bluuebunny/crossref_metadata_2025 huggingface dataset:
Fish poisonings‐their diagnosis, pharmacology, and treatment
Authors: Halstead Bruce W.
Published: January 2016

The general subject of fish poisonings is reviewed. Fish poisoning concerns both oral and parenteral toxins. Four general types of fish poisonings are recognized: ichthyosarcotoxins, of which there are at least nine kinds; ichthyootoxism; ichthyohemotoxism; and ichthyoacanthotoxism. The pharmacology and chemistry of fish poisons are discussed, but most of them have not been characterized. Treatment for the most part is symptomatic.
Pollution of the water environment by organic pesticides
Authors: Faust Samuel D.
Published: January 2016

Man is exposed to organic pesticides in his water environment through their use in the control of aquatic weeds, insects, and trash fish; percolation and runofJ from agricultural lands; drift from aerial and land applications; and discharge of industrial waste waters. Chemical and biologiC evidence indicates that most surface waters of the United States, in general, are polluted with the chlorinated hydrocarbon insecticides. In specific and localized situations, ground and surface waters have been polluted with the herbicide, 2,4‐D. These organiC pesticides are routed to man through drinking water and indirectly through edible fish. The general evidence suggests that adsorption on solid surfaces, biologic and chemical degradation, hydrolysis, uptake, retention, and release by biologic systems, and chemical precipitation reactions do not eliminate organic pesticides quickly from water. Organic pesticides affect drinking water quality through off‐tastes and off‐odors. Since the concentrations of several organic thiophosphates and 2,4‐D producing tastes and odors are far below subtoxic levels by factors ranging from 17 to 113,000, threshold taste and odor levels can be used to establish drinking water standards with the appropriate safety factors. Organic pesticides do not appear to represent a health hazard, chronic or acute, to man at the microgram per liter and milligram per liter concentrations believed to be in ground and surface waters at the present time.
The influence of acetylator phenotype on the effects of treating depression with phenelzine
Authors: Price Evans David A. , Davison K. , Pratt R. T. C.
Published: January 2016

There is a clear polymorphism for the acetylation of isoniazid, sulfamethazine, and hydralazine, so that human beings are clearly divisible into either slow or rapid acetylators. From its molecular configuration, it is likely that phenelZine is a substrate for the enzyme liver acetyl transferase which is responsible for the polymorphism. In the present investigation the responses of 47 depressive patients treated with phenelZine were observed. These responses were later correlated with acetylator phenotypes. Two results were obtained. First, there were no significant differences in the improvement of rating scores between the two phenotypes. Second, severe adverse effects were more common among slow acetylators treated with phenelzine than among rapid acetylators on the same treatment schedule.
An experimental study in the treatment of narcotic addicts with cyclazocine
Authors: Martin W. R. , Gorodetzky C. W. , McClane T. K.
Published: January 2016

The potent narcotic antagonist, cyclazocine, has a long duration of action and is effective when administered orally. Although tolerance develops to many of the effects of cyclazocine, including dysphoria and sedation, tolerance does not develop to the drug's ability to antagonize the toxic, euphoric properties of morphine. Subjects who had received cyclazocine orally twice daily on a continuing basis experienced only a very mild degree of euphoria when given very large doses of morphine, and developed only a very mild degree of physical dependence after continued administration of large doses of morphine. Cyclazocine antagonizes pharmacological actions of importance in the addiction to narcotic analgesics, and it could be useful in the ambulatory treatment of the abstinent addict.
The effect of the dosage form on serum levels of indoxole
Authors: Wagner John G. , Gerard Earl S. , Kaiser David G.
Published: January 2016

The influence of dosage form on serum levels of indoxole (2,3‐bis‐[p‐methoxyphenyll]‐indole), an anti‐inflammatory agent with low water solubility, was studied. Serum concentrations (fluorometric assay) were observed for 16 hours after the last dose in a short‐term multiple‐dose tolerance study when the compound was administered orally at four dose levels in Lipomul‐Oral emulsion. A good dose response was obtained when the average serum concentrations of individual subjects in the last dosage interval were plotted against the milligram per kilogram dose. Serum concentrations were also measured after oral administration at two dose levels in four different dosage forms. The order of serum level response was: Lipomul‐Oral emulsion ≃ soft elastic capsule 〉 aqueous suspension 〉 powder in a capsule. Potency estimates were 1.00: 1.10: 0.47: 0.16 following the first dose and 1.00: 0.72: 0.27: 0.16 following the sixth dose for the emulsion, soft elastic capsule, aqueous suspension, and powder in a capsule, respectively. Additional information is reported and discussed. The advantage of defining the serum level of a drug after the first dose and during a dosage interval at the equilibrium state is pointed out. The attempt to measure peaks and nadirs of drug concentration in the blood in multiple dose studies is less desirable than the method described above.
Penicillin therapy‐Newer semisynthetic penicillins
Authors: Friend Dale G.
Published: January 2016

It is obvious that the perfect penicillin has not been developed as yet. There is need for an acid‐stable, highly absorbable, penicillinase‐resistant, broad‐spectrum penicillin. Progress, so far, has been exciting and most promising. Many agents are now heing studied, and many more will soon be available.
Clinical‐pharmacological evaluation of p‐chlorophenylalanine: A new serotonin‐depleting agent
Authors: Cremata Vincent Y. , Koe B. Kenneth
Published: January 2016

