors: Bross Irwin D. J.
Published: January 2016

A simple theory is presented describing the methodology for assuring continuing high quality of the scientific statements. A communication network for drug‐testing information is used
as an example. It is shown that there can be a close connection between the degree of concordance of the statements circulating in the communication network and the proportion of true statements providing that the procedures used in generating the statements are based strictly on factual evidence. Standard statistical methods for putting confidence intervals on relative potency are used to derive and to illustrate this point. It is argued that there is historic evidence from the record of drug testing in the past generation for the improvement in the quality of scientific statements through use of modem technology for error control.
Controlled clinical trials have clearly improved the quality of statements about drugs and other modalities of clinical intervention during this time.
Treatment of malignant melanoma with methyl CCNU
Authors: Young Robert C. , Canellos George P. , Chabner Bruce A. , Schein Philip S. , Brereton Harmar D. , DeVita Vincent T.
Published: January 2016

Twenty‐eight patients with disseminated malignant melanoma were treated with methyl‐1‐(2‐chloroethyl) 3‐(4‐methyl cyclohexyl‐1‐nitrosourea (MeCCNU) administered as a single dose orally every 6 weeks. Six patients (21%) had a complete or partial regression of measurable disease. The median duration of the partial remissions was 2 months and for the 1 complete remission, 18 months. The median survival of those responding to therapy (10.6 months) was significantly longer than those who failed to respond (4.2 months). Regressions of skin, intracutaneous, and nodal disease were most common, but 4 patients had regression of lung metastasis and 1 patient had regression of bone metastasis. Toxicity was primarily delayed thrombocytopenia and to a lesser extent leukopenia occurring within 4 to 6 weeks. Hematopoietic toxicity was significant but manageable. Most patients received treatment as outpatients. The response rate, ease of administration, and absence of sex difference in response make MeCCNU potentially useful in the chemotherapeutic management of disseminated malignant melanoma.
Evaluation of a new mucolytic drug
Authors: Steen S. N. , Ziment I. , Freeman D. , Thomas J. S.
Published: January 2016

In a double‐blind crossover trial, the effect of a new mucolytic drug, the sodium salt of 2‐mercaptoethane sulfonic acid (Mistabron) (6 ml, 200 mg per milliliter) was compared with 0.9% sodium chloride (6 ml) over 16 consecutive days in 31 sub;ects with chronic bronchitis. Drugs were assigned randomly and were self‐administered by nebulization. Pulmonary function measurements were made pre‐nebulization, 5 minutes, and 45 to 60 minutes after nebulization each day. Symptomatic assessment of cough, sputum production, and dyspnea were recorded daily. No changes attributable to either treatment were noted in blood pressure, electrocardiographic tmcings, chest radiographs, blood chemistries, and urinalyses during the study. Pulmonary function tests (which included whole body plethysmography) showed clinically insignificant changes, though most subjects claimed to have experienced clinical improvement after taking 2‐mercaptoethane sUlfonic acid. Sputum production was measured in the last 18 patients who entered the study, and 2‐mercaptoethane sulfonic acid consistently resulted in greater production than saline. The difference was significant (p = 0.001). It is concluded that 2‐mercaptoethane sulfonic acid (20%) is as safe as an equivalent volume of normal saline administered by inhalation to subjects with chronic bronchitis, and that it is a more effective mucolytic agent.
From animals to man: Metabolie eonsiderations
Authors: Conney A. H. , Coutinho C. , Koechlin B. , Swarm R. , Cheripko J. A. , Impellizzeri C. , Baruth H.
Published: January 2016

Metabolie studies that are helptul tor the extrapolation of animal data trom one species to another, and from animals to man, include the investigation of speeies differenees in rates and pathways of drug metabolism and the determination of whether or not plasma eoneentrations of a drug and/or its metabolites are eorrelated with the drug's pharmaeologie aetion or toxieity. Individual differenees in the metabolism of a new drug in man should also be eonsidered, and the dose of the drug should be adjusted to the metabolie eapaeity of the individual. Metabolie studies early in the investigation of an experimental anti‐inflammatory eompound are presented as an example of how metabolie studies may be helpful during the development of a new drtlg.
Pharmacodynamic and pharmacokinetic measurements of antiepileptic drugs
Authors: Kutt Henn
Published: January 2016

