bluuebunny/crossref_metadata_2025 huggingface dataset:
Nefopam and morphine in man
Authors: Sunshine Abraham , Laska Eugene
Published: January 2016

A new analgesic, nefopam, is chemically distinct and pharmacologically unrelated to any presently known analgesic. A comparison was made of morphine and nefopam in 74 patients who required parenteral analgesia for moderate to severe postoperative and somatic pain, using a single administration, 2‐dose level, double‐blind design. A significant dose‐response curve was obtained with nefopam and with morphine, and there was no significant deviation from parallelism. The time‐effect curves for the 2 drugs were similar. The estimated relative potency of nefopam to morphine indicates that 20 mg of neJopam HCI is the approximate analgesic equal of 12 mg of morphine SO4. There were no adverse effects with nefopam and one adverse reaction to morphine.
Spuriously low plasma propranolol concentrations resulting from blood collection methods
Authors: Cotham Reta H. , Shand David
Published: January 2016

Spuriously low values of plasma propranolol concentrations resulted when one commercial brand of collection tube was used. The mechanism of this effect was established and was due to the presence of the stopper containing substances that reduced plasma propranolol binding and resulted in a redistribution of the drug in whole blood so that more was present in the cells and less in the plasma. A similar phenomenon was noted some years ago when a needle for intravenous infusion was used as an indwelling cannula. The mechanism in this case could not be established as in the interim the phenomenon was no longer detectable. Although it was established that these findings do not apply to all drugs, the data suggest that collection methods should be routinely checked at intervals unless separate venipuncture and all glass collection tubes are used.
The relationship of plasma guanethidine levels to adrenergic blockade
Authors: Walter Ingeborg E. , Khandelwal Jai , Falkner Fred , Nies Alan S.
Published: January 2016

Seventeen hypertensive patients receiving guanethidine for therapy were studied to determine the relationship of guanethidine plasma levels to adrenergic blockade. Plasma levels of guanethidine were measured by gas chromatography‐mass spectrometry, and adrenergic blockade was defined by determining the venous reflex response to Valsalva maneuver or deep breath. A significant correlation was found between the change in the venous reflex response and the fall in mean standing pressure when guanethidine is given to patients maintained on a sodium restricted diet. A linear relationship was found between dose and plasma guanethidine concentration (p < 0.0001), but there was a 6‐fold interindividual variation in the plasma levels resulting from any given dose. Adrenergic blockade occurred when plasma levels were 8 ng/ml or higher. These results indicate that the large individual variation in dose requirements for the hypotensive effects of guanethidine most likely is not due to requirements for greatly different plasma levels of the drug; that the variation must result from pharmacokinetic determinants of differing plasma levels between individuals or from other factors, such as increased plasma volume, which maintain elevated arterial pressure in the face of adrenergic blockade.
Plasma concentrations and the time‐course of beta blockade due to propranolol
Authors: McDevitt Denis G. , Shand David G.
Published: January 2016

The effectiveness of intravenously administered propranolol in antagonizing the chronotropic effect of isoproterenol and exercise has been investigated, and has been found at all times to be a predictable function of its plasma concentrations according to the classical drug‐receptor theory for competitive antagonism. The data show further that the relationship between effectiveness and time depends on the way in which antagonism is measured. If the dose ratio to isoproterenol (DR) is measured, then (DR‐1) declines with time in parallel with drug concentration. On the other hand, if propranolol's effects are measured as percentage reduction in a given response, then this declines linearly with time, even though plasma concentrations decline exponentially. This fact explains why confusion has in the past arisen concerning the relationship of the duration of beta blockade and pharmacokinetic half‐life.
Action of delta‐9‐tetrahydrocannabinol An approach to the active metabolite hypothesis
Authors: Hollister Leo E. , Gillespie Hampton K.
Published: January 2016

The active metabolite hypothesis, that delta‐9‐tetrahydrocannabinol (THC) must be converted to its 11‐hydroxy metabolite before it becomes active, was tested in a study of subjects chosen as rapid and slow hydroxylators of drugs on the basis of antipyrine and phenylbutazone plasma disappearance rates. Although the sample of subjects showed the customary wide variations in effects experienced after an intravenously administered dose of THC, it was impossible to correlate either the speed of onset, total intensity, or duration of these effects with speed of hydroxylation of drugs. Although 11‐hydroxy‐THC has unquestioned activity indistinguishable from THC itself, it need not necessarily be solely responsible for the pharmacologic activity of THe.
Clinical pharmacology and pharmacokinetics of clonidine
Authors: Dollery C. T. , Davies D. S. , Draffan G. H. , Dargie H. J. , Dean C. R. , Reid J. L. , Clare R. A. , Murray S.
Published: January 2016

A 300‐µg oral dose of clonidine was administered to 5 normal volunteers and measurements of plasma concentration and effects upon blood pressure, heart rate, circulatory reflexes, sedation, and dry mouth were made for the following 8 hr. The plasma concentration rose to a peak of 1.02 ± 0.52 ng/ml (SD) at 90 min andfell with a mean half‐life of 12.7 hr. Blood pressure of the group fell from 111.0/77.0 to 87.2/60.4 after 3 hr and was 95.2/62.2 mm Hg at 8 hr. Heart rate in recumbency was slowed. Marked sedation and a fall in sativary flow followed the same time‐course as the plasma concentration. The cold pressor response was reduced but the Valsalva overshoot was tiftle affected.
The renal elimination of procainamide
Authors: Galeazzi Renato L. , Sheiner Lewis B. , Lockwood Thomas , Benet Leslie Z.
Published: January 2016