This paper reports the first human trials of p‐chlorophenylalanine, which in animals has been shown to deplete brain and peripheral serotonin. In 6 normal prison inmate volunteers, a dose of 3,000 mg. per day of p‐chlorophenylalanine produced a decline in blood serotonin to 60 to 70 per cent of pretreatment levels and in urinary excretion of 5‐hydroxy‐3‐indolylacetic acid to 10 to 50 per cent. Symptoms reported by the subiects were tiredness, dizziness, nausea, uneasiness, fullness in the head, paresthesias, headache, and constipation. These generally began at the 1,000 mg. per day dose. The availability of a compound that appears to inhibit biosynthesis of serotonin without interfering with serotonin binding sites or with catecholamine metabolism provides a valuable new tool to explore the action of serotonin in the brain.
The clinical pharmacology of hexamethylmelamine: Phase I study
Authors: Louis John , Louis N. B. , Linman J. W. , Donnelly W. J. , Isaacs B. L. , Schwartz S. O.
Published: January 2016

The human pharmacology for a new oncolytic agent, hexamethylmelamine, is described. The dose tolerated by 80 per cent of the population treated for 28 days was 10 mg. per kilogram per day. The principal adverse effects requiring discontinuation of therapy were gastroenteric and hematologic. Despite discontinuation of therapy, a latent effect associated with prolonged therapy was peripheral neuropathy, which was not reversible in some of the patients. No adverse drug effects on liver, renal, pulmonary, and cardiovascular function were observed.
The botulinal, tetanal, and enterostaphylococcal toxins: A review
Authors: Lamanna Carl , Carr C. Jelleff
Published: January 2016

The applications of the purified bacterial neurotoxins have not been exploited to their full potential by research workers in the fields of neurophysiology and neuropharmacology. These chemically identified purified proteins have very selective sites of action in the central and autonomic nervous systems. As laboratory tools for the identification of the locus of action of drugs and neurotransmitter substances, these agents have proved to be very useful. Since they are not available from chemical suppliers, agencies such as the Public Health Service and the National Institutes of Health should consider the subsidization of the production of these biological substances in order to make them easily accessible to the nonbacteriologist researcher. In this review the authors have pointed out the problems for future research in this field and they have highlighted the issues confronting the clinician attempting to treat these rare but acute and sometimes fatal poisonings.
The treatment of scopolamine‐induced delirium with physostigmine
Authors: Crowell Edward B. , Ketchum James S.
Published: January 2016

Thirty‐three male volunteers were divided into four groups and given 24 mcg. per kilo gram of scopolamine hydrobromide intramuscularly, after which serial physiologic and quantitative mental function studies were done. Maximum scopolamine effects were seen 90 minutes (lfter in;ection. Three of the groups were treated with 50 mcg. per kilogram physostigmine salicylate intramuscularly, one group each at 15, 30, and 90 minutes after the scopolamine. The group treated at 90 minutes had a good therapeutic effect, whereas the groups treated at 30 and 15 minutes had, progressively, less desirable effects. While physostigmine will effectively reverse the delirium produced by scopolamine in humans after it has occtlTred, it is less effective in preventing it. Physostigmine is recommended as an antidote in cases of accidental overdosage of anticholinergic drugs.
Effect of oral contraceptives on vitamin K—dependent clotting activtiy
Authors: Schrogie John J. , Solomon Harvey M. , Zieve Philip D.
Published: January 2016

Vitamin K‐dependent clotting factor activity was studied in young, healthy women being treated with various oral contraceptive drugs. In one series of studies, the anticoagulant response to a dose of bishydroxycoumarin was diminished following treatment with an estrogen‐progestin mixture; the metabolism of the anticoagulant was unaffected. Thus the amount of coumarin‐type drug required to produce a desired anticoagulant effect in women taking oral contraceptives may be increased. In other studies, a marked shortening of the prothrombin time was observed in the plasmas of a majority of the women treated with oral contraceptives for two months or longer. This effect was demonstrated only after storage of the patients' plasmas in plastic tubes for 16 hours or more at 4 to 6°C. Following storage, the vitamin K‐dependent clotting activity of pooled treated plasma was 4.8 times that of pooled control plasma. This effect persisted for at least seven days following discontinuance of therapy but disappeared after one month. Assays of specific factors demonstrated an increase in the activity of factor X in stored plasmas from treated subjects. Oral contraceptives may affect the plasma of treated subjects so that there is in vitro activation of one or more of the inactive precursors of the vitamin K‐dependent clotting factors.
Ethanol metabolism in subiects possessing typical and atypical liver alcohol dehydrogenase
Authors: Edwards John A. , Price Evans David A.
Published: January 2016

Ethanol degradation rate (EDR) following intravenous administration of ethanol was determined in 23 subjects prior to abdominal operation. The liver alcohol dehydrogenase ( LA D H) was typed as typical or atypical on a liver biopsy specimen obtained at the time of the operation. Two subjects, one man and one woman, were found to possess the atypical form of LADH. The EDR was lower in women than in men among subjects possessing typical LADH. The male subject with atypical LADH had an EDR closely similar to those of men possessing typical LADH. The female subject with atypical LADH had an EDR significantly higher than that of females possessing typical LADH. Stratumcorneum and urine concentrates contained no LADH activity. Intravenous ethanol infuSion and computation of EDR cannot be used as a phenotyping procedure for LADH for genetic studies. A lcohol dehydrogenase activity cannot be demonstrated in either skin or urine concentrates; therefore, these techniqltes are similarly inapplicable for genetic studies. The results ca~t doubt on the concept that LADH is a rate‐limiting factor in human ethanol metabolism.
Alpha receptor blockade by thymoxamine in the human eye
Authors: Turner Paul , Sneddon J. M.
Published: January 2016

