bluuebunny/crossref_metadata_2025 huggingface dataset:
Fetal therapeutics‐challenges and responsibilities
Authors: Chez Ronald A. , Fleischman Alan R.
Published: January 2016

It is possible to categorize fetal therapeutics into three medical goals: therapy directed at bringing the fetus to a stage of extrauterine viability as in the treatments of erythroblastosis fetalis and pregnancy complicated by diabetes mellitus; therapy directed at bringing the neonate to a stage of postnursery survival as with the use of agents administered to the mother to prevent physiologic hyperbilirubinemia and respiratory distress syndrome in the newborn infant; and therapy directed at bringing the infant to childhood and subsequent adulthood, such as changes in maternal nutrition, personal habits, and total environment. The advances in diagnosis, therapeutics, and prophylaxis of each of these diseases are derivatives of the successful application of present knowledge. Continued advancement requires increased information about the normal and pathologic processes of pregnancy, the degree of control that the fetus‐placenta exercises in regulating metabolic processes of the mother, the interdependence as well as independence of the fetal and maternal endocrine systems, and the time‐related specificity of fetal metabolic pathways. Furthermore, because most of the present prophylactic and therapeutic approaches are not enzyme‐ or process‐specific, appraisal of the steps taken by the physician managing the fetus and its environment requires a focus more refined than the relatively gross standard of perinatal survival or mere absence of disease.
Hypertensive response to propranolol in a patient treated with methyldopa—a proposed mechanism
Authors: Nies Alan S. , Shand David G.
Published: January 2016

A patient is presented who had a hypertensive response to intravenous propranolol after having been treated for several days with methyldopa. Experimental work in dogs demonstrated that the pressor activity of alpha‐methyl‐norepinephrine, a metabolite of methyldopa, is enhanced by propranolol. We postulate that, during stress, the patient released alpha‐methyl‐norepinephrine and that propranolol acted to potentiate the pressor activity of this metabolite, resulting in a hypertensive response.
XXIV. The role of randomization in sampling, testing, allocation, and credulous idolatry (conclusion)
Authors: Feinstein Alvan R.
Published: January 2016

The process of randomization can be used statistically in at least three different ways in scientific research. In the first way, randomization is employed to select a sample of people who will represent a larger parent population. As discussed in the first paper16 of this “trio” on randomization, random samples are regularly chosen for research in social Or political science, but seldom in clinical or epidemiologic investigation. In the second use of randomization, an inferential test of “statistical significance” is performed through random rearrangements that show the relative frequency with which “exceptional” results would occur among all the distinctive permutations of data for the investigated people. As discussed at our last meeting,17 this type of “permutation” or “randomization” test for the observed data has major advantages over its conventional counterparts in t‐tests or X2 tests, but is also seldom employed in current biostatistical activities.
Circadian rhythms of drug effectiveness and toxicity
Authors: Ede Martin C. Moore
Published: January 2016

Circadian rhythms have been reported in the therapeutic and toxic effects of many drugs. Much of the work has been done in animals, but increasingly these circadian rhythms are being demonstrated in man. Initial steps have been made toward investigating the physiological mechanisms underlying the rhythmicity. Circadian rhythms in the rates of absorption, hepatic conjugation, and urinary excretion may all contribute toward the overall circadian variation in responsiveness to a drug. The choice of the correct time of day for drug administration has been shown to be important in certain clinical situations.
Impairment of performance with low doses of marihuana
Authors: Evans Michael A. , Martz Robert , Brown Daniel J. , Rodda Bruce E. , Kiplinger Glenn F. , Lemberger Louis , Forney Robert B.
Published: January 2016

Eight volunteers smoked marihuana cigarettes under controlled laboratory conditions on 4 separate occasions. The cigarettes were calibrated to deliver doses of 0, 3, 6, and 9 µg per kilogram of delta‐9‐tetrahydrocannabinol (THC). The experimental design was a double‐blind random block with a 1 week interval between sessions. Analysis of variance revealed a significant linear decrease in stability with increase in dose of THC. The tracking scores with Pursuit Meter (PM) demonstrated a significant increase above control for all three doses of THC. Mental performance, as evaluated by Delayed Auditory Feedback (DAF), and subjective evaluation revealed no consistent change with dose.
Methadone‐naloxone in combination for the treatment of heroin addicts
Authors: Parwatikar Sadashiv D. , Knowles Raymond R.
Published: January 2016

A methadone‐naloxone (10:1) combination was compared to methadone alone in the maintenance of heroin addicts. No abnormalities in blood clinical chemistry that could be attributed to the combination treatment were observed. The data indicate fewer nonspecific and narcotic side effects. There was a suggestion of some narcotic antagonist effects, but this did not achieve statistical significance. This double‐blind study showed the oral efficacy and safety of a methadone‐naloxone combination (in 30 subjects), which is known to induce abstinence in narcotic addicts if injected parenterally. Hopefully, such a mixture can prevent the diversion of methadone for parenteral abuse.
Oxprenolol: Long‐term effects in arterial hypertension
Authors: Gysling Etzel , Regoli Domenico
Published: January 2016