The question of pR or flow dependence for the renal elimination of procainamide (PCA) was studied under 4 conditions in each of 4 subjects. Each subject received 500 mg of PCA intravenously at weekly intervals while in astate of (1) acid load (NR4Cl) and water deprivation, (2) acid load and water excess, (3) alkali load (NaRCO3) and water deprivation, and (4) alkali load and water excess. Plasma and urine were collected at frequent intervals for PCA and N‐acetyl PCA (NAPA) analysis. Urine flow rates varied markedly between the water deprivation and water excess states (approximately 1.2 vs 5 ml/min, respectively), and urine pH varied markedly between the acid and alkali load states (pH = ca 5 vs 8, respectively). Despite this marked variation, there were no signijicant changes in PCA renal clearance or 24‐hr PCA or NAPA excretion. If passive diffusion of PCA were taking place, such flow and pR changes would have caused marked changes in PCA clearance were the pH partition hypothesis true. We therefore conclude that passive diffusion is not an important mechanism in the renal elimination of PCA in man and that there must be tubular secretion. The implication for the clinical use of the drug is that dose adjustments need not be made in response to variations in urine flow and pH.
Erythromycin and clindamycin absorption and elimination in pregnant women
Authors: Philipson Agneta , Sabath L. D. , Charles David
Published: January 2016

Thirty‐nine pregnant women admitted for therapeutic abortions during early or mid pregnancy were given erythromycin estolate, erythromycin base, or clindamycin hydrochloride orally in single or multiple doses. Peak serum levels oj clindamycin were 3.4 to 9.0 µg/ml foliowing a single dose of 450 mg, whereas peak serum levels of erythromycin were 0.29 to 7.2 µg/ml foliowing 500 mg in a single dose. The individual variability of serum concentrations of erythromycin was greater than that reported in normal men and nonpregnant women, whereas the serum levels of clindamycin were rather uniform, and similar to what has been reported in nonpregnant individuals. Following multiple doses of each antibiotic, high serum levels were obtained in virtually all subjects, and urine levels were also higher. Following single doses the mean urinary recovery was 2% for erythromycin and 16.8% for clindamycin.
Spironolactone. I. Disposition and metabolism
Authors: Karim A. , Zagarella J. , Hribar J. , Dooley M.
Published: January 2016

This study describes absorption, excretion, and metabolism of [20−3 H]‐spironolactone (SP) in 5 healthy men. After a single oral dose (200 mg + 200 p,Ci) of the drug given in alcoholic solution, the peak serum levels of the ethyl acetate‐extractable tritium and the dethioacetylated metabolite canrenone were 763 ± 400 ng/ml (mean ± SD) and 415 ± 145 ng/ml, respectively. These levels occurred within 3 hr. The serum half‐life (T½) of the extractable materials was 37.3 ± 6.53 hr. Canrenone levels declined in two phases. The Tdrom 2.5 to 12 hr was 4.42 ± 1.07 hrandfrom 12 to 72 hr was 16.8 ± 2.75 hr. In the blood both SP and canrenone were confined largely in the plasma, and their protein binding exceeded 89% at concentrations of 550 and 710 ng/ml, respectively. In 5 days 31.6 ± 5.87% of the radioactivity was excreted in the urine and 22.7 ± 14.1% in the feces. Unchanged SP was not detected in the urine. The major urinary metabolites were canrenone (5.04 ± 2.83% of dose), 6ß‐OH‐sulfoxide (5.21 ± 0.93% of dose), and canrenoate ester glucuronide (6.2% of dose).
Spironolactone. II. Bioavailability
Authors: Karim A. , Zagarella J. , Hutsell T. C. , Chao A. , Baltes B. J.
Published: January 2016

The bioavailability of commercial 25‐mg spironolactone tablets and a new tablet preparation containing 100 mg of the drug has been determined in 12 healthy male subjects. After a 200‐mg oral dose of the drug given in a solution of polyethylene glycol‐400, the peak plasma level of the dethioacetylated metabolite canrenone was 633 ± 154 ng Iml (mean ± SD) and was reached at 1.4 ± 0043 hr. This peak was higher and was achieved earlier than after either eight 25‐mg tablets (480 ± 155 ng/ml at 2.9 ± 1.03 hr) or two 100‐mg tablets (474 ± 182 ng/ml at 3.0 ± 1.37 hr). From the ratio of the 24‐hr area under the plasma concentration‐time curves, the bioavailabilities of the two tablet preparations relative to the solution were 99.6 ± 18.2% and 92.1 ± 22.9%, respectively. The amount of canrenone excreted in the urine by 48 hr was 4048 ± 1.26 mg (solution), 6.36 ± 2.02 mg (eight 25‐mg tablets), and 7.81 ± 1.87 mg (two 100‐mg tablets), representing 2% to 4% of the administered dose. It is concluded that urinary excretion of canrenone alone is not a reliable method for determining the bioavailability of spironolactone.
Spironolactone. III. Canrenone—maximum and minimum steady‐state plasma levels
Authors: Karim A. , Zagarella J. , Hutsell T. C. , Dooley M.
Published: January 2016

Steady‐state plasma levels of canrenone have been examined in 23 healthy men who received repeated doses of spironolactone for 15 days. The dose regimens were 200 mg once a day and 50 mg 4 times a day. With both treatments the steady‐state levels were reached after 3 to 4 days. With once‐a‐day treatment, the maximum and minimum steady‐state levels were about 500 and 100 nglml, respectively. The minimum levels with treatment 4 times a day were about 200 ng/ml. The post steady‐state half‐life of canrenone with once‐a‐day treatment (19.2 ± 6.57 hr) was longer (p < 0.01) than the half‐life obtained in the 4‐times‐a‐day treatment (12.5 ± 3.39 hr). The former half‐life was similar to the log‐linear phase half‐life of canrenone in the single‐dose studies.
Lead intoxication: Effects on cytochrome P‐450‐mediated hepatic oxidations
Authors: Alvares Alvito P. , Fischbein Alf , Sassa Shigeru , Anderson Karl E. , Kappas Attallah
Published: January 2016