Thymoxamine blocks α‐adrenergic receptors in experimental animals. The instillation of 0.1 per cent thymoxamine into the human eye produces miosis which is maximal at 45 to 60 minutes and disappears after 1 to 2 hours. Pretreatment with thymoxamine eye drops prevents the production of mydriasis by phenylephrine 10 per cent or ephedrine 2 per cent. When mydriasis has been established by hydroxyamphetamine 1 per cent, thymoxamine reverses it, and miosis is apparent after 25 minutes. The importance of α‐adrenergic receptors in the mydriatic action of sympathomimetic amines is thus confirmed. This study illustrates the value of pupillary responses in studying the interaction of sympathomimetic amines with adrenergic neuron‐ and receptor‐blocking drugs in man.
The effect of trimethaphan camphorsulfonate on the human digital circulation
Authors: Mendlowitz Milton , Naftchi Nosrat E. , Wolf Robert L. , Gitlow Stanley E.
Published: January 2016

The effect of l‐norepinephrine (NE) infusion on the digital circulation was studied in four groups of patients: normotensive subjects prepared by indirect heating supplemented by (a) intravenous 2,6‐dimethyl,‐1‐diethyl piperidinium bromide (SC‐1950) or (b) by intravenous trimethaphan camphorsulfonate (TMCS); and hypertensive subjects prepared in the same way, the supplementing drug again being either (c) SC‐1950 or (d) TMCS. Less NE was required in the normotensive groups to produce a given degree of vasoconstriction when TMCS was the supplementing drug. The same effect was probably true of the hypertensive groups although this could not be demonstrated statistically from these data. This effect of TMCS cannot be satisfactorily accounted for by the liberation of histamine or by more efficient vasodilatation but is probably attributable to direct peripheral blockade by the drug of the entrance of NE into neural stores.
Absorption of intestinal antiseptics derived from 8‐hydroxyquinolines
Authors: Berggren Lennart , Hansson Olle
Published: January 2016

Urinary excretion for 10 hours after a small oral dose of several halogenated 8‐hydroxyquinolines was spectrophotometrically determined in a series of normal human sub;ects. No free forms of drug were found. The determinations were made on the glucuronic acid con;ugates, and the excretions in per cent of the dose were: di‐iodo‐8‐hydroxyquinoline, 4.6 per cent; di‐bromo‐8‐hydroxyquinoline, 10.2 per cent; chloro‐iodo‐8‐hydroxyquinoline, 12.6 per cent; di‐chloro‐methyl‐8‐hydroxyquinoline, 34.9 per cent. Three normal children and two patients (suspected of having 8‐hydroxyquinoline toxicity) who received chloro‐iodo‐8‐hydroxyquinoline had a similar excretion. Human absorption and ocular toxicity are discussed.
The renal excretion of indomethacin and its inhibition by probenecid
Authors: Skeith Maurice D. , Simkin Peter A. , Healey L. A.
Published: January 2016

The renal excretion of labeled indomethacin (indomethacin‐2‐C14) was measured in human volunteers with and without the concurrent administration of probenecid. Acute clearance studies provided evidence of tubular secretion of indomethacin. Less of the drug was excreted when probenecid was given. It is postulated that indomethacin is secreted by the same probenecid‐sensitive tubular mechanism as penicillin and other organic acids.
Naloxone in heroin dependence
Authors: Fink Max , Zaks Arthur , Sharoff Robert , Mora Arnoldo , Bruner Alfred , Levit Stephen , Freedman Alfred M.
Published: January 2016

Naloxone is a potent and rapidly acting narcotic antagonist, with a duration of action which is shorter (3 to 4 hours) than that of heroin. In a clinical trial of naloxone in the treatment of heroin dependence, a daily oral dose of 100 mg. at 8 A.M. and 7 P.M. effectively blockaded 20 mg. of heroin, with partial blockade of 40 mg., for up to 10 hours after the morning dose. In narcotic antagonism therapy of opiate dependence, naloxone has the advantages of potency, rapid action, absence of secondary effects, and acceptability. It has the disadvantages of brief action and high cost.
Drug combinations with orphenadrine for pain relief associated with muscle spasm
Authors: Birkeland J. W. , Clawson D. K.
Published: January 2016

Analgesic potency of graded doses of a combination of orphenadrine with the common APe tablet was tested and compared with each of its ingredients and a placebo in a double blind study. The subiects were 325 patients whose pain was largely associated with muscle spasm. Pain responses were scored at 6 hourly intervals after a single administration of medication. The data were analyzed by 3 statistical methods. Results show the combination to have a sustained pain‐relieving action and a statistically significant faster onset of analgesia than either of its components or placebo. Unexpected drug reactions were minimal.
Effects of hyoscine butylbromide on gut motility
Authors: Guignard J.-P. , Herxheimer A. , Greenwood R. M.
Published: January 2016

The effect of intravenous and oral hyoscine butylbromide (HBB) on gut motility has been assessed by tape recording bowel sounds in 7 healthy volunteers, with the use of a double‐blind procedure. In 6 of these intravenous administration of 8 mg. of HBB reduced the bowel sounds for 15 to 30 minutes; this was followed by a considerable increase in bowel sounds. Oral administration ot 200 mg. HBB to the same 6 subjects had no effect on the bowel sounds in the succeeding 21,2 to 3 hours. In the seventh subject an impressive increase in bowel sounds occurred promptly after both intravenous and oral HBB. These results show that HBB is poorly absorbed trom the gut and also make it seem very unlikely that the drug has any effect on normal bowel when given by mouth.
Evaluation of a method for assessing potent analgesics
Authors: Loan William B. , Morrison James D. , Dundee John W.
Published: January 2016

