bluuebunny/crossref_metadata_2025 huggingface dataset:
Human pharmacology and clinical evaluation of an oral carbenicillin preparation
Authors: Bran Jose L. , Karl Diane M. , Kaye Donald
Published: January 2016

Oral carbenicillin was administered to 6 healthy subjects and to 28 patients with urinary tract infection. Following a 1 Gm. dose, the mean peak serum concentration was 10.4 µg per milliliter. Urine concentrations ranged from 640 to 2,560 µg per milliliter during the first 6 hours. Probenecid increased the mean peak serum level to 23.7 µg per milliliter. Symptoms disappeared during the first 72 hours and the infecting organism was eliminated from all. Four weeks after discontinuing therapy 16 patients (57 per cent) were abacteriuric and 4 relapsed within 4 weeks, while 8 became reinfected with a new organism. Because of severe nausea and vomiting after ingestion of the drug, 3 patients were dropped from the study.
Oxypertine and thiothixene in newly admitted schizophrenic patients; A further search for specific indications of antipsychotic drugs
Authors: Hollister Leo E. , Overall John E. , Katz George , Higginbotham Warren E. , Kimbell Isham
Published: January 2016

Seventy‐one newly admitted schizophrenic patients were treated with thiothixene or oxypertine. On the basis of previous, separate uncontrolled studies of these drugs, we had postulated that thiothixene would be more effective in paranoid and oxypertine more effective in nonparanoid patients. Results from the present controlled study confirmed these hypotheses, suggesting that various categories of schizophrenic patients may respond differently to drugs. Oxypertine seemed to have a profile of action somewhat different from that of other types of antipsychotic drugs in that it was highly effective for depressed schizophrenic patients.
Carbamazepine‐induced acceleration of diphenylhydantoin and warfarin metabolism in man
Authors: Hansen J. Mølholm , Siersbæk-Nielsen K. , Skovsted L.
Published: January 2016

Diphenylhydantoin half‐life was determined in 5 patients before and during treatment with carbamazepine. It caused a significant decrease in the diphenylhydantoin half‐life from 10.6 hours to 6.4 hours. Seven patients who for a period had been given diphenylhydantoin were also started on carbamazepine. This resulted in a fall in serum diphenylhydantoin levels in 3 of the patients. Alterations in warfarin half‐life, serum warfarin, and plasma prothrombin‐proconvertin concentration during carbamazepine treatment were compatible with a stimulation of warfarin metabolism. The effect of carbamazepine on diphenylhydantoin and warfarin metabolism is probably explained by an induction of the drug‐metabolizing enzyme system in the liver.
IX. How do we measure “safety and efficacy“?
Authors: Feinstein Alvan R.
Published: January 2016

The phrase safety and efficacy has become an accepted pharmacologic slogan. Whenever journal editors, sanctioning committees, advertising managers, legislative inquirers, or practicing physicians engage in the evaluation of drugs, this slogan usually serves as a label for the evidence to be presented and for the goal to be attained.
Propranolol
Authors: Corbascio Aldo N.
Published: January 2016

I would like to file a brief in favor of the propranolol (Inderal)‐treated patient who may develop an acute asthmatic attack and anaphylactic shock upon exposure to therapeutic or natural allergens (drugs, pollens, etc.). The number of patients receiving propranolol is already considerable and bound to increase as new indications for beta adrenergic blockade are found (angina pectoris, hypertension, psychosis, etc.); hence, such a brief may be more than a therapeutic curiosity. It is indeed conceivable that in the not too distant future medical practitioners will be faced with a large population of epinephrine‐resistant patients whose response to catecholamines is likely to be absent or poor.
Monoamine precursors in the treatment of depression
Authors: Carroll Bernard J.
Published: January 2016

The current biological theories of depression are united in postulating a role for brain monoamine deficiency in this group of disorders. The relative importance of the various amines, dopamine (DA), norepinephrine ( NE ), serotonin (5–HT ) and tryptamine, is still unsettled, and several versions of the monoamine deficit theory of depression have been put forward with emphasis on one or other of these compounds.5, 56, 94, 128
Technique of controlled drug assay in hypertension.; V. Comparison of hydrochlorothiazide with a new quinethazone diuretic, metolazone
Authors: Pilewski Robert M. , Scheib Eileen T. , Misage John R. , Kessler Edward , Krifcher Emanuel , Shapiro Alvin P.
Published: January 2016

The effects of two chemically different diuretic agents, hydrochlorothiazide and metolazone, a new quinethazone derivative, were studied in a group of 21 hypertensive patients. A change‐over, double‐blind design was used for 50 mg. of hydrochlorothiazide, 2.5 mg. of metolazone, and 5.0 mg. of metolazone. Body weight, blood pressure, blood urea nitrogen, electrolytes, uric acid, and blood sugar one hour after carbohydrate load were the measurements used to examine the efficacy of the drugs. Blood counts and serum glutamic oxalacetic transaminase also were monitored. The results showed no differences among the three treatments, but all showed the same significant response when compared to placebo for all measurements, except for blood counts, serum glutamic oxalacetic transaminase, and blood sugar.
XI. Sources of ‘chronology bias’ in cohort statistics
Authors: Feinstein Alvan R.
Published: January 2016