Acute administration of lead to rats caused significant decreases in cytochrome P‐450, ethylmorphine N‐demethylase, and aniline hydroxylase activities and prolonged hexobarbital‐induced sleeping times. However, chronic administration of lead to weanling rats caused no significant changes in hepatic cytochrome P‐450 levels or in the microsomal oxidative enzymes over a 12‐wk period. Eight patients exposed to lead in the process of burning through lead‐painted steel structures for at least 3 mo showed marked effects of chronic lead intoxication on the erythropoietic system: inhibition of erythrocyte δ‐aminolevulinic acid dehydratase, increased erythrocyte protoporphyrin levels, and increased urinary excretion of δ‐aminolevulinic acid. Chelation therapy greatly alleviated the inhibitory effects on dehydratase activity and decreased urinary δ‐aminolevulinic acid excretion. The plasma elimination rate of antipyrine, a drug primarily metabolized by hepatic microsomal enzymes, was determined in the 8 subjects prior to and following chelation therapy. In 7 of 8 subjects, chelation therapy shortened the antipyrine half‐lives, but the effect was minimal. These studies show that chronic lead exposure results in significant hematopoietic inhibition of the heme biosynthetic pathway without causing significant changes in hepatic cytochrome P‐450‐associated enzymic activities.
Pharmacokinetics of divided‐dose ifosfamide
Authors: Nelson Robert L. , Alien Larry M. , Creaven Patrick J.
Published: January 2016

The pharmacokinetics of a divided‐dose schedule of ifosfamide was investigated in 3 patients given 1,600 to 2,400 mg/sq m/day for 3 days, with a second course of treatment 21 days later. In contrast to the biexponential decay seen with single‐dose ifosfamide (5,000 mg/sq m), data for divided low‐dose plasma ifosfamide are best fitted by a monoexponential decay function compatible with a one‐compartment open model. Plasma half‐life for ifosfamide given in the divided‐dose schedule was 6.9 hr, less than half that previously reported for high single‐dose ifosfamide. Renal excretion rates and clearances for unchanged drug were similar in both schedules. The proportion of drug metabolized was larger and amount of unchanged drug excreted in the urine was smaller than after single large doses. The elimination constant for unchanged ifosfamide increased from day I to day 2 of treatment and remained relatively stable from day 2 to day 3 in the multidose regimen, with all parameters reverting to the pretreatment values 21 days later.
A bureaucratic determinant of scientific precedence or: “Scooped by the drug lag”
Authors: Morgan John P.
Published: January 2016

The lust for precedence in publication is the most important dirty secret of the scientific working class. Certainly, scientists know that hasty publication may be inaccurate, or that the first announcement of a finding may at best pale before the significance of further workings and modifications of that finding. Regardless, the mental restlessness of scientists may be as much due to anguish provoked by searching Current Contents for a feared scooping, as to struggles for the next truth.
Observations on the pharmacokinetics of acebutolol
Authors: Kaye C. M. , Kumana C. R. , Leighton Monica , Hamer John , Turner Paul
Published: January 2016

Using a balanced, randomized, crossover design, single intravenous (1 mg/kg) or oral (3 X 100 mg) doses of acebutolol were administered at weekly intervals to 6 healthy volunteers. For each subject venous blood samples and timed urine collections were obtained after each treatment. Plasma and urinary acebutolol levels were measured by a spectrophotometric method that measures acebutolol and its N‐acetyl metabolite (which has equivalent cardiac activity). Using a computer program, various pharmacokinetic parameters were estimated from the data of each subject. From the intravenous data (obtained up to 6 hr after dosing), the following mean (±SD) values were found: distribution half‐life (T½D), 0.60 (±0.43) hr, plasma elimination half‐life (T½El), 3.2 (±1.1) hr, apparent volume of distribution (VD), 224 (±69) L, and apparent VD/kg, 3.0 (±0.8) L/kg. Using the oral data (obtained up to 10 hr after dosing), the value for T½El was 3.2 (±0.9) hr. The mean cumulative urinary recovery (expressed as % dose) after the intravenous route was about 60%, while that after the oral route was of the order of 35%, suggesting that about half of the oral dose reached the systemic circulation. The mean creatinine clearance of the 6 subjects was 103 (±7) ml/min, while the value (obtained between 2 and 4 hr after intravenous dosing) for renal clearance of acebutolol as measured was 298 (±68) ml/min and the corresponding plasma clearance was 818 (±64) ml/min. These results support the occurrence of substantial nonrenal elimination and renal tubular secretion.
Biliary elimination of diazepam in man
Authors: Mahon W. A. , Inaba T. , Umeda T. , Tsutsumi E. , Stone R.
Published: January 2016