Oxprenolol, a new beta adrenergic blocking drug, was used as the sole antihypertensive agent for a minimum of 14 weeks in 20 patients with mild to moderate essential hypertension. The results demonstrate a definite, but not prominent, antihypertensive activity of this drug. Oxprenolol does not lower the blood pressure sufficiently in an unselected group of patients, but its effect is clinically satisfactory and well tolerated in some cases of mild “borderline” hypertension. In the latter, low doses of oxprenolol influence equally the systolic and diastolic blood pressure in both supine and standing position. The decrease in heart rate is relatively small. No maior side effects were noted.
Interactions in man of delta‐9‐tetrahydrocannabinol I. Alphamethylparatyrosine
Authors: Hollister Leo E.
Published: January 2016

The interaction of alphamethylparatyrosine (AMPT) and delta‐9‐tetra‐hydrocannabinol (THe) was studied in three separate experiments, two giving THe orally, one administering it intravenously. Pretreatment with doses of 2.0 to 4.0 gm of AMPT produced no major qualitative or quantitative change in the effects of THe. Some accentuation of the total intensity of THe was apparent in each of these experiments, but one could not be certain whether this difference was due to additive pharmacologic effects or diminished catecholamine concentrations in brain. It would appear that mental effects of THe are not mediated primarily through catecholamines, but rather by the balance between the concentrations of these amines and others, such as acetylcholine or serotonin.
Effect of oral contraceptives on drug metabolism
Authors: Carter Dean E. , Goldman Joel M. , Bressler Rubin , Huxtable Ryan J. , Christian C. Donald , Heine M. Wayne
Published: January 2016

The effects of chronic steroid contraceptive use on drug‐metabolizing activity were studied by using plasma antipyrine (ap) and phenylbutazone (pbz) half‐lives in women and in vitro N‐demethylation of O‐ethylmorphine by female rat liver preparations. After 3 months of oral steroid therapy (norethynodrel plus mestranol), the antipyrine half‐life was increased in 5 of 8 sub;ects (as compared to their previous half‐lives), whereas the pbz half‐life was not COnsistently altered. After chronic injections of norethynodrel‐mestranol (200 p.g per rat per day plus 4 p.g per rat per day, respectively) for 10 days or 6 weeks, ethylmorphine demethylation by rat livers was significantly increased. A higher dose of norethynodrel‐mestranol but not a lower dose also stimulated ethylmorphine demethylation activity. The acute addition of norethynodrel or mestranol in vitro competitively inhibited ethylmorphine demethylation. Under the conditions of the observations, therefore, the rat cannot be used as a model for the effects of the chronic use of oral steroid contraceptives in women.
N‐oxidation of a tertiary amine (N,N‐dimethylaniline) by human fetal liver microsomes
Authors: Rane Anders
Published: January 2016

Human fetal liver microsomes were shown to catalyze the N‐oxidation of a tertiary amine, N,N‐dimethylaniline. The reaction was dependent on reduced nicotinamide adenine dinucleotide phosphate but was not inhibited by CO. The results are in agreement with those obtained from studies on N‐oxygenation of secondary and tertiary amines by animal liver microsomes, which show that this reaction appears to proceed independently of cytochrome P‐450. The findings are of interest from a toxicologic and teratologic point of view since the N‐oxygenation of some amine drugs may lead to the formation of potentiaUy toxic metabolites.
Renal action, therapeutic use, and pharmacokinetics of the diuretic bumetanide
Authors: Davies David L. , Lant Ariel F. , Millard Nicholas R. , Smith Anthony J. , Ward John W. , Wilson Graham M.
Published: January 2016

The diuretic activity of bumetanide has been studied in 16 normal subiects and 40 hospitalized patients with fluid retention. The drug produced a rapid diuretic response with a pattern of salt and water excretion resembling that of furosemide (Lasix). At the time of maximal natriuresis, which amounted to 13% to 23% of the filtered load of sodium, urinary calcium and magnesium also increased. Urinary urate was unchanged in the first 2 hours after bumetanide, following which there was a phase of urate retention. Free water clearance during maximal hydration was not significantly altered. Comparative studies in edematous patients showed that 1 mg bumetanide was equivalent to 60 mg furosemide. Oral doses of 15 mg bumetanide evoked effective diuresis without adverse effects in 3 edematous patients with advanced renal disease. Prolonged therapy over 7 to 14 weeks with daily doses of 0.25 to 4 mg bumetanide plus potassium supplements controlled edema in 12 patients; asymptomatic hyperuricemia occurred in most, and decreased carbohydrate tolerance in 1. There was no evidence of significant metabolism of bumetanide in vivo. The drug was distributed in a “central” compartment of approximately 5 L. The over‐all elimination rate constant was high and indicated that despite rapid renal drug clearance, a substantial part of infected drug left the “central” compartment by one or more extrarenal routes.
Quantitative evaluation of neuropharmacological trials
Authors: Potvin A. R. , Albers J. W. , Repa B. S. , Henderson W. G. , Walker J. E. , Stribley R. F. , Pew R. W. , Tourtellotte W. W.
Published: January 2016

The clinician's ability to classify a patient's neurophysiological deficits into such categories as mild, moderate, and severe does not readily allow the detection of small but significant changes in function over time. Clinical neurologists, for example, are discovering that the standard neurological examination is not sufficient to critically evaluate new drugs and surgical techniques that purport to improve the performance of patients in the activities of daily life.1 As a result, the quantitative evaluation of the functional capacity of patients with
Quantitative relationship between blood alcohol concentration and psychomotor performance
Authors: Evans Michael A. , Martz Robert , Rodda Bruce E. , Kiplinger Glenn F. , Forney Robert B. , Neel Mary Ann , Ray Gary
Published: January 2016