In the previous paper of this series,13 a cohort was defined as a group of people who are followed forward in time to observe the effects of a maneuver to which they have been exposed. The results are usually expressed statistically as a ratio, or rate, in which the denominator of the cohort contains the number of people exposed to the maneuver, and the numerator contains the number of those people who later developed a particular target event.
Lung tissue and serum levels of methacycline
Authors: Timmes Joseph J. , Demos Nicholas J. , Chong Sun II
Published: January 2016

Methacycline serum levels and lung tissue concentrations were assayed, using samples taken from 15 patients undergoing lobectomy or pneumonectomy. One group of patients received 300 mg. of methacycline 20 hours before surgery and an additional 300 mg. 8 hours before surgery; a second group received a single 300 mg. capsule 8 hours before intervention. Therapeutic levels were achieved in both serum and lung tissue, with the average concentration in tissue being significantly higher than in blood in the first group. In the group receiving two doses of the drug, methacycline levels in serum were double those with the one dose, but rose to a lesser extent in the lung.
Endocrine and metabolic indices during administration of a lipophilic bis‐phenol, probucol
Authors: Danowski T. S. , Vester J. W. , Sunder J. H. , Gonzalez A. R. , Khurana R. C. , Jung Y.
Published: January 2016

The administration of a cholesterol‐lowering drug, 4,4‐(isopropylidenedithio) bis(2,6‐di‐tbutylphenol), probucol (DH‐581) at a dosage of 1,000 mg. per day for 6 months, usually did not affect other serum solutes, serum enzymes, hepatic indices, tests of thyroid function, plasma 11(OH)‐corticosferoids (including diurnal variation, dexamethasone suppression, and ACTH stimulation effects), urinary creatinine, creatinine clearance, 17‐ketosteroids, Porter‐Silber chromogens, 11‐desoxycortisol metabolites, the responses of urinary steroids to metyrapone, glucose tolerance tests, insulin and growth hormone responses to oral carbohydrate, hematologic indices including eosinophil counts in peripheral blood, or electrocardiographic tracings. Serum total cholesterol decreased in the ma;ority of the patients, but serum total triglycerides were usually unaffected. Minor changes in serum CO2, aldolase, and growth hormone were recorded in some of the treatment periods, but final values were still within the normal range.
Clinical pharmacology of l‐β‐D‐arabinofuranosyl cytosine
Authors: Ho Dah Hsi Wang , III Emil Frei
Published: January 2016

Pharmacologic studies were performed in man with tritiated 1‐β‐D‐arabinofuranosyl cytosine (ara‐C). Most of the plasma and urine radioactivity was in 1‐f3‐D‐arabinofuranosyl uracil (ara‐U), and all of the radioactivity could be accounted for as ara‐C and ara‐U. The plasma disapperance curve of ara‐C when plotted on a semilog scale was biphasic with an initial fast phase (mean half‐time 12 minutes) and a slower second phase (mean half‐time 111 minutes). There was a linear correlation between the dose and plasma concentration of ara‐C. The initial plasma ara‐U to ara‐C ratio was lower at the high doses, suggesting saturation of ara‐C deaminase activity. Eighty per cent of the radioactivity was recovered in the urine by 24 hours, 8 per cent as ara‐C, and 72 per cent as ara‐U. Prior treatment with ara‐C had no effect on the pharmacology of ara‐C. The plasma ara‐C deaminase activity was very low. The total amount in plasma was less than one per cent of that present in the liver. The ara‐C deaminase activity of red blood cells (RBC) of normal subjects was 7 per cent that of the liver, and the RBC of solid tumor patients contained significantly higher enzyme activity. Following a loading dose, ara‐C was given by constant intravenous infUSion. This resulted in constant plasma ara‐C levels which were dose related. At steady state the cerebrospinal fluid (CSF) to plasma ratio of ara‐C was 0.4. Intrathecal injection of ara‐C resulted in high initial CSF levels and an exponential decrease with a half‐time of 2 hours. This very long half‐time as compared to the plasma is a function of the very low ara‐C deaminase activity in CSF and brain.
Remission induction of adult acute leukemia with combination chemotherapy
Authors: Rodriguez Victorio , Gutterman Jordan U. , Scotti Michael J.
Published: January 2016

Intensive chemotherapy was administered to 20 adults with acute leukemia for remission induction. A combination of 6‐mercaptopurine, methotrexate, vincristine, and predni50ne was used in 8 patients. Arabinosyl cytosine and cyclophosphamide in combination with or without vincristine and prednisone was used in 12 patients. Six of 8 patients with acute myelogenous leukemia and 5 of 8 patients with acute nonmyelogenous leukemia who received adequate therapy responded. The response rate for all patients including those who died without the benefit of adequate therapy was 60 per cent. Nonfatal hemorrhage occurred commonly during therapy. Gram‐negative infections were the most common complications causing death in the patients who did not achieve remission. Supportive care in the form of transfusion of platelets, packed red blood cells and prompt effective antibiotic therapy wm essential for the success of antileukemic therapy. These modalities of therapy have resulted in an improvement of the remission rate and survival in patients with acute leukemia at Brooke General Hospital.
Treatment of arrhythmias with pindolol
Authors: Aronow Wilbert S. , Uyeyama Ronald R.
Published: January 2016