The metabolism of 14C‐5‐diazepam has been studied in 5 patients with T tube biliary drainage. A single bolus of 40 to 50 μCi was given intravenously and blood, urine, and bile were analyzed from 5 to 14 days. The mean half‐life of elimination from blood was 93.2 hr; the major metabolite noted in blood was N‐desmethyl‐diazepam. in urine the average recovery of radioactivity was 48.9% and consisted of 3 OH‐diazepam, 4'OH‐diazepam, and oxazepam. in bile the average recovery of radioactivity was 5.35% (corrected to a bile flow of 700 ml was 15.0%) and consisted of the same metabolites as in the urine. Essentially no diazepam or N‐desmethyl‐diazepam was found, and therefore an enterohepatic circulation cannot be held to account for the prolonged half‐life of these substances in man.
Atenolol in essential hypertension
Authors: Myers Martin G. , Lewis Gerald R. J. , Steiner Jan , Dollery Colin T.
Published: January 2016

The effect of atenolol, a beta adrenoceptor autogonist, on arterial pressure in patients with benign essential hypertension has been investigated. Eighteen patients were started on atenolol, 75 mg/day; the dose was increased at 2‐wk intervals to a maximum of 900 mg if tolerated. When the maximum effective dose was determined, each patient was randomly allocated into a double‐blind crossover study comparing atenolol and placebo treatments. The mean supine and erect arterial pressures of the 16 patients completing the run‐in period were markedly reduced by atenolol therapy. The pretreatment mean (± SEM) supine and erect arterial pressures of the 16 patients completing the run‐in period (187 ± 4.7/114 ± 2.6 and 182 ± 4.5/115 ± 3.0 mm Hg, respectively) were reduced (150 ± 5.3/97 ± 2.9 and 151 ± 5.9/100 ± 2.7 mm Hg) with atenolol therapy (p < 0.01). In the crossover study, the mean (± SEM) supine arterial pressure after 8 wk of atenolol therapy in 14 patients (144 ± 5.2/89 ± 1.7 mm Hg) was lower (p < 0.01) than at the end of placebo therapy (163 ± 4.4/105 ± 2.8 mm Hg). Similar reductions in pressure were recorded in the erect position and after exercise. No severe side effects were observed.
Antiarrhythmic efficacy of N‐acetylprocainamide in patients with premature ventricular contractions
Authors: Lee Woong-Ku , Strong John M. , Kehoe Richard F. , Dutcher John S. , Atkinson Arthur J.
Published: January 2016

Oral administration ofa 1.5‐gm dose of N‐acetylprocainamide (NAPA) to 9 patients with premature ventricular contractions (PVCs) confirmed previous indirect evidence that this metabolite of procainamide has antiarrhythmic efficacy and potency comparable to those of procainamide. Although the mechanism by which NAPA acts as an antiarrhythmic drug is not known, it was found that the 6 patients with coupled PVCs responded to NAPA therapy and that the 3 patients without coupled PVCs failed to respond. Coupling interval prolongation also occurred during NAPA therapy in 4 of the 6 responding patients. These observations suggest that NAPA may terminate coupled PVCs by slowing and then interrupting conduction of re‐entrant impulses, as has been proposed for procainamide. NAPA plasma concentrations of 7.4–17.2 f,μg/ml were well tolerated by the patients and produced an average fall of 3 mm Hg in mean arterial pressure and a 7.6% mean increase in corrected QT interval.
Intestinal absorption, demethylation, and enterohepatic circulation of imipramine
Authors: Dencker Hans , Dencker Sven Jonas , Green Anders , Nagy Adam
Published: January 2016

The intestinal absorption and metabolism of single oral doses of imipramine (ip) have been studied in man by portal catheterization. The concentration of ip and the formed desipramine (dmi) was followed in blood‐plasma obtained from the portal and cubital veins. The absorption of ip seemed to be completed 80 min after the administration of the drug. There was no sign of demethylation of ip during the passage across the intestinal wall. Evidence was found of an enterohepatic circulation of both ip and dmi.
Antibacterial activity and pharmacokinetics of bacampicillin and ampicillin
Authors: Rozencweig Marcel , Staquet Maurice , Klastersky Jean
Published: January 2016

Single equimolar oral doses of bacampicillin and ampicillin were given to 9 healthy subjects on a crossover randomized basis. Data were interpreted in terms of a 3‐compartment pharmacokinetic open model. Intestinal absorption of bacampicillin was found to be faster and more complete than that of ampicillin, yielding an increase in bioavailability of 30% to 40% as measured by the area under serum levels curve, the urinary excretion and absorption rate constants. After the administration of bacampicillin, much higher and sharper peaks were achieved in the serum and in the “tissue” water than after the administration of ampicillin. The maximum bactericidal dilution (MBD) of the serum samples taken 1 hr after the administration of the antibiotics against 10 strains of Diplococcus pneumoniae was higher following bacampicillin (p < 0.01), as was the MBD of the 0 to 2 hr urine specimens against 10 strains of Escherichia coli. Further clinical trials are required to accurately assess the possible greater therapeutic effectiveness of bacampicillin than of ampicillin.
Clinical trial methodology in intestinal parasitic diseases
Authors: Botero David
Published: January 2016

The high prevalence of intestinal parasitic infections as an index of underdevelopment, especiaily in tropical countries, is related to poverty, poor housing, lack of sanitation, malnutrition, and ignorance. The effects are lowered work capacity, physical and mental retardation, leading to recurrences and exacerbations of the parasitism and malnutrition. The most prevalent parasites, methods of detection by specific tests in patients in clinical trials involving antiparasitic drugs are dealt with. How and by whom investigations of new drugs should be undertaken, the need for a basic knowledge of parasitology and techniques of the discipline, of biostatistics, and use of such controls as randomized ailotment to treatment groups, placebo administration, and double‐blind assessments are emphasized. The justification for undertaking an evaluation of an antiparasitic drug is predicated on the demonstration of safety in exhaustive in vitro and animal studies and of the drug' s potential superiority as to efficacy and lower incidence of unwanted side effects, as compared with existing agents. Tolerance and dose‐range studies should be conducted in male adult hospitalized patients under close supervision. The evaluation of amebicides in clinical trials, as weil as of anthelmintics, is considered in terms of differentiation and reproductive habits of specific causative agents and tests for detecting their elimination to determine improvement under drug therapy. The problem of reinfection, particularly of nonhospitalized patients under the adverse conditions of life, is stressed.
Patterns and problems of drug consumption in a developing country
Authors: Káldor A.
Published: January 2016