In a retrospective analysis of data which evaluates the influence of various factors on the outcome of a clinical assessment of potent analgesie drugs, (1) the method of assaying success of treatment, (2) the influence of different observers in the results obtained, (3) the influence of other factors, viz., age, sex, and weight of the patient, site and duration of operation, and initial severity of pain, were considered. It was concluded that methods based on the subjective assessments of either the patient or observer were valid and sensitive. Changes in spirometrie measurements following treatment were not in themselves valid indices of pain relief, but may be of value in certain circumstances. There was good correlation between the different observers' estimates of pain relief. Low pain severity before treatment was associated with a high er rate of placebo response than was severe pain. Age, sex, body weight, and duration of operation were without significant effect.
Experimental production of pain in man: Sensitivity of a new method to 600 mg. of aspirin
Authors: Smith Gene M. , Beecher Henry K.
Published: January 2016

The acetylsalicylic acid equivalent of two standard commercial aspirin tablets significantly delays development of ischemic pain induced experimentally in man by the submaximum‐effort tourniquet technique. Results of the present study, in confunction with previous findings, indicate that a wide range of analgesic potency may be assessed with this method, and thus a long‐sought procedure for testing, in man, the potency of new analgesics, studied under controlled experimental conditions, is provided. Efforts are presently under way to refine and sensitize the method in order to increase its practical usefulness for study of analgesics with only modest potency.
Relationship of pentazocine plasma levels to pharmacological activity in man
Authors: Berkowitz Barry A. , Asling Joseph H. , Shnider Sol M. , Way E. Leong
Published: January 2016

A spectrophotofluorometric method for the quantitative determination of pentazocine plasma levels in man, which detects concentrations as low as 0.03 µg per milliliter is described. Following intramuscular and oral administration, plasma levels of pentazocine coincide closely with onset, duration, and intensity of analgesia, as well as with other pharmacologic effects. The mean peak plasma level after 45 mg. per 70 Kg., intramuscularly, was 0.14 p,g per milliliter. The mean peak plasma level after 75 mg. orally was 0.16 µg per milliliter, but as much as 25 per cent are biotransformation products. The plasma half‐life is about 2 hours after intravenous or intramuscular administration. Side effects of pentazocine may be more prominent in ambulatory subjects or in those experiencing minimal pain.
Studies on absorption, excretion, and metabolism of 3H‐reserpine in man
Authors: Maass Alfred R. , Jenkins Bernard , Shen Yvonne , Tannenbaum Philip
Published: January 2016

Following oral administration of 0.25 mg. of 3H‐reserpine, dissolved in water, to 6 normal male volunteers, tritium was rapidly absorbed into the blood, reaching a peak in approximately one to 2 hours. Radioactivity was found in both the red blood cell and plasma, with a greater concentration in the plasma. Tritium was tightly bound to the red cells; a fixed concentration of radioactivity was found in the red blood cell during 96 hours of observation, while the plasma concentration continued to fall. The rate of plasma disappearance gave two biological half‐lives of 4.5 and 271 hours. Initial urinary excretion averaged approximately 6 per cent of the dose in 24 hours; the major excretory product was trimethoxybenzoic acid. Urinary excretion averaged 8 per cent of the dose in 4 days, but radioactivity was still detectable in plasma, urine, and feces 11 to 12 days after administration of 3H‐reserpine, indicating the very slow release of radioactivity from the body. The major portion of radioactivity appearing in the feces was identified as reserpine by paper chromatography.
The metabolism of phenacetin in patients with renal disease
Authors: Prescott L. F.
Published: January 2016

Phenacetin metabolism was investigated in 11 patients with renal disease, 9 of whom had previously abused analgesics. Comparative studies were carried out in 6 healthy adult volunteers. Following an oral dose of 1.8 Gm. of phenacetin, the mean plasma concentrations of phenacetin and unconjugated N‐acetyl‐p‐aminophenol (APAP) were similar in the patients with renal disease and the healthy volunteers. Absorption often appeared to be slow and irregular. There was marked individual variation in the plasma concentration of phenacetin and free AP AP, and the values observed at one and 2 hours varied by a factor of 4 when the healthy volunteers received different preparations of phenacetin. The 24 hour urinary recovery of phenacetin, p‐phenetidine, 2‐sulfonyloxy‐4‐ethoxyaniline, and free AP AP was essentially the same in the patients with renal disease and healthy volunteers. The renal excretion of conjugated AP AP was significantly reduced in patients with renal disease, and this reduction was correlated with the glomerular‐filtration rate. AP AP, 2‐hydroxyphenacetin, and 3‐amino‐7‐ethoxyphenoxazone were identified on thin‐layer chromatograms of glusulasehydrolyzed urine extracts, and other unidentified metabolites were observed.
The metabolism of amiloride hydrochloride in man
Authors: Weiss Peter , Hersey Roscoe M. , Dujovne Carlos A. , Bianchine Joseph R.
Published: January 2016

Amiloride hydrochloride labeled with C14 was given to 5 volunteers. Serum level peaked at 3 hours, and the half‐life was 6 hours. There was no evidence of metabolic transformation of amiloride. Approximately half the oral dose was recovered in the urine. Amiloride is cleared by tubular transport and should be used with caution in patients with renal insufficiency.
Magnesium pemoline and iob performance in mentally handicapped workers
Authors: Greenblatt David J. , DiMascio Alberto , Messier Michael , Stotsky Bernard
Published: January 2016

