bluuebunny/crossref_metadata_2025 huggingface dataset:
Mechanisms of hypolipidemic action of nicotinic acid
Authors: Kudchodkar B. J. , Sodhi Harbhajan S. , Horlick Louis , Mason Dean T.
Published: January 2016

The effects of NA treatment were investigated in 5 normolipidemic and 10 hyperlipidemic subjects. Nicotinic acid lowered the levels of plasma lipids in alt patients on normal American diets but had no effect on plasma lipids of patients on HCD. NA did not affect intestinal absorption of cholesterol. Its effects on cholesterol balance were variable. Its action on cholesterol synthesis was investigated in 11 patients by three additional methods, each one of which indicated that synthesis of cholesterol was markedly inhibited. NA did not reverse the increase in synthesis of cholesterol in patients on HCD but it did reverse the increase in synthesis caused by cholestyramine. Hypocholesterolemic effect of NA was associated with mobilization of tissue cholesterol and (as reported by us previously for clofibrate) the drug also reversed an apparent increase in tissue pools of cholesterol in a patient given cholestyramine. Nicotinic acid had no effect on the activity of plasma lecithin‐cholesterol acyltransferase. NA treatment was associated with a decrease in the turnover of plasma TG. The increase in the fractional turnover rate of plasma TG seen after NA treatment was perhaps secondary to the decrease in the levels of plasma TG. Such e.ffects were not observed in patients on HCD. The primary mechanism of hypolipidemic action of NA appears to be its antilipolytic action on adipose tissue. Its effects on hepatic metabolism of lipids are probably secondary to the reduction in the circulating pool of plasma free fauy acids.
Enhanced biotransformation of theophylline in marihuana and tobacco smokers
Authors: Jusko William J. , Schentag Jerome J. , Clark John H. , Gardner Mark , Yurchak Anthony M.
Published: January 2016

Single oral doses of theophylline were administered to 7 chronic marihuana smokers, to 7 chronic users of both marihuana and tobacco, and to 43 appropriate control subjects. Theophylline was cleared from the blood more rapidly in both marihuana and tobacco smokers with a mean increase in total clearance from 52 ml/kg/hr in nonsmokers to 74 ml/kg/hr in subjects who smoked either material alone. There was an additive increase in clearance to 93 m/lkg/hr in those who smoked both substances. Concern over enhanced metabolism of other drugs is probably warranted in tobacco and cannabis smokers.
Clofibrate kinetics after single and multiple doses
Authors: Gugler Roland , Hartlapp Joachim
Published: January 2016

The kinetics of chlorphenoxyisobutyric acid (CPIB) were studied in 5 healthy subjects after single 500‐mg, 1,000‐mg, and 2,000‐mg doses of clofibrate, and in steady‐state after 8 days' treatment with 1,000 mg twice daily. Maximum plasma concentrations of CPIB were observed 4 to 6 hr after dosing. A mean plasma half‐life of 16.7 hr was recorded which was independent of dose and duration of treatment. Total plasma clearance (Cl) calculated from area under the curve with the use of the total plasma concentration was 5.6 mllmin for the 500‐ and the 1,000‐mg doses but increased to 6.8 ml/min for the 2,000‐mg dose and was even higher (8.1 ml/min) in steady‐state. This change in Cl is a consequence of a progressive reduction in the plasma protein binding of clofibrate at plasma concentrations above 50 µg/ml, since Cl rises in association with reduced protein binding at the high plasma concentrations measured after the 2,000‐mg single dose and in steady‐state. Cl and apparent volume of distribution were identical for all doses tested when calculations were based on the nonprotein‐bound CPIB concentrations only. Due to the inconsistant protein binding of CPIB, total steady‐state concentrations could not be predicted from the single dose kinetic data.
Gynecomastia induced in normal males by spironolactone
Authors: Huffman David H. , Kampmann Jens P. , Hignite Charles E. , Azarnoff Daniel L.
Published: January 2016

The short‐term (1 week) and long‐term (10 month) effects of spironolactone have been determined in normal males. There were no adverse effects or changes in plasma testosterone, luteinizing hormone, or progesterone levels during one week of treatment with spironolactone (200 mg/day) in 6 normal men. A continuous 4‐hr sampling technique to provide an integrated plasma sample resulted in plasma hormone concentrations similar to the mean values for intermittent sampling. There was considerable intraindividual variability in the levels of each hormone. To evaluate the long‐term effects of spironolactone, 30 normal males were randomly divided into three groups: placebo, 100 mg spironolactone per day (low dose), and 100 mg spironolactone per day increased at two months to 200 mg spironolactone per day (high dose). The study was double blind and lasted 10 months. The presence of gynecomastia was determined clinically and confirmed by thermography. Two metabolic clearance studies with either 3H‐testosterone or 3H‐androstenedione were obtained (1) just before spironolactone treatment and (2) again with the same steroid either the last day of the 10‐month treatment period or with the development of gynecomastia. The concentrations of testosterone, estradiol, estriol, luteinizing hormone, follicle stimulating hormone, progesterone, and prolactin were also determined before treatment and at two‐month intervals during treatment. Eighteen individuals received spironolactone (10 in the low‐dose group and 8 in the high‐dose group); of these, 8 developed gynecomastia. There were none in the placebo group. The incidence of gynecomastia was 30% in the low‐dose group and 62% in the high‐dose group. In addition, one individual in the high‐dose group discontinued taking the drug early because of decreased libido, bringing the incidence of adverse effects in this high‐dose group to 75%. Spironolactone induced no significant changes in the metabolic clearance of androstenedione or testosterone. Plasma concentrations of the various hormones did not change as a result of either spironolactone or the development of gynecomastia. Inhibition of testosterone synthesis or alteration in its metabolic clearance by spironolactone does not appear to be the cause of spironolactone‐induced gynecomastia in man.
Dobutamine pharmacokinetics in severe heart failure
Authors: Kates Robert E. , Leier Carl V.
Published: January 2016