Delayed and sometimes total lack of communications, lower standards of medical care, low physician :population ratio, absence of monitoring systems affect alt phases of drug consumption in developing countries—from procedures for introducing a new drug to its marketing on a broad scale, and ultimate decline. The number of prescriptions and the choice of drug are determined only partly by physicians. Such other factors as medicaments furnished by the government either free or at a small charge, the type of health service, accessibility to paramedical and nonmedical advice, as well as hard‐sell marketing practices, often through the mass media, tend to set the pattern of drug usage. The practice of drug storing in “home pharmacies,” a phenomenon surveyed by the author, is described and the reasons for it analyzed. In general, the categories of drugs (e.g., antibiotics, cardiovascular, analgesics) consumed are the same as in the rest of Europe, the United States, and Latin America. Among the minor tranquilizers, the consumption of meprobamate has risen by about a third, chlordiazepoxide markedly, while phenobarbital consumption has remained about the same from 1969 to 1973. This is said to illustrate the pattern of an upward curve in consumption of a new drug, and the displacement of an old one. The overall rise of these drugs during this period was 72.1% in Hungary. Similar surveys are reported for oral hypoglycemic and antiarrhythmic drugs. Of hypotensive drugs, rauwolfia usage has declined and methyldopa has increased by over 200%.
Session IV. Prevalence and variability of disease; Culture, morbidity, and the effects of drugs
Authors: Blackwell Barry
Published: January 2016

In the evaluation of drug efficacy, despite the customary device of randomization, regional differences of prevalence of a given disease, unique culturally determined practices in treatment, and differential tolerances to side effects are complicating factors in transeultural pharmacology that must be taken into account in the interpretation of efficacy and toxicity. This thesis is doeumented by illustrations from psychiatrie practice, e.g., prevalence and morbidity of alcoholism, cultural differenees as to prevalenee, diagnosis, and symptomatology of schizophrenia, even to the point of widely discrepant diagnosis of a given patient, depending upon whether the examination was done by an American or British psychiatrist. Similar differenees concerning the existence of disease entities other than psychiatrie are cited, e.g., hepatic insufficiency eonsidered eommon in some Latin populations; low blood pressure a recognized and treatable condition in Eastern Europe. The ineidence of side effeets from the same drug may also vary in different cultures, making the interpretation of their significance difficult, and cross‐cultural comparisons hazardous. To avoid some of these pitfalls, it is essential to recognize (1) the many complexities inherent in trials involving differing cultures and (2) to design the studies insofar as possible to include measurement of population variables.
A completely absorbed oral preparation of digoxin
Authors: Johnson B. F. , Bye Carole , Jones Glynne , Sabey G. A.
Published: January 2016

Digoxin absorption was studied in healthy volunteers by determination of peak plasma concentrations, areas under plasma concentration curves, and urinary excretion after single‐dose administration. By comparison with an aqueous solution, increased rate and extent of absorption occurred from experimental soft gelatin formulations of digoxin in solution. Enhanced bioavailability of the capsules was not affected by altered volume of contained solvent. Digoxin was considerably better absorbed from capsules than from tablets of moderately high dissolution rate. Mean percentage intestinal absorption was 75% from tablet and 97% from capsules. Reduced between‐subject variability accompanied the enhanced absorptionfrom capsules.
Kinetics of the oral antiarrhythmie lidocaine congener, tocainide
Authors: Lalka David , Meyer Melvin B. , Duce Benjamin R. , Elvin Alfred T.
Published: January 2016

Tocainide, a primary amine analogue of lidocaine, is effective against some experimental and clinical arrhythmias. Its pharmacokinetic behavior was studied in 6 healthy male subjects. Peak blood levels (CB max) and area under the blood concentration‐time curve (AUC) were linearly related to dose with slopes of 0.0067 mcg/ml and 6 min mcg/ml per milligram of dose, respectively. Renal clearance of tocainide averaged 59 ml/min when urinary pH was uncontrolled or acidified, while it was reduced to 13 ml/min during intense sodium bicarbonate loading. Blood levels following intravenous infusion were well described by a 2‐compartment open model with a volume of the central compartment of 0.92 L/kg. The t1/2β was 11 hr and total body clearance was 166 ml/min. Loo‐Riegelman analysis of the absorption rate did not allow unequivocal assignment of an “order” to the absorption process. Bioavailability approached 100%. Administration of drug 5 min after a test meal suppressed CB max 40% but minimally affected AUC. Approximately 50% of the drug was found to be plasma protein bound at clinically effective concentrations.
Effects of dextroamphetamine on psychomotor skills
Authors: Evans M. A. , Martz R. , Lemberger L. , Rodda B. E. , Forney R. B.
Published: January 2016

Twelve healthy male volunteers were given 0,5, 10, 15 mg/70 kg dextroamphetamine orally in a randomized double‐blind fashion. Blood pressure increased linearly with dose while heart rate was unchanged. Although selected individual tests of stance stability and motor function improved in a dose‐related fashion, a generalized improvement in performance was not found. Delayed Auditory Feedback (DAF) failed to show improvement in mental performance after dextroamphetamine.
Effeets of marijuana extract and tetrahydrocannabinol on electroencephalographic sleep patterns
Authors: Feinberg Irwin , Jones Reese , Walker James , Cavness Cleve , Floyd Thomas
Published: January 2016

