bluuebunny/crossref_metadata_2025 huggingface dataset:
Control of drug utilization in the context of a national health service: The New Zealand system
Authors: Wardell William M.
Published: January 2016

A national health service, which includes government payment for pharmaceuticals, has existed in New Zealand for over thirty years. In terms of clinical pharmacology, its most distinctive feature is that for most of this time there was no control over the access of drugs to the market. Instead, powerful control has always been exerted at an alternate point; namely, the manner in which drugs are utilized in general practice. These controls over utilization stem from the conditions required to obtain reimbursement of drug costs from the government. The controls include restriction of some drugs to hospital pharmacies, restriction to specialists, restriction to use in approved indications, and limits to the duration of supply on a single prescription. The effectiveness of some of these measures has been demonstrated experimentally. Their success probably depends on the existence of a relatively structured system of medical care, particularly with regard to general practice. Controls over drug utilization appear to be a valid and growing alternative to controls over the access of drugs to the market. Since they generally originate from a different source (third‐party payment), the criteria on which decisions are made are more subtle than the “simple” criteria of safety and efficacy customarily demanded by agencies that regulate the access of drugs to the market. Other features of interest in New Zealand include the prOVision of information on clinical pharmacology and therapeutics from sources independent of the pharmaceutical industry; namely, the government and an independent company.
Effects of diethylpropion and d‐amphetamine after subcutaneous and oral administration
Authors: Jasinski Donald R. , Nutt John G. , Griffith John D.
Published: January 2016

The effects of diethylpropion were determined and compared with those of d‐amphetamine in 9 subiects using a crossover design. Diethylpropion produced effects qualitatively similar to those of d‐amphetamine, but significantly less potent. Orally diethylpropion was Yo to 1lt1 as potent as d‐amphetamine while subcutaneously diethylpropion was ;10 to ;20 as potent as d‐amphetamine. A striking difference between diethylpropion and d‐amphetamine was the relatively greater oral efficacy of diethylpropion. Diethylpropion was twice as potent orally as subcutaneously while oral and subcutaneous d‐amphetamine were eqUipotent.
A safe method for rapidly achieving plasma concentration plateaus
Authors: Wagner John G.
Published: January 2016

The classical procedure of administering a loading dose as a bolus intravenous iniection and at the same time starting an infusion at a constant rate could be dangerous or lead to toxicity with certain drugs. Under such conditions the ratio of the initial plasma concentration (Co1) to the steady‐state plasma concentration (Ceq1) is often large. The higher the ratio of drug in tissues/drug in plasma (i.e., the more "two compartment" the drug is) the higher will be the Co1/Ceq1ratio. A method is proposed in which initially a constant‐rate infuSion at the rate of Q1 is given over T hours (0.25 to 3 hr); then the rate is abruptly changed to a lower rate Q 2 which is maintained as long as steady state is desired. A simple relationship is given that shows what the ratio of Q1Q2 must be to attain steady state most rapidly and to minimize the ratio CMAX1C/Ceq where CMAX1 is the maximum plasma concentration attained at time T, iust as the infusion at the higher rate ceases. A simple linear graph is given that allows rapid determination of the needed ratio Q 1Q 2 Variables needed for a given drug to use the method are plasma clearance and plasma half‐life.
Bioavailability and efficacy of a sustained‐release theophylline tablet
Authors: Mitenko Paul A. , Ogilvie Richard I.
Published: January 2016

To determine bioavailability of theophylline in a new dosage form, plasma drug concentration time curves were observed in 5 normal male sub;ects after an intravenous dose of 4 mg per kilogram and after an oral dose of 700 mg as 2 oral tablets. Using kinetic parameters derived from the intravenous study, the mean oral absorption rate constant was calculated to be 0.316 ± 0.042 hr‐l with an absorption half‐time of 2.2 hr. Peak concentrations of 9 mg/l (range 7.9 to 11.7) and concentrations greater than 5 mg/l were observed from 2 to 14 hours after an oral dose. The absolute bioavailability of the oral dosage was 77.1 ± 5.4%. One 350 mg tablet every 12 hours was compared with placebo in a double‐blind Latin square trial in 10 sub;ects with intrinsic bronchial asthma. During active drug therapy, the mean observed theophylline concentration of 11.6 mg/l was associated with a 11.2 ± 2.4% improvement in vital capacity and a 13.0 ± 2.9% improvement in forced eXpiratory volume. It is concluded that this oral theophylline preparation will prOVide therapeutic drug concentrations on a 12 hr dose schedule.
Bioavailability of diphenylhydantoin
Authors: Albert Kenneth S. , Sakmar Ermelinda , Hallmark Margarette R. , Weidler Donald J. , Wagner John G.
Published: January 2016

A four‐way crossover study was performed in 8 adult volunteers using a Latin square design with 4 groups of 2 subiects arranged in order of increasing body weight. Single 100 mg doses of diphenylhydantoin (DPH) sodium were administered as an aqueous solution (treatment A), the innovator's capsule (treatment B), alld a commercially available generic capsule (treatment D). A single 300 mg dose (treatment C) was also administered as three 100 mg (innovator's) capsules. DPH capsules from both manufacturers gave plasma levels that were not significantly different at any sampling time. Although DPH follOWing treatment A was absorbed more rapidly, prodUCing higher initial plasma levels than treatments B and D, the areas under the curves for the three treatments were equivalent. The area under the curve for treatment C was also three times that for treatment B. Plasma DPH concentrations were related to the reciprocal of body weight, but plasma protein binding had no effect on the observed intersubiect variance in plasma levels.
Pharmacokinetics of oral propranolol in chronic renal disease
Authors: Lowenthal David T. , Briggs William A. , Gibson Thomas P. , Nelson Howard , Cirksena William J.
Published: January 2016

