bluuebunny/crossref_metadata_2025 huggingface dataset:
Phenytoin: Pharmacokinetics and bioavailability
Authors: Gugler Roland , Manion Carl V. , Azarnoff Daniel L.
Published: January 2016

The pharmacokinetics of a single 300‐mg oral and intravenous and 14 daily 300‐mg oral doses of phenytoin were studied in 6 healthy volunteers. The mean plasma elimination t½ was the same following intravenous (16.8 ± 1.3 hr) and oral (17.1 ± 1.5 hr) doses ofphenytoin; however, following chronic oral administration, the t½ increased to 18.9 ± 1.5 hr (p < 0.05). The absolute bioavailability of an oral dosage form (Dilantin Kapseals) varied from 57.7 to 85.6% when based on the relationship between the corresponding single dose areas under the curve (AUCs). When based on the comparison of the A UC for multiple oral dosing with the single iv dose area, average bioavailability was 85.9% (71.8 to 106.3). Since the variation in the bioavailability and elimination of phenytoin does not allow accurate prediction of the steady‐state plasma concentration, monitoring plasma levels may be of special importance.
Human serum and myocardium digoxin
Authors: Härtel G. , Kyllönen K. , Merikallio E. , Ojala K. , Manninen V. , Reissell P.
Published: January 2016

Linear correlation was demonstrated between serum digoxin and papillary muscle digoxin concentrations in patients undergoing mitral valve surgery. The mean ratio of myocardial tissue to serum digoxin concentrations was 67/1. This result supports the use of serum digoxin as a guide for assessing the degree of digitalization under steady‐state conditions.
Blood ethanol concentrations during and following constant‐rate intravenous infusion of alcohol
Authors: Wilkinson Paul K. , Sedman Alien J. , Sakmar Ermelinda , Earhart Robert H. , Weidler Donald J. , Wagner John G.
Published: January 2016

Blood ethanol concentrations were determined in 7 subjects during and subsequent to a 2‐hr constant‐rate intravenous infusion of ethyl alcohol (8% V/V). Eight to 10 capillary blood samples were collected during the infusion and 10 to 21 samples were obtained after the infusion ceased. Thus, the total time course of blood ethanol concentrations in man was defined, both during and postirifusion. Blood ethanol concentration data from each of 6 subjects were fitted simultaneously to the two equations for the one‐compartment open model with zero order input and Michaelis‐Menten elimination kinetics. The average Vm [0.232 mg/(ml × hr)] and Km [0.0821 mg/ml] obtained from these fittings correspond very closely with corresponding values estimated by the fitting of all the mean concentration‐time data obtained following oral administration of 4 different doses of ethanol to 8 other fasting subjects in another study. A disproportionate increase in area under the concentration‐time curve with increase in dose (gmlkg) was observed in a single subject who was infused with equal volumes of a 4% and an 8% (V/V) ethanol solution at the same constant rate.
Tissue and erythrocyte distribution of digoxin in infants
Authors: Gorodischer Rafael , Jusko William J. , Vaffe Sumner J.
Published: January 2016

The distribution of digoxin in the myocardium, skeletal muscle, erythrocytes, and plasma (or serum) was studied in 19 infants. There was a linear relationship between myocardium and serum concentrations and no saturation was observed over the serum concentration range of 0.5–8.6 ng/ml. Myocardium uptake of digoxin was nearly twice as great in infants as in adults at any given serum concentration. Erythrocyte :plasma concentration ratios of digoxin were one‐third smaller during digitalization than during maintenance digoxin therapy. The latter ratios were also three times greater in infants than found previously in adults. Their findings are consistent with a greater apparent volume of distribution of digoxin in infants and may partly explain the unusually large therapeutic doses needed in infants.
Disposition of propoxyphene and propranolol in children
Authors: Wilson John T. , Atwood Gerald F. , Shand D. G.
Published: January 2016

The disposition of propoxyphene and propranolol was studied in children by means of two protocols which minimized the number of blood samples taken from each child. Propoxyphene and its metabolite, norpropoxyphene, were measured in two plasma samples obtained from different children at various times after a single oral dose. These data were pooled and a plasma concentration/time curve was obtained which was consistent with an average T½ of 3.5 hr in this population. The bioavailability of tablets and a solution of propranolol was compared with a crossover design by obtaining plasma samples at the end of the dosage interval during chronic oral administration of various doses. No clear differences in the bioavailability of the two formulations could be detected. Both drugs showed marked interindividual differences in plasma concentrations following oral administration. These findings are consistent with the high hepatic extraction ratio and large presystemic (first pass) effect previously described in adults. The large individual variability supports the concept of monitoring plasma levels as an aid to therapy and demonstrates that the use of a weight‐adjusted dose in children can be only an approximation for initial treatment.
Azidomorphine: Subjective effects and suppression of morphine abstinence
Authors: Clark Stewart C. , Jasinski Donald R. , Pevnick Jeffrey S. , Griffith John D.
Published: January 2016

In man, azidomorphine, a new morphine congener, constricted pupils, produced morphine‐like subjective effects and euphoria, and suppressed the morphine abstinence syndrome. Azidomorphine was 10 to 50 times as potent as morphine. It is concluded that in man azidomorphine is a typical morphine‐like drug.
Antihypertensive effectiveness of oxprenolol administered twice daily
Authors: Materson Barry J. , Oster James R. , Michael Ulrich F. , Perez‐Stable Eliseo C.
Published: January 2016