Magnesium pemoline has been shown to exert CNS‐stimulating effects in animals and in man. Many investigators have questioned the applicability of these effects to job performance. This study examined the stimulating or antifatiguing effects of magnesium pemoline on a series of tasks involved in clothing manufacture. The tasks required various combinations of perceptual‐motor processes that must be carried out accurately and rapidly over the course of a 6 to 8 hour work day. A group of 30 to 40 patients had been trained in these tasks and were paid on a piecework basis. A daily record was kept of the various tasks, number of hours worked, amount earned, and mental status changes. The over‐all design entailed a double‐blind crossover procedure with a placebo control. The results indicated that magnesium pemoline did not increase work output or hours worked. It did produce some mood changes characteristic of caffeine.
Cytochromes P‐450 and bs in human liver microsomes
Authors: Alvares Alvito P. , Schilling Gayle , Levin Wayne , Kuntzman Ronald , Brand Leonard , Mark Lester C.
Published: January 2016

Cytochromes P‐450 and b, have been demonstrated in human liver microsomes. The carbon monoxide and ethyl isocyanide difference spectra of cytochrome P‐450 in human liver are similar to those observed with rat or rabbit liver. The kinetic properties of 3,4‐benzpyrene hydroxylase in human liver have been determined.
Atropine on the electrocardiogram
Authors: Gravenstein J. S. , Ariet Mario , Thornby J. I.
Published: January 2016

Six normal volunteers were given graded doses of atropine. Analysis by a computer indicated that R‐T duration, P‐R segment, and R‐R intervals of the electrocardiograms were correlated, whereas the duration of the P wave was not dose related or linked to heart rate.
The rate of decline of diphenylhydantoin in human plasma
Authors: Arnold Keith , Gerber Nicholas
Published: January 2016

The rate of disappearance of diphenylhydantoin from plasma was studied in 70 healthy volunteers by giving them 100 mg. orally 3 times daily for 3 days and measuring the plasma diphenylhydantoin concentration for 4 consecutive days after the last dose of the drug. The mean plasma half‐life was 22.0 ± 9.0 hours and the difference between that of Negro and Caucasian males, 26.5 and 18.5 hours, respectively, was Significant. Dose dependency of the half‐life was demonstrated in 10 subjects studied. The decline in plasma diphenylhydantoin concentration in many subfects was not exponential and the disappearance of the drug from plasma was not always a first‐order process. The diphenylhydantoin half‐life in some subjects was shorter after long‐term administration than after short‐term administration of the drug. Saturation, autoinduction, or product inhibition, singly or in combination, of the drug‐metabolizing enzyme system are possible mechanisms involved in the dose dependency and nonexponential decline of plasma diphenylhydantoin concentration.
Metabolism of SU‐13437‐a new hypolipidemic drug in man
Authors: Bianchine Joseph R. , Weiss Peter , Peaston M. J. T. , Hersey Roscoe M. , Lasagna Louis
Published: January 2016

The metabolism of 5U‐13437 (2‐methyl‐2‐{p‐(1,2,3,4‐tetrahydro‐1‐naphthyl)‐phenoxylpropionic acid) labeled with C14 in the carboxyl group was studied in 12 healthy adult male subjects. Approximately 75 per cent of the orally administered label was recovered, 50 per cent from urine and 25 per cent from stool. No radioactivity appeared in expired air. 5erum half‐life for total radioactivity and for 5U‐13437 (or closely related metabolite) was 135 minutes and 95 minutes, respectively. Peak concentrations of radioactivity in urine occurred at 4 to 6 hours. Only 2 per cent of the radioactivity in urine is parent compound, while an additional 5 per cent of radioactivity represents conjugated derivative of parent compound. Eighty‐eight per cent of radioactivity in urine is ethyl acetate extractable. The compounds of the ethyl acetate fraction, while distinct from 5U‐13437 on thin‐layer chromatography, remain unidentified. While 25 per cent of the administered radioactivity appeared in the stool, only about 3 per cent of this is 5U‐13437. The remaining radioactivity in stool probably represents metabolites excreted in bile.
Biochemieal, endocrine, and other indices during quinestrol therapy
Authors: Danowski T. S. , Kenny F. M. , Wilson H. R. , Sabeh G. , Sunder J. H. , Corredor D. G.
Published: January 2016

Quinestrol (ethinylestradiol‐3‐cyclopentyl ether), a synthetic estrogenic compound with prolonged duration of action, was administered for 6 months to women at a dosage of 0.025 mg. twice daily with a minimum 01 untoward clinical efJects. This dosage produced a number of efJects indicative of or compatible with estrogenic activity, including increased cornification of menopausal vaginal epithelium, a slight rise in serum protein‐bound iodine and creatine, and a decrease in beta lipoprotein cholesterol. Unexplained slight decreases in serum acid phosphatase activity and in cephalin flocculation were recorded, and blood lymphocytes increased transiently. Also during quinestrol therapy ACTH produced a greater increase in plasma ll‐hydroxycorticosteroids at the 30 minute point of the stimulation test, but the values in the 1, 2, and 3 hour plasma sampies were comparable in the control and intratherapy studies. Urinary ll‐desoxycortisol metabolites diminished, but the change was very slight. Glucose‐induced hypophosphatemia was accentuated in nondiabetic individuals, glucose tolerance appeared to improve in patients with diabetes, and in both groups the increases in serum insulin evoked by a glucose load were less during quinestrol therapy. Other indices remained unchanged, including blood and serum solutes, a variety of serum enzymes, hematologic and hepatic indices, plasma ll‐hydroxycorticosteroids, urinary 17‐ketosteroids and Porter‐Silber chromogens, plasma ll‐hydroxycorticosteroid responses to intravenous ACTH (the 30 minute exception has been cited) and to pyrogen, and urinary pressor activity, gonadotrop ins, and total estrogens. The efJects of ll‐beta hydroxylase blockade by metyrapone on urinary steroids were not altered by 6 months of quinestrol therapy.
The effect of MK‐185 on some aspects of uric acid metabolism
Authors: Jain Adesh , Ryan Jerome R. , Hague David , Hague David
Published: January 2016