Determinations of blood levels of antiepileptic drugs by gas‐liquid chromatography offer a high degree of specificity; by this method determinations of several drugs can be made simultaneously. Data from various laboratories and clinics show a correlation between: dose and blood level, blood level and therapeutic effects, and blood levels and certain toxic effects, subject to interindividual variations among patients. Data are given for diphenylhydantoin, phenobarbital, primidone, ethosuximide, and trimethadione. In clinical management, monitoring of antiepileptic drug levels has proved useful in several ways: (I) it enables the physician to detect noncompliance; (2) it helps to confirm suspected intoxication in comatose patients or in the very young when clinical signs cannot be elicited; (3) it helps in evaluating the patient with inadequate seizure control; and (4) by establishing the base line level on the current dose, it is helpful in selecting the appropriate dose if a change becomes necessary.
Monitoring of plasma levels of a hypolipemic agent
Authors: Baer J. E.
Published: January 2016

A gas chromatographic method to monitor halofenate, a hypolipemic agent, provided an accurate means for studying its pharmacokinetics, the correlation of plasma level with pharmacologic effect, and estimation of patient compliance. In double‐blind studies, data on interval sampies showed: (1) plasma half‐life about 2 days; (2) almost complete plasma protein binding of the free acid after oral administration of the ester; (3) very low clearance rate; (4) long duration in over 85% of patients. A once‐a‐day schedule is, therefore, feasible with plasma levels being adequate even if the patient skips a day or more of medication. Cood correlation was demonstrated between total halofenate and triglyceride or urate lowering, but not with cholesterollowering.
Canrenoate in normal man
Authors: Mroczek William J. , Davidov Michael E. , Horoschak Alan , Finnerty Frank A.
Published: January 2016

Canrenoate, which has mineralocorticoid blocking activity, was evaluated in 3 normal subiects. The drug was administered by intravenous iniection twice daily for 7 days after 3 days of placebo. Loss of body weight and changes in serum and urine electrolytes were consistent with mineralocorticoid blocking activity. Canrenoate did not appear to have any effect on arterial blood pressure or cardiac output. A small increase in resting heart rate was demonstrated in 2 of the 3 patients, but this was thought to be secondary to volume depletion due to a diuretic action. A transient cardiac arrhythmia was noted in one sub;ect and was unexplained on the basis of serum electrolytes or plasma drug level. The only advantage of canrenoate over spironolactone appeared to be the parenteral administration.
Estimation of pharmacokinetic parameters of lithium from saliva and urine
Authors: Groth Ulrich , Prellwitz Winfried , Jahnchen Eberhard
Published: January 2016

The salivary and urinary excretion of lithium was studied in three healthy male sub;ects after oral administration of two or three different doses. In all individuals the concentration of lithium in salivary fluid was found to be 2.2 to 3.3 times as high as the concentration in plasma. In each sub;ect the saliva:plasma concentration ratio remained constant over more than a 100 fold concentration range for at least 3 months. This ratio was not markedly affected by about tenfold changes in saliva flow rate. Thus, pharmacokinetic parameters obtained from salivary excretion data are in agreement with those obtained from plasma concentration and urinary excretion rate data, and renal clearance of lithium can be estimated from salivary excretion data. Diurnal rhythms in the urinary excretion rate of lithium were observed. Thus, once the saliva:plasma concentration ratio is established (by taking only a few blood samples), the measurement of saliva concentrations should prOVide all pharmacokinetic information necessary for rational dosage regimens.
A method for shifting from oral to intramuscular diphenylhydantoin administration
Authors: Wilder B. J. , Serrano E. E. , Ramsey Eugene , Buchanan R. A.
Published: January 2016