Oxprenolol, a beta‐blocker, is an effective antihypertensive when administered 3 or 4 times daily. We evaluated the antihypertensive effect of oxprenolol given twice daily (bid). The subjects were 15 ambulatory men whose standing diastolic blood pressure (BP) was at least 100 mm Hg after 3 wk of treatment with hydrochlorothiazide and oxprenolol placebo. Oxprenolol 40 mg twice daily was then substituted for the placebo. On subsequent weekly visits oxprenolol was titrated to 80 and 160 mg bid if the standing diastolic BP was greater than 90 mm Hg. Blood pressures on the last visit on placebo were compared to those on the last visit on oxprenolol. Standing BP declinedfram 145 ± 4/108 ± 1 to 130 ± 4/98 ± 4 on a mean dose of 256 mg of oxprenolol (p < 0.001 syst.; p < 0.01 diast.). Recumbent BP fell from 146 ± 4/107 ± I to 138 ± 5/93 ± 2 (p < 0.06 syst.; p < 0.01 diast.). During the final week, 13 of the 15 patients were admitted to the hospital for 24‐hr monitoring of BP. The 24‐hr BP readings showed a mean coefficient of variation of 6.6% recumbent and 7.2% standing. We conclude that bid oxprenolol will maintain 24 hr BP control in most patients.
One‐year trials with halofenate, clofibrate, and placebo
Authors: Dujovne Carlos A. , Azarnoff Daniel L. , Huffman David H. , Pentikainen Pertti , Hurwitz Aryeh , Shoeman Don W.
Published: January 2016

The hypolipidemic as well as other laboratory and clinical effects of halofenate, clofibrate, and placebo were compared in 29 patients with type IV hyperlipoproteinemia in a double‐blind, controlled, therapeutic trial of 1 yr duration. Plasma drug levels were obtained to monitor compliance. Clofibrate and halofenate lowered serum triglycerides to a similar extent. The hypotriglyceridemic effect of halofenate was significant only when data from noncompliant patients were discarded. Only clofibrate lowered baseline levels of plasma cholesterol. Very low density lipoproteins were decreased and low density lipoproteins were increased by clofibrate but not by halofenate. Halofenate had a marked hypouricemic effect that was greater than that of clofibrate. The hypouricemic effect of halofenate and clofibrate was paralleled by a concomitant decrease in serum bilirubin. Abnormal increases in serum creatine phosphokinase were observed with both drugs primarily in patients who had abnormal initial levels.
Oral and intramuscular phenytoin
Authors: Wilder B. Joe , Ramsay R. Eugene
Published: January 2016

Twelve epileptic patients, after 1 wk on their previously established oral dose of phenytoin, were given a 50% larger dose intramuscularly for 1 wk after which they were put on an oral phenytoin regimen for 1 wk on a dose one‐half the original oral dose. Plasma phenytoin levels did not show a sharp decrease in the intramuscular (im) nor a dangerous increase in the second oral phase. Those receiving drug once a day maintained remarkably stable levels. By the end of the im phase, patients receiving drug in multiple daily doses had some increase in plasma levels proportional to the dose increase. Seizure control was maintained equally well throughout all phases of the study. Except for local irritation at the site of injection, there were no adverse experiences. The data indicate that the dosage regimen described is suitable for patients on oral phenytoin who have to be transferred to im drug for short periods.
Effects of acetylmethadol on plasma testosterone
Authors: Mendelson Jack H. , Inturrisi Charles E. , Renault Pierre , Senay Edward C.
Published: January 2016

Plasma testosterone levels were measured in a group of 13 men maintained on acetylmethadol for treatment of opiate dependence. Prior to acetylmethadol administration, plasma testosterone levels were within normal adult ranges. Four hours following ingestion of acetylmethadol, plasma testosterone levels were significantly depressed and continued to fall 7–9 hr after drug administration. Plasma testosterone levels remained low 24–25 hr after the drug was taken, but, 48 hr following drug, plasma testosterone levels rose to values approximating those prior to drug. Depression of plasma testosterone levels following acetylmethadol ingestion was not only statistically but also biologically significant, since in many patients the levels were below the normal range for adult males.
Antiarrhythmic effects of a lidocaine congener, tocainide, 2‐amino‐2',6'‐propionoxylidide, in man
Authors: McDevitt Denis G. , Nies Alan S. , Wilkinson Grant R. , Smith Raphael F. , Woosley Raymond L. , Oates John A.
Published: January 2016

Eight patients with frequent premature ventricular contractions (PVCs) were given single oral doses of 2‐amino‐2', 6'‐propionoxylidide hydrochloride (APX),* a lidocaine congener, to investigate the drug's efficacy, toxicity, and pharmacokinetics. Of the 7 patients receiving more than 100 mg, 5 demonstrated at least 60% reduction in PVCs in the 5‐hour period following one of the doses; the responsiveness to APX was similar to that observed when intravenous lidocaine was given to the same patients. There were side effects of transient dizziness, lightheadedness, and nausea in 3 patients 20 to 30 min after doses of 400 to 800 mg; slightly smaller doses in 2 of these patients retained efficacy without side effects. There were no effects on arterial blood pressure, heart rate, or the electrocardiogram of normally conducted beats. Laboratory values remained within normal limits, although the hemoglobin level and hematocrit showed a small but significant fall probably related to repeated blood sampling during the study. Drug plasma levels at 1 and 2 hr after administration and the area under the plasma concentration‐time curve were proportional to dose, and the drug disappeared with a mean elimination half‐life of 14.7 ± 1.7 hr (mean ± SD). Plasma levels resulting in suppression of PVCs ranged from 1 to 5 μg/ml. A mean of 39.7 ± 12.4% of an orally administered dose was recovered unchanged in 48‐hr urine collections. Comparison of the present results with those previously obtained after intravenous administration of APX indicates that oral bioavailability of the drug was essentially complete. APX appears to be a promising orally effective antiarrhythmic drug with suitable pharmacokinetic characteristics to warrant studies designed to establish dosage regimens for chronic therapy.
Heart rate responses during treatment of hypertension with propranolol; The clinical usefulness of the nitroglycerin test
Authors: Zweifler Andrew J. , Hansson Lennart
Published: January 2016

