bluuebunny/crossref_metadata_2025 huggingface dataset:
A study of hospital staff attitudes concerning the comparative merits of antibiotics
Authors: Macaraeg Placido V. J. , Lasagna Louis , Bianchine Joseph R.
Published: January 2016

In an attempt to describe and explain doctors’ preferences for antibiotics, a survey was performed in a major university hospital. A questionnaire was filled out by 75.1 per cent (160) of the interns and residents on all the services in the hospital. In addition, every inpatient who received ampicillin during aperiod of 6 weeks was followed so as to compare actual utilization and performance of this antibiotic with the usage reported in the questionnaire. The results illustrate the diversity of motivations involved in the prescribing habits of the physicians surveyed and the serious disagreement between some of the practices and opinions of the house staff and those of infectious disease experts at the same institution.
The effects of MK‐185 on thyroid function
Authors: Ryan Jerome R. , Jain Adesh , Maha George E. , McMahon F. Gilbert
Published: January 2016

MK‐185, (2‐acetoamidoethyl [4‐chlorophenyl] [3‐trifluoromethyl phenoxy] acetate) produced a significant reduction in serum protein‐bound iodine and an increase in triiodothyroxine resin uptake in 11 patients with types III and IV hyperlipoproteinemia. The drug was administered orally at dosages of 10, 15, and 20 mg. per kilogram per day each for a period of 4 weeks, respectively. There were 4 week pre‐ and posttreatment periods with placebo. The free thyroxine levels and 1311 24 hour thyroidal uptake before and after MK‐185 therapy did not show significant change. Although thyroid‐binding globulin capacity was reduced, the change was not significant. It is proposed that the drug interferes with the binding of thyroxine by plasma proteins.
Cortisol production in epileptic patients treated with diphenylhydantoin
Authors: Werk Emile E. , Thrasher Katherine , Sholiton Leon J. , Olinger Charles , Choi Young
Published: January 2016

Cortisol production and metabolism were compared in 21 patients with convulsive disorders before and during diphenylhydantoin (DPH) therapy up to 24 months. Cortisol secretion rates (CSR) were measured by the ‐urinary isotope‐dilution method, based on the specific activity in urine of the metabolites tetrahydrocortisol and tetrahydrocortisone. Cortisol metabolism was evaluated by the ratio in urine of 6‐hydroxycortisol to 17‐hydroxycorticosteroids (6‐OHF/17‐OHCS). During DPH therapy there was a positive correlation of CSR with the increase in ratio of 6‐OHF/17‐OHCS. A significant mean increase in CSR, of 35 per cent above control, was found when the ratio increased more than 0.14. Since the increase in 6‐OHF/17‐OHCS is probably related to enhancement of hepatic microsomal enzyme activity by DPH, it can be concluded that, in epileptic patients treated with the drug, cortisol production will increase if there is sufficient enzyme stimulation. No deleterious effect has been observed in association with these changes in cortisol production and metabolism.
Drug distribution and pharmacologic effects
Authors: Gibaldi Milo , Levy Gerhard , Weintraub Howard
Published: January 2016

Drugs which move relatively slowly in and out of body “compartments” thereby confer pharmacokinetic characteristics of a multicompartment system and elicit a considerably different time course of pharmacologic effect than do drugs which are distributed in the body extremely rapidly. The time course of pharmacologiC effects in multicompartment systems is considered here as a function of dose and site of action and duration of repetitive dosings. The durationdose and intensity‐time patterns thus obtained are consistent with the results of clinical studies. An appreciation of these relationships should be helpful in designing effective and safe dosage regimens.
Interaction of chloral hydrate and ethanol in man: I. Metabolism
Authors: Sellers Edward M. , Lang Mary , Koch‐Weser Jan , LeBlanc Eugene , Kalant Harold
Published: January 2016

The interaction of chloral hydrate and ethanol metabolism was studied in 5 normal male volunteers. Compared to chloral hydrate alone, ingestion of ethanol30 minutes after chloral hydrate results in significantly higher and more prolonged concentrations of plasma trichloroethanol and in lower plasma trichloroacetic acid levels and urinary trichloroethanol glucuronide. Chloral hydrate ingestion in turn affects ethanol metabolism and causes peak blood ethanol concentrations to be reached earlier and to be higher than after ethanol alone. Accompanying the higher blood ethttnollevels are lower blood acetaldehyde concentrations. Blood ethanol concentration one‐half hour after ethanol ingestion is linearly related to the plasma trichloroethanollevel at the time of ethanol ingestion. In vitro studies on the mechanism of these metabolic interactions showed that the elevated blood ethanol concentrations are due to competitive inhibition of alcohol dehydrogenase by trichloroethanol (Ki = 8. 7 × 10−5M). Ethanol stimulates NADH production and thereby increases the rate of chloral hydrate reduction to trichloroethanol by liver alcohol dehydrogenase. Human red blood cells also reduce chloral hydrate to trichloroethanol (Km 4.0 × 1D−4M, Vmax, = 3.6 p,m per minute per cubic centimeter RBC).
Comparison of a new beta adrenergic blocker (MK 950) and propranolol in man
Authors: Ulrych Milos , Franciosa Joseph , Conway James
Published: January 2016