Pindolol, a beta adrenergic blocking agent, was given intravenously to 30 patients with cardiac arrhythmias. A rapid ventricular rate was slowed in 7 patients with atrial fibrillation, with later spontaneous conversion to sinus rhythm in 2 patients. A rapid ventricular rate was slowed in 6 of 7 patients with atrial flutter. In 3 of these 7 patients, the rhythm converted to atrial fibrillation. In 2 of these 3 patients, the rhythm later converted to sinus rhythm, probably due to drug in one patient. One patient with atrial tachycardia became hypotensive after a second dose of pindolol. Atrioventricular junctional tachycardia was converted to sinus rhythm in 2 patients, one with digitalis toxicity. Sinus tachycardia was converted to sinus rhythm in 3 patients. Paroxysmal repetitive ventricular tachycardia due to digitalis toxicity was abolished in one patient. Pindolol abolished or greatly mduced frequent premature ventricular beats in 10 patients, 6 with definite or possible digitalis toxicity. Pindolol had no effect on frequent ventricular premature beats in 4 patients, none receiving digitalis. Pindolol abolished frequent atrial premature beats in 3 patients, one with definite and one with possible digitalis toxicity. The pindolol was useful in the treatment of cardiac arrhythmias in 24 of these 30 patients.
Interaction of chloral hydrate and ethanol in man: II. Hemodynamics and performance
Authors: Sellers Edward M. , Carr Gordon , Bernstein Jerrold G. , Sellers Sirje , Koch‐Weser Jan
Published: January 2016

Changes in heart rate, arterial pressure, and skin temperature and in performance tests were studied in 5 male volunteers after ingestion of placebo, ethanol, chloral hydrate, both drugs, or ethanol after 7 days of chloral hydrate pretreatment. Ethanol ingestion was always associated with an increase in heart rate at 0.5 and 1.0 hours; this tachycardia was enhanced by pretreatment with chloral hydrate. Chloral hydrate followed by ethanol also caused greater increases in skin temperatures than other treatments. In one subiect this sequence led to a marked vasodilation reaction characterized by flushing, palpitations, and headache. At the peak of the reaction the blood acetaldehyde level was only half that after ethanol alone which had caused no reaction. The ability to perform a complex motor task was poorest when chloral hydrate was taken with ethanol. Auditory vigilance was significantly impaired by ethanol; concurrent chloral hydrate treatment further decreased performance. The “knock‐out” drop effect was not seen.
Blind comparison of once‐daily and twice‐daily dosage schedules in a methadone program
Authors: Goldstein Avram
Published: January 2016

In a large methadone program, 120 patients were randomly assigned to two groups at the time of admission. One received the daily methadone dose in two equal portions, morning and evening. The other received the whole daily dose in the morning and a placebo in the evening. The experiment continued for 3 months. Results were evaluated periodically by a number of criteria such as symptom complaints, heroin use, and survivorship in the program. The results in the two groups did not differ at all except in a few respects, in which the advantage lay with the once‐daily schedule. There is no reason, therefore, to administer methadone more than once daily.
Digitoxin kinetics in patients with impaired renal function
Authors: Rasmussen Knut , Jervell Jak , Storstein Liv , Gjerdrum Kjell
Published: January 2016

Serum digitoxin levels were recorded during maintenance therapy, absorption‐distribution, and elimination of digitoxin in patients with poor renal function. The analysis was carried out with a modified Rb86 method and the results were compared with results in subjects with normal renal function. During both absorption and maintenance therapy serum digitoxin levels of the patients with poor renal function were significantly lower than those of the control group. However, most of these differences could be ascribed to different concentrations of serum proteins in the two populations. When this factor was corrected for, most of the differences disappeared and became non‐significant. The elimination of digitoxin was not significantly different in the two groups. The absence of impaired digitoxin elimination during uremia indicates the development of compensatory mechanisms for the elimination of active glycosides. Although the elimination of digitoxin may be normal in uremia, the myocardial sensitivity to the drug may be changed. Digitoxin is probably the glycoside of choice in uremia, since other glycosides are more dependant on renal excretion for elimination.
Cerebral dehydration action of glycerol; I. Historical aspects with emphasis on the toxicity and intravenous administration
Authors: Tourtellotte Wallace W. , Reinglass James L. , Newkirk Tracy A.
Published: January 2016

Oral glycerol (1 Gm. per kilogram every 6 hours) has a dehydration effect on the central nervous system. Prolonged continuous administration of glycerol does not produce marked alteration of fluid and electrolytes. It is almost totally excluded from the brain, which excludes the problem of rebound overhydration. It has significant nutritional value nad none of the side effects of steroids. The major toxic effects of glycerol (hemolysis, hemoglobinuria, and renal failure) can be prevented and are a function of concentration and route of administration. Glycerol does not hemolyze red blood cells when it is prepared with isotonic saline in concentrations up to 40 per cent. Human intravenous glycerol has been used safely on a number of occasions with plasma levels reaching 10 mmoles per liter to measure turnover rates in adults and infants. The same oral glycerol dose is effective in lowering ocular tension and cerebrospinal fluid pressure. The plasma concentration response curve for normal human eyes has been previously determined. Intraocular pressure begins to fall when plasma glycerol is approximately 10 mmoles per liter. It is proposed that continuous intravenous glycerol be considered for treatment of cerebral edema in patients not able to take oral glycerol.
The doctor‐patient relationship and drug effect
Authors: Freund Jack , Krupp George , Goodenough Donald , Preston Lester W.
Published: January 2016