and (2) propranolol in a dose of 160 mglday induces near‐maximal cardiac blockade.
Quinine disposition during malaria and during induced fever
Authors: Trenholme Gordon M. , Williams Roger L. , Rieckmann Karl H. , Frischer Henri , Carson Paul E.
Published: January 2016

Quinine disposition was studied in 5 subjects before and during an experimentally induced infection with a chloroquine‐resistant strain of Plasmodium falciparum and in 2 individuals before and during artificially induced fever. Plasma quinine levels were determined by both a benzene extraction method (QB), which measures principally unmetabolized quinine, and a metaphosphoric acid precipitation method (QMPA), which measures quinine and quinine metabolites. The ratio QB/QMPA in plasma was used to estimate the extent of metabolism of quinine. In all individuals plasma levels of quinine and QB/QMP A ratios were increased during malaria, suggesting impaired hepatic metabolism of quinine. The changes observed during malaria were not due to altered renal excretion of quinine. In 2 subjects in whom fever was artificially induced there were similar changes in quinine metabolism. These observations suggest that quinine dosage should be modified during the initial period of treatment, when symptoms and fever are greatest, in acute falciparum malaria.
The effect of arterial oxygen tension on antipyrine half‐time in plasma
Authors: Cumming James F.
Published: January 2016

Hospital patients with depressed arterial oxygen tensions (PaO2) from pulmonary disease were given antipyrine orally or intravenously. The half‐time (t½) of disappearance from plasma was measured. Other patients with normal Pa02 measurements were treated similarly. Patients whose PaO2 was 55 or below had longer t½ times than those of patients with a PaO2 above 55. This observation parallels that made previously in rats.
Adverse drug reactions—a matter of opinion
Authors: Karch Fred E. , Smith Carol L. , Kerzner Boris , Mazzullo John M. , Weintraub Michael , Lasagna Louis
Published: January 2016

The accurate identification of adverse drug reactions (ADRs) is difficult because ADRs usually present no unique clinical or laboratory findings that demarcate them from the manifestations of concurrent illnesses. The identification of ADRs depends on the clinical assessments of physicians‐sometimes the clinician treating the patient and at other times a clinical pharmacologist. Considering the complex and subjective nature of clinically identifying ADRs, how accurately are ADRs identified? To answer this question, three clinical pharmacologists each independently evaluated 60 selected cases to determine if medication, alcohol, or “recreational” drugs had caused the hospitalization. The three clinical pharmacologists agreed on only 30 cases (50%), and 27 of these were thought to be unrelated to medications. In 19 of the 30 cases about which the clinical pharmacologists disagreed, they disagreed on whether or not a medication‐ or alcohol‐related event had occurred at all. The clinical pharmacologists disagreed with the physicians treating the patient in 22% to 37% of the cases, but because of the differences among the pharmacologists, the treating physicians agreed with at least one of them in 95% of the cases. Complete agreement between the clinical pharmacologists and the treating physicians occurred in 47% of the cases. This degree of disparity in the clinical identification of ADRs shows that the evaluation of ADRs is subjective and imprecise. The accurate identification of ADRs awaits the development of an objective technique for recognizing ADRs.
Effect of smoking on theophylline disposition
Authors: Hunt Susan N. , Jusko William J. , Yurchak Anthony M.
Published: January 2016

The pharmacokinetics of theophylline were examined in a group of nonsmokers and in heavy smokers (1 to 2 packs/day) before and 3 to 4 mo after cessation of cigarette smoking. The half‐life of theophylline in smokers averaged 4.3 (SD = 1.4) hr, significantly shorter than the mean value in nonsmokers (7.0, SD = 1.7 hr). The apparent volume of distribution of theophylline was somewhat larger in smokers (0.50 ± 0.12 L/kg) than in nonsmokers (0.38 ± 0.04 Llkg). The body clearance of theophylline was appreciably larger and relatively more variable in smokers (100 ± 44 ml/min/1.73 m2) than in nonsmokers (45 ± 13 ml/min/1.73 m2). Serum concentrations of thiocyanate, a biotransformation product of cyanide which is inhaled with smoke, were used to monitor the smoking status of the subjects. The body clearances of theophylline showed a good correlation (r = 0.785, p < 0.001) with the serum thiocyanate concentrations. Of the 8 smokers, only 4 managed to refrain from smoking for at least 3 mo, and these subjects showed no significant change in theophylline elimination. The increase in theophylline clearance caused by smoking is probably the result of induction of drug‐metabolizing enzymes that do not readily normalize after cessation of smoking.
Sleep laboratory studies of flurazepam: A model for evaluating hypnotic drugs
Authors: Kales Anthony , Bixler Edward O. , Scharf Martin , Kales Joyce D.
Published: January 2016