Dobutamine pharmacokinetics was investigated in 7 patients with severe cardiac failure. Dobutamine was administered by a constant intravenous infusion at rates of 2 .5, 5.0, 7.5, and 10.0 µg/kg/min. Steady‐state plasma levels increased in proportion to the infusion rate, indicating that there was no saturation of the disposition processes. The average total body clearance was found to be 2.35 ± 1.01 L/min/m2. After termination of the final infusion, plasma levels of dobutamine were monitored to determine the elimination half‐life. The disappearance half‐life of dobutamine was calculated to be 2.37 ± 0.7 min and the distribution volume was 0.202 ± 0.084 L/kg. The limited data suggest that the volume of distribution of dobutamine was related to the extent of edema.
Effects of probenecid on furosemide response
Authors: Brater D. Craig
Published: January 2016

Furosemide gains access to its intraluminal site of action by active secretion by the organic acid transport system of the proximal tubule. Inhibition of this transport by probenecid would predictably decrease the effect of furosemide. In this study in 8 normal volunteers, however, the opposite occurred; namely, pretreatment with probenecid increased the overall response to furosemide by prolonging its effect. Sodium excretion in 8 hr due to 40 mg of furosemide rose from 262 ± 16 to 358 ± 11 mEq after probenecid. Urine volume increased from 3,265 ± 275 to 4,165 ± 183 ml after probenecid. Analysis of the time‐course of the increased diuresis and natriuresis showed that probenecid actually decreased the response for the first 60 to 90 min after furosemide but increased the subsequent response sufficiently to result in a greater overall effect. Possible explanations include access of furosemide to its active site from the serum, an effect of probenecid on prostaglandin transport, and a changing pharmacokinetic interaction between probenecid and furosemide.
Oral nefopam and aspirin
Authors: Sunshine Abraham , Laska Eugene , Slafta Jean
Published: January 2016

Analgesia through nefopam (30 mg, 60 mg, 90 mg), aspirin (325 mg, 650 mg), and placebo were compared in 122 hospitalized patients with moderate to severe postoperative, fracture, or other somatic pain. A double‐blind noncrossover study design was used, and patients were evaluated for pain intensity and pain relief over a 6‐hr period. Based on sum of pain intensity differences (SPID) scores, treatment effects were consistent and indicative of good dose response to both active medications. Pain relief scores were more variable but were generally in accordance with SPID values. Time‐effect curves were similar. Estimated relative potency of nefopam to aspirin was 10.4 with a 95% confidence interval of 6.3 to 20.8for SPID, indicating that the analgesic potency of nefopam, 60 mg, was equivalent to that of aspirin, 650 mg. Side effects were minimal.
Drug concentration in saliva
Authors: Mueklow J. C. , Bending M. R. , Kahn G. C. , Dollery C. T.
Published: January 2016

It is possible to predict plasma concentrations of drugs by measurement in saliva, obviating the need for venipuncture. Using a selection of weakly acidic and basic drugs, we have found this prediction reliable for drugs largely nonionized at normal plasma pH (phenytoin, phenobarbital, antipyrine) but unreliable for ionized drugs (chlorpropramide, tolbutamide, propranolol, meperidine). Deliberate alteration of saliva flow rate and pH using different stimuli have produced twofold changes in saliva drug concentrations. Wide interindividual variability of saliva pH is the likely explanation for the inconstancy of saliva to plasma concentration ratios for ionized drugs.
Interaction of chloramphenicol with phenytoin and phenobarbital; Case report
Authors: Koup Jeffrey R. , Gibaldi Milo , McNamara Patrick , Hilligoss Donald M. , Colburn Wayne A. , Bruck Erika
Published: January 2016

The effect of chloramphenicol therapy (48 mg/kg/day) on the serum concentrations of phenytoin and phenobarbital was studied in a patient previously stabilized on anticonvulsant medications. Phenytoin, 12 mg/kg/day, and phenobarbital, 5 mg/kg/day resulted in serum concentrations averaging 10.8 µ/ml before and 30.5 µ/ml, after chloramphenicol therapy. A reduction in dose of both phenytoin and phenobarbital was required to minimize adverse effects during the course of chloramphenicol therapy. An average daily dose of phenytoin of 9.1 mg/kg resulted in an average serum concentration of 17.8 µ/ml. A daily dose of phenobarbital of 4.0 mg/kg resulted in an average serum concentration of 37.1 µ/ml. These changes indicate 50.5% and 40.4% decreases in clearance of phenytoin and phenobarbital. Multiple‐dose nonlinear regression analysis of phenytoin and phenobarbital serum concentration data obtained during chloramphenicol therapy indicated a 62.5% and a 29.5% decrease in clearance. Subsequent serum concentration monitoring demonstrated a similar reduction in phenobarbital clearance when chloramphenicol was added to phenobarbital alone.
Interaction of disulfiram with benzodiazepines
Authors: MacLeod S. M. , Sellers E. M. , Giles H. G. , Billings B. J. , Martin P. R. , Greenblatt D. J. , Marshman J. A.
Published: January 2016