The effects of an anorexigenic agent (dextroamphetamine) and a placebo on weight loss in 64 obese female patients were evaluated over a period of 4 weeks. Half of the patients were field dependent and half were field independent. This psychological categorization of the patients refers to individual differences in analytic functioning in perception that can be objectively evaluated and appears to parallel personality trait differences that have been noted between placebo reactors and nonreactors. An investigational drug or known drug treatment condition was created. Data from the study showed that: (1) Patients on dextroamphetamine lost more weight than patients on placebo. (2) Patients who were treated under known drug conditions lost more weight during the first week but not during the full 4 weeks. (3) Field‐dependent patients under known drug conditions did not lose any more weight than field‐independent patients under the same conditions. (4) There was considerable variation in the weight loss achieved by the patients of the same physician.
On the metabolism of propantheline in man
Authors: Beermann Björn , Hellström Kjell , Rosén Anders
Published: January 2016

Propantheline, 60 mg., labeled with 14C in its xanthene carboxylic moiety, was given orally or intrajejunally to 5 healthy subjects. The absorption of label did not reflect the uptake of the intact drug. Samples of intestinal aspirates obtained a few minutes after administration of the test solution contained label with chromatographic properties the same as those of the free xanthene carboxylic acid. Following incubations in duodenal bile, the 14C‐propantheline showed marked modification. According to the autoradiogram of the thin‐layer chromatogram, most of the label was localized in two spots. The ma;or one had an Rf value identical to that of xanthene carboxylic acid, while the other one was unidentified. The modification of propantheline in the incubates was more pronounced in alkaline solutions but decreased markedly when the drug was incubated with samples of duodenal aspirates that had been brought to boil and then cooled. The absorption of intact drug after oral administration was estimated to be less than 50 per cent.
The effect of aspirin on serum indomethacin
Authors: David Champion G. , Paulus Harold E. , Mongan Edward , Okun Ronald , Pearson Carl M. , Sarkissian Edmund
Published: January 2016

Two studies were conducted to determine the effect of aspirin administration on serum concentrations of indomethacin in human subjects. Indomethacin was determined specifically free of its metabolites by spectrofluorometry following heptane extraction. In Study 1, mean serum indomethacin levels and estimated mean plasma half‐times of elimination after the administration of 50 mg. oral doses to 8 normal volunteers were not significantly changed by concurrent administration of aspirin (3.6 Gm. per day) and indomethacin. Following a fasting dose, mean half‐time without aspirin was 1.82 hours and that with aspirin was 2.24 hours (0.1 > P > 0.05). In Study 2, serum concentration of indomethacin were also unaffected by aspirin administration in patients with arthritis. Thus, claims based on 14C‐indomethacin radioactivity studies6,20 that an aspirin‐indomethacin interaction is mediated by alterations in serum concentration of indomethacin were not supported.
Effects of d‐amphetamine on quantitative measures of motor performance
Authors: Domino Edward F. , Albers James W. , Potvin Alfred R. , Repa Brian S. , TourtelloHe Wallace W.
Published: January 2016

The effects of 10 mg. of d‐amphetamine and a placebo of similar appearance were determined by means of a battery of quantitative objective measures of motor performance in normal volunteers. The medication was administered in a random, double‐blind, crossover design on two occasions one week apart. No significant differences between the effects of the medications on resting and sustention tremor or precision hole steadiness were found. However, several compematory tracking tasks which required sustained concentration and motor coordination were significantly improved with d‐amphetamine.
The significance of advisory‐review committees during clinical investigations of drugs
Authors: McCawley Elton L. , Hart Harold C. , Crowe Austin W.
Published: January 2016

During the two years experience of the advisory‐review committee, members of our staff and the advisory‐review committee were defendants in one civil law suit and have been threatened with two others concerning the right to be given an investigational drug and for the death of one patient. Finally, the Bureau of Narcotics and Dangerous Drugs threatened to terminate the program. The review committee has so far been successful in shielding the investigator and the program continues.
Content analysis of speech samples to determine effect of lorazepam on anxiety
Authors: Gottschalk Louis A. , Elliott Henry W. , Bates Daniel E.
Published: January 2016

A study is described illustrating the me, in neuropsychpharmacologic studies, of an objective measure of psychological states, such as anxiety, through the content analysis of 5 minute samples of speech. In this report, the psychoactive drug tested was a new benzodiazepine, lorazepam. It was found to exert significant antianxiety effects (p <0.05) as measured by the content analysis method when administered parenterally at a dosage of 5.0 mg. compared to anxiety changes occurring after no drug or 3.0 mg. of lorazepam. Interesting physiological changes in relation to drug dose and anxiety inhibition were followed and are also reported.
Effect of triamterene on nucleic acid synthesis
Authors: Chang Jae C. , Hall Thomas C.
Published: January 2016

The Division of Oncology and Department of Medicine, University of Rochester School of Medicine and Dentistry, and Strong Memorial Hospital, Rochester, N. Y.
Pharmacokinetics and metabolism of diphenoxylate in man
Authors: Karim A. , Ranney R. E. , Evensen K. L. , Clark M. L.
Published: January 2016