The results from six separate evaluations of flurazepam 30 mg in the sleep laboratory were combined to determine the effectiveness of the drug in inducing and maintaining sleep and its effects on sleep stages in a large sample of insomniac subjects. The combined studies provide a model from which a detailed profile of the effects of a hypnotic drug over short‐, intermediate‐, and long‐term conditions can be thoroughly evaluated. Although sleep was significantly improved on the first night of flurazepam administration, peak effectiveness of the drug did not result until the second and third consecutive drug nights. Flurazepam continued to be effective in inducing and maintaining sleep with intermediate‐ and long‐term drug use with only a slight loss of effectiveness with long‐term use. Sleep was also significantly improved on the first and second nights of drug withdrawal. Carryover effectiveness of active metabolites of flurazepam from one drug night to the next drug night and to withdrawal nights is discussed. The clinical implications are discussed with regard to the time of peak effectiveness of the drug, dosage recommendations and schedule, minimizing possible effects of the drug on daytime performance, and the rationale and method for using drug holidays in the treatment regimen. With this comprehensive profile of the drug's actions, the physician is able to more rationally and effectively utilize the drug in treating the insomniac patient. With short‐term administration, flurazepam produced a slight decrease in rapid eye movement (REM) sleep and an increase in REM latency. These effects were much more pronounced with intermediate‐term drug administration, again possibly due to the accumulation of active metabolites. After withdrawal there was no rebound in REM sleep. Stages 3 and 4 sleep decreased progressively through short and intermediate drug administration. With initial withdrawal, there was a slight recovery in both sleep stages.
The background pattern of drug usage in Australia
Authors: Wade Denis N.
Published: January 2016

The pattern of drug usage by urban populations has been studied in two typical Australian cities: Traralgon, Victoria, and Sydney, New South Wales. The study, lasting 1 year, involved questioning of 10% of the residents in households selected by random sampling and records of pharmacists. The questions related to state of health, recurrent or chronic disability, and drug exposures during 2 wk preceding the interview. Figures obtained from the Pharmaceutical Benefit Scheme (a system of partial federal subsidy) and the Morbidity Survey of the Royal Australasian College of General Practitioners showed Australians to be near the top of the world's drug takers, in comparison for example with Americans: between 6 and 7 prescriptions per capita in Australia and between 4 and 5 prescriptions in the United States in 1973. The consumption of over‐the‐counter drugs (OTC) was estimated from the Commonwealth Statistician's figures by subtracting the expenditure for prescription drugs from the total annual ehernist sales—$A450,000, 000. This represents a cost of $A33.85 for every man, woman, and child. Of this amount $A19.07 was spent for OTC drugs, analgesics and cough suppressants being the two largest items. Roughly 60% of Australians average two or more doses of analgesics per day, with some patients consuming 12 or more doses a day. An association between this high consumption of analgesics and an alarming incidence of iatrogenic disease‐analgesic nephropathy and gastrointestinal hemorrage‐is postulated. It is concluded that this level of drug usage must be symptomatic of underlying stresses and pressures of urban society in that country, along wlth a cultural factor of ready acceptance of the social use of drugs.
Variations in disease prevalence in the Americas
Authors: Cedillos Rafael A.
Published: January 2016

Data are presented from North American and Latin American countries of the leading causes of death and death rates, demonstrating the sharp differences based on social and economic development of these respective countries. Whereas ischemic heart disease and malignant neoplasms head the list of deaths in the United States and Canada, infective and parasitic diseases of the gut, with diarrhea very common, are the principal causes of death in Latin America. Nutritional deficiency, the most important contributory cause associated with infections and diarrhea, accounts for the very high infant mortality rate in the lauer countries. These pathologie conditions have a direct relationship to the degree of social and economic level of development in Latin America, and constitute a complex public health problem of enormous proportions.
Respiratory and circulatory effects of intravenous butorphanol and morphine
Authors: Nagashima Hideo , Karamanian Agop , Malovany Robert , Radnay Paul , Ang Manuel , Koerner Spencer , Foldes Francis F.
Published: January 2016

The respiratory and circulatory effects and other side effect liability of intravenous doses of 30 and 60 μg/kg butorphanol, 150 to 300 μg/kg norphine, and a placebo were investigated in a crossover double‐blind study.
Amitriptyline plasma levels and therapeutic response
Authors: Ziegler Vincent E. , Co Bun Tee , Taylor John R. , Clayton Paula J. , Biggs John T.
Published: January 2016

Eighteen depressed outpatients were treatedfor 6 wk with amitriptyline. Clinical improvement was monitored using the Hamilton Depression Rating Scale administered by two psychiatrists blind to the tricyclic used for treatment, dosage, and plasma levels. Amitriptyline and its desmethyl metabolite, nortriptyline, were assayed twice weekly by gas chromatography‐mass fragmentography. For the 17 patients having total tricyclic plasma levels between 0 and 250 ng/ml, there was a negative correlation between the Hamilton score and the mean total tricyclic level (p < 0.01) and amitriptyline level (p < 0.005). The mean nortriptyline level did not signijicantly correlate with the Hamilton score. The 10 patients having me an total tricyclic levels above 95 ng/ml had lower median Hamilton scores at week 3 (p < 0.025) and at week 6 (p < 0.0025) than those whose tricyclics were lower. The percentage of recovered patients increases significantly as the plasma levels rise to 250 ng/ml, the maximum plasma level considered in this study.
Absorption of pyrvinium pamoate
Authors: Smith T. C. , Kinkei A. W. , Gryczko C. M. , Goulet J. R.
Published: January 2016