In the first part of this study patients received constant daily doses of diphenylhydantoin (DPH) during oral, intramuscular, and subsequent oral periods. The data demonstrate that there is a profound fall in plasma DPH levels and urinary 5‐(p‐hydroxyphenyl)‐5‐ phenylhydantoin (HPPH) excretion after intramuscular (IM) administration and that this fall is followed by significant rebound when oral administration is resumed. The second part presents data for a regimen, confirmed by clinical and laboratory findings, for switching from oral to IM dosage and back without dramatic changes in plasma DPH levels or urinary HPPH excretion.
Present status of clinical pharmacology and of regulatory requirements for preclinical and clinical evaluation of new drugs in Japan
Authors: Ishizaki Takashi , Sugita Minoru
Published: January 2016

The present status of regulatory requirements for preclinical and clinical evaluation of new drugs in Japan is discussed. The issue of the necessity for clinical pharmacology has been increasingly raised in Japan. It is emphasized that the public problem of the “drug explosion or pollution” of the past quarter‐century must be overcome by national or international cooperation on a basis of medicosocial responsibilities. Finally, clinical pharmacology units with an independent academic affiliation are needed in the near future. This hopefully, will facilitate and hasten the development of additional scientific methodology for the evaluation of drugs in man and will contribute to the public health.
Clinical pharmacology in Spain
Authors: Erill Sergio
Published: January 2016

There are clinical phramacology programs in three Spanish medical centers. All have developed from pharmacology departments, and ioint appointments with clinical departments do not exist at this early stage in the development of clinical pharmacology. Recent legislation exerting increased regulatory control over drug products (specialties) has been exacted, but the challenges facing clinical pharmacology in evaluating and selecting useful and safe therapeutic agents from the myriad of new and existing preparations remains immense.
Pharmacokinetics of furosemide in advanced renal failure
Authors: Huang Chia M. , Atkinson Arthur J. , Levin Murray , Levin Nathan W. , Quintanilla Antonio
Published: January 2016

The pharmacokinetics of furosemide were studied in 12 patients with advanced renal failure. The elimination half‐life of furosemide averaged 9.7 hours. Renal furosemide clearance was reduced, but furosemide elimination by non renal mechanisms was unimpaired in uremic patients without liver disease and accounted for 86% to 98% of total elimination. Nonrenal furosemide clearance also was reduced in 3 uremic patients with liver cirrhosis, and elimination half‐life was prolonged to 20 hours in 1 of these patients. The diuretic response to intravenous furosemide appeared to be adversely affected by poor renal function and dehydration. Diuretic response was always less after oral than after intravenous furosemide, and the slow, intravenous infusion of this drug is recommended for maximal efficacy in uremic patients.
Absence of gastrointestinal bleeding with controlled‐release potassium chloride tablets
Authors: Cavaliere M. Beth Maggio , Dukstein Walter G. , Arnold John D. , Berger Arthur E.
Published: January 2016

No evidence of intestinal bleeding after administration of a controlled‐release potaSSium chloride KCI tablet was adduced using 51Cr‐labeled red blood cells in 30 male volunteers. Controlled‐release KCI was compared with placebo (double‐blind) and aspirin (openlabel). Blood and stool samples were collected daily during control (7 days) and drug (14 days) periods. Fecal blood loss in the controlled‐release KCI and placebo groups averaged < 1.00 ml/day during control and treatment periods. Mean blood loss (2.11 ml/day) in the aspirin group was more than double the control period value. Blood loss differences between aspirin and controlled‐release KCI and between aspirin and placebo were Significant (p < 0.01), but no differences were demonstrated between controlled‐release KCI and placebo. Mild gastrOintestinal symptoms possibly related to medication were reported by 6 patients, with no notable differences between groups.
The biochemical pharmacology of abused drugs; II. Alcohol and barbiturates
Authors: Caldwell John , Sever Peter S.
Published: January 2016