The absorption, excretion, and biotransformation of 14C‐diphenoxylate hydrochloride (5 mg. containing 20.2 µc of 14C) when administered orally in ethanolic solution and without the presence of atropine sulfate was studied in 3 men. The mean urinary and fecal excretion of the total label in a 96 hour period was 13.65 ± 1.18 per cent and 49.20 ± 2.24 per cent, respectively. Thin‐layer radiochromatographic analysis of the label in excreta indicated extensive biotransformation of the parent drug. In the urine, the maior metabolites were characterized as diphenoxylic acid and hydroxydiphenoxylic acid. These acids were present in both the free and coniugated fractions. Radioactivity in the plasma was associated largely with diphenoxylic acid and to a smaller extent with the unchanged drug. Pharmacokinetic analysis using a one‐compartment open model showed a rapid absorption (t½ = 19.7 ± 1.7 minutes; peak level at 2.0 hours) of diphenoxylate followed by its rapid elimination (t½ = 2.50 ± 0.34 hours). The plasma half‐life (t½ = 4.38 ± 1.04 hours) of diphenoxylic acid was higher than that of diphenoxylate.
Pharmacokinetic studies of minoxidil
Authors: Gottlieb Thomas B. , Thomas Richard C. , Chidsey Charles A.
Published: January 2016

The disposition of minoxidil, a new direct arterial vasodilator and potent antihypertensive, was studied in 7 hypertensive patients. Following oral administration of 14C‐labeled minoxidil, there was a rapid removal of the drug with a plasma half‐life of 4.2 hours. The radioactive label was recovered quantitatively in the urine, predominantly in the form of 3 metabolites. The major metabolite in the first 12 hours after giving the drug was a glucuronide conjugate. The other 2 metabolites have not been identified but appeared to be excreted predominantly after the first 12 hours, when minoxidil had been essentially cleared from the circulating blood. These observations suggest a dissociation between the drug in circulating blood and its pharmacologic activity. Since the prolonged hypotensive response to minoxidil cannot be attributed to slow removal, we suggest that it may be exerting a persistent effect on receptor sites.
The absorption and metabolism of dibromodulcitol in patients with advanced cancer
Authors: Belej M. A. , Troetel W. M. , Weiss A. J. , Stambaugh J. E. , Manthei R. W.
Published: January 2016

In patients with advanced cancer 14C‐Dibromodulcitol (DBD) was rapidly absorbed from the gastrointestinal tract, entered the systemic circulation within 15 minutes after administration, and reached a maximum blood level within one hour. Plasma half‐life of carbon‐14 compounds was 8 hours. The drug was readily hydrolyzed in the plasma to monobromodulcitol and various epoxides so that within 2 hours after administration, less than 5 per cent of the unchanged drug remained. 14C‐DBD compounds entered spinal, pleural, and ascitic fluids and reached a maximum concentration in 5 hours. Biopsy specimens indicated that DBD was present in both normal and malignant tissues. In autopsy specimens, radioactivity equivalent to 1 to 4 p.g of drug per gram of tissue was detectable for as long as 6 days after administration. Renal excretion was the only apparent route of elimination of 14C‐DBD, since neither expired and metabolites was rapid; 68 to 79 per cent of the administered radioactivity appeared in the urine within 48 hours. Chromatography of urine indicated the presence of unchanged DBD as well as 7 metabolic products.The metabolites tentatively identified are: monobromodulcitol; a diepoxy derivative, 1,2‐5,6‐dianhydrodulcitol; an epoxide, anhydrodulcitol; dulcitol; and bromide ion. Two products remain unidentified.
Cardiovascular effects of delta‐9‐tetrahydrocannabinol in man
Authors: Weiss James L. , Watanabe August M. , Lemberger Louis , Tamarkin Norman R. , Cardon Philippe V.
Published: January 2016

The effects of a pharmacologic dose of delta‐9‐tetrahydrocannabinol (Δ‐9‐THC) on the human circulatory system were investigated. Their relation to plasma drug levels, urinary catecholamine excretion, and psychic effects was observed. Δ‐9‐THC (0.3 mg. per kilogram) was administered orally to 8 male volunteers. Four subjects also received tracer amounts of C14‐Δ‐9‐THC. Recumbent and upright heart rate, recumbent mean arterial blood pressure, forearm blood flow, and calculated forearm conductance all increased significantly following drug administration. Significant shortening of ventricular pre‐ejection period and attenuation or abolition of reflex venoconstriction in response to a deep breath were also seen. Mean arterial pressure decreased transiently with head‐up tilt and was associated with presyncope in 7 subjects, although cardioacceleratory response and forearm arteriolar constriction remained intact. Plasma levels of C14Δ‐9‐THC and its metabolites were maximal at 3 hours. Gastrointestinal absorption was 95 per cent complete. Urinary excretion of free epinephrine was significantly higher during the 6 hour period following Δ‐9‐THC administration than during a similar control period. Free norepinephrine excretion was unchanged. Several of the cardiovascular effects seen appear to be consistent with increased sympathoadrenal activity. This suggests the possibility that augmented epinephrine secretion is in part responsible for these Circulatory changes.
Determination of bioavailability of diazepam in various formulations from steady state plasma concentration data
Authors: Berlin Anita , Siwers Bo , Agurell Stig , Hiort Åke , Sjöqvist Folke , Ström Sven
Published: January 2016

The plasma concentrations of diazepam (Valium, Roche Labs., Nutley, N. J.) and its maior metabolite, N‐desmethyldiazepam, after treatment with 5 mg. oral doses three times a day were investigated in 7 subfects. There was a twofold variation in the steady‐state concentrations between subiects. The plasma half‐lifes of diazepam varied between 26 and 53 hours. A crossover study with an evaluation of the bioavailability of 3 manufacturers' tablet products and a suspension of diazepam was included in the investigation. The tablets gave similar intraindividual plasma levels while the suspension showed lower values during steady state, thereby indicating incomplete absorption.
Discussion
Authors: Calabresi Paul
Published: January 2016