Following aseries of doses of alcohol calculated to produce a BAC of 0, 25, 50, 75, and 100 mg%, 14 males were evaluated for psychomotor impairment, and sub;ective impressions. Actual BAC's were estimated at selected intervals during each session by a Breathalyzer. Covariance analysis indicated that performance deteriorated linearly with increasing BAC for both PM and WB test. DAF also demonstrated increased impairment with an increase in BAC. Similar results were found for sub;ective evaluation measmcd by a modified CMI questionnaire. At a mean BAC of 61 mg%, 11 of 14 subjects indicated that their driving ability would be impaired and, at a mean BAC of 89 mg%, all 14 subjects judged that their driving ability would be impaired.
Nonlinear plasma level response to high doses of naproxen
Authors: Runkel Richard , Forchielli Enrico , Sevelius Hilli , Chaplin Melvin , Segre Eugene
Published: January 2016

The plasma level curves of oral doses of naproxen ranging from 125 to 900 mg were studied in normal sub;ects. Areas under plasma concentration vs time curves increased linearly with dose incmments up to 500 mg twice a day, but larger doses resulted in a plateau effect. Experiments with tritium‐labeled naproxen showed that there was no difference in the fraction of drug excreted in the stools whether the dose was 250 or 900 mg, eliminating incomplete absorption as a factor. Accelerated renal clearance at high doses because of disproportionate increases in the amount of unbound drug appeared to be the most likely explanation for the plateau effect.
A comparison of intermediate‐dose aspirin and placebo in rheumatoid arthritis
Authors: Multz Carler V. , Bernhard Gerson C. , Blechman Wilbur C. , Zane Sheldon , Restifo Ronald A. , Varady John C.
Published: January 2016

This double‐blind study evaluates the time required fOT exacerbation to appear on substituting placebo for aspirin (ASA) in 33 patients with classical or definite rheumatoid arthritis. A daily record of symptoms and weekly grip strength and joint counts were evaluated. Three days of placebo exposure were as effective in demonstrating the anticipated exacerbation as langer exposures.
Effects of plasma from hypertensive patients on the responses to angiotensin and norepinephrine in dogs and rats
Authors: Greenberg S. , Goldstein B. , Wilson W. R.
Published: January 2016

The effect of peripheral venous plasma (PVP) from normotensive sub;ects (Group A), and hypertensive patients who received placebo (Group B) or thiazide therapy (Group C) on vascular reactivity and resistance was evaluated in intact rats and dogs. Plasma electrolytes and serum levels of creatinine were normal in the three groups. Administration of 100 pl per kilogram of pVP from Groups A, B, or C did not affect the systemic pressure or the pressor responses to norepinephrine (NE) and angiotensin (A) in the anesthetized rat. The canine paw was perfused with autologous blood at constant flow. Intra‐arterial infusions of pVP (0.5 ml per minute) from Groups A, B, and C transiently reduced vascular resistance by 23 ± 11 %,35 ± 8%, and 8 ± 6% respectively. However, paw perfusion pressure returned to control values within 30 minutes. Pressor responses to NE were similar before and during infusion of pVP from each group. The pressor responses to tyramine (T) were enhanced by 33% during infusion of pVP from Group A and 67% (p < 0.05) and 62% (p < 0.05) during infusions of pVP from Groups Band C, respectively. Since PVP from Groups A, B, and C enhanced the pressor response to T but did not affect the response to NE, we conclude that a substance in human PVP enhances T‐induced catecholamine release. This substance probably does not play a role in essential hypertension.
Pharmacologic effects and physiologic disposition of delta6a,10a dimethyl heptyl tetrahydrocannabinol (DMHP) in man
Authors: Lemberger Louis , McMahon Robert , Archer Robert , Matsumoto Ken , Rowe Howard
Published: January 2016

14C‐DMHP (200 µg/70 kg man) was administered by the intravenous route to 3 healthy male casual marihuana smokers. Tachycardia occurred within 10 minutes and persisted for from 11 1/2 to 6 hours. Blood pressure fell slightly with time when subiects were supine, while standing for less than 1 minute resulted in marked hypotension. In these 3 subjects, except for dizziness on standing there were essentially no demonstrable psychologic effects, neither euphoria nor dysphoria. Subiects did, however, report symptoms similar to those after marihuana or Δ9‐THC, including dry mouth, decreased salivation, and drowsiness. After intravenous dimethyl heptyl tetrahydrocannabinol (DMHP), plasma levels of total radioactivity and 14C‐DMHP declined in a multiphasic fashion; the half‐life of the terminal phase for DMHP was 39 hours. Approximately 69% of the administered radioactive dose was recovered in 7 days. Radioactivity was excreted predominantly in the feces (58%) and to a lesser extent in urine (11%) during the 7 day collection period.
Kinetics of digoxin absorption and relation of serum levels to cardiac arrhythmias in children
Authors: Larese Ricci J. , Mirkin Bernard L.
Published: January 2016