Marijuana extract, given in daily doses containing 70 to 210 mg delta‐9‐tetrahydrocannabinol (THC), induced effects on sleep that were virtually identical to those produced by the same doses of relatively pure (96%) THC. Both drugs reduced eye movement density with some tolerance developing to this effect. Stage 4 tended to increase with drug administration. Abrupt withdrawal led to extremely high densities of eye movement, increased rapid eye movement (REM) durations, and a sharp but transient fall in stage 4 to baseline levels. These effects may be useful in the elucidation of the pharmacology of sleep. The effects on sleep of THC administration (but not withdrawal) closely resemble those induced by lithium. For this reason, we suggest further studies of THC in affective disorders . Evidence available thus far suggests that THC produces dysphoric symptoms in unipolar but not in bipolar depressed patients; these differences in response may prove of diagnostic value. An adequate therapeutic trial of THC in bipolar depressed patients has not yet been carried out.
Correspondence; Renal elimination of procainamide
Authors: Koch-Weser Jan
Published: January 2016

The artic1e by Galeazzi and co‐workers on renal elimination of procainamide1 is summarized in the table of contents as showing “that the tubular secretion of procainamide is its major route of renal elimination and that glomerular filtration rate, passive absorption, and urinary pH are not of c1inical significance.” This summary is at variance with the results, discussion, and summary of the authors, who conclude that passive tubular diffusion of procainamide is relatively unimportant, but recognize the importance of its filtration through glomeruli. Glomerular filtration is a major and at high serum concentrations may be the predominant mechanism for the renal elimination of procainamide.2‐5 The good correlation between renal clearances of creatinine and procainamide makes the former clinically useful in the individualization of procainamide dosage.4
Therapeutics and government: 1776 and 1976
Authors: Abrams William B.
Published: January 2016

It may be of interest to those who struggle to cope with the bewildering array of new and proposed regulations dealing with drug use to note that our predecessors in the Colonies were not spared the agonies. In 1649 a law was passed in Massachusetts which prohibited practitioners from putting “forth any act contrary to the known approved Rules of Art, in each Mystery and occupation, nor exercise any force, violence or cruelty upon, or towards the body of any, whether young or old (no, not in the most difficult cases), without the advice and consent of such as are skillful in the same art or at least some of the wisest and gravest then present, and consent of the patient or patients if they be mentes compates .... ”9 The legislators were certainly thinking of patients' rights and professional standards. In 1665 the Duke of York extended this law to cover New York and New Jersey.
Studies on digitalis. VI. The effect of heparin on serum protein binding of digitoxin and digoxin
Authors: Storstein Liv , Janssen Helge
Published: January 2016

The aim of the present study was to investigate the nature of the previously reported changes in the serum protein binding of digitoxin and digoxin in uremic patients under treatment with hemodialysis. Kinetic studies on protein binding during hemodialysis showed that the free fraction of digitoxin rose from 2.6% to 6.9% after 5 min of hemodialysis and remained elevated during the dialyzing period. Free digoxin rose from 78.3% to 87.1 % during the same period. In vitro hemodialysis experiments showed that such changes occurred only in vivo. Injection of heparin (5,000 IU) to control subjects produced similar kinetic changes in the protein binding of digitoxin and digoxin. Free fatty acids changed in the same way. These results indicate that the heparin‐induced release of free fatty acids causes displacement of digitoxin and digoxin from their albumin‐binding sites. Patients on hemodialysis have lower serum levels of digitoxin and cardioactive metabolites (mean, 8.9 ng/ml) than control patients (mean, 16.7 ng/ml) (p < 0.005) on similar doses (mean, 0.085 mg/day). They should be maintained on the same digitoxin doses as uremic and control patients, but serum digitoxin levels should be adjusted to 10 to 15 ng/ml in hemodialysis patients compared to 15 to 25 ng/ml in uremic patients and in patients with normal renal function.
Plasma binding and the affinity of propranolol for a beta receptor in man
Authors: McDevitt Denis G. , Frisk‐Holmberg Marianne , Hollifield John W. , Shand David G.
Published: January 2016

The effects of plasma drug binding on the relationship between propranolol concentration and the antagonism of isoproterenol tachycardia have been investigated in 8 normal subjects and 8 hypertensive patients. During chronic intravenous infusion of propranolol giving a narrow range of total plasma concentrations (22.5 to 50 ng/ml), there was, at best, a poor correlation with effects. On the other hand, there was excellent correlation between efficacy and free drug concentration, which fitted the predictions of the receptor theory of competitive antagonism. The true affinity constant for the binding of propranolol to its receptor can be calculated in terms offree drug concentration (KAfree) and was found to vary 2‐fold compared to the a.ffinity constant in terms of total plasma concentration (KA4 total) which varied 4‐fold, the greater variation being due to plasma binding differences. Compared to normal subjects, KAfree and KAtotal were smaller in hypertensive subjects, implying lesser sensitivity to the drug, and plasma propranolol binding was greater. There was no difference in KAfree between high‐ and low‐renin essential hypertensives, but KAtotal was smaller in the high‐renin group due to increased plasma binding which did not reach statistical significance. It is concluded that the effect of propranolol on heart rate is a predictable function offree drug concentration in man and that the contribution of individual variation in receptor sensitivity to differences in oral dosage requirement is minor compared to that of variations in bioavailability.
Antipyrine: Radioimmunoassay in plasma and saliva following administration of a high dose and a low dose
Authors: Chang R. L. , Wood A. W. , Dixon W. R. , Conney A. H. , Anderson K. E. , Eiseman J. , Alvares A. P.
Published: January 2016

A simple and sensitive radioimmunoassay has been developed for the determination of antipyrine levels in plasma and salim of man. Antiserum to antipyrine was obtained from rabbits immunized with an immunogen prepared by covalently coupling N‐(4‐antipyrinyl)‐succinamic acid to bovine serum albumin (BSA). The radioimmunoassay can detect antipyrine levels as low as 10 ng/ml of plasma or saliva, using a 0.1‐ml sample. This contrasts with the sensitivity of a commonly used spectrophotometric method that can measure about 4,000 ng/ml using a 2‐ml plasma sample. Agreement between the radioimmunoassay and spectrophotometric assay of antipyrine was excellent for plasma (r = 0.98) and saliva (r = 0.97) when samples were analyzed from 6 subjects receiving 18 mg/kg of antipyrine. The correlation between plasma and saliva antipyrine half‐lives using the radioimmunoassay and an 18 mg/kg dose of antipyrine was r = 0.90 (p < 0.005). After a dose of 1.8 mg/kg of antipyrine, the drug disappeared monoexponentially from plasma and salim for at least 51 hr, and the correlation between plasma half‐life and saliva half‐life was r = 0.97 (p < 0.001) in the 6 subjects. Excellent agreement was also observed between half‐lives after the high and low doses of antipyrine (r = 0.99, p < 0.001 for plasma and r = 0.98, p < 0.001 for saliva).
The enantiomers of phenprocoumon: Pharmacodynamic and pharmacokinetic studies
Authors: Jahnchen Eberhard , Meinertz Thomas , Gilfrich Hans-Joachim , Groth Ulrich , Martini Albrecht
Published: January 2016

The pharmacodynamics and pharmacokinetics of the optical enantiomers of phenprocoumon were studied in 5 normal subjects and compared to the racemic mixture. Each subject received a single oral dose of 0.6 mg /kg of racemic, S (−), and R (+) phenprocollmon. S (−) phenprocoumon was 1.6 to 2.6 times as potent as R (+) phenprocollmon when the area under the effect/time curve was used to quantify the total anticoagulant effect per dose. Comparing the plasma concentrations that elicited the same anticoagulant effect, S (−) phenprocoumon was 1.5 to 2.5 times as potent as R (+) phenprocoumon. The anticoagulant activity of the racemic mixture was between that of the enantiomers. There was no distinct difference in the rate of elimination between the enantiomers. The apparent volume ()f distribution and the plasma clearance for S (−) phenprocoumon were less than those for R (+) phenprocoumon. When the binding of the enantiomers to human serum albumin was compared, S (−) phenprocoumon was more highly bound than R (+) phenprocoumon. The protein binding of racemic phenprocoumon was between that of the enantiomers. The results show that S (−) phenprocoumon is a more potent anticoagulant than R (+) phenprocoumon and that the pharmacokinetic d~fferences between the enantiomers are due mainly to differences in their distribution.
Paradoxical urinary excretion of o‐glucaric acid in acute viral hepatitis
Authors: Sorrell Michael F. , Burnett David A. , Tuma Dean J, , Barak Anthony J.
Published: January 2016

The urinary excretioll of D‐glucaric acid alld the plasma clearance of antipyrine were estimated dllring the acute phase of viral hepatitis and agaill during recovery. The plasma c1earallce of antiprrille was impaired durillg the acute stage of hepatitis, while the IIrillarr excretioll of D‐gilicaric acid was paradoxically high. Both parameters returned to Ilormal dllring recovery. These filldings suggest that the lise of urinary D‐glucaric acid excretion as an illdex of microsomal ellzyme induction is unreliable whell there is liver injury.
Factors affecting antipyrine metabolism in West African villagers
Authors: Fraser Henry S. , Bulpitt Christopher J. , Kahn Clare , Mould Geoffrey , Mucklow John C. , Dollery Colin T.
Published: January 2016

Saliva half‐life of antipyrine was studied in 49 healthy Gambians between 20 and 60 yr of age of whom 27 were male (mean age, 44.5) and 22 female (mean age, 39.1). Body weight, height, ponderal index, albumin, and hemoglobin were moderately reduced compared to accepted normal values. Antipyrine half‐life was 13.6 ± 0.58 (SEM) hr. Multiple regression analysis showed that sex, cola nut consumption, hemoglobin in women, and height in men were statistically significant independent predictors of antipyrine half‐life. Half‐life was shorter in women, decreased with an increase in height in men, and was prolonged by cola nut consumption. Half‐life in women increased with hemoglobin. These factors explained 36% of the variation and suggest that geographic differences in the environment could be important in drug metabolism in man.
Effect of sulfasalazine on digoxin bioavailability
Authors: Juhl Randy P. , Summers Robert W. , Guillory J. K. , Blaug Seymour M. , Cheng Frank H. , Brown Donald D.
Published: January 2016

Low levels of digoxin were noted in a patient receiving digoxin and sulfasalazine (SSA). Discontinuation of SSA resulted in a significant increase in serum digoxin levels. To determine whether or not SSA consistently interfered with the therapeutic effect of digoxin, both drugs were administered to 10 normal subjects in a crossover study. Each received 2 doses of digoxin (0.5 mg, elixir): one dose given alone, and a second dose after 6 days of treatment with SSA. When digoxin was given with SSA, the average area under the serum digoxin curve fell from the control value of 8.79 ng hr ml−1 to 6.66 ng hr ml−1 (p < 0.05), fell and total urinary excretion decreased from 278 mcg/10 days to 228 mcg/10 days (p < 0.025). These changes suggest interference with the bioavailability of digoxin by SSA. Studies were conducted to determine whether SSA inhibited digoxin absorption by physically absorbing the glycoside from solution. In vitro tests failed to reveal any significant adsorptive properties for SSA.
Effect of furosemide on the renal excretion of digoxin
Authors: Brown Donald D. , Dormois John C. , Abraham George N. , Lewis Kathy , Dixon Keith
Published: January 2016

Digoxin serum and urine levels were determined by radioimmunoassay in 6 subjects (4 patients with heart disease and 2 volunteers without heart disease) who had been maintained on oral digoxin (0.25 or 0.5 mg daily). Observations were made during a 3‐day control period and then during 8 days of concomitant digoxin and oral furosemide (40 mg daily) therapy. Serum digoxin levels determined 10 and 24 hr after each dose of digoxin averaged 1.2 ± 0.1 ng/ml (M ± SE) during control and 1.3 ± 0.1 during the last 3 days on digoxin and furosemide. The daily urinary excretion of digoxin averaged 51 ± 6% of the oral dose during control and 52 ± 6 during the entire period of furosemide administration. The renal clearance of digoxin and creatinine averaged 94 ± 7 and 87 ± 11 ml/min, respectively, during control; corresponding values were 88 ± 8 and 85 ± 9 for urine collections demonstrating a distinct diuretic effect of furosemide and 87 ± 8 and 75 ± 10 for urine collections not demonstrating such an effect during diuretic therapy. The results suggest that the diuretic effect of furosemide does not significantly affect the excretion of digoxin.
Protein binding of salicylate in uremic and normal plasma
Authors: Borgå Olof , Odar‐Cederlöf Ingegerd , Ringberger Vivi‐Ann , Norlin Allan
Published: January 2016

Protein binding of salicylate was studied by equilibrium dialysis at 37° C in plasma from uremic patients and healthy subjects. The protein binding was considerably lower in the uremic plasma at all salicylate concentrations studied (14 to 1,400 μg/ml). Scatchard plots of the data were computer‐analyzed assuming binding to two classes of binding sites. According to this analysis, the binding to the class of primary binding sites was considerably decreased in the uremic plasma. In addition to the effect of the uremic state, the binding was considerably decreased at high therapeutic plasma levels and at low albumin levels. The combined effect of two or three of these factors may lead to unexpectedly high unbound fractions of salicylate, which should be considered in the monitoring of plasma salicylate levels in patients.
Effectiveness of intermediate‐term use of secobarbital
Authors: Kales Anthony , Hauri Peter , Bixler Edward O. , Silberfarb Peter
Published: January 2016

Secobarbital, 100 mg, was evaluated in two separate sleep laboratory drug evaluation studies, each with 4 insomniac patients. In both studies, the effect of secobarbital in inducing and maintaining sleep was evaluated, as welt as the effects of the drug on sleep stages. Statistical analysis demonstrated that the results of the two studies could be combined. With short‐term drug administration of secobarbital (up to 3 nights), there was an improvement in both sleep induction and sleep maintenance. Total wake time was decreased 43% below baseline and was consistently decreased in each third of the night. With intermediate‐term drug administration (2 wk), total wake time was decreased only 14% (not statistically significant). Following drug withdrawal, the degree of sleep difficulty returned to baseline levels. The results indicate that secobarbital 100 mg is effective for short‐term use but loses much of its effectiveness with intermediate use and suggest that the drug is of limited value for insomniac patients who require nightly medication beyond aperiod of 1 wk. With short‐term administration, secobarbital induced a slight decrease in rapid eye movement (REM) and slow‐wave sleep and a significant increase in stage 2 sleep. With intermediate administration, sleep stage values were similar to baseline levels. Following withdrawal, there was only a minimal increase in REM sleep above baseline levels, a significant increase in stage 3 sleep, and a significant decrease in stage 2 sleep. The rebound increase in stage 3 sleep is similar to that reported following withdrawal of pentobarbital.
Gastric and biliary excretion of meperidine in man
Authors: Dunkerley R. , Johnson R. , Schenker S. , Wilkinson G. R.
Published: January 2016

The role and importance of enterogastric secretion in the disposition and elimination of the weak base, meperidine (pKa 8.63), was studied after intravenous administration (50 mg) of the drug to 6 normal volunteers. Continuous collection of the gastric fluid over a 4‐hr period demonstrated the establishment of high gastric fluid/plasma concentration ratios for meperidine (mean about 50, range, 10 to 200). However, the total amount of drug recovered, even after correction for incomplete collection, was only a small percentage of the administered dose. Under basal conditions a mean ± SE of 1.9 ± 0.3 mg, equivalent to 3.7% ofthe administered dose, wasfound in the total gastric aspirate. Stimulation of gastric secretion by subcutaneous injection of betazoie (1.5 mg/kg) increased this recovery to 3.6 ± 0.3 mg (7.2%) primarily due to the increase in gastric volume output. Aspiration of the gastric fluid in either the basal or stimulated situation had no observable effect upon the plasma concentration/time profile of meperidine whether assessed by the terminal half‐life, t½β or the plasma clearance; control values were 3.8 ± 0.5 hr and 1,190 ± 130 ml/min, respectively. In 2 subjects “bile fluid” was also collected for 2.5 hr and found to contain less than 0.2% of the administered dose. Enterosystemic recycling is therefore of minor importance in the disposition and elimination of meperidine in man.