Dr. Ayd has given us an extremely lucid presentation, with impressive documentation, both from the literature and his personal experience. From several very important points, I have chosen to discuss three that have struck me as particularly cogent from the standpoint of motivation and reward.
The effect of guancydine on blood pressure, vascular reactivity, and norepinephrine uptake in essential hypertension
Authors: Russo Carlo , Mendlowitz Milton
Published: January 2016

Guancydine was administered to 10 patients for a period of 3 weeks to 6 months. The drug produced a decrease in both supine and standing blood pressures as well as in digital vascular reactivity but caused no change in tritiated norepinephrine uptake. Its action appears to be direct inhibition of vascular smooth muscle. Side effects were minimal and transitory.
Daunorubicin metabolism in acute nonlymphocytic leukemia
Authors: Huffman David H. , Benjamin Robert S. , Bachur Nicholas R.
Published: January 2016

The pharmacokinetic evaluation of daunorubicin and its principal human metabolites, daunorubicinol and two previously unidentified metabolites, has provided information concerning the in vivo metabolism of daunorubicin in patients with acute non lymphocytic leukemia. Daunorubicinol was the maior fluorescent material present in plasma and urine and was a significant metabolite in the tissues. For 8 patients, the mean plasma half‐lifes of daunorubicin and daunorubicinol were 18.5 ± 4.86 hours S.D. and 26.7 ± 12.8 hours S.D., respectively. In 4 of these patients the plasma half‐lifes of daunorubicin and daunorubicinol were equal, indicating a variability of the pharmacokinetics in different individuals. These observations together with the earlier demonstration of increased production of daunorubicinol in vitro by leukemic leukocytes from responding patients indicate a significant role for daunorubicinol in the pharmacodynamics of daunorubicin therapy. One of the new metabolites, D5, was the predominant fluorescent material in human heart.
Uptake and metabolism of catecholamines by the human red blood cell
Authors: Danon Abraham , Sapira Joseph D.
Published: January 2016

The uptake and metabolism of 14C‐labeled norepinephrine (NE) and epinephrine (E) by the human red blood cell (RBC) was studied in platelet‐free blood in vitro. RBC incubated at 37° C. accumulated NE and E against a concentration gradient and reached an equilibrium distribution ratio, intracellular‐extracellular concentration, of about 2 at 2 hours. Uptake was temperature dependent and saturable, both phenomena characterizing an active transport system. During the incubation period, increasing concentration of metabolites, identified as the O‐methyl derivative of NE and E, respectively, appeared both in the RBC and in plasma, the concentration of the metabolite in the RBC always exceeding that in the plasma at any given point in time. Treatment with iodoacetate or quinidine resulted in increased ratios of intracellular to extracellular concentration of NE, while ethylenediaminetetraacetate decreased this ratio. Conversely, drugs known to interfere with the uptake and release of catecholamines in the adrenergiC neuron and blood platelet were without effect on the ratio of intracellular to extracellular concentration in the red cell.
Physiologic and clinical effects of chlorpromazine and their relationship to plasma level
Authors: Sakalis George , Curry Stephen H. , Mould Graham P. , Lader Malcolm H.
Published: January 2016

Ten patients suffering from functional psychoses who had not received medication for one month were studied. After investigation before treatment, they received chlorpromazine in liquid form, 100 mg. every 8 hours for 5 to 6 weeks. Testing was carried out on Days 4, 8, 15, 22, 29, and 36 or 43 of treatment: (1) Blood samples were taken for chlorpromazine assessment at 0, 2, 4, and 6 hours after the morning dose; (2) blood pressure and pulse rate, pupil size, sweat gland activity, and electroencephalogram (EEG) were recorded at these times; (3) salivary secretion, EEG‐evoked response, auditory reaction time, and handwriting tests were carried out at the 2 hour point; and (4) clinical ratings were made between 2 and 4 hours. Wide interpatient variation in plasma level was found; concentrations were maximal in the first 2 weeks, then consistently declined. Changes in the peripheral autonomic measures correlated with those in plasma level, but changes in the central measures were inconsistent. Plasma levels and clinical improvement were weakly related during the first 2 weeks of treatment only. Clinical improvement correlated with palmar skin conductance (sweating) and with some latencies of the electroencephalographic‐evoked response. The determination of chlorpromazine plasma levels should be of use in investigating nonresponders and patients with severe autonomic effects.
Intra:Extraceliular lithium ratios and clinical course in affective states
Authors: Elizur Avner , Shopsin Baron , Gershon Samuel , Ehlenberger Alfred
Published: January 2016

Our data suggest that manic or depressed patients may be distinguished from normal individuals or manic‐depressives in illness interphase by red blood cell:plasma lithium ratios. The findings also revealed that the intraerythrocyte concentration of lithium was a sensitive index of clinical change and impending toxicity in psychiatric patients, whereas blood lithium alone was not a reliable indicator. Confirmation of these data would contribute to the concept of biologic heterogenicity within the affective illnesses and may influence the procedure of lithium stabilization and chronic maintenance based on monitoring only blood levels of this ion.
Future drug research—drugs of the future
Authors: Gross F.
Published: January 2016