The effects of oral doses of MK 950 and propranolol on heart rate in the sitting and standing positions were measured in 6 volunteers. Although the response to beta blockade is related to the initial heart rate and to the log of the dose of the drug, multiple regression analysis made it possible to separate these interactions. In a dose of 2.5 mg. orally, MK 950 reduced heart rate to the same degree as did 20 mg. of propranolol. The regression lines relating dose to response of the heart rate was steeper for MK 950 than for propranolol. There was a fall of about 20 per cent in heart rate and cardiac output after 5 mg. of MK 950, with little change in stroke volume or blood pressure. MK 950 blocked the response to isoproterenol infusion in doses up to 8 µg per minute and reduced the heart rate response to tilting and amylnitrite inhalation and the pressure overshoot in Valsalva maneuver.
Absorption and excretion of a monoureide hypnotic, capuride
Authors: Johnson Philip C. , Cressman William A. , Driscoll Theda B.
Published: January 2016

Capuride is a monoureide with a duration of hypnotic effect similar to that of the short‐acting barbiturates. The absorption and excretion of 100, 200, 400, and 800 mg. doses of capuride•4,5•3H were studied by use of a complete crossover design. The drug was rapidly and completely absorbed. Plasma levels of radioactivity were directly proportional to the dose administered. Plasma levels and the 0 to 48 hour cumulative urinary excretion showed a linear correlation to total body weight and to each other. Chronic administration of 400 mg. capuride daily was not found to affect its metabolism.
Absorption, metabolism, and excretion of salicylazosulfapyridine in man
Authors: Schröder Hasse , Campbell Dag E. S.
Published: January 2016

Salicylazosulfapyridine (SASP), 4 Gm. daily, was ingested by 9 healthy subfects for 10 days, and the serum concentrations and urinary and fecal excretion of the parent drug and its metabolites were studied. SASP is extensively metabolized by reductive cleavage of the azo linkage, presumably by the action of the gut flora. The sulfapyridine moiety thus formed is subfect to N4‐acetylation or ring hydroxylation followed by confugation to glucuronic acid, or both. The 5‐aminosalicylic acid moiety is N‐acetylated. The steady‐state serum concentrations of the parent drug and its metabolites, obtained by Day 5, for SASP ranged from 4.7 to 45 p.g per milliliter (median 12 p.g per milliliter), for total sulfapyridine metabolites from 37 to 92 p.g per milliliter (median 50 p.g per milliliter), and for total 5‐aminosalicylic acid metabolites to less than 2 p.g per milliliter. The urinary excretion of unchanged SASP ranged from 1.7 to 10 per cent of the dose. About 80 per cent of the dose was excreted in the urine as metabolites of sulfapyridine and one third of the dose was excreted as the metabolite of 5‐aminosalicylic acid. Feces did not contain any SASP, but about 5 per cent of the dose was present as metabolites of sulfapyridine and an unknown amount as metabolites of 5‐aminosalicylic acid.
Impairment of human drug metabolism by oral contraceptive steroids
Authors: O'Malley Kevin , Stevenson Ian H. , Crooks James
Published: January 2016

The effect of oral contraceptive steroids on drug‐metabolizing capacity was determined by the use of plasma antipyrine and phenylbutazone half‐lifes as indices. Drug‐metabolizing capacity seemed to be impaired in women taking oral contraceptive steroids since the mean plasma antipyrine half‐life in female control subjects was 10.8 ± 2.4 hours (N = 36) while that in the “pill” group was 14.1 ± 3.1 hours (N = 26). The difference between the groups was significant (p < 0.001). With phenylbutazone, the mean control value was 70.6 ± 30.1 hours (N = 18) and that for the subjects taking oral contraceptives 80.2 ± 30.6 hours (N = 18). In this case the difference was not statistically significant (p > 0.05).
Methylphenidate in mildly depressed outpatients
Authors: Rickels Karl , Gingrich Russell L. , Mclaughlin F. W. , Morris Richard J. , Sablosky Lester , Silverman Howard , Wentz Henry S.
Published: January 2016

A double‐blind placebo‐controlled trial of methylphenidate (30 mg. per day) was conducted with 101 general practice and symptomatic volunteer patients diagnosed as mildly to moderately depressed with concomitant fatigue or apathy. Patient but not physician measures demonstrated significantly more improvement with methylphenidate than with placebo. More than 50 per cent of the patients reported side effects, somewhat unexpectedly. Patients on placebo reported side effects as frequently as did those on methylphenidate.
Oil dialysis for ethchlorvynol intoxication
Authors: Welch Larry T. , Bower John D. , Ott Cobern E. , Hume Arthur S.
Published: January 2016

A case report of acute ethchlorvynol intoxication treated by hemodialysis with the use of soybean oil as the dialysate is presented. Detoxification of the patient by removal of drug was judged to be more effective when the dialysate was soybean oil than when its conventional aqueous counterpart was employed. The efficacy of drug removal was indicated by lowering of drug levels in the patient's blood and reversal of the state of coma. Supportive data from correlative studies performed in vitro with the use of dog's blood indicated effective removal of drug by lipid dialysis. Similar information was obtained with the use of a model dialysis cell. A twentyfold greater solubility of the drug in oil compared to aqueous dialysate probably explains the greater effectiveness of hemodialysis with oil.
Marihuana metabolites in urine of man
Authors: Hollister Leo E. , Kanter Saul L. , Moore Frances , Green Donald E.
Published: January 2016

Single doses of hashish extract containing 20 mg. of Δ‐9‐tetrahydrocannabinol (THC) were followed by excretion of what appeared to be both cannabinol and cannabidiol but no unchanged THC. A new material in the urine appeared to be a compound related to a cannabinoid. The pattern of metabolism of cannabinoids appears to differ between different subjects. Following single doses of the same amount of THC alone, only a new drug‐related metabolite could be found in the more polar range. With repeated doses, a material in the cannabinoid range was excreted in small amounts. On the whole, repeated doses of hashish extract or THC as given in the present schedule did not lead to any significant accumulation of drug or metabolites.
The clinical pharmacology of oral and inhaled salbutamol
Authors: Walker S. R. , Evans M. E. , Richards A. J. , Paterson J. W.
Published: January 2016