Following oral administration of MK‐185 to 10 patients with types III, IV, or V hyperlipoproteinemia at doses of 10, 15, and 20 mg. per kilogram per day for a period of 4 weeks at each of the 3 dose levels, the serum uric acid decreased significantly with the progression of dosage. A specific metabolic study designed to evaluate the mechanism of this hypouricemic action showed that MK‐185, 20 mg. per kilogram per day for 3 days, produced a gradually increasing (p < 0.05) uricosuria in the 3 patients studied. The results of the other drugs used in metabolic study, namely, probenecid, allopurinol, and clofibrate are discussed in relation to those of MK‐185.
Long‐term monitoring during clofibrate therapy
Authors: Vester J. W. , Sunder J. H. , Aarons J. H. , Danowski T. S.
Published: January 2016

Clofibrate, 2.0 Gm. per day, was taken by 22 patients with diabetes mellitus for 2 to 5 years. Bromsulphalein retention of unknown origin developed in one patient and muscle pain unrelated to the drug appeared in another. Mean serum total cholesterol and triglycerides and their alpha and beta lipoprotein fractions, within the nonelevated range prior to therapy, remained at or below this range during treatment. Most of the other clinical and laboratory indices remained unchanged during the second, third, fourth, and fifth years of therapy. These included body weight, blood pressure, pulse rate, and serum sodium, potassium, total protein, albumin, calcium, inorganic phosphorus, creatinine, malic acid dehydrogenase, creatine phosphokinase, alkaline and acid phosphatase, serum glutamic pyruvic transaminase, and total bilirubin. Also, the hemoglobin, hematocrit, the erythrocyte and platelet count in peripheral blood, and the prothrombin time did not change. Nonsustained changes, i.e., present in one or 2 of the 2 to 5 years of treatment, were observed in a minority of the indices. These comprised serum non esterified fatty acids, carbon dioxide, chloride, globulin, lactic acid dehydrogenase, ado lase, serum glutamic oxalacetic transaminase, and thymol turbidity, urine creatinine and pressor activity, and bleeding and coagulation time. Increases in the serum uric acid in the group with adult‐onset diabetes and in the serum creatine in those with iuvenile type of diabetes were more persistent and could well be concomitants of aging and maturation. The lesser hyperglycemia observed during oral glucose tolerance tests in the juvenile group may also represent the amelioration of the diabetes as a part of the natural course of the disorder
Comparative effects of smoking marihuana or placebo on human motor and mental performance
Authors: Manno Joseph E. , Kiplinger Glenn F. , Haine Susan E. , Bennett Ivan F. , Forney Robert B.
Published: January 2016

Motor and mental performance was tested after smoking a placebo cigarette and after smoking a marihuana cigarette calibrated to deliver 5 mg. of delta‐9‐tetrahydrocannabinol. A significant decrement in all motor performance tests and in five of nine mental performance tests was observed after the marihuana cigarette. We were not able to detect any cannabinols in the blood or urine of subjects who smoked the marihuana.
Treatment of Parkinson's disease with levodopa and Ro 4‐4602
Authors: Barbeau André , Joffroy Lise Gillo , Mars Harold
Published: January 2016

The authors report their experience over a 14 month period in the treatment of 20 parkinsonian patients with the combination of levodopa and an inhibitor of peripheral dopa decarboxylase, Ro 4‐4602. The results obtained are comparable to those previously reported from the same center with levodopa alone and, in fact, appear to offer distinct advantages. The average daily dose of levodopa required for satisfactory results (after 3 months of treatment) was reduced from 4.S Gm. of levodopa alone to SOD mg. on the combination. The maximum daily dose of Ro 4‐4602 recommended to obtain this effect is 200 mg.
Dose response to codeine in patients with chronic cough
Authors: Sevelius Hilli , McCoy John F. , Colmore John P.
Published: January 2016

A dose‐response curve for oral codeine phosphate was established in 12 adult male patients with chronic cough. The response measured was the per cent reduction in cough counts following 4 doses of codeine as compared to placebo. The curve of response on the log of the dose used was found to be linear, and a single oral dose of 15 to 20 mg. of codeine seemed to be optimum under the conditions of this study. No correlation between the objective cough counts and the patient's subiective evaluation of the drugs was established.
Effects of large intramuscular doses of atropine on cardiac rhythm
Authors: Hayes Arthur H. , Copelan Herbert W. , Ketchum James S.
Published: January 2016

Atropine sulfate, 175 µg per kilogram, was administered intramuscularly to 6 healthy, adult male volunteers. A continuous electrocardiogram revealed an initial slight increase in sinus rate followed approximately 5 minutes after drug by simple atrioventricular dissociation. This was usually complete with synchronization of atrial and ventricular rates. No significant cardiovascular symptoms were noted.
Treatment of benign prostatic hypertrophy with medrogestone
Authors: Rangno Robert E. , McLeod Peter J. , Ruedy John , Ogilvie R. I.
Published: January 2016