During the period from 1935 to 1965, pharmacology and drug research have made greater progress than in all the time that drug actions have been studied scientifically, and today we are inclined to speak of those 30 years as of the golden age of drug development.9 All of us who have at least in part experienced this era remember it as a most exciting and rewarding succession of years, characterized not only by an apparently continuous flow of new inventions, but also by their rapid realization, unrestrained by complex regulations that today not infrequently are prohibitive to the development of new drugs.
Clinical safety of haloprogin, a new topical antimicrobial
Authors: Hermann Harold W.
Published: January 2016

Extensive clinical safety studies indicate that one per cent haloprogin cream is safe for repeated topical applications. Its potential for irritancy, allergic contact sensitization, phototoxicity, or allergic contact photosensitization was low. There was no evidence of systemic toxicity elicited by repeated massive dermal applications. In dermal penetration studies it was concluded that the penetration of haloprogin through the skin was of a low order of magnitude.
Pharmacokinetic studies of practolol, a beta adrenergic antagonist, in man
Authors: Bodem Gunter , Chidsey Charles A.
Published: January 2016

The disposition of practolol after oral and intravenous administration was studied in hypertensive patients. The plasma half‐life was 13.2 hours. After intravenous administration practolol was recovered quantitively in the urine. Its volume of distribution was larger than that of body water, 1.6 L. per kilogram, and its clearance from this volume, 135 ml. per minute, was equal to renal clearance of the drug; both were slightly higher than the creatinine clearance. Despite its weakly basic character, this aromatic alkylamine was not affected by changes in urinary pH from 5.4 to 8.0. These studies indicate that practolol is slowly removed from the body and that it is excreted entirely by the kidneys.
Perinatal development of human blood esterases
Authors: Ecobichon D. J. , Stephens D. S.
Published: January 2016

Erythrocyte acetylcholinesterase, plasma proteins, pseudocholinesterase, and arylesterase development was investigated in groups of premature infants of varying gestational ages, comparing the detected levels with those observed in groups of healthy older children and adults. A rapid increase in protein concentration was evident between 28 and 40 weeks gestation, followed by a slower rate of increase until 1 year of age. A rapid increase in plasma pseudocholinesterase and arylesterase activity occurred from 28 weeks gestation to 1 year of age, with no significant changes in activities from those of adults occurring after 1 year. In contrast, the erythrocyte acetylcholinesterase levels increased most markedly between 40 weeks gestation and 1 year of age. Premature infant plasma degraded procaine hydrochloride and insecticide paraoxon more slowly than full‐term infants, while the rates of hydrolysis for these 2 groups were significantly lower than those detected for children older than 1 year or for adults.
Disposition of diazoxide in children
Authors: Pruitt Albert W. , Dayton Peter G. , Patterson Joseph H.
Published: January 2016

Pharmacokinetic studies in 4 children with hypo glycemia who required diazoxide therapy revealed a half‐life of the drug in blood of 9.5 to 24 hmlrs. The blood level of diazoxide in these children while receiving maintenance therapy was 15 to 50 p.g per milliliter. Hyperglycemia and acidosis developed in one of these patients in the presence of a persistent blood level above 100 ug per milliliter. Twenty‐four hour urinary excretion of unchanged drug in 2 patients was 20 and 33 per cent of the initial dose, and 80 per cent in one patient on maintenance. In order to investigate the fate of the drug better, 3H‐diazoxide was purified for use in adult volunteers and animals. The half‐life of the drug in plasma of 2 adults was 24 and 36 hours. In these subiects as much as 94 per cent of the radioactive dose was recovered in the urine. About half the radioactivity in urine was present as unchanged drug. The plasma half‐life of 3H‐diazoxide in rats and dogs was much shorter than in man.
Ampicillin and hetacillin pharmacokinetics in normal and anephric subiects
Authors: Jusko William J. , Lewis George P. , Schmitt Gunther W.
Published: January 2016

Plasma concentrations of ampicillin and hetacillin were measured after intravenous administration to anephric patients (on and off hemodialysis) and to normal subiects. Hetacillin, an inactive precursor of ampicillin, can be considered chemotherapeutically equivalent to ampicillin because of its rapid, complete hydrolysis to ampicillin in plasma. In normal subiects, 92 ± 8 per cent of a dose of ampicillin is excreted by the kidney; in patients with impaired renal function there is a marked retention of the antibiotic. Equations were developed to quantitate drug dialysis from plasma, and it was found that 40 per cent of an ampicillin dose was usually dialyzed in 7.5 hours. The data from this study, along with ampicillin clearances from patients with partial renal function, were used to determine the maintenance dose requirements of ampicillin for patients with various degrees of renal impairment.
Drugs for a Future
Authors: Modell Waiter
Published: January 2016

There are two categoric bases for drug predicting. The usual is quantitative and is based on the projection of the Future as simply more of the Present, and its predictions deal with drugs and diseases as we know them now.
Effect of pindolol, a beta receptor antagonist, in hyperthyroidism
Authors: Schelling J. L. , Scazziga B. , Dufour R.J. , Milinkovic N. , Weber A.A.
Published: January 2016

Thirty hyperthyroid subjects were allocated to control, low‐dose (15 mg.), and high‐dose (30 mg.) groups and were observed for one week. Thyroid function tests were unchanged. Heart rate was decreased by pindolol, the effect being dose‐dependent. The duration of ankle jerk was prolonged, and half the patients were subjectively improved. Blood pressure and forearm blood flow were not influenced. Nausea occurred in 2 patients.
Effects of practolol on pressor responses to noxious stimuli in hypertensive patients
Authors: Traub Yehuda , Shaver James A. , McDonald Robert H. , Shapiro Alvin P.
Published: January 2016