The disposition of chlordiazepoxide (50 mg, intravenously), diazepam (0.143 mg/kg, orally), and oxazepam (0.429 mg/kg, orally) were studied in normal and alcoholic men before and after chronic disulfiram administration. Decreases in the plasma clearance of chlordiazepoxide (54%, p < 0.05), diazepam (41%, p < 0.05), and their active N‐desmethyl metabolites were observed. Oxazepam has no important active metabolites and its net disposition is minimally altered by disulfiram. Oxazepam disposition is unaffected by age and liver disease. These considerations together with that of the short half‐life of oxazepam (median, 6.1 hr) suggest that oxazepam may be the drug of choice if benzodiazepine therapy is used for patients taking disulfiram.
High‐dose intravenous and hepatic artery infusions of thymidine
Authors: Ensminger William D. , Frei Emil
Published: January 2016

Thymidine (TdR) was administered by constant infusion at progressively escalated dose rates to 4 patients with colon cancer metastatic to liver in whom hepatic arterial (HA) and hepatic venous (HV) catheters had been placed. Serum levels ofTdR and hepatic extraction ofTdR were determined as a function of dose rate. With intravenous infusions, serum levels of TdR rose progressively with dose rate, going from 1.3 to 3.4 µM at 8 gm/M2/day to 1,200 µM at 128 gm/M2/day. The hepatic extraction ratio at dose rates up to 16 gm/M2/day was high, ranging from 0.64 to 0.95, but when, as was done in one patient, dose rates were increased from 16 gm/M2/day to 128 gm/M2/day, the extraction ratio fell progressively from 0.85 to 0.17. With direct HA infusion hepatic extraction ofTdR was high (94% to 98%) at 8 gm/M2/day, but fell progressively as dose rates were increased to 16 gm/M2/day and 32 gm/M2/day. Thus, it appears that, though efficient, hepatic extraction processes for TdR are saturable. Our data also suggest that high TdR levels falling in millimolar ranges, such as have been shown previously to induce cytotoxicity in preclinical models, are achievable by peripheral intravenous infusions at dose rates of 64 to 128 gm/M2/day and that selectively higher hepatic levels can be maintained at dose rates of 16 to 32 gm/M2/day by HA infusions.
The predictable relationship between plasma levels and dose during chronic propranolol therapy
Authors: Walle Thomas , Conradi Edward C. , Walle U. Kristina , Fagan Timothy C. , Gaffney Thomas E.
Published: January 2016

The present study has examined the relationship between plasma propranolol concentrations and dose during chronic propranolol therapy and the between‐patient variation in this relationship under rigorously controlled conditions. Peak (2 hr) and trough (6 hr) plasma concentrations were measured at carefully established steady‐state conditions in 46 patients with hypertension or coronary artery disease. All patients were hospitalized in a clinical research unit. Propranolol doses ranged from 40 to 960 mg/day (every 6 hr). Propranolol was measured by gas chromatography‐mass spectrometry using a stable isotope‐labeled internal standard. Peak plasma propranolol (ng/ml) was linearly related to dose over the range 160 to 960 mg (y = 1.11x − 111; correlation coefficient = 0.96); a non linear relationship exists over the range 40 to 160 mg. Trough plasma concentrations were 51 ± 9% (mean ± SD) of the peak concentrations over the entire dose range. Between‐patient variation in plasma propranolol was much smaller than has previously been reported in spite of the fact that the patient population studied was quite heterogeneous and that numerous other drugs were concomitantly used with propranolol. A maximum, 3‐fold, variation was observed at the 40‐mg dose level and decreased linearly with dose to an only 1.3‐fold variation at doses exceeding 600 mg/day. The fact that the oral dose of propranolol can be used to predict a very narrow plasma concentration range indicates a very uniform pattern in the way patients handle propranolol, a pattern that could prove useful as an aid in dose selection as well as a basis for an evaluation of patient compliance.
Altered drug binding due to the use of indwelling heparinized cannulas (heparin lock) for sampling
Authors: Wood Margaret , Shand David G. , Wood Alastair J. J.
Published: January 2016

The effect of the use of the so‐called heparin lock for blood sampling on the binding of propranolol has been studied and a cumulative dose‐response curve to heparin constructed. The use of this method of blood sampling introduced considerable artifactual changes into the measurement of propranolol's plasma binding. The free fraction rose from 9.9% to 13.4% after only 50 U of heparin was used to flush the cannula. The increase in the free fraction of propranolol showed excellent correlation with the increase in free fatty acid levels (p < 0.001, r = 0.996). The importance of ensuring that sampling techniques do not introduce artifactual changes in pharmacokinetic studies is emphasized.
Metabolism of drugs and carcinogens in man: Antipyrine elimination as an indicator
Authors: Kalamegham R. , Krishnaswamy K. , Krishnamurthy S. , Bhargava R. N. K.
Published: January 2016