Twenty‐four patients with established benign prostaue hypertrophy (BPH) uiere treated at random in a double‐blind manner with one of two drug schedules: medrogestone [or 24 weeks followed by placebo for 24 weeks, or the reoerse order. Analysis of effects of treatment was made by assessment of frequency, nocturia, hesitancy, intermittency, [orce and size of urine stream, digital grading of prostete size, residual urine measured isotopically, cystoscopy with prostate needle biopeies, and cystogram. Medrogestone produced a significant reduction in the seoeriti] of BPH.
Effects of placebo and flurazepam on sleep patterns in insomniac subjeets
Authors: Kaies Joyce , Kaies Anthony , Bixler Edward O. , Slye Elaine S.
Published: January 2016

In 12 insomniac subiects placebo had no significant effects on sleep induction, sleep maintenance, or sleep stages, while flurazepam 30 mg. produced clear‐cut decreases in sleep latency, wake time after sleep onset, total wake time, and number of wakes. The decreases were maintained throughout the drug administration period as well as on the first several withdrawal nights, indicating a carry‐over effect. There was agreement between the subjectioe estimates of sleep and the electroencephalogram (EEG) data in terms of both improvement in sleep induction and sleep maintenance with flurazepam and in the lack of effects with placebo. Flurazepam produced either no change or a slight decrease in the percentage of rapid eye movement (REM) sleep, There were no increases above base line following withdrawal. Stages 3 and 4 sleep decreased considerably with drug administration, this decrease being maintained during the drug withdrawal period.
Antibiotic tolerance and serum levels after intravenous administration of multiple large doses of lincomycin
Authors: Novak Ervin , Vitti T. G. , Panzer J. D. , Schlagel C. , Hearron M. S.
Published: January 2016

High doses of lincomycin ranging from 4,800 mg. to 8,400 mg. daily for 7 days were infused into 32 healthy volunteers on a 4 times a day basis in saline infusion volumes of 250 ml. given over a 120 minute period. Placebo groups given saline only in a similar manner were used as controls. No gross abnormalities in vital signs occurred at any time, and no statistically significant differences occurred between the drug and placebo groups. The laboratory tests were always within normal limits; there were no shifts or drug‐related findings. All electrocardiograms and audiometric tracings were normal, and there were no changes from prestudy readings. Side effects were minor and few. Serum levels averaged from approximately 24 to 37 flg per milliliter (peaks) and 10 to 12 μg per milliliter (nadir) for the low‐to high‐dose drug groups. The equilibrium state was reached early in the schedule with little or no drug accumulation after 26 doses. The elimination rate constant K averaged 0.0987 how‐1 with a corresponding average half‐life (T1/2) of 7.16 hours.
The intravenous toxicity and clearance of bupivacaine in man
Authors: Mather L. E. , Long G. J. , Thomas J.
Published: January 2016

Bupivacaine hydrochloride has been administered to volunteers at a dose of 1.35 mg. per kilogram by intravenous infusion. No significant changes in blood pressure, electrocardiogram, or heart rate were observed. Subjective signs of toxicity were mild. Plasma levels were determined for 8 hours following injection and these indicated that, after an initial phaw of rapid changes in plasma levels due to distribution, bupivacaine has a half‐life of approximately 21,2 hours. The highest plasma level recorded was 22.5 Pg per milliliter in arterial blood. Less than 10 per cent of the dose administered was excreted unchanged in the urine and urinary excretion was complete within 24 hours. The maior route of clearance is through metabolism. Bupivacaine is more than 90 per cent bound to plasma proteins at concentrations of 1 Pg per milliliter. Hence systemic toxicity of bupivacaine is lower in man than might be predicted from acute toxicity studies in animals. The rate of clearance of bupivacaine is approximately the same as lignocaine and mepivacaine but it has a much longer duration of action. Consequently plasma levels of bupivacaine do not rise to the same extent as with lignocaine or mepivacaine during prolonged analgesia.
The pharmacodynamics and biotransformation of pentaerythritol trinitrate in man
Authors: Davidson I. W. F. , Rollins F. O. , DiCarlo F. J. , Miller H. S.
Published: January 2016

Pentaerythritol trinitrate (PE‐trinitrate), a metabolite in man of pentaerythritol tetranitrate (PETN), has been found to possess considerably greater vasodilator activity than its parent drug. Pharmacokinetics and metabolism of PE‐trinitrate were studied after single sublingual and oral doses of 14C‐PE‐trinitrate given in clinical dosage form. Drug absorption rate constants obtained from blood concentrations of drug radioactivity showed that absorption was rapid with both modes of administration. Metabolism and elimination after both dosage modes were nearly identical. The drug was not found in urine or in blood except within a few minutes of administration. Urinary elimination of metabolites accounted for 92 per cent of the dose, with less than 2 per cent recovered in fecal excretion as pentaerythritol (PE). The principal urinary metabolites were PE (30 per cent) and PE‐mononitrate (69 per cent). Excretion of these metabolites was first order with half‐times of elimination of 10.5 and 7.3 hours, respectively. From a comparison of the pharmacokinetics and biotransformation of PE‐trinitrate with those previously observed for PETN in similar experimental conditions, it is suggested that the rates of absorption and intracellular accumulation at tissue sites of action are primary determinants of the pharmacological activity and relative potencies of the organic nitrates.
Effects of lithium on adrenergic function in man
Authors: Fann William E. , Davis John M. , Janowsky David S. , Cavanaugh John H. , Kaufmann John S. , Griffith John D. , Oates John A.
Published: January 2016

Lithium is an effective agent in the treatment of mania. Since an abnormality of biogenic amines has been postulated to be a causative factor in mania and depression and since lithium has been found to alter biogenic amines in many animal systems, the effects of lithium on adrenergic function in man was investigated. The blood pressure response to infused norepinephrine (NE) and tyramine was investigated in 8 hypomanic patients who were studied during a control period and after 7 to 10 days of lithium treatment. Lithium decreased the pressor effect produced by NE by 22 ± 0.6 per cent. Lithium failed to alter the pressor effect to infused tyramine. Lithium failed to alter platelet serotonin content. Lithium decreased the pressor response to infused NE in man.
Assessment of the biologic availability of tetracycline products in man
Authors: Barr William H. , Gerbracht Louise M. , Letcher Kenneth , Plaut Martin , Strahl Nathan
Published: January 2016

Significant differences were found in the absorption characteristics of three commercial tetracycline preparations. These differences were observed after both single‐dose and multiple‐dose administration. The relative amount of tetracycline absorbed (biological availability) but not the relative rate of absorption was greater for a standard preparation than for two other similar preparations. These differences provide a means to evaluate general methods to assess differences in the biologic availability of tetracycline products. It was e0tablished that the pharmacokinetic parameters obtained from single‐dose urinary excretion studies would reflect the differences observed in the areas under the serum curve of single‐dose studies and the mean serum concentrations in multiple‐dose studies. It is suggested that single‐dose studies with urine collections for 48 to 72 hours are adequate to assess differences between brands of tetracycline, evaluate formulation and physiologic variables affecting biologic. Vailability, and develop correlations with in vitro dissolution rates. From these results on a very small sample of commercial preparations, it is considered possible that there may be sufficient differences between products which, in some clinical situations, may result in therapeutic failures.
Limited capacity for salicyl phenolic glucuronide formation and its effect on the kinetics of salicylate elimination in man
Authors: Levy Gerhard , Tsuchiya Tamehiro , Amsel Lewis P.
Published: January 2016

Evidence is presented which shows that man has a limited capacity to form salicyl phenolic glucuronide from salicylic acid and that this process is describable by Michaelis‐Menten kinetics in the therapeutic dose range. The discovery of this saturation phenomenon, together with the previous characterization of the capacity‐limited kinetics of salicylurate formation (i.e., conjugation of salicylate with glycine), has led to the elaboration of the total kinetics of salicylate elimination in man. Theoretic maximum formation rate and in vivo apparent Michaelis constants for phenolic glucuronide and salicylurate formation, apparent first‐order rate constants for the formation of salicyl acyl glucuronide and gentisate, and the apparent first‐order rate constant for salicylate excretion (which is highly urine pH dependent) have been determined in healthy adult volunteers. Excretion (or elimination) rate constants of metabolites were estimated by direct administration of these metabolites, by synthesis blocking methods, or by curve‐fitting procedures. Digital computer simulations based on these comtants are in excellent agreement with experimental data over more than a fifteenfold dose range. Thm, almost 100 years after the introduction of salicylic acid to medicine, its effective pharmacokinetic characterization in man has been accomplished.
Use of stable isotopes in pharmacology‐clinical pharmacology
Authors: Knapp Daniel R. , Gaffney Thomas E.
Published: January 2016

The greatest advantages offered by stable isotopes over their radioactive counterparts is the absence of problems associated with radiation. Absence of possible radiation damage to living systems is very important in human studies, especially in the case of children or pregnant women. Absence of radiation hazard also makes the synthesis and handling of stable isotope‐labeled compounds much simpler.
XV. The process of prognostic stratification (Part I)
Authors: Feinstein Alvan R.
Published: January 2016

As noted in the previous paper of this series, 6 the purposes of prognostic stratification are to improve the efficiency of research design and data analysis, to enh: mce confidence in prediction, and to demarcate phenomena for scientific explication. Without such stratifications, erroneous or distorted results will continue to be produced when conventional statistical “models” are applied to the data of medical cohorts. The statistical “models” are based on the analysis of response to the maneuver of a single experiment, but in most medical forms of cohort research, the investigator observes the results of a double experiment 2 : a maneuver arranged by man is imposed on the response to a previous maneuver arranged in essence by nature.
Flucloxacillin: A new semisynthetic isoxazolyl penicillin
Authors: Bodey Gerald P. , Vallejos Carlos , Stewart Dorothy
Published: January 2016

Flucloxacillin is a new isoxazolyl penicillin active in vitro against gram‐positive cocci. Of 190 clinical isolates of Group A ß‐hemolytic streptococci, pneumococci and both penicillin G‐sensitive and penicillin G‐resistant Staphylococcus aureus, were inhibited by 0.78 µg per milliliter or less of isoxazolyl penicillin. Mean peak serum levels in normal volunteers following the oral administration of 250 mg. and 500 mg. of flucloxacillin were 5.7 and 11.4 µg per milliliter, respectively. The mean peak serum level was 11.8 µg per milliliter following the intramuscular administration of 250 mg. of flucloxacillin. Serum levels with flucloxacillin wMe lower than those obtained with dicloxacillin, but greater than those with cloxacillin. Flucloxacillin was 92.6 per cent bound to human serum proteins and provided higher serum levels of free drug than the other isoxazolyl penicillins.