Eight volunteers with normal renal function and 11 patients with chronic renal insufficiency were each given propranolol (P), 80 mg orally while in the fasting state. Sera were collected over a 24 hour period and assayed for P by spectl'Ophotofluorometer. Absorption was rapid in both groups. In the patients P appeared in the serum within 0.5 hour of oral administration and maximal concentrations, with mean 154.6 ± 40 ng/ml in 1.5 ± 0.3 hr, whereas in the control group, maximal concentrations, mean 51.6 ± 1.0 ng/ml developed in 2.0 ± 0.19 hr. The mean T% for the patient group was 3.2 ± 0.67 hr and that for the control wa:s 4.4 ± 1.0 hr (p > 0.3).011 chronic administration, the higher the daily dose, the higher the serum level of P and the lower the peripheral renin activity. In vivo hemodialysis of P was very small compared with that in vitro, probably due to protein binding of P.
Gastrointestinal blood loss caused by tolmetin, aspirin, and indomethacin
Authors: Beirne James A. , Bianchine Joseph R. , Johnson Philip C. , Wortham G. Forrest
Published: January 2016

Two independent short‐term studies were conducted to compare fecal blood loss produced by anti‐inflammatory doses of tolmetin, aspirin, and indomethacin administered orally. Thirty healthy volunteers with no known history of gastrointestinal abnormalities were given one drug during a 4 or 6 day treatment period. The fecal blood loss was quantitated on the basis of recovery of previously iniected 51Cr‐tagged erythrocytes in the daily stool collection. No significant increase over control daily fecal blood loss followed tolmetin and indomethacin, but a Significant increase over the control daily fecal blood loss followed the aspirin. Side effects were not reported by any subiect receiving tolmetin but were reported by subiects receiving aspirin and indomethacin.
Absorption and decomposition of potassium‐35S‐phenoxymethyl penicillin
Authors: Hellström Kjell , Rosén Anders , Swahn Åke
Published: January 2016

As evidenced by the nonabsorbable marker included in the test solution, about 45% of the radioactivity given orally as 35S‐phenoxymethyl penicillin (PcV) was absorbed in the upper part of the gastrointestinal tract of healthy men. In gastrointestinal aspirates, about 10% of 35S‐PCV had been degraded to material tentatively identified as the penicilloic acid that was poorly absorbed. There was no evidence of biliary excretion of radioactivity, and it appeared that the excretion of label in the urine (mean, 49%) essentially represented the total uptake of intact drug. The cumulative recovery of 35S‐PCV in “intact” form in the urine averaged about 30% of the dose. Comparisons of the total concentrations of PcV and its metabolite(s) in the plasma (radioassay) and that of the intact drug demonstrated the presence of substantial amounts of microbiologically inactive metabolite(s). The half‐life of this material was considerably longer than that reported for PcV. It is concluded that the incomplete recovery of orally administered PcV in the urine is due not only to a poor absorption but also to decomposition of the drug before as well as after absorption.
Aspects of pharmacology pertinent to the skin
Authors: Handschumacher Robert E.
Published: January 2016

The increased use of systemic therapy in dermatology, as well as the recognition that skin pathology is often a manifestation of systemic disease, has rendered essentially all aspects of pharmacology pertinent to the practice of a dermatologist.
Mechanisms of inflammation
Authors: Melmon Kenneth L. , Bourne Henry R.
Published: January 2016

Fifteen years ago Sutherland and RaIl identified adenosine 3',5'‐monophosphate (cyclic AMP) as an intracellular “second messenger” mediating epinephrine's stimulation of hepatic glycogenolysis.20, 21 The discovery of cyclic AMP triggered a geometrically increasing series of investigations, n which rapidly encompassed much of endocrinology and spread to such diverse fields as neurophysiology, microbiology, plant biochemistry, and the study of cell growth and differentiation.18 More recently, cyclic AMP research has begun to intersect with the equally rapidly growing field of immunology. In the past 3 years, it has been shown that cyclic AMP, acting as a second messenger for vasoactive hormones and mediators of inflammation, modulates a wide variety of immune processes in vitro, and in experimental models of immediate and delayed hypersensitivity and the humoral antibody response (Table I). Both the newly deciphered immunologic “messages” transmitted by cyclic AMP and the hormones that appear to initiate them form a distinctive and consistent pattern. In each in vitro system, cyclic AMP inhibits an immunologic or inflammatory action of one or another subclass of leukocytes; in each system, production of cyclic AMP is stimulated by beta adrenergic catecholamines, histamine, and the E series prostaglandins.
Drug interactions: Clinical significance
Authors: Azarnoff Daniel L.
Published: January 2016

The potential for drug interactions exists in one of thirteen prescriptions, according to a recent study in California.13 There is little doubt that interactions between drugs can have serious clinical consequences, although in general their importance has been overestimated. Recently, physicians have become affiicted by a new disorder, the “drug‐interaction‐anxiety‐syndrome.” In its extreme form, the physician develops therapeutic paralysis that can be quite harmful to the patient, who thereby receives inadequate therapy. A misinterpretation of the importance of drug interactions has arisen because long, uncritical lists of supposed interactions have been published, but are based on animal studies, case reports, and clinical impression without confirmation of their clinical significance. Even when specific drug interactions do occur in humans, their clinical consequences still depend upon the dose, sequence of administration, and, within the patient, genetically controlled factors related to drug metabolism and response.
Effect of prednisolone on the electromechanical activity of isolated human atrial muscle
Authors: Prasad K.
Published: January 2016

The effects of prednisolone in the concentrations of 1, 10, 20, and 40 p,glml on the simultaneously recorded action potential and contractility of human atrial muscles obtained from patients undergoing corrective open heart surgery were studied for 20 to 45 minutes. 1n the concentration of 1 p,glml, prednisolone was ineffective in producing any changes in action potential and contraction in the muscles, but in higher concentrations (10,20, and 40p,glml) it produced concentration‐dependent decreases in contractility and amplitude of action potential, and it lengthened duration of action potential. The effects appeared within 5 minutes. The per cent decreases in the contractility at the end of 20 minutes were approximately 7, 37, and 47 with 10, 20, and 40 µg/ml of prednisolone, respectively. It depressed conduction in the atrium. The effects of prednisolone were reversible. Ouabain in similar preparation shortened the duration of action potential and increased contractility. Prednisolone, 40 µ.g/ml, abolished the ouabain‐induced positive inotropic effect. It appears that prednisolone affects contractility and action potential duration through stimulation of NaLK4‐ATPase. Its probable involvement in the genesis of congestive heart failure and the poor response of digitalis in congestive heart failure in Cushing's syndrome are discussed.
Flurazepam hydrochloride
Authors: Greenblatt David J. , Shader Richard I. , Koch-Weser Jan
Published: January 2016

Flurazepam (Dalmane, Ro 5‐6901) was introduced in 1970 in the United States as an hypnotic. Its popularity has increased rapidly. In 1973 more than 6.5 million prescriptions for flurazepam were filled at American retail pharmacies, at a total expenditure exceeding 8 million dollars.
Meperidine kinetics in man; Intravenous injection in surgical patients and volunteers
Authors: Mather Laurence E. , Tucker Geoffrey T. , Pflug A. Eugene , Lindop Michael J. , Wilkerson Carol
Published: January 2016

The plasma concentration‐time profiles of meperidine following intravenous injection in surgical patients and volunteers were investigated by reference to a classical two‐compartment open model. Physiologic characteristics of the subject and variables associated with the surgery and anesthesia were screened as determinants of the kinetic patterns observed. When meperidine administration preceded induction of anesthesia, induction was consistently followed by an increase in venous plasma concentrations that prevented classical kinetic analysis. To facilitate calculations in subsequent studies in patients, meperidine injections were made following induction of anesthesia. Type of anesthesia or premedication, patients' sex, or cigarette smoking did not appear to be important factors in this evaluation. Increasing alcohol consumption was associated with increasing volumes of distribution. Increasing age was associated with increasing fraction of drug unbound in plasma. These factors may relate directly to clinical observations that heavy alcohol consumers tend to be more refractory to central nervous system (CNS) depressants and that elderly patients are more susceptible to respiratory depression from narcotics.
Morphine binding to human plasma proteins
Authors: Olsen George D.
Published: January 2016

The interaction of [N‐methyl‐14C] morphine with purified human albumin and gamma globulin and with human plasma was studied by equilibrium dialysis. Morphine binds to albumin and, to a lesser extent, to gamma globulin, but probably does not bind to plasma lipoproteins. The per cent of drug bound to protein was dependent on protein concentration but independent of drug concentration in the therapeutic range of plasma morphine concentration. In this range, 34.0% to 37.5% of the drug is bound to human plasma, largely to the albumin fraction. This study is compared to an earlier one on the interaction of methadone with plasma proteins. It is likely that the lower lipid solubility of morphine compared to methadone is related to its decreased affinity for plasma proteins.
Fetal acquisition and neonatal elimination of a large amount of salicylate
Authors: Garrettson Lorne K. , Procknal Josephine A. , Levy Gerhard
Published: January 2016

The purpose of this study was to determine the amount of salicylate acquired by a newborn infant from a mother who took 6.5 gm of aspirin a day during her entire pregnancy, and to characterize the kinetics of salicylate elimination by the infant. This healthy female infant was born with a salicylic acid concentration of 25 mg/100 ml plasma and 75 mg/kg body weight. The drug was eliminated during the first 5 days of life, primarily in the form of salicyluric acid. Salicylate elimination was relatively slower than in normal adults, but more rapid than in newborn infants of mothers who had taken only one small dose of aspirin shortly before delivery. The apparent in vivo KM and Vmax for salicylurate formation, on a body weight basis, were at the adult level. The slower elimination of salicylate (relative to adults) by the infant was due to immaturity of the glucuronidation and renal excretory pathways.
The effect of pindolol on exercise‐induced cardiac acceleration in relation to plasma levels in man
Authors: Gugler Roland , Höbel Werner , Bodem Gunter , Dengler Hans J.
Published: January 2016

The correlation between the beta receptor blocking activity of pindolol and plasma level was studied in 8 subjects after a 10‐mg oral dose. Exercise tachycardia was markedly reduced over a period of at least 6 hr. Significant effects were recorded 30 min after the drug. For each individual there was a close correlation between log plasma level and beta blockade. The regression lines were parallel as shown by analysis of covariance; the intercepts, however, were significantly different. It can be concluded that there is a correlation between plasma level and beta adrenergic blockade by pindolol, but the data failed to establish in different individuals the blood levels necessary to achieve effective adrenergic blockade.
Radioimmunoassay and pharmacokinetics of saralasin in the rat and hypertensive patients
Authors: Pettinger W. A. , Keeton K. , Phil M. , Tanaka K.
Published: January 2016

A radioimmunoassay for the new angiotensin antagonist, saralasin (1‐Sar‐8‐Ala‐angiotensin II), was developed and applied to pharmacologic studies in rats and hypertensive man. Specificity of the assay was established using naturally occurring angiotensins, potential saralasin metabolites, and other synthetic angiotensin analogues. Saralasin pharmacologic half‐life of 3.9 min after intravenous administration to rats was similar to the biochemical half‐life of 4.2 min. The pharmacologic half‐life in high‐renin hypertensive patients averaged 8.2 with a biochemical half‐life of 3.2 min. These observations suggest that metabolites of saralasin do not accumulate in sufficient quantity in man or rat to interfere with the assay. The biochemical half‐life of 3.2 min is consistent with infusion time of less than 20 min required to achieve a stable plasma concentration and pharmacologic activity of saralasin during constant saralasin infusion into hypertensive man. These studies provide a rational basis of future experimental design for saralasin and possibly other peptide analogues.
Disposition of methadone in methadone maintenance
Authors: Ånggård Erik , Gunne Lars-M. , Holmstrand Jan , McMahon Robert E. , Sandberg Carl-Gustaf , Sullivan Hugh R.
Published: January 2016

Six detoxified opiate addicts housed in a closed metabolic ward received methadone in stepwise increasing doses of 10, 20, 40, and 80 mg/day during 1 month. Four were given 14C‐methadone at the lowest dose and again at the highest dose. Of the subjects receiving radiomethadone, 2 excreted the major part of the radioactivity in urine and 2 about equally in urine and feces. In addition to methadone, 7 metabolites were isolated and identified in urine and 3 metabolites in feces. About 75% of the urinary and fecal radioactive metabolites were unconjugated. Urinary excretion of methadone and its major N‐monomethylated metabolite accounted for 17% to 57% of the given dose. The ratio of metabolite to parent drug increased in 5 of 6 subjects, and the urinary recovery of unchanged methadone decreased during the period. The results indicate that enhanced demethylation of methadone may occur during oral administration to man.
Bioavailability of different lots of digoxin tablets from the same manufacturer
Authors: Lindenbaum John
Published: January 2016

The bioavailability of single doses from 4 randomly selected lots of digoxin from a single manufacturer that were recently marketed in the United States was compared. In a crossover study in 6 normal volunteers, serum digoxin concentrations for 0 to 6 hr and urinary glycoside excretion for 24 hr after 0.5‐mg doses were measured by radioimmunoassay. The variation in bioavailability between the 4 lots was no greater than that seen when one of them was taken twice. Intersubject variation in areas under the serum concentration‐time curves and in the 24‐hr urinary digoxin measurements was more than twice that of intrasubject variation. The variability of the urinary digoxin determinations was somewhat less than that of the areas under the serum concentration‐time curves.
Pharmacokinetics of bethanidine in hypertensive patients
Authors: Shen D. , Gibaldi M. , Throne M. , Bellward G. , Cunningham R. , Israili Z. , Dayton P. , McNay J.
Published: January 2016

The pharmacokinetics of bethanidine‐14C was studied in three hypertensive patients. A 25‐mg dose of bethanidine‐14C hemisulfate was administered intravenously. Plasma levels of drug were measured over the first 6 hr. In 3 to 4 days, 89% to 94% of the dose was excreted in the urine. Thin‐layer chromatography (TLC) and isotope dilution analysis of the urine samples indicated that only intact bethanidine was excreted. Plasma level and urinary excretion rate profiles had multiphasic characteristics. Estimated half‐lives of the terminal phase ranged from 7 to 11 hr. A verage renal clearance over the initial 6 hr approached renal plasmafiow. In 2 of the patients, renal clearance between 2 and 4 hr after administration was reduced to one‐half that observed during the initial 2‐hr period. After single oral administration of a 25‐mg dose of bethanidine‐14C hemisulfate, 48% to 61% was excreted in urine and 15% to 48% infeces. Peak urinary excretion rates were reached 6 hr following administration. The urinary excretion kinetics of bethanidine during and after repetitive oral dosing was also studied. A 25‐mg dose was divided into 12 to 16 equal doses and administered every 6 hr. A larger fraction of the cumulative dose was recovered in the urine (72% to 74%) than after the single dose, suggesting higher availability at the lower dose. Steady‐state urinary excretion rates were achieved in 4 to 7 doses. The steady‐state urinary excretion levels were consistent with pharmacokinetic predictions based on single oral dose data. When 2 of the patients were given imipramine for 2 days prior to an oral 25‐mg dose of bethanidine‐14C hemisulfate, the terminal half‐lives of the urinary excretion rate profiles were shorter than those in the same patients not given imipramine.
Determinants of the renal clearance of digoxin
Authors: Halkin H. , Sheiner L. B. , Peck C. C. , Melmon K. L.
Published: January 2016

The renal clearances of digoxin, creatinine, and urea nitrogen were determined simultaneously in each of 41 patients receiving digoxin, in most of whom there was prerenal azotemia. Mean ± SD values were: blood urea nitrogen (RUN), 26.1 ± 12.8 mg per 100 ml; creatinine, 1.1 + 0041 mg per 100 ml; creatinine clearance, 78 ± 42 ml/min/1.73 m2; digoxin clearance, 66.6 ± 42.1 ml/min/1.73 m2; urea nitrogen clearance, 27.8 ± 19.2 ml/min/1.73 m2. Correlation analysis revealed that urea clearance is superior to creatinine clearance, and RUN is superior to serum creatinine concentration in the degree of relationship to renal digoxin clearance. Moreover, using partial correlation techniques, it is apparent that in these patients digoxin clearance was significantly related to urine flow rate independent of creatinine clearance, and to urea nitrogen clearance independent of both creatinine clearance and urine flow rate. These findings are compatible with the hypo thesis that digoxin undergoes some degree of tubular reabsorption as welt as filtration and secretion.
Ticarcillin vs carbenicillin: Clinical pharmacokinetics
Authors: Libke Robert D. , Clarke John T. , Ralph Edward D. , Luthy Ruedi P. , Kirby William M. M.
Published: January 2016

The pharmacokinetic characteristics of ticarcillin, a semisynthetic penicillin more active than carbenicillin against Pseudomonas, were compared to those of carbenicillin in 12 healthy volunteers. Following an intravenous infusion of 2 gm in 5 min, there was a lower average serum levelfor ticarcillin (218 µg/ml) thanfor carbenicillin (301 µg/ml), but after 2 hr the differences were not significant. The biologic half‐life of ticarcillin was slightly longer than that of carbenicillin (72 and 65 min, P < 0.01 )and its volume of distribution was larger (15.7 and 12.31, P < 0.01). Eighty‐six per cent of the dose of ticarcillin and 99% of the dose of carbenicillin was recovered in the urine in 24 hr. Similar but much less marked blood level differences were noted with 2 gm, 30‐min infusions. An intravenous infusion of 1 gm Ihr gave average steady‐state blood levels of about 124 µg/ml for both antibiotics. Probenecid, administered 1 hr before the infusion, caused significant and similar increases in blood levels, half‐lives, and volumes of distribution of the 2 antibiotics. Protein binding in 100% human serum was 50% and 65% for carbenicillin and ticarcillin, respectively. These relatively small but definite differences in the pharmacokinetics of ticarcillin and carbenicillin are not likely to be of clinical signijicance.
Pseudoproteinuria in tolmetin‐treated patients
Authors: Ehrlich George E. , Wortham G. Forrest
Published: January 2016

In a clinical study of the new nonsteroidal anti‐inflammatory drug tolmetin, the urines of 5 patients reacted positively when tested for protein by the standard sulfosalicylic acid method. Pseudoproteinuria, due to the precipitation by acid of the major metabolite of tolmetin, was suspected. The urines were subsequently tested for protein by the following alternate methods: solubility of acid precipitate test, heat coagulation test, Upjohn modification of the sulfosalicylic acid test, biuret test, Albustix, and electrophoresis. All were negative for protein. These results confirmed that the reactions with the sulfosalicylic acid test did not indicate true proteinuria but pseudoproteinuria. It is suggested that patients who receive tolmetin be tested for proteinuria by methods other thon those involving acid precipitation.
Plasma levels and symptom complaints in patients maintained on daily dosage of methadone hydrochloride
Authors: Horns William H. , Rado Madeline , Goldstein Avram
Published: January 2016

Plasma methadone levels, symptom complaints, and urine tests for illicit opiate use were followed weekly in 17 patients on a methadone maintenance program. There were very large differences between patients in the plasma level established at a given dosage, implying large differences in the rate of methadone metabolism. Despite virtually constant daily dosage, the plasma methadone levels fluctuated greatly from week to week and from day to day in individual patients. With rare exceptions there was no relationship between plasma methadone level and symptom complaints or between weekly changes in plasma methadone level and changes in symptom complaints. Except possibly to identify the occasional patient with unusually low plasma methadone levels, the determination of methadone levels is not likely to be of practical value in methadone programs.
Fenmetozole in acute alcohol intoxication in man
Authors: McNamee H. Brian , Mendelson Jack H. , Korn Jeffrey
Published: January 2016

Forty healthy adult male volunteers were studied to determine the efficacy of fenmetozole to antagonize the effects of acute alcohol intoxication. Twenty subjects received placebo and 20 fenmetozole in dosage of 100 mg and 200 mg in a double‐blind paradigm. Pretreatment with fenmetozole failed to antagonize or attenuate cognitive, perceptual, motor and affective changes associated with acute alcohol intoxication.
Reduction of enzyme efflux from skeletal muscle by diethylstilbestrol
Authors: Dempsey Robert , Morgan Juliet , Cohen Louis
Published: January 2016

We have previously shown that oral diethylstilbestrol (DES) lowers the high serum enzyme levels characteristic of Duchenne' s muscular dystrophy (DMD). The present studies were undertaken to assess the effect of DES on the efflux of enzymes from isolated mouse skeletal muscle. Thirty‐four male mice were used. Half received daily subcutaneous injections of 10 µg diethylstilbestrol‐diphosphate (DES‐DP) in saline for up to 3 wk and half daily saline injections. Left gastrocnemii were isolated from control and treated mice, and placed in separate incubation media at 37° C. The efflux of creatine phosphokinase (CPK) and lactate dehydrogenase (LDH)from each was compared over a 4‐ to 5‐hr period. In 15 of 18 there was a reduction in efflux of both enzymes from muscles isolated from DES‐DP‐treated mice. The greatest effect was noted during the second hour, when the mean efflux of each enzyme was reduced about 30%. Minor differences in muscle weight, water content, and enzyme activities did not explain the reduced efflux. These results suggest that DES has either reduced the permeability of the sarcolemma or enhanced the intracytoplasmic stability of these enzymes. This is the first drug reported to reduce the spontaneous enzyme efflux from isolated skeletal muscle. It remains to be established that a similar effect accounts for the reduction in serum enzyme levels when DES is administered to persons with DMD.
A complex pattern of disposition of phenytoin in severe intoxication
Authors: Pruitt Albert W. , Zwiren Gerald T. , Patterson Joseph H. , Dayton Peter G. , Cook Clarence E. , Wall Monroe E.
Published: January 2016

A 5‐year‐old child developed phenytoin (diphenylhydantoin, DPH) toxicity after receiving 500 mg of the drug daily for 3 weeks. Plasma, urine, and duodenal fluid were collected for assay of DPH and its metabolites. The peak plasma concentration of DPH was 108 µg/ml, and the decline in plasma level did not fit first‐order kinetics. The para‐hydroxy, meta‐hydroxy, and dihydrodiol metabolites of DPH were measured in urine; duodenal aspirate contained both DPH and the para‐hydroxy metabolite. Plasma pH may affect distribution of DPH since in vitro binding of DPH to human albumin increased as pH increased.
Alpha and beta adrenergic‐induced renin release in man
Authors: Leenen Frans H. H. , Redmond Daniel P. , McDonald Robert H.
Published: January 2016

Changes in hemodynamic variables and renin release, induced with both alpha and beta adrenergic agonists, were studied in 5 normal men. Saline (0.9% NaCl), methoxamine (1.6 and 5.9 µg/kg/min), and isoproterenol (0.015 and 0.026 µg/kg/min) were infused individually in a random order for 30 min. Methoxamine and isoproterenol caused the predicted directionally opposite cardiovascular changes but caused nearly equal and dose‐related increases in plasma renin activity, as measured by radioimmunoassay. Saline irifusion had no effect. Propranolol (0.125 mg/kg) caused decreases in systolic pressure and heart rate, and a significant decrease in plasma renin activity. Propranolol prevented the renin‐releasing effects of isoproterenol and methoxamine, but only the cardiovascular effects of isoproterenol. It appears that alpha or beta agonists stimulate renin release equally in man and that at least one step in renin release is propranolol‐sensitive. Such sensitivity may be independent of its beta receptor blocking activity.
Decreased plasma protein binding of diazoxide in uremia
Authors: O'Malley Kevin , Velasco Manuel , Pruitt Albert , McNay John L.
Published: January 2016

The effect of uremia on the binding of diazoxide to plasma proteins was studied. An equilibrium dialysis technique, using diazoxide‐14C at approximately 30 and 300 µg/ml in the plasma phase, was used to measure diazoxide binding to plasma. Serum albumin concentration (Alb) and serum creatinine (Cr) or blood urea nitrogen (BUN) were negatively correlated. By single regression analysis, per cent free diazoxide (%FD) correlated negatively with Alb and positively with Cr or BUN. When %FD was regressed simultaneously against Alb and Cr or BUN, Alb emerged as the sole determinant of %FD (p < 0.001), indicating that creatinine or BUN correlated with %FD by their inverse correlation to Alb rather than by an effect on drug protein binding. At the levels of Alb studied, %FD varied over a 2‐fold range. In a retrospective study of the influence of uremia on diazoxide effect in hypertensive patients, a relatively low correlation (r, 0.59) was found between BUN and hypotensive effect. Prospective studies involving correlations of drug effect with renal function and %FD are required to assess the clinical importance of decreased binding of diazoxide to uremic plasma.
Hemodialysis of phenytoin in a uremic patient
Authors: Adler David S. , Martin Ernst , Gambertogli John G. , Tozer Thomas N. , Spire Jean‐Paul
Published: January 2016

Removal of phenytoin by hemodialysis was determined in a uremic patient. The rate of appearance of the drug in dialysate, the plasma concentration with time, and the plasma clearance by dialysis were measured. Plasma protein binding of phenytoin was also determined. In spite of greatly reduced plasma protein binding in the uremic patient, removal rate was observed to be less than 10% of the rate of presentation to the dialyzer. During the 6‐hr period of dialysis, the plasma concentration showed little change. The amount collected in the dialysate, 43.6 mg, was only a small fraction of drug in the body. These results indicate that replacement of phenytoin based on the amount of drug removed by dialysis is unnecessary in chronically dialyzed uremic patients. In addition, the utility of hemodialysis in phenytoin overdose is questioned.
Effects of marihuana and placebo marihuana smoking on hemodynamics in coronary disease
Authors: Prakash Ravi , Aronow Wilbert S. , Warren Max , Laverty Wayne , Gottschalk Louis A.
Published: January 2016

The effects of smoking 1 marihuana and 1 placebo marihuana cigarette on cardiovascular hemodynamics were evaluated by echocardiography in a double‐blind crossover study in 10 patients with angina pectoris. Smoking marihuana increased the heart rate and systolic and diastolic blood pressures, did not significantly change the end‐systolic volume and cardiac index, and decreased the end‐diastolic volume, stroke index, and ejection fraction. Smoking placebo marihuana did not significantly change the heart rate, blood pressure, and end‐systolic volume, and decreased the end‐diastolic volume, stroke index, cardiac index, and ejection fraction. The decrease in stroke index and ejection fraction after marihuana was greater and lasted longer than after placebo marihuana. The decrease in stroke index, cardiac index, and ejection fraction after placebo marihuana may be attributed to increased carboxyhemoglobin level. The increase in heart rate and blood pressure after marihuana is attributed to delta‐9‐tetrahydrocannabinol (THC). The decrease in stroke index and ejection fraction after marihuana may be attributed to delta‐9‐THC in addition to increased carboxyhemoglobin level.
Major drug‐prescribing patterns in general hospitals
Authors: Sicé Jean
Published: January 2016

Prescriptions of major drug classes were surveyed for one year in five teaching and five nonteaching general hospitals. Their overall rates varied over a two‐ to three‐fold range in medicine, surgery, and pediatrics, but were uniform throughout the hospitals. Parenteral fluids and antibiotics represented over one half of the pharmacotherapy used in every specialty except medicine, where tranquilizers were the mostfrequently prescribed drugs. Prescribing patterns lacked consistency in obstetrics and newborn services, and generally with steroids, vasopressors, and anticoagulants. Significant variations also involved the use of fluids in pediatrics, diuretics in surgery, and vasodilators in medicine. These variations were too unpredictable and large to be attributed to specific differences among patient populations. Only two discrepancies were noted between teaching and nonteaching hospitals: tranquilizers were prescribed more often in the former, and vasopressors in the latter.
A loading‐maintenance regimen for more rapid initiation of the effect of guanethidine
Authors: Shand David G. , Nies Alan S. , McAllister Russell G. , Oates John A.
Published: January 2016

A regimen has been devised for achieving the pharmacologic effects of guanethidine relatively rapidly, using the concept of loading and maintenance doses based on the kinetics of guanethidine elimination. This regimen was tested in 6 hypertensive patients with creatinine clearances greater than 69 ml/min in balance on a 10‐mEq sodium diet. Reduction of blood pressure in the standing position was achieved with guanethidine 150 to 525 mg administered over a period of 1 to 3 days. Maintenance doses ranging from 20 to 65 mg daily were calculated from the loading dose, assuming an approximation of a one‐compartment model with a daily loss of 1/7 of the drug from the body. Satisfactory control of the standing blood pressure was maintained during 7 days following the guanethidine load without side effects.
Nonemergency use of slow infusions of diazoxide
Authors: Lee Won Ro , Mroczek William J. , Davidov Michael E. , Finnerty Frank A.
Published: January 2016

Slow infusions of diazoxide were administered to 10 hypertensive patients who had stable, nonaccelerated hypertension. The 10‐min diazoxide infusion was associated with a 16% average reduction in arterial pressure, a 21% average increase in heart rate, a 16% average increase in cardiac output, and a 36% reduction in total peripheral resistance. These changes in hemodynamic parameters lasted for an average of 70 min. It was concluded that slow infusions of diazoxide produce a consistent and predictable antihypertensive effect in patients witli stable, nonaccelerated hypertension. Slow infusions of diazoxide may have a limited use in nonemergency situations where an abrupt change in arterial pressure is to be avoided and a parenteral antihypertensive agent is needed.
Sex differences in the intramuscular absorption and bioavailability of cephradine
Authors: Vukovich Robert A. , Brannick Leo J. , Sugerman Arthur A. , Neiss Edward S.
Published: January 2016

Six male and six female volunteers each received a single intramuscular injection of cephradine, a new cephalosporin antibiotic, once weekly for 3 consecutive weeks. The drug was injected into the gluteus maximus, vastus lateralis, or deltoid muscle groups. Injection sites were rotated each week so that each subject received an injection into each muscle. Pharmacokinetic evaluation of serum concentrations and urinary excretion data indicated a sex difference with respect to the rate and extent of cephradine absorption from the three injection sites. Smaller areas under the curve and absorption rate constants were observed for females after injection into each muscle group. The most striking difference was observed when cephradine was injected into the gluteus maximus muscle, where the exponential function describing the a phase was observed to be 1.16 ± 0./7 hr−1 for females and 2.70 ± 0.34 hr−1 for males. Total area under the mean serum concentration‐time curves, mean time to peak, and peak height parameters consistent with the slower rate of absorption and lesser bioavailability in females were observed. These results show that the vastus lateralis or deltoid muscle groups are preferable to the gluteus maximus as injection sites because of the more rapid rates of drug absorption from those muscles.
5‐Fluorouracil with cytosine arabinoside in metastatic gastrointestinal cancer
Authors: Muss Hyman B. , Lokich Jacob J. , Frei Emil
Published: January 2016

A 2‐drug combination chemotherapy regimen of 5‐fluorouracil (FU) and cytosine arabinoside (ara‐C) was used in 23 patients with gastrointestina1 cancer. The drugs were administered as a mixture by daily continuous infusion for 5 days at 4‐wk intervals. Dosages for each drug were: FU, 1.1 gm/m2/day and ara‐C, 50 mg/m2/day, The incidence of leukopenia (WBC, <3,500/mm3) was 36% and of thrombocytopenia (platelets, <125,000/mm3), 18% during 33 courses administered at full doses. No clinical antitumor effects were observed in 18 patients evaluable for therapeutic response. The addition of ara‐C to a nonmyelosuppressive dose schedule of FU results in potentiated marrow suppression, and the antitumor effect for the combination is less than would have been predicted for either drug alone.
Cardiovascular effects of prolonged delta‐9‐tetrahydrocannabinol ingestion
Authors: Benowitz Neal L. , Jones Reese T.
Published: January 2016

In contrast to the tachycardia and unchanged or increased blood pressure seen after single doses, prolonged delta‐9‐tetrahydrocannabinol (THC) ingestion produced significant heart rate slowing and blood pressure lowering in hospitalized volunteers. Impaired circulatory responses to standing, exercise, Valsalva maneuver, and cold pressor testing suggest a state of sympathetic insufficiency. Marked weight gain was observed in all subjects, which has been shown to be related to fluid retention and plasma volume expansion. Tolerance developed to orthostatic hypotension, possibly related to plasma volume expansion, but did not develop to the supine hypotensive effects. Nearly complete tolerance developed to the tachycardia and psychological effects produced by smoked marijuana while ingesting THC. Electrocardiographic changes were minimal despite the large cumulative dose of THC. The hypothesis that THC has a biphasic effect on the sympathetic nervous system in man, producing excitation with single doses and inhibition with prolonged administration, is discussed.
Penfluridol steady‐state kinetics in psychiatric patients
Authors: Cooper Sam F. , Dugal Robert , Albert Jean-Marie , Bertrand Michel
Published: January 2016

Twenty‐two hospitalized schizophrenic patients, participating in a large‐scale phase II double‐blind dose‐effect study (30, 60, and 120 mg weekly) of penfluridol, a new diphenylbutylpiperidine neuroleptic, were maintained on a regular dosage regimen for 13 wk. Several blood samples were taken during the last dosage interval. Results show that the peak concentration develops within 12 hr after the last dose. A rapid decline, probably due to tissue re‐equilibration, then occurs and is followed by a much slower falloff. Detectable concentrations 168 hr after administration are consistent with the long duration of action of penfluridol. Statistically significant differences between doses were found in the analysis of variance of plasma concentrations at all sampling times and in mean steady‐state plasma concentrations. Wide differences in plasma concentrations were noted in patients receiving the same absolute dose, but a good relationship was defined between mean steady‐state concentration and the dose expressed as mg per either kg of body weight or square meter of body surface area.
Correlation of plateau serum salicylate level with rate of salicylate metabolism
Authors: Gupta Niroo , Sarkissian Edmund , Paulus Harold E.
Published: January 2016

The range of plateau serum salicylate concentrations was 4.4 to 33 mg/100 ml in patients with rheumatoid arthritis after they were treated with 50 mg/kg of aspirin daily for 5 days. Individual plateau serum levels correlated better with urinary excretion rates of the metabolite, salicylurate (whose maximum production is capacity‐limited), than with total urinary excretion of salicylates. These observations suggest that large intersubject variations in plateau serum salicylate levels are determined, at least in part, by similar differences in the maximum rates of capacity‐limited metabolic reactions. For optimal therapeutic responses, individualization of aspirin dosage by following serum salicylate levels is recommended.
Combination 6‐mercaptopurine‐adriamycin in refractory adult acute leukemia
Authors: Rodriguez Victorio , Bodey Gerald P. , McCredie Kenneth B. , Freireich Emil J. , Minow Robert A. , Casey John H. , Luna Mario
Published: January 2016

Remission induction therapy with 6MP and adriamycin in combination was administered to 19 adult leukemic patients refractory to previous therapy. Eight patients also received vincristine and prednisone. Thirteen patients had acute myelogenous leukemia, 3 undifferentiated leukemia, and 3 blastic transformation of chronic myelogenous leukemia. Four patients who died of severe infection received less than 6 wk of therapy. Four patients achieved remission but in only 2 were the remissions complete. Eleven patients failed to respond. Ten of the 19 patients developed unexpected severe liver toxicity manifested by a clinical picture of cholestasis (in the majority) or ascending cholangitis (in 2 patients). In the postmortem examination of 8 patients there was cholestasis and mild to severe hepatocellular damage in all.
Pharmacokinetics of ampicillin in cirrhosis
Authors: Lewis George P. , Jusko William J.
Published: January 2016

Ampicillin pharmacokinetics was studied in 9 cirrhotic patients and in 8 healthy subjects to assess liver disease‐related differences in distribution, elimination, and bioavailability of ampicillin. Plasma, urine, and ascites fluid samples were analyzed microbiologically. After intravenous doses, the cirrhotic patients have lower initial plasma concentrations of ampicillin because of the larger volume of distribution. Such patients usually have diminished renal function, which, because renal tubular secretion is the main route of excretion of ampicillin, causes prolonged retention of ampicillin. Metabolic‐biliary clearance of ampicillin, normally accounting for removal of only 10% of the dose in normal subjects, is three times as great in cirrhotic patients. Peak ascites fluid concentrations of ampicillin ranged from 2 to 7 mcg/ml after 600 mg iv doses, and very slow clearance of ampicillin from the peritoneal cavity results in persistence in this compartment. Though absorption of ampicillin from capsules was often erratic, its bioavailability was similar in normal and cirrhotic subjects. These findings suggest that the usual course of ampicillin therapy of infections should not be altered in cirrhotic patients. On the other hand, reduction in dosage may be called for when there is renal impairment.
XXXIV. The other side of ‘statistical significance’: alpha, beta. delta, and the calculation of sample size
Authors: Feinstein Alvan R.
Published: January 2016

‘Statistical significance’ is commonly tested in biologic research when the investigator has found an impressive difference in two groups of animals or people. If the groups are relatively small, the investigator (or a critical reviewer) becomes worried about a statistical problem. Although the observed difference in the means or percentages is large enough to be biologically (or clinically) significant, do the groups contain enough members for the numerical differences to be ‘statistically significant’?