Pyrvinium pamoate, tablets and suspension, was administered as single 350‐mg doses to 12 healthy male volunteers to determine whether there had been any systemic absorption. Six subjects received tablets and 6 received suspension on the first day; on day 8, subjects received the other dose form. Up to 4 days after administration there was no evidence of drug in blood and urine by spectroflorometric assay. Metabolic studies in rats showed minute quantities of drug in the liver and plasma but not of any metabolites.
Pharmacokinetics and hemodialyzability of cefazolin in uremic patients
Authors: Craig Charles P. , Rifkin Stephen I.
Published: January 2016

Cefazolin may be used in azotemic patients at reduced dosage as suggested by others. Although hemodialysis removes some of the drug, therapeutic levels are maintained throughout dialysis after a single intravenous dose of 500 mg. lmperfect transport from blood to dialysate is related to protein binding but varies with the degree of azotemia. Small amounts of cefazolin may be administered to patients during dialysis by addition to dialysate.
Studies on digitalis. V. The influence of impaired renal function, hemodialysis, and drug interaction on serum protein binding of digitoxin and digoxin
Authors: Storstein Liv
Published: January 2016

The aim of the present investigation is to study digitoxin and digoxin protein binding in patients with normal renal and hepatic function, in patients with uremia, and in patients under treatment with hemodialysis for renal failure. The binding of digitoxin and cardioactive metabolites to serum proteins was studied using equilibrium dialysis (an in vitro chemical assay) alone and in combination with a modified 86Rb method. The following values for protein binding were found: DT‐3 (digitoxin), 95.7%; DT‐2 (digitoxigenin‐bis‐digitoxoside), 96.5%; DT‐1 (digitoxigenin‐mono‐digitoxoside), 98.7'; DT‐0 (digitoxigenin), 92.7'; DG‐3 (digoxin), 21.2 %; DG‐2 (digoxigenin‐bisdigitoxoside), 16.3%; DG‐1 (digoxigenin‐mono‐digitoxoside), 18.5%; and DG‐0 (digoxigenin), 13.3%. In vitro addition of procainamide, phenytoin, heparin, and rifampicillin did not influence the in vitro binding of digitoxin. Protein binding of digitoxin showed small individual variations in patients with normal renal and hepatic junction. Uremia per se did not influence the in vitro binding of digitoxin. There were marked changes in digitoxin and digoxin protein binding during an 8‐hr hemodialysis, digitoxin binding decreasing from 97.1% to 93.7% (p < 0.0025) and digoxin binding from 23.5% to 15.4% (p < 0.05). In the uremic patient the metabolic pattern of digitoxin tended toward a decrease in protein‐bound metabolites.
Plasma levels and effects of metoprolol on blood pressure, adrenergic beta receptor blockade, and plasma renin activity in essential hypertension
Authors: von Bahr Crister , Collste Per , Frisk‐Holmberg Marianne , Haglund Kjell , Jorfelt Lennart , Orme Michael , Östman Jan , Sjöqvist Falke
Published: January 2016

The effects of metoprolol, a selective beta adrenergic receptor antagonist, on blood pressure, beta receptor blockade (antagonist of isoproterenol and exercise tachycardia), and plasma renin activity (PRA) have been compared with those of placebo in 16 patients with essential hypertension. The dose of metoprolol was 25 mg three times daily for 1 wk and thereafter 100 mg three times daily for 5 wk. The mean decrease in blood pressure during treatment with metoprolol was 24 ± 3.8 (SEM)/10 ± 2.1 mm Hg in the lying position and 23 ± 4.419 ± 3.1 mm Hg after 1 min in the standing position. At a dose of 2.9 to 5.4 mg/kg, steady‐state plasma concentrations of metoprolol varied 17‐fold (from 20 to 341 ng/ml) between patients and correlated with the interindividual variability in isoproterenol antagonism (r = 0.58, p < 0.05) and decrease in exercise tachycardia (r = 0.65, p < 0.01). By contrast, neither of these variables correlated with the dose of metoprolol in mglkg. Metoprolol decreased PRA by 67 ± 1.9 and 71 ± 1.2% in the lying and standing positions, respectively. The decrease in the mean arterial blood pressure in the lying position was significantly correlated to the PRA during the placebo period (r = 0.61, p < 0.05) but not to the plasma steady‐state levels ofmetoprolol, the degree of beta receptor blockade, and the decrease in PRA.
Effects of prazosin in patients with hypertension
Authors: Bolli Peter , Wood Alan J. , Simpson F. Olaf
Published: January 2016

A double‐blind placebo crossover trial (2 periods, each of 6 wk) was carried out in 12 patients. In the first period the patients were randomly allocated to either their individual established dose of prazosin or to the same number of placebo tablets; treatment was reversed after 6 wk. Blood pressure was higher by 17/8 mm Hg in the lying posture and by 24/14 mm Hg in the standing posture during placebo than during prazosin treatment. Standing pulse rate and body weight were higher and plasma renin activity lower during prazosin treatment. Postural hypotension occurring 1 to 2 hr after the first few doses was noted in one third of the patients when they resumed prazosin treatment after the placebo course.
Studies on digitalis; VII. Influence of nephrotic syndrome on protein binding, pharmacokinetics, and renal excretion of digitoxin and cardioactive metabolites
Authors: Storstein Liv
Published: January 2016