The clinical pharmacology of 3H‐salbutamol has been investigated in 12 asthmaltic patients. Peak plasma levels of between 212 and 489 nm. were seen at one to 3 hours after an oral dose (4 to 8 mg.) in 6 patients. The drug was well absorbed and 65 to 84 per cent of the dose was excreted in the urine. There was a correlation between plasma levels and one‐second forced expiratory volume (FEV1) response. Peak plasma levels after inhalation of 3H‐salbutamol (0.04 to 0.10 mg.) ranged from 2.55 to 5.69 nm. and were seen at 3 to 5 hours after inhalation; 78 to 97 per cent of the inhaled dose was excreted in the urine. The FEV, rose within 10 minutes of inhalation, and the results indicate that although the maiority of an aerosol dose is swallowed, bronchodilatation is due to local deposition of salbutamol in the lung. Salbutamol was excreted unchanged and as a maior metabolite (34 to 49 per cent of the dose) not previously seen in any animal species.
Maternal and fetal distribution of drugs in pregnancy
Authors: Mirkin Bernard L.
Published: January 2016

The disposition of drugs in the maternal‐placento‐fetal unit is influenced by several inter‐reacting processes. Placental transfer of pharmacologically active molecules is modulated by characteristics of the drugs (e.g., lipid solubility, degree of ionization at physiologic pH, molecular weight) and properties of the placenta (e.g., maternal and fetal blood flow, drug metabolism, placental age). The distribution of drugs in the fetus may be determined by differences in permeability of specialized membranes (blood‐brain barrier, renal tubule), binding to specific cellular constituents (binding proteins), selective distribution of the fetal circulation, and active secretion of drugs by the yolk sac. In a general sense the pattern of drug distribution in the fetus frequently resembles that of the mother; however unique differences in absolute tissue concentrations of drugs may occur as a result of increased drug transfer rates into specific tissues. Many compounds crossing the placenta initially concentrate in the fetal liver so that levels in systemic fetal blood may be Significantly different from umbilical venous concentrations. Consequently, the detection of unusual patterns of drug distribution in the fetus that may prove useful in assessing the potential hazards of maternal drug therapy will require more comprehensive data than can be provided by umbilical vessel blood concentrations alone.
Maternal drug exposure and fetal abnormalities; Material and methods
Authors: Slone Dennis , Heinonen Olli P. , Monson Richard R. , Shapiro Samuel , Hartz Stuart C. , Rosenberg Lynn
Published: January 2016

Data derived from a cohort of 50,897 pregnancies that occurred between 1959 and 1965 are currently being evaluated to determine whether any associations between maternal drug exposure and abnormalities in the offspring exist. In this report, the cohort being studied is briefly described, and the methods used to identify associations, together with factors that confound them, are outlined. Also presented are the techniques used to control for these factors in evaluating the associations. Issues concerning causal interpretation of associations that remain after confounding factors have been controlled are discussed.
Plasma diphenylhydantoin levels after loading and maintenance doses
Authors: Wilder B. J. , Serrano E. E. , Ramsay R. Eugene
Published: January 2016

Sixty‐one patients received 1 gm loading doses of diphenylhydantoin (DPH) followed by constant daily maintenance doses of 300 to 400 mg. Seizure control was obtained rapidly in all patients who responded to DPH. Serial plasma DPH determinations were followed in 7 patients for 4 days and in 8 patients for 50 days. One or more DPH plasma levels were obtained in the remaining 46 patients. Therapeutic DPH plasma levels (7.5 µg per milliliter) were obtained in 14 of 15 patients within 8 to 24 hours following loading dose administration. The 24 hour plasma DPH values were predictive of the long‐term steady‐state DPH plasma levels. Peaking of plasma levels occurred between 48 and 96 hours after loading. However, the few mild signs and symptoms of toxicity occurred within the first 24 hours. In the group of 61 patients, only 1 became grossly intoxicated. Patients tolerated the loading doses well, and therapeutic DPH levels were rapidly achieved with a minimum of undesirable effects.
Amphetamine metabolism in amphetamine psychosis
Authors: Änggård Erik , Jônsson Lars-Erik , Hogmark Anna-Lena , Gunne Lars-M.
Published: January 2016

The metabolism of 3H‐d,l‐amphetamine was investigated in 11 subjects with amphetamine psychosis. In 3 patients with acidic urine (pH < 6.6), renal elimination of unchanged amphetamine (67% to 73%) was associated with plasma half‐life of 7 to 14 hours and rapid clearing of psychotic symptoms. In 4 patients with alkaline urinary pH metabolism became the dominant route of elimination and plasma half‐life increased to 18 to 34 hours. In these subfects the psychosis was also more long‐lasting. Parahydroxyamphetamine, p‐hydroxynorephedrine, and norephedrine constituted 3% to 8% and hippuric acid 14% to 16% of the metabolites in acidic urine, and 6.8% to 13% and 22% to 52%, respectively, in alkaline urine. The intensity of the psychosis was positively correlated to the amount of basic polar metabolites of amphetamine excreted in urine but not to the amphetamine level in the plasma. Our results indicate that amphetamine metabolites may be of importance in the development of the paranoid psychosis in chronic amphetamine abusers.
Methadone‐naloxone mixtures for use in methadone maintenance programs; I. An evaluation in man of their pharmacological feasibility; II. Demonstration of acute physical dependence
Authors: Nutt John G. , Jasinski Donald R.
Published: January 2016