The effect of route of administration on the uptake and elimination of digoxin and the relationship of serum digoxin levels to cardiac arrhythmias was investigated in 15 children with congenital cardiac defects who were receiving maintenance doses of digoxin. The highest serum digoxin concentrations were noted 1 hour after oral and parenteral administration. This probably does not represent the peak levels achieved with the parenteral routes since that first samples were taken 1 hour after the digoxin. The magnitude of the (steady state) serum digoxin concentration and the level obtained at 1 hour were dose‐related. Group 1 subjects (half‐daily maintenance dose: 0.005 ± 0.0015 mg per kilogram) had a steady‐state serum concentration of 0.98 ± 0.41 ng per milliliter 12 hours after the last maintenance dose and a level of 1.8 ± 0.6 ng per milliliter 1 hour after the test dose. In contrast, Group II subjects (half‐daily maintenance dose: 0.011 ± 0.002 mg per kilogram orally) had a 12 hour steady‐state serum concentration of 2.54 ± 0.35 ng per milliliter and a 1 hour peak of 5.1 ± 0.49 ng per milliliter that were both apprOXimately two and one‐half times as great as those occurring in Group 1. Parenteral administration of digoxin intramuscularly and intravenously in doses eqUivalent to those used in Group II subjects produced serum concentrations that were of the same magnitude. In the limited number of patients there was no apparent relationship between the serum digoxin level and the onset or persistence of cardiac arrhythmias.
Plasma concentrations of diazepam and of its metabolite N‐desmethyldiazepam in relation to anxiolytic effect
Authors: Dasberg Haim H. , van der Kleijn Eppo , Guelen Pieter J. R. , van Praag Herman M.
Published: January 2016

Fifteen nonpsychotic patients suffering from acute anxiety in a crisis situation, admitted for a short inpatient treatment, were treated orally with diazepam (Valium), 20 mg daily, for a period of at least 5 consecutive days. Measurements were made on 3 levels: (1) psychometric measurements, using rating scales, for the degree of improvement of a wide variety of anxiety symptoms, (2) pharmacochemical measurements of plasma levels of diazepam and its main active derivative N‐desmethyldiazepam, (3) clearance rates relative to body weight were calculated, (4) correlation between improvement ratings on the one hand and plasma concentrations and clearance ratings of both substances on the other hand. A control group consisted of 15 similar patients receiving placebo. The design was double‐blind and randomized. Our results suggest that the degree of the diazepam effect is directly proportional to plasma concentrations and reCiprocal clearance values of diazepam and N‐desmethyldiazepam. The minimal effective plasma concentration in the steady state is 400 ng per milliliter. The desmethyl metabolite has a slightly different action than diazepam, even a disturbing action on certain symptoms, with plasma levels of 300 ng per milliliter or more. Monitoring of diazepam treatment on the basis of plasma concentrations seems to be advisable.
Propranolol enhancement of hypoglycemic sweating
Authors: Molnar George W. , Read Raymond C. , Wright F. Elvis
Published: January 2016

Oral propranolol doubled sweating during insulin‐induced hypoglycemia in 19 men. Two of 7 hypoglycemic patients studied with propranolol alone did not sweat, establishing that propranolol does not initiate sweating either by discharges from the hypothalamus or by direct action on sweat glands. Therefore, propranolol enhances hypoglycemic sweating by either blocking a beta adrenergic agent (perhaps epinephrine) that inhibits secretion or by potentiating the discharge of impulses by glucopenic neurones of the hypothalamus (possibly by competitive displacement of membrane calcium).
Effect of naloxone on the analgesic activity of methadone in a 1:10 oral combination; Time and cost of flirting with the null hypothesis in tests of equivalence
Authors: Calimlim J. F. , Wardell W. M. , Lasagna Louis , Gillies A. J. , Davis H. T.
Published: January 2016

The effect of oral naloxone on the analgesic efficacy and side effects of oral methadone was examined in one hundred patients with postoperative pain. Doses of methadone of 5 mg and 15 mg were compared with combinations containing the same amount of methadone plus one‐tenth as much naloxone. No consistent or statistically significant effect of naloxone was detected on analgesia, sedation, or side effects. However, the statistical power of this study was low, its chance of detecting a real difference of 20% being at best 10%. To increase this chance to 95%, nearly 4,500 subiects would be needed. This analysis has implications for the general problem of testing drug equivalence.
Comparative efficacy of ibuprofen and aspirin in episiotomy pain
Authors: Bloomfield Saul S. , Barden Tom P. , Mitchell Jeanette
Published: January 2016

Substitutes for aspirin devoid of troublesome effects are needed. A potential candidate, ibuprofen, heretofore marketed outside the United States as an antiarthritic, was compared in single oral doses of 300 and 900 mg with aspirin, 900 mg, and placebo in a parallel balanced randomized double‐blind design in 80 patients with pain due to episiotomy. Over the 6 hours of evaluation, there was pain reduction greater than 50 per cent in 17 of 20 patients treated with either dose of ibuprofen (p < 0.01), in 18 of 20 patients treated with aspirin (p < 0.001), and in only 6 of 20 patients treated with placebo. With the two doses of ibuprofen, pain relief, as measured by pain intensity differences (PID) was similar to that with aspirin with respect to time of onset, degree and duration of analgesia. Reported side effects with ibuprofen were insignificant.
Validity of screening methods for drugs of abuse in biological fluids; II. Heroin in plasma and saliva
Authors: Gorodetzky Charles W. , Kullberg M. Peter
Published: January 2016