The suitability of the most commonly used “prototype” drug, viz, antipyrine, in predicting drug and carcinogen metabolism was evaluated, by studying in vivo antipyrine elimination rate (Ke) and in vitro metabolism of drugs and carcinogens in liver preparations in the same individuals. Our subjects were 20 adult males undergoing abdominal surgery for gastrojejunostomy, although antipyrine Ke could be studied in only 16 subjects. Correlations of the various in vitro‐in vivo parameters were positive between the parameter pairs: in vivo antipyrine Ke—in vitro benzopyrene hydroxylase; benzopyrene hydroxylase—aniline hydroxylase; and benzopyrene hydroxylase‐γ‐glutamyl transferase. Aminopyrine demethylase did not correlate with any of the parameters studied. The degree of correlation between antipyrine Ke and benzopyrene hydroxylase was statistically significant but was not satisfactory for predictive purposes. Our study indicates some of the problems and limitations of in vivo‐in vitro comparisons and confirms earlier doubts on the usefulness of antipyrine as a “prototype” drug for predicting drug and carcinogen metabolism in man.
Physostigmine in coma due to drug overdose
Authors: Nattel Stan , Bayne Les , Ruedy John
Published: January 2016

Twelve patients with coma due to drug overdose were treated with physostigmine salicylate in a double‐blind, placebo‐controlled crossover trial. Three of the 9 patients who had taken drugs without anticholinergic action (methyprylon, barbiturates, ethchlorvynol, benzodiazepines) and 2 of 3 who had taken drugs with anticholinergic action (amitriptyline) showed dramatic decrease of depth of coma after physostigmine. Among patients with non‐anticholinergic overdose, in 10 min physostigmine induced an increase in mean arterial pressure from a mean of 80.3 mm Hg to 103.8 mm Hg (p < 0.05) and in heart rate from a mean of 87.9 beats/min to 98.3 beats/min (p < 0.001). When given to patients with anticholinergic drug intoxication, physostigmine induced a fall in mean arterial pressure from a mean of 105.4 mm Hg to 96.1 mm Hg (p < 0.01) and in heart rate from a mean of 104 beats Imin to 91.3 beats/min (p < 0.10). Physostigmine induced dilation of pupils in all patients with non‐anticholinergic overdose and in none with anticholinergic overdose (p < 0.01). The effects of physostigmine in non‐anticholinergic overdose appear to be due to a nonspecific action on the central nervous system. Physostigmine may also be of value in the differential diagnosis of coma. Its routine use in the treatment of drug‐induced coma is not recommended except in anticholinergic drug overdose unless standard measures fail and artificial mechanical ventilation cannot be provided to patients with severe drug‐induced respiratory depression.
Noninvasive kinetic approach to the estimation of total hepatic blood flow and shunting in chronic liver disease—a hypothesis
Authors: McLean Allan , du Souich Patrick , Gibaldi Milo
Published: January 2016

The intact hepatocyte theory of chronic liver disease suggests a relationship between the degree of shunting of total liver blood flow around the functional liver cell mass and the fraction of functional liver cell mass. By defining this relationship we have developed pharmacokinetic equations to permit the estimation of both total hepatic blood flow and the extent to which this blood flow is shunted. The method requires the determination of the systemic (hepatic) clearances of a high (e.g., indocyanine green [JCG]) and a low (e.g., antipyrine [AP]) extraction ratio drug in the same patient. Applying these equations to literature data obtained from patients with moderate or severe chronic liver disease and from patients with a surgical portacaval shunt, we find.: (1) a modest decrease in total hepatic blood flow (16%) and a significant degree of shunting (27%) in patients with moderate chronic liver disease; (2) a substantially reduced total hepatic blood (52%) and extensive shunting (72%) in patients with severe chronic liver disease, and (3) a degree of shunting comparable to that estimated in patients with moderate chronic liver disease but a seriously compromised total hepatic blood flow (a reduction of 55% compared to normal) in patients with surgical portacaval shunts.
Inhibition of hepatic drug metabolism by noret
Authors: Field Barry , Lu Cherry , Hepner Gershon W.
Published: January 2016

In order to assess the effect of norethindrone on hepatic drug metabolism in man, hepatic N‐demethylation of aminopyrine was studied by means of the aminopyrine breath test (ABT) in 7 healthy women during two menstrual cycles. Aminopyrine metabolic clearance rates were also studied in 3 women. The women were examined at the ends of the first, second, and third weeks before starting progestogen therapy and at the same times during a second menstrual cycle during which they took norethindrone, 350 µ/day. The ABT was 5.1 ± 1.9% (mean ± SD) during the three control weeks and lower (p < 0.001) during the three weeks on norethindrone, 3.9 ± 0.9%. Aminopyrine metabolic clearance rate also fell during norethindrone therapy. The data suggest that progestogens inhibit hepatic microsomal function.
Assessment of antibiotic efficacy in acute bacterial meningitis
Authors: Beam Thomas R. , Allen James C.
Published: January 2016

Currently, antibiotic efficacy in acute bacterial meningitis is evaluated in several stages. First, animals are used to assess antibiotic penetration into cerebrospinal fluid (CSF) in the absence and presence of an inflammatory stimulus. Second, concentrations of drug are correlated to in vitro killing studies. Third, clinical evaluations compare the new drugs to currently available antimicrobics—but drug failures nevertheless occur, e.g. the experiences with cephalosporins and aminoglycosides. We propose that brain tissue levels of antibiotics are an additional parameter to be monitored. Drugs that penetrate the brain substance should yield higher ventricular concentrations than drugs that penetrate the choroid plexus alone. A protective benefit may also be afforded to brain tissue per se. Experience with chloramphenicol, which penetrates the blood‐brain barrier, supports these concepts; so also, do the failures with cephalosporins and aminoglycosides which, despite high CSF concentrations of these agents, afford, evidence that currently monitored parameters are inadequate predictors of therapeutic‐efficacy.
Medication packaging: Simple solutions to nonadherence problems
Authors: Rudd Peter
Published: January 2016