The effect of practolol, a ß‐adrenergic blocker, on the cardiovascular response to noxious stimuli was studied in 10 patients with mild to moderate hypertension. Two oral dose levels of 400 and 800 mg. per day were employed in a short‐term study that was carefully monitored by blood levels of the drug; the effects were compared to that of an identical placebo administered in a double blind fashion. Results indicated no change in the resting blood pressure or pulse rate in these patients at either dose level. Similarly, the pressor responses to ischemic pain and cold pressor testing were not affected. However, responses of the pulse rate to the stimuli and to 60 degree tilt were Significantly dampened. Hemodynamic studies were done in 3 patients and revealed no consistent patterns of change in the relationships between cardiac output and peripheral resistance during the pressor responses. No adverse symptomatic or systemic side effects were noted at either dose level. The results confirmed the relative ineffectiveness of this compound as a sole agent in treating hypertensive patients but suggest it may be of some value as a supplement to vasodilator compounds.
Comparison of guanadrel and guanethidine
Authors: Hansson Lennart , Pascual Arturo , Julius Stevo
Published: January 2016

Both guanadrel and guanethidine caused a statistically significant reduction of blood pressure when compared to placebo, but there was no significant difference between the 2 drugs, regarding antihypertensive potency. With guanadrel it was possible to achieve significantly more control of the blood pressure throughout the day. There also were fewer complaints of early morning dizziness during the guanadrel period, and there was less diarrhea. The effects of both drugs on cardiac output and total peripheral vascular resistance were identical in the resting recumbent position and during tilting.
Effects of fenoprofen and aspirin on gastrointestinal microbleeding in man
Authors: Ridolfo Anthony S. , Rubin Alan , Crabtree Ross E. , Gruber Charles M.
Published: January 2016

The 51Cr‐labeled erythrocyte assay was used to compare the effects of equipotent doses of fenoprofen and aspirin—600 mg.:1 Gm.; 400 mg.:650 mg. Based on the appearance of label in the feces of normal men, we conclude that (1) both fenoprofen and aspirin produced measurable gastrointestinal microbleeding in man and (2) the amount of microbleeding after fenoprofen was significantly less than that after the aspirin preparations used in this study.
Comparison of anticoagulant activity of two preparations of purified heparin
Authors: Baltes Bernard J. , Diamond Seymour , D'Agostino Richard J.
Published: January 2016

The results of a double‐blind, balanced crossover trial of 2 commercial brands of sodium heparin on the clotting times and partial thromboplastin times (PTT) in healthy adult human volunteers is reported. The data showed no clinically or statistically significant differences between sodium heparin derived from hog intestinal mucosa and that derived from beef lung.
Methaqualone: Metabolie, kinetie, and dinical pharmaeologie observations
Authors: Brown Stanley S. , Goenechea Sabino
Published: January 2016

Interest in the medicinal chemistry of quinazoline derivatives was stimulated in the early 1950's by the elucidation of the structure of febrifugine (Formula 1), the active principle of the ancient antimalarial preparation Ch'ang Shan.75 Few other quinazoline alkaloids are known,68 but many synthetic derivatives of quinazoline are now available and some display interesting pharmacological properties. Armarego8 has comprehensively reviewed the general chemistry and pharmacology of quinazoline derivatives.
Excretion and metabolism of reserpine In renal failure
Authors: Zsotér Thomas T. , Johnson Gordon E. , DeVeber George A. , Paul Hindy
Published: January 2016

The effect of renal failure on the excretion and metabolism of 3H‐reserpine was studied in 15 patients. The plasma level and urinary and fecal exeretion of the drug were followed for 7 days. There was a correlation between the urinary excretion of total radioactivity, plasma half‐life, and creatinine clearance, but no correlation between fecal excretion and degree of renal impairment.
Parkinsonism treated with 3‐0‐methyldopa
Authors: Calne Donald B. , Reid John L. , Vakil Sarosh D.
Published: January 2016

In comparison with levodopa, 3‐0‐methyldopa (30MD) is inadequate treatment for Parkinsonism. Therapeutic concentrations of levodopa could not be detected in the blood of patients receiving 6 gm per day of 30MD for 10 weeks. It is concluded that 30MD is not demethylated to levodopa in appreciable quantities in man. A possible explanation is the inability of man to excrete 30MD in the bile and the consequent failure of the intestinal bacterial flora to bring ab out demethylation.
Potentiation of levodopa stimulation of human growth hormone by systemic decarboxylase inhibition
Authors: Mars Harold , Genuth Saul M.
Published: January 2016

Plasma levodopa, homovanillic acid (HVA), and human growth hormone (HGH) were monitored in 10 normal subiects over 4 hours following an oral dose of 250 mg levodopa alone, and following pretreatment with the systemic dopa decarboxylase inhibitor MK‐486. The addition of the MK‐486 resulted in a fivefold potentiation of plasma levodopa (p < 0.001), a 65% reduction in HVA (p < 0.001), and a twofold increase in HGH (p < 0.05). An analysis of the individual curves suggests that a minimallevodopa level of 400 ng per milliliter plasma is necessary to evoke an unequivocal HGH response in healthy individuals.