Serum protein binding of digitoxin was lower (p < 0.05) in 7 patients with nephrotic syndrome (96.2%, SD 1.4) than in 51 control patients (97.3%, SD 0.5). Urine protein binding of digitoxin was 60.1% in the 6 nephrotic patients in whom it was determined. Simultaneous serum and urine measurements of digitoxin and cardioactive metabolites were performed in 5 patients after a single intravenous dose of 0.6 mg digitoxin. A modified 86Rb method was used. Mean T/2 of serum elimination was 4.8 days and 8.1 days in 5 control subjects (p < 0.05). Serum concentrations 24 hr after the dose were lower in the nephrotic group (p < 0.0025). The urine concentration T/2 with a mean value of 5.0 days was not significantly different from controls (7.2 days). The cumulative renal exeretion was higher in the nephrotic group (23.2% of dose) than in controls (15.8%) for 8 days. The excretion during one serum T/2 was the same in the two groups. Increased renal excretion thus explains the shortened serum T/2 in nephrotic patients. Preliminary data on the metabolic pattern of digitoxin and cardioactive metabolites in serum and urine suggested that drug metabolism may be changed in patients with nephrotic syndrome. As renal excretion is enhanced, patients with nephrotic syndrome will require higher doses of digitoxin. They should be maintained at lower than usual serum levels of total drug due apparent increased volume of distribution and hypoalbuminemia with consequent increased free drug fraction.
Blood levels and electroencephalographic effects of diazepam and bromazepam
Authors: Fink Max , Irwin Peter , Weinfeld Robert E. , Schwartz Morton A. , Canney Allan H.
Published: January 2016

Blood levels and electroencephalographic (EEG) data were collected for 2 hr after single oral doses of bromazepam (9 mg), diazepam (10 mg), and placebo in 13 male adult volunteers. Both drugs caused an increase in beta activity (above 13 Hz) and a decrease in alpha activity (9 to 11 Hz) in the EEG. Blood levels of 100 nglml of diazepam or 50 ng Iml of bromazepam were associated with significant changes in EEG beta activity. Temporal changes in the EEG after administration of diazepam or bromazepam paralleled development of plasma levels of these drugs. Although a weakly significant correlation was found between measurable diazepam blood levels and amount of increased EEG beta activity, the relationship between measurable bromazepam blood levels and the degree of EEG changes was not significant. Quantitative EEG is a sensitive continuous response measure, useful in defining cerebral activity, response latency, and relative potency of psychoactive benzodiazepines.
The influence of food on nitrofurantoin bioavailability
Authors: Rosenberg Howard A. , Bates Theodore R.
Published: January 2016

The effect of food on the absorption of five commercial dosage forms of nitrofurantoin varying widely in drug release and dissolution characteristics was assessed in man after oral administration. Four healthy fasting and nonfasting male subjects received. in a crossover fashion. a single 100‐mg dose of microcrystalline nitrofurantoin as an aqueous suspension, three different compressed tablets, and a single 100‐mg dose of macrocrystalline nitrofurantoin in a capsule. Both the absorption and the duration of therapeutic urinary concentrations of nitrofurantoin were significantly increased after administration of the five products to nonfasting subjects. The enhancement in the bioavailability of the drug in the presence offood ranged from 20% to 400%, with the greatest absorption‐enhancing effect occurring with those dosage forms exhibiting the poorest dissolution characteristics. It is concluded that single‐dose comparative bioavailability studies of drug products normally administered with food should be performed in both nonfasting and fasting subjects.
Absolute quinidine bioavailability
Authors: Ueda Clarence T. , Williamson Blake J. , Dzindzio Barry S.
Published: January 2016

The absolute bioamilability of quinidine was studied in II hospitalized patients. A 400‐mg dose of quinidine gluconate was administered to each patient In intravenous infusion and as an oral solution. Drug treatments were separated by a 72‐hr period. In 8 patients. peak plasma quinidine concentrations were reached in 65 min after the oral dose; in the remaining 3 subjects. peak concentrations were reached later. From the ratio of the roral area under the plasma concenfration‐time curves (AUCoralAUCir). the absolute bioamilability of quinidine rangedfrom 44% to 89%, (mean. 72). In 8 patients. the ratio of the total amount of quinidine excreted in the urine in 48 hr (Auoral/Auir) indicated that the extent of quinidine biovailability varied from 47% to 96% (mean. 73). The predicted biovailability of quinidine due to first‐pass effects was 76 = 11%. It is concluded that absorption atter the oral solution was rapid and that the reduction of quinidine bioavailability was due to first‐pass hepatic drug revoral.
Relationship between the pharmacokinetics and pharmacodynamics of procainamide
Authors: Galeazzi Renata L. , Benet Leslie Z. , Sheiner Lewis B.
Published: January 2016