Five subjects received 3 single intravenous doses of heroin, 2.5, 5, andd 10 mg per 70 kg and 1 oral dose of dextromethorphan, 60 mg per 70 kg; another 4 subjects received morphine, 30 mg, subcutaneously, 4 times per day for 3 months. Saliva and plasma samples were collected at intervals for 48 hours following each single drug dose and hourly for 6 hours between chronic doses. Plasma samples were analyzed for opiate by RIA, and saliva samples by RIA, a modified FRAT, and the EMIT. The low dose of heroin was not consistently detectable at any sampling time in either the plasma or the saliva. The medium and high doses were detectable with high probability for 2 to 4 hours in plasma and 1 to 2 hours in saliva. Dextromethorphan was not detectable in plasma hut was detected with high probability in saliva for 30 minutes by EMIT and 2 hours by FRAT. During chronic administration there were high probabilities of detection of morphine in plasma for at least 6 hours and in saliva for 3 to 4 hours after the last morphine dose. While these fluids do not appear to be as useful as urine in routine screening for herOin, they may be useful in the detection of high‐dose chronic abuse.
Platelet aggregation in hyperadhesive states
Authors: Bicher Haim I. , Kuperminc Mario
Published: January 2016

A method for the determination of adenosine diphosphate (ADP) and collagen‐induced platelet aggregation in whole blood based on the measurement of the capacitance changes that parallel aggregation was previously reported. Experiments were undertaken to determine the clinical reliability of the method when used in parallel with Born's technique and a platelet‐to‐glass adhesiveness technique. Daily determinations were made on 40 healthy volunteers, 40 patients during the first two weeks after acute myocardial infarction, and 40 patients prior to and a week following major abdominal surgery. Platelets from the last two groups were overreactive, although daily and individual variations occur. Each group showed a typical course in the dynamic day‐to‐day fluctuations of the hyperadhesive state. Parallelism between the three methods studied was good but not absolute. A double‐blind clinical study of the effectiveness of 5(5‐hydroxindol‐3‐indoleyl‐methyl) Tetrazol, a potent antiadhesive drug, in vivo and in vitro was conducted using similar methodology. Forty postacute myocardial infarction patients were treated during the first two weeks following the event. Half were given the drug and half were given placebo. No consistent effect of the drug on platelet aggregation or adhesiveness could be detected with any of the three methods used. It is hereby concluded that there is a need for a more potent drug for clinical use.
Comparative pharmacokinetics of amikacin and kanamycin
Authors: Clarke John T. , Libke Robert D. , Regamey Claude , Kirby William M. M.
Published: January 2016

Pharmacokinetic parameters of amikacin and kanamycin were compared in a crossover study using healthy adult male volunteers. Following an intravenous infusion of 3.33 mg per kilogram for 1 hour, an infusion of 1.00 mg per kilogram per hour over the next 3 hours produced a steady state with serum levels of approximately 12 mcg per milliliter. The apparent volumes of distribution were about 28% of total body weight, a relatively large value consistent with the observation that neither antibiotic is protein‐bound. Amikacin and kanamycin had serum half‐lives of about 2 hours, and renal clearance of the antibiotics (84 ml per minute) was less than the creatinine clearance (120 per milliliter per minute), indicating tubular reabsorption. Although 94% of the total dose was eventually recovered in the urine, clearance of the antibiotics from the serum was greater than renal clearance (100 versus 84 ml per minute), implying a small component of unidentified distribution or elimination. After single intramuscular injections of 7.5 mg per kilogram (about 0.6 gm), peak blood levels of about 18 mcg per milliliter were found, and the serum half‐life of each antibiotic was again about 2 hours. Thus the pharmacokinetic parameters of amikacin and kanamycin were Virtually identical.
Morphine metabolism in man
Authors: Brunk S. Fred , Delle Margrieta
Published: January 2016

Morphine metabolism was studied in 6 normal men at weekly intervals after intravenous, intramuscular, subcutaneous, and oral administration. Morphine was rapidly absorbed after intramuscular and subcutaneous iniection, producing plasma levels of free morphine, from 15 minutes to 3 hours, which are significantly higher than levels after intravenous administration. Intravenous morphine, while initially higher, undergoes more rapid distribution, metabolism, and excretion. Morphine is well absorbed from the gastrointestinal tract, but is so rapidly coniugated with glucuronide in the cells of the intestinal mucosa and liver that significant levels of free morphine are not found in either the plasma or urine, whereas the levels of coniugated morphine are high. N‐demethylation of morphine is greater after oral than after parenteral administration. While route of administration alters plasma levels of free morphine, it does not alter plasma half‐life.
Factors causing interindividual variations of drug concentrations in blood
Authors: Vesell Elliot S.
Published: January 2016

Multiple factors in carefully controlled animal studies produce individual variations in drug blood levels. Since the hepatic microsomal enzyme metabolizing system is particularly sensitive to many environmental and genetically controlled factors, it is not surprising that variations in drug blood levels can be induced by any one of these numerous factors. Numerous factars can also alter drug absorption, distribution, and excretion, thereby exerting significant influence on blood drug levels. For several commonly used drugs, large interindividual variations in plasma half‐lives have been shown to be controlled predominantly by genetic fact ars in man. Both twin and family studies established these results for phenylbutazone, antipyrine, bishydroxycoumarin, ethanol, halothane, and nortriptyline. When a variety of environmental perturbations are imposed on this genetically controlled basal drug‐metabolizing capacity, alterations can also occur in drug absorption, distribution, and excretion. A commonly encountered example of environmental factors afJecting drug blood levels is coadministration of other drugs. Twin studies suggested that large interindividual variations in the response of plasma antipyrine half‐lives to phenobarbital were genetically controlled. Large variations also exist in the extent to which numerous drugs inhibit the metabolism of other drugs. Disease states can alter basal drug‐metabolizing capacity, e.g., in hyperthyroidism, drug‐metabolizing capacity is accelerated, and in hypothyroidism, retarded. Swiftly changing cardiovascular or renal status can also alter drug blood levels. In various disease states, the drug receptor site may become altered so that it no longer responds as expected to a given drug blood level. Operation of several of these factors in severely ill patients renders interpretation of drug blood levels difficult.
Drug levels in the target tissue and effect
Authors: Ariëns E. J.
Published: January 2016

The dose‐response relationship in drug therapy, and the dose‐effect curve and how it is affected by many variables and differences between individuals, are discussed and schematized. The sequence of events is considered under three phases: (1) pharmaceutical (disintegration of the dosage form‐tablets, capsules, suppositories, etc.); (2) pharmacokinetic (processes determining the drug concentration in the various compartments); and (3) pharmacodynamic (interaction of the drug moleeules with their sites of action or receptors). The bioactivity of the compound in relation to receptor moleeules is in part based on the concentration in the target tissue; mass‐action law may therefore be expected to govern the relationship hetween this concentration in the target tissue and the etJect. The role of feedback mechanisms in regulating the biochemical sequence of conversions is analyzed in terms 01 the steps that are involved in a rate‐limiting process; the effect of a particular dose is modified by counterbalancing feedback mechanisms, unless it interferes with the appropriate homeostatic maintenance of the parameter involved. Another determinant in the relationship between drug concentration in the target tissue and efJect is the physiologie condition of the involved organ system, such as the capacity to release endogenous mediators. The relationship between the concentration in the plasma and that in the target tissue is dependent on factors such as the vascularity of the organ, lipophilic barriers surrounding compartments, and bioactivation and biotoxification in target tissues. Reactive short‐lived intermediate drug products released in the course of drug metabolism may contribute to long‐term toxicity, carcinogenesis, mutagenesis, further cell damage, and allergie reactions. In drug design, special attention should be paid to metabolism‐resistant drugs as a means of avoiding such drug toxicity.
Plasma levels and tricyclic antidepressants
Authors: Glassman Alexander H. , Perei James M.
Published: January 2016

In four separate studies, attempts were made to examine the relationships between the plasma levels of trieyclie antidepressants and clinieal outeome. In eaeh of the four studies a different relationship was found. Two maior underlying methodologie problems that have eontributed to these apparent diserepaneies are examined. These problems are the heterogeneity of the depressive population and individual variability in plasma protein binding.
Pharmacodynamic and pharmacokinetic measurements of antitumor agents
Authors: Mellett L. B.
Published: January 2016

Blood level assays of antitumor drugs in the mouse, rat, hamster, dog, monkey, and man were done to determine the toxicologic and therapeutic responses by species. F or cyclophosphomide and amethopterin, the predicted maximum tolerated dose for man, based on all animal data, correlated rrwre closely with clinical toxicity when related to body surface area thon to body weight. Doses of 18 drugs including antimetabolites, alkylating agents, and other antitumor agents carried to the toxicologic end point, LD10 in small animals, the maximum tolerated dose (MTD) in dogs and monkeys, showed that the ratios of animal/human toxicity on the mg per square meter basis were remarkably close to unity. Also, when doses are expressed on this basis, equal doses give equivalent values in difJerent species for the area under the serum curve, i.e., the product of drug concentration × time, C × T (µg/ml × minutes). Three agents, arabinosylcytosine (ARA‐C), methotrexate (MTX), and CTX, selected for their differential presumed sites of primary biochemical action and the concept of unbalanced growth and cell death, were studied for the interrelationships between dosage, schedule, and blood levels and turrwr response in the L1210 leukemia system. The optimal schedules both regarding the total tolerated dose and increase in host life span vs untreated control subfeets difJered fOT the three classes of agents. The difJerences may be related to the difJering mechonisms of action, e.g., ARA‐C, which inhibits deoxyribonucleic acid (DNA) synthesis, killing the cells in S phase; MTX, which inhibits DNA, ribonucleic acid (RNA), and protein synthesis, may destroy only proliferative integrity in S phase; and alkylating agents, which complex with DNA may affect proliferative integrity, regardless of cell cycle phase. Clinical results in adults with acute myelogenous leukemia (AML) treated with ARA‐C indicate that the principles of optimal scheduling developed in the mouse L1210 system are applicable to this disease in humans. Optimal scheduling of MTX in the treatment of L1210 leukemia, human acute lymphocytic leukemia, and choriocarcinoma is also similar. The clinical results of long‐term, tumor‐free survivors in some patients with disseminated Burkitt's lymphoma on a single high dose of CTX or several high doses at appropriate intervals are not inconsistent with the data obtained in the L1210 system.
Instructional goals for physicians in the use of blood level data—and the contribution of computers
Authors: Sheiner Lewis B. , Melmon Kenneth L. , Rosenberg Barr
Published: January 2016

A knowledge of pharmacokinetics provides the potential for improving the physician's therapeutic decision‐making relating to such quantitative aspects of the drug regimen as the required individual dose, temporal sequence in dosing, best route of administration, and form of preparation. Based on available studies of adverse drug reactions and serum drug levels (SDL), it is possible to optimize efficacy while preventing toxicity. The instructional goals for preparing physicians to use SDL data in this context are to be trimmed to his needs, namely, to understand the basic concepts of the science of pharmacokinetics, e.g., half‐life, absorption rates, volume of distribution and clearance of drugs, and how to apply such data selectively and more precisely to the individual patient. l'his is particularly important for drugs with narrow therapeutic indices. Accordingly, a syllabus has been outlined for the teaching of the qualitative aspects of pharmacokinetics (stripped of the mathematical procedures for deriving the formulas) to physicians as well as house staff and medical students. The use of a feedback‐responsive computer system as an aid to making dosage decisions for the individual patient under therapy with such drugs is defended as a means of personalizing and improving medical care. Results of such a a system using the drug digoxin, are presented.
Influence of serum digoxin concentration measurements on frequency of digitoxicity
Authors: Koch‐Weser Jan , Duhme David W. , Greenblatt David J.
Published: January 2016

During 1966 to 1968, 64 of 459 (13.9%) prospectively monitored, digoxin‐treated patients at Massachusetts General Hospital suffered adverse reactions to the drug. Measurements of serum digoxin concentrations for therapeutic guidance began at Massachusetts General Hospital in 1969, and trom Gctober, 1970, to June, 1972, they were performed on 40% of all digoxin recipients. During that same period, only 15 of 2.53 (5.9%) monitored, digoxin‐treated patients became digitoxic. At 7 other monitored hospitals the frequency of adverse reactions to digoxin in 2,425 digoxin‐treated patients ranged from 13.1% to 19.4%. Detailed comparison of patients treated with digoxin during 1970 to 1972 at Massachusetts General Hospital and Peter Bent Brigham Hospital, 2 very similar Harvard Medical School teaching hospitals, showed the risk of aigitoxicity to be 2.12 times greater at the latter where serum digoxin assays were not commonly performed. These findings suggest that the use of serum digoxin determinations for ad;ustment of digoxin dosage reduces the frequency of digoxin toxicity.
Absorption of digoxin from different oral preparations in normal subjects during steady state
Authors: Huffman David H. , Manion Carl V. , Azarnoff Daniel L.
Published: January 2016

Digoxin bioavailability was studied in 6 normal volunteers during chronic dosing. The absorption of digoxin was estimated by: (1) steady‐state serum dtgoxin levels; (2) the area IInder the serllm concentration‐time curve (AUC) du ring a dosittg interval; and (3) the excretion of digoxin in the urine during one dosing interval during steady state. Using the mean of these three methods, the absolute bioavailability of the 0.25 mg digoxin tablet (Lanoxin) was 62%, and an equivalent dose of digoxin solution was 77%. When the dose of digoxin administered was doubled (0.125 mg to 0.25 mg), the steady state serum level increased by 50% for oral administration and 80% for intravenous administration. Despite failure to double serum level and AUC, there was doubling in urinm‐y digoxin excretion. Results indicate that urinary excretion of digoxin is the most valid measure of bioavailability of oral digoxin preparations.
Pharmacokinetics of metolazone in normal subjects and in patients with cardiac or renal failure
Authors: Tilstone W. J. , Dargie H. , Dargie Elizabeth N. , Morgan H. G. , Kennedy A. C.
Published: January 2016

The pharmacokinetics of metolazane (Zaroxolyn) have been studied in normal adult volunteers after oral or intravenous administration and after oral administration in patients requiring diuretic therapy fOT severe renal failure, fOT moderate renal failure, and for heart disease. Following intravenous administration in normal subjects, plasma concentration fell in a bi‐exponential fashion. The data were fitted to the two‐compartment open model and the appropriate kinetic parameters were calculated. The drug was faund to be extensively distributed in the tissue compartment, anly one third of the body cantent after equilibrium being in the plasma compartment. The elimination rate constant was 0.13 hr‐1. Clearance of metolazone from the central compartment was approximately equal to creatinine clearance and ranged from 110 ml per minute in normal subjects to 20 ml per minute in severe renal failure. Absorption was 64% in normal controls, hut as little as 40% of the oral dose was ahsorbed in some patients. Abaut 95% of plasma metolazone was bound to plasma pro teins in normal controls. This figure fell to 90% in severe renal failure. About 10% of the dose was excreted in bile by normal subjects.
Studies on the optical enantiomorphs of warfarin in man
Authors: Reilly Robert A. O
Published: January 2016

The optieal enantiomorphs of warfarin were studied in 10 normal sub;ects. Eaeh sub;ect was given in separate experiments a single oral dose of R(+) warfarin, S(‐) warfarin, and the racemate, R,S(±) warfarin, in the amount of 1.5 mg of drug per kilogram of body weight. The biologie half‐life for (+) warfarin, (‐) warfarin, and raeemie warfarin was 58 ± 5, 33 ± 4, and 42 ± 2 hours, respeetively, a highly significant differenee (p < 0.01) between the enantiomorphs. The blood level of drug for (+) warfarin was 94% greater than that tor (‐) warfarin. The area under the pro thrombin time curve plotted logarithmically showed a 76% greater effect for (‐) warfarin than for (+) warfarin. Thus, the intrinsic activity of (‐) warfarin was 3.4 times as great as thot of (+) warfarin in the induction of hypoprothrombinemia. A high degree of direct correlation was found between the area for the blood level of drug and the hypoprothrombinemic effect for both the (+) and (‐) warfarin enantiomorphs. It is concluded that the greater intrinsic activity of (‐) warfarin than (+) warfarin does not result primarily from the blood level of the enantiomorphs but may result from a difference in permeability or affinity for the receptor site.
Effects of e99 yolk and moctamide on serum lipids in man
Authors: Takeuchi Nozomu , Yamamura Yuichi
Published: January 2016

Forty‐one healthy male volunteers received 9 egg yolks daily in addition to their ordinary meals for 14 days. Mean elevation of serum cholesterollevels was 21,6 mg per 100 ml (11.4%) of the initial level. Middle‐aged men (40 to 45) showed more elevation of serum cholesterollevel than young men (18 to 20). After the first egg yolk fee ding period, 6 young men and 3 middle‐aged men, whose serum cholesterol levels increased by more than 10%, were selected to examine the etfect of moctamide on dietary hypercholesterolemia. They were given a daily oral dose of 300 mg of moctamide during the second egg yolk feeding period of 2 weeks, which was started 4 to 8 weeks after the end of the first period. In the third period, they were given 150 mg per day of moctamide in the same way. Daily doses of 300 mg of moctamide completely inhibited the elevation of serum cholesterol, while 150 mg suppressed it significantly.
Pentazocine binding to blood cells and plasma proteins
Authors: Ehrnebo M. , Agurell S. , Boreus L. O. , Gordon E. , Lonroth U.
Published: January 2016

The binding of pentazocine to human whole blood, plasma, and blood cells was investigated in 20 normal subjects and 22 patients by means of equilibrium dialysis. Plasma protein binding was 56% to 66% in the control sub;ects and 48% to 75% in the patients. In control sub;ects, 48% of the total amount of pentazocine in whole blood is present in blood cells and 33% is bound to plasma proteins. The remaining 19% is in the plasma water. Whole blood concentrations of pentazocine may be expected to be about the same as the plasma concentrations in sub;ects with normal hematocrit.
Assessment of the biologic availability of digoxin in man
Authors: Fleckenstein Lawrence , Kroening Bruce , Weintraub Michael
Published: January 2016

Low serum digoxin levels were found in 8 institutionalized patients with congestive heart failure despite daily administration, in standard dosage, of a digoxin preparation for 4 weeks. All 8 patients developed serum levels within the accepted therapeutic range after receiving another digoxin preparation for 1 week. Analysis revealed that the first preparation did not meet USP reqUirements of content uniformity. In vitro testing demonstrated marked differences in dissolution characteristics between preparations. Large differences in the extent of availability were demonstrated in a single‐dose crossover study in 5 healthy volunteers. It was established that the pharmacokinetic data obtained from cumulative urinary excretion reflected differences in the area under the 8 hour serum digoxin curve during single‐dose studies and the postdistribution serum concentrations in multiple‐dose studies. Single‐dose studies with urine collections for 24 hours seem adequate to assess differences between formulations of digoxin tablets affecting biological availability and to develop correlation with in vitro dissolution tests.
Diazepam metabolism in normal man
Authors: Hillestad L. , Hansen T. , Melsom H. , Drivenes A.
Published: January 2016

It is demonstrated that serum concentrations obtained by administration of diazepam to normal subjects are dependent on the mode of administration. After intravenous injection the maximal level of about 1,600 ng per milliliter is reached in 15 minutes. Oral and intramuscular administration is followed by maximal levels of about 490 ng per milliliter in 30 minutes and of 290 ng per milliliter in 60 minutes, respectively. The clinical effects exhibited an accurate relationship to the serum concentration levels. At high levels of diazepam in the serum the sedative effect was accompanied by a marked deterioration of several mental functions and of coordination. Acute administration of single doses of diazepam did not produce significant amounts of the metabolite, N‐desmethyldiazepam, which therefore was unlikely to have contributed to the clinical effects.
Diazepam metabolism in normal man
Authors: Hillestad L. , Hansen T. , Melsom H.
Published: January 2016

Diazepam given orally over a period of days produces cumulation in the serum of diazepam as well as N‐desmethyldiazepam. A balanced serum level is achieved at the end of the first week for diazepam, at the beginning of the second week for N‐desmethyldiazepam, and from this time on it is higher than the mother substance. The biologic half‐life of diazepam was found to be 54 hours, and the apparent biologic half‐life of N‐desmethyldiazepam, 92 hours. There was close correspondence between the serum levels of diazepam and its clinical effects. During continued administration over one to two weeks, some development of tolerance could be demonstrated. Cumulation of the metabolite was marked during continuous oral administration of diazepam, but clinical effects of the metabolite could not be demonstrated; effects seem to be related solely to serum levels of diazepam.
Introduction
Authors: Besselaar G. Hein , Tempero Kenneth F.
Published: January 2016

In the course of the last ten years, there have been several international meetings between clinical pharmacologists for the specific purpose of discussing medical education, drug research, or governmental regulations. However, the low denSity of clinical pharmacologists coupled with a wide diversity of interests has virtually precluded a representative sample of clinical pharmacologists from attending any meeting from which a comparative overview could be generated.
Clinical pharmacology in Ireland
Authors: Bourke Edmund
Published: January 2016

Ireland has an effective National Drugs Advisory Board. Ethical considerations for human experimentation are unifonn throughout the country. The need for full‐time clinical pharmacology units has gained acceptance, but none has yet been established. Nonetheless, a contribution is being made to research in the field of clinical pharmacology.
Clinical pharmacology in Nigeria
Authors: Danisa Kola
Published: January 2016

Nigeria, today, with a strongly developing economy, is laying the fQUndation for future achievement. While there is no specific unit of clinical pharmacology yet in the country, the principle is recognized and the need appreciated. There are many features in Nigeria that, if properly appreciated and utilized, will aid the progression of clinical pharmacology from an accepted principle to a gratifying and satisfactorily functioning discipline.