Medication nonadherence represents a well‐documented, highly prevalent obstacle to successful long‐term management of chronic illnesses. Recent research has focused on predictors of nonadherence, interventions for improving adherence, and measurement of medication adherence. Better medication packaging has received little attention as a partial solution to nonadherence complexities. Packaging has the obvious advantages of being continuous, inexpensive, and patient‐oriented, while demanding little physician extra involvement. The ideal packaging solution should include six component functions: storage, education, cueing, monitoring, dispensing, and reinforcement. Practically, all six functions are highly interrelated, necessitating tradeoffs. Combining several functions usually results in increased cost and decreased portability. A number of proposed devices for specific adherence‐improving functions are described, ranging from complex to simple. The need for more and better research to define and validate interventions is more critical, now that we recognize the consequences of nonadherence.
Notes of the American Society for Clinical Pharmacology and Therapeutics; National Council on Drugs
Authors: Gifford Ray W.
Published: January 2016

Two years ago the American Society for Clinical Pharmacology and Therapeutics joined with seven other organizations to organize the National Council on Drugs to fill a void created by the demise of the National Academy of Science‐National Research Committee Drug Research Board. Dr. F. Gilbert McMahon has served as the Society's representative to the National Council since its inception. Dr. Ray Gifford, representing the American Medical Association, served as the first Chairman of the Council.
Methodology for demonstrating sustained efficacy of hypnotics: A comparative study of triazolam and flurazepam
Authors: Sundaresan P. R. , Warden William M. , Weintraub Michael , Lasagna Louis
Published: January 2016

To test for sustained hypnotic efficacy, triazolam (0.6 mg) or flurazepam (30 mg) was given to chronic insomniac patients for 7 consecutive nights in parallel, double‐blind design. Triazolam at this dose was an effective hypnotic by all usual subjective measures and did not produce appreciable hangover. Flurazepam performed similarly. For either drug, comparison of the mean scores for the first 2 nights with that for the last 2 nights for any of the parameters did not reveal any significant difference. Thus, both triazolam and flurazepam showed sustained efficacy for I week at these doses. Some interesting theoretical and practical questions about the measurement of sustained efficacy of hypnotics in situations of repetitive dosing were addressed by the study. While a placebo control is desirable, the results obtained may be uninterpretable. An acute‐care hospital setting may not be the ideal setting for doing such studies. There were indications from the study that the first‐night results in a hypnotic clinical trial may be atypical.
Cardiovascular effects of intravenous delta‐9‐tetrahydrocannabinol: Autonomic nervous mechanisms
Authors: Benowitz Neal L. , Rosenberg Jon , Rogers Walter , Bachman John , Jones Reese T.
Published: January 2016

The contribution of autonomic nervous system activity to the cardiovascular effects of delta‐9‐tetrahydrocannabinol (THC) was evaluated in 4 normal subjects. The peak heart rate rise after THC was attenuated by atropine and by propranolol, and nearly abolished by atropine‐propranolol pretreatment. Blocking drugs also attenuated THC‐induced changes in forearm blood flow and vascular resistance but did not affect changes in fingertip temperature. The data suggest that THC acts to induce sympathetic stimulation and parasympathetic inhibition of cardiovascular control pathways. Cardiovascular responses in an additional subject who developed hypertension after either intravenous or smoked marijuana are described.
Biotransformation and elimination of digoxin with normal and minimal renal function
Authors: Gault M. H. , Sugden D. , Maloney C. , Ahmed M. , Tweeddale M.
Published: January 2016

Six subjects with normal renal function (NRF) and 6 patients with minimal renal function (MRF) on 3 times weekly hemodialysis received 150 µCi 3H‐digoxin‐l2α orally. Serial urine collections were made for five days or more. Digoxin and metabolites were separated using diethylaminoethyl Sephadex LH‐20 column chromatography. Mean cumulative percentages of the ingested radioactivity excreted over five days in NRF and MRF groups were: digoxin, 54.5% and 14.7%; bis‐digitoxoside of digoxigenin, 2.0% and 0.50%; mono‐digitoxoside, 0.8% and 0.19%; digoxigenin, 0.25% and 0.03%; and dihydrodigoxin, 0.3% and 0.03%. Half‐lives based on the mean rates of disappearance from urine comparing NRF and MRF groups were: for digoxin, 40 hr and 120 hr; for bis‐digitoxoside, 11.5 hr and 46 hr; for mono‐digitoxoside, 8.5 hr and 12 hr; for digoxigenin, 2 hr and 7.5 hr; and for dihydrodigoxin, 1.2 hr and 7.0 hr. Considering the relationships of the five‐day cumulative excretion and half‐lives of digoxin and metabolites in the NRF and MRF groups, it appears unlikely that there is a major alteration in the biotransformation of digoxin in advanced renal failure when there appears to be a shift from renal to slower biliary excretion.
Cefadroxil kinetics in patients with renal insufficiency
Authors: Cutler Ralph E. , Blair Andrew D. , Kelly Michael R.
Published: January 2016

Kinetic parameters and bioavailability of cefadroxil were studied in 20 subjects with differing renal function as measured by endogenous creatinine clearance (CCr). Two subjects were on hemodialysis. After an overnight fast, each subject ingested two 500‐mg capsules of cefadroxil. The peak serum concentration was variable (12 to 57 mg/L) and correlated inversely with the CCr. All but one patient had maximum absorption within 4 hr of ingestion and in most patients the peak was reached within the 2‐hr sample. Urinary recovery within 48 hr was 45% to 106% when CCr > 8 ml/min. Even in patients with the most severe renal failure (CCr < 10 mll/min), urine concentrations of cefadroxil were adequate to treat susceptible bacteria. The rate of oral absorption, ka, was not affected by the state of renal function and was 0.76 ± 0.50 hr−1. The apparent distribution volume (Vdext) was 0.28 ± 0.09 L/kg. The plasma elimination rate was dependent on CCr with a small fraction of drug being removed by nonrenal routes. Except in advanced renal failure, tubular secretion was present since renal clearance of cefadroxil exceeded CCr. The data suggest that little drug accumulation will occur with the usual 8‐ to 12‐hr dosing schedule except when the CCr is less than 25 ml/min.
Site of renal action of xipamide
Authors: Gold Clive H. , Viljoen Margaretha
Published: January 2016

Xipamide, hydrochlorothiazide, andfurosemide were given to normal volunteers on a double‐blind basis. During maximal water diuresis, there was a reduction in free water clearance and an increase in osmolar clearance after administration of xipamide and hydrochlorothiazide, but not in the case of furosemide. During maximal hydropenia, both xipamide and hydrochlorothiazide increased free water reabsorption in a linear relationship to osmolar clearance, while furosemide increased osmolar clearance with little change in free water reabsorption. It was concluded, therefore, that, as with hydrochlorothiazide, the site of action of xipamide was on the distal convoluted tubule, and that of furosemide on the loop of Henle.
Selectivity of beta adrenoreceptor antagonist drugs assessed by histamine bronchial provocation
Authors: Ruffin R. E. , Frith P. A. , Anderton R. C. , Kumana C. R. , Newhouse M. T. , Hargreave F. E.
Published: January 2016

In a double‐blind, within‐patient, randomized study, 12 mild asthmatics were given single oral doses of propranolol (80 mg), metoprolol (100 mg), timolol (10 mg), or placebo. Resting heart rate and forced expiratory volume in one sec (FEV1) were measured before and 90 min after treatment. Nonspecific bronchial reactivity was measured by inhaled histamine at 90 min. Following each active drug, resting heart rate changed to a similar extent and to a greater degree than after placebo (p < 0.01). Changes in FEV1 were small and not different from those after placebo. In contrast, after each active drug, bronchial reactivity increased more than after placebo. The degree of reactivity with each active drug was similar but the differences from corresponding placebo values were significant (p < 0.05). We conclude that, in mild asthmatics, nonspecific bronchial reactivity is a more sensitive index of airway effects than resting FEV1. Moreover, in the context of this study, since the β‐blockers were given in doses likely to induce equivalent cardiac β‐blockade, there is no evidence to suggest that any one of them is more “cardioselective” than the others.
Effects of isosorbide dinitrate on pulmonary hypertension in chronic obstructive pulmonary disease
Authors: Danahy Daniel T. , Tobis Jonathan M. , Aronow Wilbert S. , Chetty Kota , Glauser Frederick
Published: January 2016

Eighteen patients with chronic obstructive pulmonary disease with pulmonary hypertension were studied to assess the hemodynamic response to acute oxygen administration and to oral isosorbide dinitrate (ISDN). All 18 patients had baseline hemodynamic measurements and hemodynamic measurements during low‐flow nasal oxygen. Following a second baseline measurement, patients received either oral ISDN (11 patients) or placebo (7 patients) in a randomized, double‐blind protocol. Heart rate decreased with oxygen administration but there were no other significant hemodynamic changes. With oral ISDN, there was a significant fall in pulmonary artery and brachial artery pressure. Cardiac output, right atrial pressure, pulmonary wedge pressure, and pulmonary vascular resistance all fell but not significantly. We conclude that oral ISDN is effective in reducing pulmonary hypertension in patients with chronic obstructive pulmonary disease.
Pirprofen and aspirin in the treatment of rheumatoid arthritis
Authors: Davis John D. , Struth Alan G. , Turner Robert A. , Pisko Edward J. , Ruchte Inez R.
Published: January 2016

Pirprofen (800 mg/day) or aspirin (3,600 mg/day) was administered in double‐blind fashion for up to one yr to 40 adult outpatients with rheumatoid arthritis, after a short, single‐blind placebo period. There were no statistically significant differences in efficacy between pirprofen and aspirin, as evidenced by patient opinion, observer opinion, grip strength, walking time, number of tender joints, number of swollen joints, or erythrocyte sedimentation rate. Clinically significant pain of gastrointestinal origin occurred in an equal number of patients from each group. Audiologic evaluation revealed 3 pirprofen‐treated patients and 5 aspirin‐treated patients in whom a sensorineural hearing loss progressed during therapy and required either discontinuation or reduction of drug dosage. Ophthalmologic evaluation disclosed a high prevalence of lesions, the most common being decreased visual acuity and cataracts not explained by previous antiarthritic therapy. The high prevalence of audiologic and ophthalmologic pathology reported in the literature in patients with rheumatoid arthritis makes it difficult to establish in our study whether pirprofen or aspirin affected these organ systems.
Treatment of alkalosis with ammonium chloride: A case report
Authors: Warren Sanford E. , Swerdlin A. R. H. , Steinberg S. M.
Published: January 2016

Coma due to ammonium chloride used in the treatment of severe metabolic alkalosis is reported in a patient with normal hepatic and renal function. All symptoms resolved following discontinuance. Ammonium chloride should be abandoned as a treatment for metabolic alkalosis.
Welcoming remarks
Authors: Fredrickson Donald S.
Published: January 2016

The National Institutes of Health (NIH) admits to being almost embarrassed by the turnout for this conference. Nevertheless, we are grateful and glad that so many of you could come today for what promises to be a very successful National Conference on Clinical Trials Methodology.
When and how to stop a clinical trial
Authors: Meinert Curtis L.
Published: January 2016

It may seem strange to begin a conference like this with the question of when and how to stop a clinical trial. But it becomes less strange when one considers the impact answers to these questions have on the overall design and operation of a trial.
Terminating a trial—the ethical problem
Authors: Meier Paul
Published: January 2016

A comparative clinical trial will often lead to the conclusion that one regimen is clearly better than another. Should the estimated difference in the regimens be large and precisely determined, continuation of the trial would constitute abuse of the participants, Some earlier proposals for ethical decision making on continuing a trial are shown to be unsatisfactory, and a more general framework for dealing with the problem is proposed.
Terminating a lang‐term clinical trial
Authors: Klimt Christian R. , Canner Paul L.
Published: January 2016

Long‐term clinical trials often include more than one active treatment group. These may be discontinued independently if found ineffective or possibly harmful. Certain subgroups of patients may be discovered, in the course of a clinical trial, who do not respond satisfactorily and are, therefore, excluded during the course of a trial. Yet another kind of termination comes when we have a therapeutic breakthrough or when hope has to be abandoned for demonstrating beneficial effects for one, several, or all treatments included in a trial. Examples from the authors' experience are presented, as are successful and unsuccessful techniques in managing terminations of various types.
Invited remarks
Authors: Stamler Jeremiah
Published: January 2016

I would like first to make a few general comments stimulated by the presentations this morning, which certainly were outstanding. My first is that we should be careful here not to limit trials to the drug area. In fact, in life this is not the case. Mention was just made of the Multiple Risk Factor Intervention Trial by the Chairman in introducing me. Although it includes for hypertensive participants the use of antihypertensive medication, it contains a sizable group of participants who are not hypertensive and for whom life style intervention is an extremely important key—and sole—form of intervention. This group was not included just to broaden the purview. If it is correct that life styles are critically important as determinants of health, and by now that is generally recognized to be correct (e.g., smoking habits, eating habits, imbibing habits), then trials on the ability to control and prevent disease by life style change are extremely important. And they have their special problems—one of which I will return to in a moment. They need our attention in terms of the conduct of trials, including the stopping of trials.
Problems of university‐based scientists associated with clinical trials
Authors: Remington Richard D.
Published: January 2016

University faculty members who participate in clinical trials face a number of difficulties in connection with this association. Publication opportunities are often limited, and individual scholarship is difficult to express and evaluate within the context of a cooperative trial. Merit increases, promotion, and the award of tenure will usually require evidence of scholarly achievement outside the trial setting. For this reason, it seems inadvisable to recommend that a young investigator devote a major portion of his scholarly and research time to such an activity. A possible exception may be a full‐time appointment for 1 to 2 years. Nonetheless, cooperative clinical trials are an important investigative tool and they should continue to be associated with academic centers. If appropriate administrative arrangements can be made, it should be possible to solve the academic problems of the young investigator associated with such trials.
Effective clinical trials investigators and adequate incentives
Authors: Stamler Jeremiah
Published: January 2016

Because of the importance of randamired controlled trials in medical research and development, the most competent and qualified individuals from a variety of medical specialties are needed as investigators for these trials. Such people must be highly dedicated to the improvement of human health and they must also be cooperative and able to work in the highly disciplined atmosphere that such a trial demands. In order that the trial investigators be persons of high caliber, certain incentives must be guaranteed, such as recognition of one's contributions to the trial itself, publications, and opportunities to present study results at various meetings. University and medical school policies on promotion and tenure need to be reassessed bearing in mind the complexity of achieving optimal recognition of the individual investigator's contributions to a clinical trial.
Appendix 1: A proposed mechanism and set of criteria for the evaluation of the scientific contribution of individual investigators in collaborative studies, including large clinical trials
Authors: Stamler Rose
Published: January 2016

Large‐scale cooperative clinical trials have become a major and effective tool of medical research. Aimed at providing a scientific methodology for evaluating therapy, such trials now involve thousands of scientists and receive a high priority in government research planning and in the allocation of research funding. Proposed solutions to some of the most challenging unsolved problems in medicine are being submitted to the rigorous test of this methodology.
Recruitment in the Coronary Drug Project and the Aspirin Myocardial Infarction Study
Authors: Schoenberger James A.
Published: January 2016

Both the Coronary Drug Project (CDP) and the Aspirin Myocardial Infarction Study (AMIS) were successfully able to recruit adequate members ofpostmyocardial infarction patients to long‐term multicenter clinical trials in the secondary prevention of coronary heart disease. Aggressive efforts to achieve the recruitment within an acceptable time limit were found to be necessary. A direct approach to the general public via the mass media and painstaking search of hospital records proved to be the most effective methods. Referral from physicians was not an effective way to recruit participants for the most part. Both the general public and the medical profession are generally supportive of this type of research.
Quality assurance of cllnlcal data
Authors: Ederer Fred
Published: January 2016

More than two decades ago, Bradford Hill, the man who taught us all how to do the randomized clinical trial, said: “One must go seek more facts, paying less attention to techniques of handling the data and far more to the development and perfection of obtaining them.”*
Communications: Should mechanisms be established for sharing among clinical trial investigators experiences in handling problems in design, execution, and analysis?
Authors: Roth Harold P.
Published: January 2016

When this meeting was first proposed, three questions were raised:
Problems in publlcatlon of clinical trial methodology
Authors: Lasagna Louis
Published: January 2016

The literature on analgesic testing in man reveals a series of informational gaps. These include a failure to document the occurrence of “trials that failed,” the problems associated with recruiting patients and in dealing with dropouts, the relative advantages and disadvantages of different methods of assessing relief from pain, the importance of baseline variables, and the utility of global and comparative judgments by patients. A trial is described in which only 100 subjects of a total of over 8,000 patients theoretically available for study proved suitable. Significant differences between conseniers and nonconsenters and selection factors that are used in choosing an experimental population have implications for the generalization of a study. Such conclusions have been largely ignored both in and out of the scientific literature.
Indoramin and prazosin as adjuncts to beta adrenoceptor blockade in hypertension
Authors: Stokes G. S. , Frost G. W. , Graham R. M. , MacCarthy E. P.
Published: January 2016

Two trials were conducted on the effects of adding alpha‐adrenoreceptor blockers to the therapy of hypertensive patients already receiving a beta‐adrenoreceptor blocking drug with or without a diuretic. The first trial was a single‐blind study in which 6 patients receiving long‐term combination therapy were crossed from prazosin, 6 to 15 mg/day, to a dose of indoramin 10 times as large. There was significant bradycardia but little change in blood pressure. The second trial was a double‐blind randomized crossover study in which 15 patients completed an 8‐wk period of treatment with each of the alpha blockers, administered in random sequence with an intervening 2‐wk washout period. Dosage was titrated for optimal antihypertensive effect. The final mean dosages were 76 mg/day for indoramin and 8.2 mg/day for prazosin; the dose ratio was 9.3:1. Both drugs reduced erect systolic blood pressure. Prazosin, but not indoramin, reduced exercise systolic and diastolic pressures. Indoramin lowered supine and exercise pulse rates. Neither drug affected peak expiratory flow rate or plasma renin activity. Analysis of individual responses in supine diastolic blood pressure showed that there were 9 prazosin and 8 indoramin responders, while 9 of the 21 subjects in the 2 trials failed to respond to either drug. Central side effects were more prominent with indoramin. The combination of one or other of these alpha‐adrenoreceptor blockers with preexisting beta‐adrenoreceptor blockade improved blood pressure control in 57% of the patients.
Influence of congestive heart failure on prazosin kinetics
Authors: Jaillon Patrice , Rubin Peter , Yee Yin-Gail , Ball Robert , Kates Robert , Harrison Donald , Blaschke Terrence
Published: January 2016

The kinetics of oral prazosin was studied in 10 healthy normal subjects (NS) and in 9 patients with congestive heart failure (CHF). NS received a single 5‐mg dose, and blood concentrations of prazosin (CB) were measured, using a specific HPLC assay, during an 8‐hr period. CHF patients received a 2‐mg dose after which CB was measured for 10 hr. These patients then received 2 to 5 mg prazosin every 8 hr for 48 hr. After the last dose of prazosin, CB was measured for 24 hr. After the initial dose, time to peak CB did not differ significantly between that of the NS (123 ± 19 SEM min) and of patients with CHF (132 ± 31.3 min). AUC/mg prazosin was greater (p < 0.001) in patients with CHF (3,385 ± 380 ng < min/ml) than in NS (1,603 ± 208 ng × min/ml). Elimination of prazosin from blood was slower in CHF patients (t½ = 374 ± 33.4 min) than in NS (t½ = 144.5 ± 4.3 min) (p < 0.001). These data suggest that in patients with CHF the elimination of prazosin is substantially slower than in NS and therefore higher steady‐state prazosin concentrations can be expected in CHF patients than in NS.
Studies with a PNMT inhibitor
Authors: Dubb J. W. , Stote R. M. , Alexander F. , Intoccia A. P. , Geczy M. , Pendleton R. G.
Published: January 2016

DCTQ (SK&F 64139) is a potent inhibitor of both adrenal and central nervous system (CNS) phenylethanolamine N‐methyltransferase (PNMT). In animal studies, a plasma level of 0.35 µg/ml was associated with 50% inhibition of both adrenal and central PNMT. We performed single‐dose phase I studies with DCTQ in man. Plasma drug levels up to 6.26 µg/ml were readily obtained. There were few subjective and no objective clinical changes. DCTQ did not alter blood pressure or cause CNS symptoms in man. Furthermore, resting plasma and urinary catecholamines did not change after DCTQ. The study suggests that acute inhibition of PNMT under resting conditions is without significant clinical effect.