The kinetics of a measure of pharmcologic effect (prolongation of the QT interval) of procainamide, as well as the kinetics of the plasma concentration, urine excretion, and saliva concentration of the drug were investigated in 14 trials in 4 subjects. A single 500‐mg dose was given by rapid intravenous infusion, and frequent subsequent determinations of the above variables were made. A 2‐compartment pharmacokinetic model with a third compartment for the saliva was used to fit the plasma, urine, and saliva data simultaneously. Analysis of the data reveals that the kinetics of the drug concentrations in saliva and of the pharmacologic effect are indistinguishable. They both must be considered to be d!fferentfrom those of the drug concentration in plasma. Thus, in normal individuals under the conditions of this study, saliva concentrations more precisely indicate the time‐course of drug at a cardiac site of action, although they do not parallel plasma drug concentrations until 6 hr or more after a rapid intravenous infusion. The following average pharmacokinetic parameters for plasma were found: terminal ha(f‐l!fe, 2.9 hr; total clearance, 828 ml!min; renal clearance, 334 ml!min; and steady‐state volume of distribution, 180 L. A verage distribution pseudoequilibrium ha(f‐time (tV2 ex) was 5.2 min from an initial volume of distribution of 36.6 L.
Antihypertensive action of propranolol in man: Lack of evidence for a neural depressive effect
Authors: Guazzi M. , Fiarentini C. , Palese A. , Olivari M. T. , Magrini F.
Published: January 2016

The hypothesis that a neural depressive action is related to the antihypertensive effects of beta blockers has been evaluated in 14 essential hypertensive male patients through the circulatory response to noxious stimuli. The pressor reaction to mental arithmetic was primarily mediated by cardiac stimulation (beta receptors activation), that to cold by vasoconstriction (alpha receptors activation). Arithmetic and cold were tested to separate the effects of peripheral beta blackade from possible neural and other influences. After propanolol (320 mg per day for 3 wk): (1) The baseline pressure was reduced; (2) appearance, peak, and disappearance time of the circulatory reaction to either stimulus was not altered; (3) the pressor e.ffect of arithmetic was decreased in an extent proportional to the reduced rise of cardiac output; and (4) pressure during cold reached the pretreatment levels through an augmented increase of vascular resistance. Our findings indicate that propranolol depresses only the circulatory reactions mediated through beta receptors activation and provide no evidence of effects other than beta blockade.
Colestipol in familial type II hyperlipoproteinemia: A three‐year trial
Authors: Harvengt C. , Desager J.-P.
Published: January 2016

Colestipol. a new bile acid sequestrant polymer. has been shown to lower the serum cholesterol level more than 30% in 13 patients with familial type 11 hyperlipoproteinemia. Placebo for 6 wk was followed by colestipol for periods up to 36 mo. A slight but not significant increase of serum triglyceride concentrations was observed during the first 18 mo. but they returned to values under the baseline level thereafter. No signs of impaired intestinal fat resorption were noted. Side effects were primarily gastrointestinal (mild and transient constipation). Colestipol seems to be an effective and safe drug in the treatment of the familial type 11 hyperlipoproteinemia. without escape phenomenon.
Effects of marihuana‐dextroamphetamine combination
Authors: Evans M. A. , Martz R. , Rodda B. E. , Lemberger L. , Forney R. B.
Published: January 2016

Under a double‐blind, randomized, complete block design, subjects were given either placebo or 10 mg 170 kg dextroamphetamine sulfate (A) orally followed 1½ hr later by a marihuana cigarette (M) prepared to deliver 50 ug/kg delta‐9‐tetrahydrocannabinol OHC), Statistical analyses sliggested that heart rate and blood pressure increased ill an additive manner when both drugs where given. Eleclrocardiogram changes, when present, were nonspecific in character and appeared to be associated with marihuana. III a second study psychofllotor performance was evalualed by a similar design using doses of 10 mg/70 kg of A and M prepared 10 deliver 25 ug/kg THC. Impairment was related 10 smoking of M, and no difference could be dislinguished belween M alone and M‐A combination. Subjective evaluation, as measured by the modified Cornell Medical Index (CMI) demonslraled only additive effects for the combination.
“Uninformed” consent and the wealthy volunteer: An analysis of patient volunteers in a clinical trial of a new anti‐inflammatory drug
Authors: Hassar Mohammed , Weintraub Michael
Published: January 2016

After a 16‐week clinical trial of a new anti‐inflammatory drug, the participants were given a factual test to determine whether they had understood and remembered the information given them when consent was solicited. They filled out a questionnaire about their reasons for volunteering and their views on clinical studies and on medical practice in general. Demographic information was also obtained. Two thirds of the participants did not remember that they had been informed about potential risk (gastrointestinal ulceration). Some subjects remembered, but misunderstood, what they had been told; others developed erroneous ideas about the trial and the study drug. The volunteers agreed to participate in the study to help both their own arthritis and that of other patients. They took pride in their self‐sacrifice and in being commended by their friends for their altruism. Analysis of the demographic data shows that indigent persons are not necessarily the most likely to participate in clinical trials. Two thirds of the subjects were from the middle class. The median family income was $13,000. To improve the informed consent procedure, we recommend group meetings in which the participants in a clinical trial can discuss the protocol and the risks of the study. Obtaining consent again, after initial anxiety has decreased, may improve comprehension.
Pharmacokinetics of oxprenolol in normal subjects
Authors: Mason William D. , Winer Nathaniel
Published: January 2016