Problems associated with the excessive consumption of alcohol are recorded as early as in the Book of Genesis, whereas the abuse of the synthetic sedatives is obviously of much more recent origin. Although a wide range of sedatives are misused,19 the problem is seen principally with the barbiturates. While many aspects of the biochemical pharmacology of alcohol and of the barbiturates are widely dissimilar, there is a considerable cross‐tolerance between them and they are alike in that rapid development of tolerance can occur as the result of a single exposure to either of them, a point which is reviewed for both groups together at the end of this article.
Isoproterenol metabolism in children after intravenous administration
Authors: Kadar D. , Tang H. Y. , Conn A. W.
Published: January 2016

The metabolism of intravenously administered isoproterenol was investigated in children with severe brain damage between the ages of 6 and 16, using isoproterenol‐7‐3H. The serum concentration of .9H declined in a biphasic manner with the half‐lives of 2.5 to 5 minutes estimated from the rapid first phase and 3 to 7 hours estimated from the second slower phase. The drug is rapidly metabolized and after 15 to 30 minutes less than 10% of the .1H in the serum represents unchanged drug and after 1 hour less than 3%. The metabolites found in the serum and urine are free and con;ugated 3‐0‐methylisoproterenol, con;ugated isoproterenol, and an unknown substance that is excreted mainly in the bile. About 4% of the dose was eliminated in the urine in 5 minutes, 60% in 6 hours, and over 90% in 24 hours. Less than 15% of the urinary radioactivity represented unchanged drug, and most of that was eliminated during the first 2 hours.
Drug use in the hospital: Evaluation of determinants
Authors: May Franklin E. , Stewart Ronald B. , Cluff Leighton E.
Published: January 2016

Factors influencing drug utilization were studied in 7,575 hospitalized patients on a 65 bed general medical service during a 3½ year period. Nine index drug groups, including analgesic, antacid, antiarrhythmic, antimicrobic, anticoagulant, antihypertensive, anti‐inflammatory, diuretic, and sedative‐tranqUilizer drugs were used to evaluate drug utilization. The average number of drugs received by each patient was 8.04, and the average patient drug exposure for the 9 index drug groups was 4.75. The average patient drug exposure to index therapeutic drug groups was found to be significantly higher during the February‐March and April‐May periods than during the August‐September and December‐January periods of the study. Factors found to have a significant influence on drug use included the formulary system and changes in the availability of drugs. Distribution of a drug letter published by the Pharmacy and Therapeutics Committee did not appear to affect drug prescribing.
Status of topical therapy
Authors: Stoughton Richard B.
Published: January 2016

Topical therapy is an ancient and honorable rite performed for eons by kings and quacks of the art of medicine not to mention the myriads of lesser informed members of human society. Considering the enormous variety and quantity of molecules the ancients and moderns have applied to skin in the ever hopeful management of skin disease, it is quite remarkable that almost all such diseases have remained steadfast and full‐blown in the face of incredibly imaginative potions and poultices.
Anti‐inflammatory drugs
Authors: Van Arman C. Gordon
Published: January 2016

In the ideal sequence of events in developing a drug, one would first select a particular disease and then proceed to learn sufficient relevant facts about it (the first difficulty); then, one would know how to predict which particular chemical structure would have the required therapeutic effects without toxicity (the second difficulty); one would then synthesize the drug (perhaps difficult but probably possible); then, one would have valid and reliable testing models of the disease in animals (not presently known for any skin disease); after proof of efficacy and safety, finally the drug would be tested in the clinic (possible). Such a sequence has never been accomplished. The etiology of inflammatory diseases, particularly, is known to a limited extent only, and the dermal manifestations of them are understood still less. The pharmacologist therefore has many good opportunities here for rewarding work.
Bacterial pyodermas
Authors: Taplin David , Allen Alfred M.
Published: January 2016

In keeping with the aims of the Workshop, this presentation is confined to common types of skin infections with the highest incidence in the population at large. The rare and exotic will not be discussed, since they seldom constitute a public health problem.