It has been proposed that mixtures of methadone and the narcotic antagonist, naloxone, be substituted for the methadone dispensed in methadone maintenance programs to reduce methadone diversion. By the oral route in nondependent subjects methadone‐naloxone mixtures are indistinguishable from methadone alone. By the parenteral route, the mixtures have significantly less miotic, behavioral, and subjective effects than methadone alone. Administration of methadone with naloxone to morphine‐dependent subjects ameliorates but does not abolish the abstinence precipitated by the naloxone. Ten milligrams of naloxone administered orally does not precipitate abstinence in rrwrphine‐dependent subjects, and doses of 15 and 30 mg produce only mild signs of abstinence. It is concluded that methadone‐naloxone mixtures could be compounded that would be interchangeable with methadone intended for oral consumption, but have less parenteral abuse liability than methadone. The observation that 4 mg of parenterally administered naloxone precipitated signs of abstinence 1 week after a single dose of methadone indicated the development of acute physical dependence on methadone.
Absorption and metabolism of orally administered beclomethasone dipropionate
Authors: Martin L. E. , Tanner R. J. N. , Clark T. J. H. , Cochrane G. M.
Published: January 2016

A 4 mg dose of beclomethasone‐17,21‐dipropionate‐16,16a‐3H(BP2‐16‐3H) has been given orally in a capsule to 4 subiects, and 2 further subjects as a micrafine suspension. The plasma levels of radioactivity reached a peak at 3 to 5 hours equivalent to 9.6 to 15.2 ng BP2‐16‐3H per milliliter in the capsule‐treated subjects, and 20 ng BP‐16‐3H per milliliter in the subjects given the suspension. Ten to fifteen per cent of the administered dose of radioactivity was excreted in the urine as both unidentified conjugated and free metabolites of the steroid. Fram radiochemical and chromatographie analyses of the feces it was estimated that 90% of the drug in the microfine suspension was absorbed compared with 61 % to 76% of that in the capsule formulation. In vitra BP2‐16‐3H was hydrolyzed by tissue and fecal esterases to beclomethasone‐17‐ propionate‐16,16a‐3H and beclomethasone‐16,16a‐3H. This study has shown that the swallowed portion of an aerosol of beclomethasone dipropionate would be absorbed fram the gastraintestinal tract, and that the lack of suppressive activity on the hypothalamo‐pituitary‐adrenal (HPA) axis of patients on therapeutic doses of the aerosolized steroid is not due to malabsorption of the drug.
Correlation of plasma levels of digoxin in cardiac patients with dose and measures of renal function
Authors: Wagner John G. , Yates James D. , Willis Park W. , Sakmar Ermelinda , Stoll Roger G.
Published: January 2016

There is a well‐established relationship between plasma concentrations of digoxin (PDC's) and therapeutic and toxic effects. The readily obtainable parameters, namely, dose, body weight, age, sex, and creatinine clearance or serum creatinine concentration, might be expected to allow accurate prediction of PDC's. We have now found that these parameters do not allow accurate prediction of PDC's in the individual patient, based on data collected in a panel of cardiac patients. Serial measurements of PDC's are therefore necessary in individual patients taking digoxin. These conclusions are based onL he following results. Forty‐eight equilibrium state PDC's were measured in 25 patients (13 males, 12 females) both under ward conditions (N = 11) and in the Clinical Research Center (N = 27). Multiple linear regression accounted for only 34% of the variance of the PDC's. Individual variables accounted for the following percentages of the total variance of the PDC's: dose, 14.3%; serum creatinine concentration, 10.9%; reciprocal of body weight, 3.1%; reciprocal of urinary excretion rate of creatinine, 0.9%; age, 0.7%, and height, 0.02%. Practically, the digoxin level (ng/ml) is equal to one fifth of the product of the μ/kg dose of digoxin and the serum creatinine concentration in mg/100 ml. Such a correlation accounts for only about one third of the variance of the PDC's; hence predicted levels have a wide confidence interval.
Naproxen‐aspirin interactions in man
Authors: Segre Eugene J. , Chaplin Melvin , Forchielli Enrico , Runkel Richard , Sevelius Hilli
Published: January 2016

Pharmacokinetic interactions between aspirin and other nonsteroidal anti‐inflammatory drugs, including naproxen, have been demonstrated in experimental animals. This study shows that simultaneous oral administration of aspirin and naproxen in man results in a small but statistically significant lowering of plasma levels of naproxen. This effect is not mediated by competition for drug absorption but is associated with enhanced renal clearance of naproxen or its metabolites. Salicylates displace naproxen from binding sites on plasma proteins, a phenomenon that may be responsible for the accelerated clearance. The clinical significance, if any, Of these findings is not yet established, but the relatively small magnitude of the effects noted suggests that the likelihood of a meaningful interaction is small.
Validity of screening methods for drugs of abuse in biological fluids I. Heroin in urine
Authors: Gorodetzky Charles W. , Angel Charles R. , Beach Douglas J. , Catlin Don H. , Yeh Shu-Yuan
Published: January 2016

In evaluating methods of detecting drugs of abuse in biological fluids it is of special importance to determine the ability of detecting a drug or its metabolites in biological fluids. To evaluate several methods of detecting heroin use by urine analysis for morphine and its metabolites, single intravenous doses of 2.5 and 5 mg/70 kg heroin were administered a week apart in random order to 10 nontolerant subjects and their urine was collected for the week following. Along with pre‐drug control urines, each sample was coded, randomized, and analyzed under blind conditions by the following methods: (1) thin‐layer chromatography (TLC) with iodoplatinate preceded by each of 4 extraction procedures, organic solvent and ion exchange resin impregnated paper extraction both without and with prior acid hydrolysis; (2) the free radical assay technique (FRAT); (3) radioimmunoassay (RIA); and (4) the Technicon Autoanalyzer. There was a high probability of detection for the first 8 hours by all methods except the Technicon Autoanalyzer (which gave a low proportion of positives 8 hours after the 2.5 mg per 70 kg heroin dose); up to 16 hours with TLC procedures with hydrolysis and FRAT; and up to 32 to 48 hours with RIA.
Effect of food on nitrofurantoin absorption
Authors: Bates Theodore R. , Sequeira Joel A. , Tembo Aubrey V.
Published: January 2016

The effect of food on the absorption characteristics of nitrofurantoin from a commercial capsule dosage form containing macrocrystalline drug and a commercial tablet dosage form containing microcrystalline drug was assessed in human subiects by a urinary excretion method. In fasting subjects, less nitrofurantoin was absorbed and at a slower rate, and attained lower body levels when the capsule rather than the tablet dosage form was orally administered. When each was administered with food, the absorption of nitrofurantoin was appreciably delayed. Food in the gastrointestinal tract produced an increase in the peak body levels of nitrofurantoin from the macrocrystalline form. No effect of food was observed on the maximum levels after the microcrystalline form. There were increases of 80% and 30% in the bioavailability of nitrofurantoin in nonfasting as compared to fasting subiects, of macro crystalline nitrofurantoin capsules and microcrystalline nitrofurantoin tablets, respectively. There was an increase in the duration of therapeutic urinary concentrations of nitrofurantoin when either form was taken with food. The comman practice of using fasting subiects in bioavailability studies of drug products normally administered with food is questionable.
Clinical pharmacology of isophosphamide
Authors: Creaven Patrick J. , Allen Larry M. , Alford Dorothy A. , Cohen Martin H.
Published: January 2016

The alkylating activity in the urine was measured in patients receiving a new antineoplastic cyclophosphomide analog, isophosphamide (IP), at doses of 2,900 to 5,000 mg per square meter body surface area (BSA) and compared with that of patients receiving 1,100 mg per square meter of cyclophosphamide (CP). Total excretion of alkylating activity after CP (1,l00 mg per square meter) lay between values for the 3,800 mg per square meter dose and the 5,000 mg per square meter dose of IP. The concentration of urinary alkylating activity was higher in patients who developed cystitis than in those who did not. Alkylating activity in the urine was unaltered by acetylcysteine bladder washout. Plasma alkylating activity was more persistent after 5,000 mg per square meter IP than after 1,100 mg per square meter CPo After [HC] IP 5,000 mg per square meter, the plasma half‐life was 13.79 hours, and the urinary recovery of radioactivity was 81.6%, of which 61.6% was unchanged drug. These values differ markedly from those published for CPo IP penetrated the blood‐brain barrier, but its metabolites did not. The greater propensity of IP than of CP to cause cystitis at apprOXimately equitoxic doses may be related to larger amounts of alkylating activity in urine of patients receiving IP. The greater dose of IP than of CP required to produce the same alkylating activity in urine correlates well with the differences in Km of the two drugs in an isolated microsomal enzyme system in vitro previously reported.
Pharmacokinetic control and clinical interpretation of steady‐state blood levels of drugs
Authors: Levy Gerhard
Published: January 2016

Avemge steady‐state blood leveL~ are a function ot the dose, fraction of dose absorbed, dosing interval, biologic half‐life, and apparent voZume of distribution of drugs that have apparently linear pharmacokinetic characteristics. The rate of accumuLation of such drugs, when admini5tered at regular intervals, is inversely proportional to the half‐life of their slowest (terminal) elimination phase. “Hidden accumulation” may occur if the terminal elimination phase of a drug reflects the characteristics of a reLatively very small pharmacokinetic compartment; this may account for a gradual increase in the intensity of a pharmacologic efJect at a time when drug concentrations in plasma are apparently at the steady state. Fluctuations of drug levels du ring a dosing interval at the steady state due to the effects of absorption, distribution, and elimination can complicate the assessment and interpretation of these levels. Contra I of steady‐state levels is particularly difficult in the case of drugs with distinct nonlinear (Michaelis‐Menten) characteristics; a change in dose (or fraction absorbed) will cause a more than proportional change in the steady‐state drug level. The clinical interpretation of steady‐state drug levels must take into consideration the possible effects of pharmacologically active metabolites and of changes in drug distribution that may modify the relationship between drug concentration in plasma and the intensity of a pharmacologic efJect.
Bioavailability of digoxin tablets and elixir in the fasting and postprandial states
Authors: Greenblatt David J. , Duhme David W. , Koch‐Weser Jan , Smith and Thomas W.
Published: January 2016

In a multicrossover study, 8 healthy male subjects received single doses (0.75 mg) of digoxin tablets and elixir in the fasting and postprandial states. Areas under the 8 hour serum concentration curve and 6 day cumulative urinary excretion of digoxin were determined for each subject after each mode of administration. Administration with food did not significantly alter peak serum digoxin concentrations after tablets or elixir, but the peak concentration after tablets was delayed in the postprandial state. Neither mean area under the serum concentration curve nor mean cumulative urinary excretion was significantly changed by postprandial administration of either tablets or elixir. In the same indiVidual, variations in bioavailability between fasting and postprandial states were similar in magnitude to those after repeated fasting administration. Postprandial administration of digoxin does not significantly alter completeness of absorption but can alter rate.
Acetaminophen‐induced hepatic injury: Protective role of glutathione in man and rationale for therapy
Authors: Mitchell Jerry R. , Thorgeirsson Snorri S. , Potter William Z. , Jollow David J. , Keiser Harry
Published: January 2016

Recent studies of acetaminophen‐induced liver damage in animals indicate that acetaminophen is converted in the liver to a chemically reactive arylating agent that normally is detoxified by conjugation with glutathione. When the dose of acetaminophen is large enough to deplete hepatic glutathione, however, there is extensive arylation of hepatic macromolecules and cell death. This paper presents evidence that administration of glutathione‐like nucleophiles, such as cysteamine, protects mice from arylation of hepatic macromolecules, hepatic necrosis, and death caused by the reactive acetaminophen metabolite. Additional studies indicate that glutathione may serve a similar protective function in man as in other animals. Thus, logical treatment of patients overdosed with acetaminophen might be based on cysteamine or other nucleophiles.
Contact dermatitis
Authors: Epstein William L.
Published: January 2016

Contact dermatitis is a common skin condition seen by dermatologists. Allergic contact dermatitis (CD) makes up 20% of the group. It is characterized by a delayed onset, perivascular mononuclear cell infiltrate, and passive transfer by lymphoid cells rather than serum, and thus is generally accepted as a variety of delayed hypersensitivity or cellular immune reaction. This brief review will consider allergic contact dermatitis from three aspects: (1) the afferent limb; (2) the central lymphoid compartment; and (3) the efferent limb.
Differential effects of propranolol on heart rate and plasma renin activity in patients treated with minoxidil
Authors: Velasco M. , Malley K. O , Robie N. W. , Wells J. , Israili Z. H. , McNay J. L.
Published: January 2016

The relationship between PPC and its effect on minoxidil‐induced increases in PHA and heart rate was examined in 9 patients with essential hypertension. Concomitant with the minoxidil‐induced depression of mean arterial pressure (30.7 ± 3.5 mm Hg, mean ± SEM), heart rate increased from 79.1 ± 3.0 to 100.4 ± 4.6 BPM, and PHA increased from 1.12 ± 0.28 to 8.58 ± 2.83 nglmllhr. Addition of propranolol to minoxidil caused a decrease in heart rate in proportion to log PPC:

Δ heart rate = 1.1 − 12.8 log PPC (r, 0.59, p < 0.005)

The relationship between PPC and the reduction in PHA was more complex. While a major reduction in PHA was observed at PPC in the range 20 to 60 nglmllhr, there was no consistent effect on PHA at higher PPC. Therefore, maximum antagonism of adrenergicaUy mediated increases in PHA is produced by much lower concentrations of propranolol than maximum suppression of adrenergically mediated increases in heart rate.
Blood flow in muscle groups and drug absorption
Authors: Evans Eleanor F. , Proctor Jack D. , Fratkin Melvin J. , Velandia Jorge , Wasserman Albert J.
Published: January 2016

Resting human muscle blood flow (MBF) was determined simultaneously in the usual intramuscular injection sites to resolve whether variance in MBF could account for differences in drug absorption. Three pairs of muscles (gluteus maximus, vastus lateralis, and deltoid) were studied in each of 20 adult subjects. Use of dual, matched linear rate meters allowed two muscles to be studied simultaneously, with the order of injection random within an incomplete block design. MBF was calculated from the 133xenon washout rate using a single exponential that the computer found to best fit the data. Deltoid MBF (11.6 ml/100 gmlmin ± 0.5) was significantly (p < 0.05) greater than gluteus MBF (9.6 ± 0.5), with vastus MBF intermediate (10.8 ± 0.6). There were no significant differences due to order of injection or between right and left sides for each muscle. These data indicate that there are consistent differences in resting MBF among specific muscle groups of sufficient magnitude (19%) to affect the rate of absorption and peak serum levels following intramuscular administration of drugs.
Furosemide binding to human albumin and plasma of nephrotic children
Authors: Prandota Jozef , Pruitt Albert W.
Published: January 2016

The extent and nature of furosemide (F) binding to human albumin (HA) and to the plasma of 6 children with nephrotic syndrome were studied by equilibrium dialysis at 37° C and pH 7.4 with 14C‐F. At a total concentration of 3.4 µ/ml (therapeutic range), the unbound fraction of F to 4 gm per 100 ml HA was 2.79 ± 0.35. The degree of binding was relatively constant from 1.8 to 36 µ/ml of F concentration. The percentage of unbound F doubled when total concentration of the drug was increased more than 130 times 0.8 to 245 µ/ml). F has two classes of binding sites (n1 = 1.42, k1 = 5.07 × 104 M−1; n2 = 3.4. k2 = 1.58 × 104 M−1); interaction with HA involves hydrophobic. ionic. and hydrogen forces. Acetylsalicylic acid (ASA). acetazolamide, diazoxide, phenylbutazone, sulfisoxazole (S), and tolbutamide (T) decreased F binding. Combinations of ASA, S, and T exerted a strong additive displacing effect. The binding of the F metabolite (4‐chloro‐5‐sulfamoylanthranilic acid, CSA) was studied at 1.3 and 2.6 µ/ml. The unbound fraction was 5 times that of F. CSA did not influence F binding. Studies with plasma of 7 healthy adults showed that albumin is the only plasma protein responsible for F binding. The plasma albumin concentration range of the children with nephrotic syndrome was 0.6 to 2.1 gm per 100 ml. There was some correlation between albumin concentration and binding of F (2.8 to 9.6% unbound); this corresponded with findings with HA. Albumin concentrations lower than 2 gm per 100 ml seemed to influence the extent of the unbound fraction of F considerably.
Pharmacological activity, metabolism, and pharmacokinetics of glycinexylidide
Authors: Strong John M. , Mayfield Douglas E. , Atkinson Arthur J. , Burris B. Cullen , Raymon Frank , Webster Leslie T.
Published: January 2016

Glycinexylidide (GX) is a metabolite of lidocaine that is frequently present in µg/ml concentrations in the plasma of patients treated with lidocaine infusions for 24 hr or more. Plasma levels of ex have 26% the antiarrhythmic activity of lidocaine in an animal model, and GX adversely affects the mental performance of normal subjects at plasma concentrations comparable to those found in patients. The total volume of ex distribution in man is similar to that of lidocaine but the plasma clearance is less, so that the 10‐hr elimination phase half‐life of GX is much longer than the 11/2‐hr half‐life reported in normal subjects for lidocaine. About half of an administered dose of GX is excreted unchanged in urine, roughly 15% appears in urine as conjugates of xylidine and p‐OH xylidine, and the fate of the rest is unknown.
1,3 Bis‐(2 chloroethyl)‐1‐nitrosourea and streptozotocin chemotherapy
Authors: Lokich Jacob J. , Chawla Prem L. , Frei Emil
Published: January 2016

Streptozotocin (STZ) was combined with 1,3 bis‐(2 chloroethyl)‐1‐nitrosourea (BC NU) and with BCNU and 5‐fluorouracil (FU) in a 2‐ and 3‐drug clinical chemotherapeutic trial. The premise that STZ and BC NU are qualitatively different with regard to marrow suppression was the primary rationale of the study. The 2‐ and 3‐drug regimens were associated with a higher incidence of severe leukopenia and thrombopenia (47% and 100%, respectively) and a lower mean nadir for each (1,700/mm3 and 15,000/mm3) than the reported experience with single drug BCNU therapy. However, this synergism did not apply to therapeutic effects. The reasons for potentiation of marrow toxicity may be related to specific aspects of direct drug interaction as well as alterations in pharmacologic reactions.
Effects of oral propranolol in normal subjects
Authors: LeWinter Martin M. , Crawford Michael H. , Karliner Joel S. , O'Rourke Robert A.
Published: January 2016

The effects of oral propranolol were evaluated in 10 normal volunteers. The resting heart rate decreased from the mean control value of 68 ± 3.3 (SE) to 56 ± 2.8 beats per minute (bpm) on propranolol (p < 0.001, paired t test). Mean systolic blood pressure also decreased from 125 ± 5.0 to 114 ± 4.2 mm Hg (p < 0.03). Resting systolic time intervals were unaffected by propranolol. Mean maximal treadmill exercise tolerance time was not significantly altered by propranolol although the mean heart rate systolic blood pressure product at maximal exertion was markedly decreased (1.91 ± 0.17 vs 2.62 ± 0.17 X 10 4 p < 0.004). The nonsignificant effect of oral propranolol on resting systolic time intervals and maximum exercise tolerance despite significant changes in heart rate and blood pressure at rest and during exercise stand in contrast to the reported effects of intravenous propranolol. Explanations for this difference between the effects of oral and intravenous propranolol in nprmal subjects are examined.
Increased incidence of isoniazid hepatitis in rapid acetylators: possible relation to hydrazine metabolites
Authors: Mitchell Jerry R. , Thorgeirsson Unnur P. , Black Martin , Timbrell John A. , Snodgrass Wayne R. , Potter William Z. , Jollow David J. , Keiser Harry R.
Published: January 2016

Approximately 10% to 20% of isoniazid recipients manifest biochemical evidence of liver injury. A smaller number of patients develop clinically overt hepatitis. Isoniazid is metabolized in man at extremely variable rates, and the rate is under genetic control. Two separate clinical studies have noted a possible relation between susceptibility of patients to isoniazid liver injury and rapid metabolism (acetylation) of the drug. For this reason, 21 patients who had recovered from probable isoniazid hepatitis and 5 patients who previously had manifested biochemical evidence of mild isoniazid liver injury were genetically phenotyped as rapid or slow isoniazid acetylators by the sulfamethazine method. The rapid phenotype was found in 86% of patients with probable hepatitis and in 60% of the possible ones, whereas the expected frequency was 45%. Examination of isoniazid metabolites revealed that rapid acetylators hydrolyze much more isoniazid to isonicotinic acid and the free hydrazine moiety than do slow acetylators. The hydrazine moiety liberated from isoniazid is primarily acetylhydrazine, and studies in animals show this metabolite to be converted to a potent acylating agent that produces liver necrosis. We suggest that release of the hepatotoxic hydrazino moiety of isoniazid in man is responsible for isoniazid liver injury.
Bioavailability of oral dexamethasone
Authors: Duggan D. E. , Yeh K. C. , Matalia N. , Ditzler C. A. , McMahon F. G.
Published: January 2016

Bioavailabilities of dexamethasone tablets and elixir in man were evaluated by each of 3 model‐independent methods of pharmacokinetic analysis employing plasma and urinary values as determined by radioimmune assay. There were no significant differences among the results determined by the 3 methods nor between the respective availabilities of the !Wo formulations; the latter averaged 82.6 ± 17.7% for the elixir formulation and 78.0 ± 12.1% for tablets.
Relative potency of prorenoate and spironolactone in normal man
Authors: Ramsay Lawrence , Harrison Ian , Shelton John , Tidd Michael
Published: January 2016

The potency of single doses of a new aldosterone antagonist, prorenoate, in reversing the renal effects of the synthetic mineralocorticoid fludrocortisone was compared to that of spironolactone in a double‐blind balanced crossover study in 12 healthy subjects, The potency of prorenoate potassium as related to elevation of the urinary log 10 10 Na/K ratio (2.69:1) and as related to potassium retention (3.75:1 ) was significantly higher than that of spironolactone. Prorenoate produced greater natriuresis (1.64: 1) but the difference was not significant. There was evidence for a qualitative difference between spironolactone and prorenoate; the latter significantly more potent in retaining potassium than in increasing sodium excretion. The simple methodology described is based on standard bioassay principles, Yielded a valid and sensitive comparison of the two drugs, and should prove useful in the evaluation of other aldosterone antagonists.
Acetylation polymorphism of sulfapyridine in patients with ulcerative colitis and Crohn's disease
Authors: Das Kiron M. , Eastwood Martin A.
Published: January 2016

Sulfapyridine (SP) is one of the main metabolites of salicylazosulfapyridine (sulfasalazine) that is used extensively in the management of inflammatory bowel disease. One hundred and twenty‐two patients with ulcerative colitis or Crohn's disease were studied, including 21 new, untreated patients and 101 previously treated patients. Patients were studied for at least one year during active disease and remission. It was shown that sulfapyridine shares the same acetylation polymorphism as sulfadimidine. The acetylation capability of each patient as determined in serum and urine was constant irrespective of dose (2 to 8 gm/day) and state of disease. A single study of serum can determine acetylator phenotype in patients on sulJasalazine therapy without using any other drug for this purpose and may help ascertain dosage and assess side effects.
Tricyclic antidepressant overdose: Clinical presentation and plasma levels
Authors: Spiker Duane G. , Weiss Alan N. , Chang Sidney S. , Ruwitch Joseph F. , Biggs John T.
Published: January 2016

Fifteen patients were studied at 8‐ to 12‐hr intervals during the first 24 hr after overdosing with tricyclic antidepressants, and subsequently followed daily for up to 144 hr. The severity of the overdose was determined by measuring the plasma tricyclic antidepressant level using gas chromatography‐mass fragmentography. No correlation was found between total, tertiary, or desmethyl tricyclic antidepressant plasma levels and maximum heart rate, lowest blood pressure, degree of unconsciousness, or EKG changes involving the P‐R interval or ST‐T wave changes. There was a weak correlation between drug plasma level and maximum pupil size (r = 0.46; P < 0.05) and a strong correlation between the duration of the QRS complex and tricyclic antidepressant plasma levels (r = 0.75; P < 0.01). All patients with a total tricyclic antidepressant plasma level ≧ 1,000 ng/ml had a QRS interval ≧ 100 msec. As the total plasma tricyclic level fell, the duration of the QRS interval returned to normal. Thus, the duration of the QRS complex on the electrocardiogram appears to be the most reliable clinical sign for evaluating the seriousness of tricyclic antidepressant overdosage.
Efficacy of beta adrenergic blockade in coronary heart disease: Propranolol in angina pectoris
Authors: Miller Richard R. , Olson Harold G. , Pratt Craig M. , Amsterdam Ezra A. , Mason Dean T.
Published: January 2016

Despite widespread clinical application of propranolol (P) in angina pectoris, convincing evidence of its efficacy has been incomplete, thereby resulting in continued controversy. Its antianginal effectiveness was investigated in 20 patients with documented coronary heart disease in a 44‐wk study incorporating a prolonged 12‐wk lead‐in period, individualization of P dosage in a 6‐wk dose‐finding period, and a 24‐wk double‐blind crossover phase. On double‐blind placebo, patients had 10.5 ± 2.1 anginal attacks and consumed 12.8 ± 3.0 nitroglycerin tablets (NTG) each week compared to 6.6 ± 1.5 anginal episodes (− 37%, p < 0.001) and 8.0 ± 1.7 NTG (− 38%, p < 0.001) when on P. No patient experienced more angina with P than with placebo. In addition, time to onset of chest pain during treadmill exercise was prolonged by P from 190 ± 16 to 248 ± 22 sec (+31%, p < 0.02) and ST depression was reduced from 1.7 ± 0.21 to 0.99 ± 0.18 mm (−42%, p < 0.05). There was correlation (r = 0.64, p < 0.01) between per cent declines in anginal frequency and resting double product with P. Thus, propranolol favorably altered several indices of myocardial ischemia in severe coronary heart disease. This investigation clearly documents the clinical efficacy of optimal beta adrenergic blockade in coronary disease and provides objective justification for the judicious application of propranolol in treatment of angina pectoris.
Clinical trials of drugs from the viewpoint of the academic investigator (a satire)
Authors: Lasagna Louis
Published: January 2016

Dr. Lasagna was unable to attend the workshop in person, and therefore delivered his remarks by videotape, in the assumed role of the newest “Secretary of Human Experimentation” at the Department of Health, Education, and Welfare addressing a public television audience. There is no difficulty in sensing the serious truths underlying the satire in his address.
Patient package inserts. II. Toward a rational patient package insert
Authors: Joubert Pieter , Lasagna Louis
Published: January 2016

Analysis of the response to a questionnaire on various aspects of drug information showed several significant trends. The importance of the physician as an information source varied directly with age and inversely with educational level of patients. The doctor's importance as a source of information was also greater for those who visited physicians' offices or clinics more and if they were on long‐term treatment. Younger persons, those with higher levels of education, and those who were not in regular contact with a physician placed greater importance on non‐physician sources. Persons consulting physicians regularly desired less information and knew less about drugs than those who did not regularly see a physician. These findings suggest that the educational role of the physician could be improved and should be directed particularly at the low‐income, older patient. In the design of the package insert, particular attention should be given to self‐prescribed medications where no other information sources will be operating.