The effect of oxprenolol administered intravenously (10 and 20 mg) and orally (20, 40, 80, and 160 mg) on plasma concentrations of the drug, resting heart rate, exercise‐induced tachycardia, and arterial blood pressure was assessed as a function of time in 6 healthy subjects. The pharmacokinetics of oxprenolol following intravenous administration are best described as 2‐compartnent open model with dose‐dependent parameters. The mean (±SD) plasma ha(f‐life for oral doses is 1.94 ± 0.37 and for intravenous doses is 2.31 ± 0.64 hr. After oral administration, peak plasma concentrations are reached within 30 to 90 min, and the area under the plasma concentration‐time curve varies linearly with the dose. Comparison of oral and intravenous data reveals the variation in bioavailabilty Qf orally administered oxprenolol to range from 19% to 74%. Unlike propranolol, oxprenolol does not show a saturable “first‐pass” elimination effect. Blockade of β‐receptors occurs at plasma levels in excess of 60 ng/ml as evidenced by significant reductions in resting heart rate and exercise‐induced tachycardia. Higher plasma concentrations of oxprenolol are required to lower blood pressure compared to those necessary to slow heart rate. These data suggest significant pharmacokinetic d(tferences between oxprenolol and other β‐adrenergic receptor allfagonists.
Bumetanide, a new loop diuretic
Authors: Carrière S. , Dandavino R. , Rochefort F. , Daigneault A. , Lanoix C.
Published: January 2016

The effect of bumetanide on renal function has been compared with that o.ffurosemide and a placebo in a double‐blind study in 9 healthy young men. The sequence for oral administration of the drug was subjected to a random assignation based upon the Latin‐square methodology under three different conditions. (I) Normal hydration: The administration of bumetanide (2 mg) produced within the next 4 hr a diuresis comparable to that induced by 80 mg offurosemide. Urinary excretion of sodium, potassium, chloride, calcium, and uric acid also followed comparable patterns. Phosphaturia occurred only under bumetanide. The effect of bumetanide seemed longer lasting. (2) Water loading: The e.ffects o.f bumetanide andfurosemide were comparable with the exception of the phosphaturic effect induced by bumetanide. The action of both diuretics on the diluting segment of the nephron was well demonstrated by the marked depression of CH2O. (3) Water deprivation: The effects o.f the two diuretics were comparable, including depression of TCH2O. In none of these conditions did the placebo produce any significant effect.
N‐Desmethyldiazepam: A new metabolite of chlordiazepoxide in man
Authors: Dixon Ross , Brooks Marvin A. , Postma Edward , Hackman Martin R. , Moore James D. , Schwartz Morton A.
Published: January 2016

Following administration of chlordiazepoxide HCI to man, N‐desmethyldiazepam, a known metabolite of diazepam (Valium), was identified in plasma. The metabolite was identified on the basis of its thin‐layer chromatographic (TLC) mobility, electron‐capture gas‐chromatographic (EC‐GC) retention time, and mass spectrum relative to authentic N‐desmethyldiazepam. Plasma levels of N‐desmethyldiazepam in subjects receiving both single and chronic doses of chlordiazepoxide were determined by an EC‐GC method with a limit of sensitivity of 10 ng/ml using 2‐ml samples and by a radioimmunoassay procedure which had a limit of sensitivity of 20 ng/ml using a 0.1‐ml sample. Both assay methods gave good agreement for the levels of N‐desmethyldiazepam. In subjects receiving a single 30‐mg oral or intravenous dose of chlordiazepoxide, measurable levels of N‐desmethyldiazepam in plasma (10 to 60 ng/ml) were obtained 24 to 72 hr after administration. In 5 subjects receiving 10 mg of chlordiazepoxide three times a day, steady‐state levels of N‐desmethyldiazepam in plasma were reached after about 1 wk of administration. The mean maximum and minimum steady‐state levels of N‐desmethyldiazepam were 260 and 220 ng/ml of plasma, respectively. Similar steady‐state levels were observed on treatment with 30 mg of chlordiazepoxide over 24 hr.
Pharmacokinetics of succinylcholine in infants, children, and adults
Authors: Cook David R. , Wingard Lemuel B. , Taylor Floyd H.
Published: January 2016

The elimination of succinylcholine appears to follow first‐order kinetics with a linear relationship between intensity of effect and logarithm of the dose. Determination of the time‐course of neuromuscular blockade following succinylcholine in infants and children allowed us to compare the rate of recovery and elimination rate constant with those determined by others in adults. The rate of recovery was independent of dose for each age group. The rate of recovery was faster in children than in il?fants; the rate of recovery of infants wasfaster than that of adults. The elimination rate constant for infants was similar to that of children; for both the infants and children the rate constants appeared dissimilar from those of adults.
Aspirin and codeine in two postpartum pain models
Authors: Bloomfield Saul S. , Barden Tom P. , Mitchell ]Jeanette
Published: January 2016

Aspirin and codeine, standard reference analgesics, are frequently used as positive controls in clinical trials of new oral analgesics. In randomized parallel double‐blind studies, single doses of aspirin and codeine were compared with placebo in episiotomy pain (99 patients) and in postpartum uterine pain (130 patients), common models in analgesic trials. With aspirin, 600 and 1,200 mg, in episiotomy pain, analgesia as measured by pain intensity difference (PID) scores began within 1 hr, peaked at the second hour (p < 0.01), and continued to the fifth hour (p < 0.01). In uterine pain, responses with aspirin, 650 mg, were observed to be equally good. With codeine, 60 mg, in episiotomy pain measurable analgesia was present by the second hour and was significant at the fourth hour (p < 0.05); in uterine pain, responses were indistinguishable from placebo throughout an 8‐hr time‐course. Codeine seemed ineffective and therefore unacceptable as a positive control in uterine pain. These data imply that the two postpartum pain models are qualitatively different: episiotomy pain seems sensitive to both aspirin alld codeine, while uterine pain appears sensitive to aspirin but not to codeine.
Drug discovery and introduction: Regulation and overregulation
Authors: Lasagna Louis
Published: January 2016

Ralph Waldo Emerson, one of America's wisest philosophers, wrote the following well over a century ago: