bluuebunny/crossref_metadata_2025 huggingface dataset:
Observations in man on some pharmacologic features of cefamandole
Authors: Grose William E. , Bodey Gerald P. , Stewart Dorothy
Published: January 2016

Comparative studies of cefamandole and cephalothin were carried out in 32 cancer patients. After rapid intravenous injection of 1 gm cefamandole or cephalothin, the peak mean serum concentrations in 11 patients achieved at 0.25 hr were 103.4 mcg/ml and 56.7 mcg/ml, respectively. Except at 6 hr, the serum concentration of cefamandole was higher (p < 0.05) at alt times. The terminal half‐lives (t½) were similar, being 1.2 hr for cefamandole and 1.0 hr for cephalothin. Cefamandole, 1 gm intramuscularly, induced a peak mean serum concentration of 26.6 mcg/ml at 1 hr, with a slow decay. Intermittent cefamandole (2 gm intravenously every 6 hr) induced very high mean serum concentrations (7 patients), but at 4 hr the concentrations were similar to those after 1 gm intravenously. Per cent of urinary excretion was simi lar for both drugs regardless of dose and mode of administration. Continuous‐infusion cefamandole or cephalothin (2 gm loading followed by 2 gm every 6 hr) in 14 patients showed consistently higher serum concentrations for cefamandole (p < 0.05) over a 5‐day period. There was no evidence of drug accumulation in the multiple‐dose studies. Both the single‐ and multiple‐dose schedules were well tolerated.
Enhanced phenacetin metabolism in human subjects fed charcoal‐broiled beef
Authors: Canney A. H. , Pantuck E. J. , Hsiao K.‐C. , Garland W. A. , Anderson K. E. , Alvares A. P. , Kappas A.
Published: January 2016

There were marked individual differences in the plasma levels of phenacetin after oral administration of a 900‐mg dose to 9 normal volunteers eating their customary home diet. Feeding a diet that contained charcoal‐broiled beeffor 4 days prior to the administration of phenacetin markedly decreased the plasma levels of this drug without appreciably influencing the plasma concentrations of phenacetin's metabolite, N‐acetyl‐p‐aminophenol (APAP), or the plasma half‐life of phenacetin. The average peak concentration of phenacetin in plasma, after a 900‐mg oral dose, fell from 1,628 ng/ml, when the subjects were fed a control diet for 7 days, to 352 ng/ml after they were fed the same diet which contained charcoal‐broiled beeffor 4 days. The average peak concentration of phenacetin rose to 1,885 ng Iml after the subjects were subsequently fed the control diet for 7 days. The ratios of the average concentrations of APAP in plasma to those of phenacetin markedly increased after the charcoal‐broiled beef diet. The results suggest that a diet containing charcoal‐broiled beef enhances the metabolism of phenacetin in the gastrointestinal tract and/or during its first pass through the liver. This effect greatly decreases the bioavailability of phenacetin.
Influence of dietary protein and carbohydrate on antipyrine and theophylline metabolism in man
Authors: Kappas Attallah , Anderson Karl E. , Conney Allan H. , Alvares Alvito P.
Published: January 2016

This study was undertaken to examine the influence of changes in dietary carbohydrate and protein content on the oxidation of antipyrine and theophylline in man. When the diets of 6 normal volunteers were changed from their usual home diets to low carbohydrate‐high protein diets, the plasma half‐life of antipyrine decreased from 16.2 hr to 9.5 hr, and the half‐life of theophylline decreased from 8.1 hr to 5.2 hr. When the subjects' diets were changed from low carbohydrate‐high protein diets to a high carbohydrate‐low protein diets, the mean antipyrine half‐life increased from 9.5 hr to 15.6 hr and the mean theophylline half‐life increased from 5.2 hr to 7.6 hr. These changes in half‐lives were accompanied by changes in metabolic clearance rates but not in the apparent volumes of distribution of the drugs tested. Qualitatively similar results were obtained when the subjects were placed on standard diets followed by the standard diets supplemented with carbohydrate or protein. Supplementing the standard diets with carbohydrate caused an increase in drug half‐lives, whereas a protein supplement caused a decrease in the drug half‐lives. These data demonstrate marked influences of nutritional factors on oxidative biotransformation of drugs in man.
Aminopyrine disposition: Studies on breath, saliva, and urine of normal subjects and patients with liver disease
Authors: Hepner Gershon W. , Vesell Elliot S.
Published: January 2016

To investigate aminopyrine disposition, breath, saliva, and urine were collected from 25 control patients, 15 patients with hepatocellular disease, and 26 patients with hepatic neoplasm after oral administration of 2 µCi [14C]aminopyrine. The percentage 14C excreted in breath 14CO2 in 2 hr (aminopyrine breath test, ABT) correlated with the breath 14CO2 elimination rate (r = 0.92, p < 0.01), with the aminopyrine metabolic clearance rate (MCR) (r = 0.85, p < 0.01), and with the plasma half‐life of 4‐aminoantipyrine (r = −0.54, p < 0.05). The ABT permits study of aminopyrine disposition with simplicity, accuracy, and safety.
Probucol: A new cholesterol‐lowering drug effective in patients with type II hyperlipoproteinemia
Authors: Salel Antone F. , Zelis Robert , Sodhi H. S. , Price James , Mason Dean T.
Published: January 2016

Type II hyperlipoproteinemia or hyperbetalipoproteinemia (B‐HLP), a condition with considerable atherogenic potential, is one of the most difficult lipid disorders requiring treatment. Since this abnormality responds minimally to dietary therapy alone, supplemental drug therapy is usually essential. Although the available bile‐sequestering resins are effective in B‐HLP, these substances are unpalatable and constipating. Since lifelong drug therapy is necessary as an adjunct to diet in the treatment of B‐HLP, the ideal drug should be both effective and well tolerated. Probucol, a new cholesterol‐lowering drug in tablet form without serious adverse effects, was evaluated in a 12‐wk double‐blind crossover trial in 11 patients with B‐HLP whose serum cholesterol levels were in excess of 275 mg/dl. Probucol, in a dosage of 500 mg twice daily, produced a 10% or greater reduction in serum cholesterol levels in all 11 patients. Serum cholesterol was lowered (p < 0.01) from 353 to 291 mg/dl in the entire group receiving probucol. There was no significant change (p > 0.1) in serum cholesterol (352 mg/dl) during placebo administration. There were no untoward drug effects during the study, and all patients maintained excellent compliance to the schedule of medication. These results indicate that probucol possesses considerable cholesterol‐lowering activity and may be a promising new nontoxic therapeutic agent in type II hyperlipoproteillemia.
Artificial kidneys and clearance calculations
Authors: Gibson Thomas P. , Matusik Edward , Nelson Lee D. , Briggs William A.
Published: January 2016

Clearance of solutes by artificial kidneys can be calculated using plasma flow and solute concentration, whole blood flow and plasma solute concentration, and midpoint of dialysis blood or plasma solute concentration and total amount of solute removed. Using these methods, the clearance of procainamide (PA) and N‐acetylprocainamide (NAPA) was determined in 4 patients. In all but one case clearances using total amount recovered were greater than clearances using whole blood flow and plasma concentration. Without exception, clearance determined using amount recovered was substantially greater than clearance using plasma flow and plasma levels, suggesting that both PA and NAPA are removed not only from plasma but alsofrom red blood cells. In vitro clearance of PA, NAPA, quinidine, and phenobarbital by 11 clinically available artificial kidneys and an XAD‐4 hemoperfusion column was determined and differences were found.
Quinine disposition during malaria and during induced fever
Authors: Carson Paul , Trenholme Gordon M.
Published: January 2016

In the report on quinine disposition during malaria and during induced fever, which appeared on page 459 of the April, 1976, issue of the Journal, we inadvertently failed to reference a paper by Elin, Vesell, and Wolff (Clin. Pharmacal. Ther. 17:447, 1975) who demonstrated retardation of antipyrine metabolism in etiocholanolone fever. Their data are in agreement with our conclusions concerning quinine metabolism during etiocholanolone fever. We hope this information will help to encourage additional studies of drug metabolism and the role of the liver during fever.
Plasma l‐α‐acetylmethadol (LAAM) after acute and chronic administration
Authors: Henderson Gary L. , Wilson B. Kent , Lau Derick H. M.
Published: January 2016

l‐α‐Acetylmethadol (LAAM) was administered orally to two groups of subjects; one group received methadone. 50 mg/day. for three months previously and the other group were heroin addicts who had no prior exposure to methadone or LAAM. Plasma elimination curves for methadone. LAAM. and its metabolites. noracetylmethadol (N‐LAAM) and dinoracetylmethadol (DN‐LAAM). were determined after acute and chronic administration. The plasma decay curve for LAAM was biexponential (t½α = 6 hr; t½β > 50 hr) following acute or chronic administration. Following chronic administration. N‐LAAM and DN‐LAAM plasma levels increased 5‐ to 10‐fold. At this time. N‐LAAM had a t½ of 31 hr and DN‐LAAM had a t½ of > 100 hr. There appear to be at least two factors which determine the long duration of action of LAAM: metabolic conversion to active metabolites and tissue or plasma binding. Both methadone and LAAM may compete for plasma protein or tissue binding sites. The clinical implications of this potential drug‐drug interaction are discussed.
Effects of intravenous tetrahydrocannabinol on experimental and surgical pain; Psychological correlates of the analgesic response
Authors: Raft David , Gregg John , Ghia Jawahar , Harris Louis
Published: January 2016

Two intravenous doses of tetrahydrocannabinol (THC) (0.022 mg/kg and 0.044 mg/kg) were compared to intravenous diazepam (0.157 mg/kg) and to placebo (Ringer's lactate) as premedication for dental extraction in 10 healthy volunteers. Pain detection and tolerance thresholds were measured and psychiatric interviews were supplemented by Minnesota Multiphasic Personality Inventories (MMPI), the Zung Depression Scale (ZDS), Beck Depression Inventories (BDI), and the State‐Trait Anxiety Inventory (STAI). Pain detection thresholds were altered unpredictably with high THC doses, but analgesia as indicated by pain tolerance was less than that after diazepam and placebo. In three subjects low‐dose THC (0.022 mg/kg) was a better analgesic than placebo but not diazepam. Six subjects preferred placebo to low‐dose THC as an analgesic; this group experienced increases in subjective surgical pain and were submissive, rigid, and less introspective with high State Anxiety and MMPI profiles that differed from subjects whose pain was not increased. STAI following THC presaged a poor analgesic response in this group.
Tricyclic antidepressant plasma levels and adverse effects after overdose
Authors: Petit James M. , Spiker Duane G. , Ruwitch Joseph F. , Ziegler Vincent E. , Weiss Alan N. , Biggs John T.
Published: January 2016

Forty patients ingesting tricyclic antidepressant (TAD) overdoses were studied as a pharmacologic model to determine whether total tricyclic antidepressant plasma levels correlated with major adverse effects and electrocardiographic findings. Maximum TAD plasma levels were higher in patients who died (p < 0.025) or had cardiac arrest (p < 0.02), needed respiratory support (p < 0.005), were unconscious (p < 0.02), had grand mal seizures (p < 0.001), ventricular rate ≥ 120/min (p < 0.01), cardiac arrhythmia (p < 0.05), QRS duration ≥ 100 msec (p < 0.00l), or bundle branch block (p < 0.05). TAD plasma levels correlated with the dose ingested by history (N = 29, r = 0.58, p < 0.001). Measurement of total TAD (free and protein‐bound) appears to correlate well with biologic response.
Antihypertensive effects of tolamolol
Authors: Vlachakis Nicolas D. , Mendlowitz Milton , Krakoff Lawrence R.
Published: January 2016

The antihypertensive and renin‐lowering efficacy and side effects of tolamolol, a beta adrenergic blocking drug with cardioselectivity, were examined in IO patients with mild essential hypertension while on regular diet. Tolamolol, at a dose of 300 to 900 mg per day, given over a period of 2 to 4 wk significantly decreased systolic and diastolic blood pressures in both the recumbent and standing positions. Normal blood pressure (140/90 mm Hg or less) was attained in 8 subjects. Mean heart rate and ambulatory midday plasma renin activity (PRA) decreased significantly; however, there was no significant correlation between blood pressure decrease and either the pretreatment PRA or decrease in PRA. Body weight did not change significantly. No adverse side effects were detected and no changes in the liver or renal function or in the blood count were observed. It is concluded that tolamolol is effective in lowering blood pressure and PRA in patients with hypertension.
Hemolytic potential of methocarbamol
Authors: Scott Robert B. , Tisdale S. A. , Cummings Walter B.
Published: January 2016

Methocarbamol, a compound related to mephenesin, has in vitro hemolytic potential. A study was performed to determine whether any hemolysis was detectable after intravenous injection. Methocarbamol and its vehicle (50% polyethylene glycol‐300) was compared with vehicle alone and with normal saline controls in high‐ and low‐dose regimens in normal volunteers. Significant increases in plasma hemoglobin were detected 30 min after intravenous injection of methocarbamol or its vehicle alone. Maximum initial plasma hemoglobin levels were approximately 10 mg/dl with vehicle alone, but only 4 mg/dl with the methocarbamol added. Serum haptoglobin levels feil after both high‐dose methocarbamol and vehicle during the 3‐day period of treatment. Hemolysis, though detectable, did not exceed levels found under physiologie circumstances such as exercise, and represents only a small fraction of the normal daily hemolysis of aged erythrocytes.
On the question of an interaction between sulindac and tolbutamide in the control of diabetes
Authors: Ryan Jerome R. , Jain Adesh K. , McMahon F. Gilbert , Vargas Ramon
Published: January 2016

The effect of sulindac and tolbutamide on the control of diabetes was studied in 12 tolbutamide‐treated maturity‐onset diabetics with stable glycemic control. After one week of hospitalization on a metabolic ward for adjustment of diet and activity, the patients were treated with sulindac, 200 mg twice daily for one week. The time‐to‐peak plasma tolbutamide concentration was 3.1, 3.1, and 3.2 hr, respectively, after tolbutamide alone, after the first dose of sulindac, and after sulindac for a week. The areas under the plasma tolbutamide curve were 23.68,22.10, and 22.78for the same periods. The half‐life for plasma tolbutamide was 7.46, 7.15, and 7.38 hr, respectively. None of the differences were statistically significant. The mean fasting plasma sugar was lower after the sulindac treatment (from 12.5 to 112.9 mg/100 ml, p < 0.05), but the postprandial values increased slightly (from 137.7 to 142.6). It was concluded that there was no clinically significant interaction between sulindac and tolbutamide.
A message trom the President, American Society tor Clinical Pharmacology and Therapeutics
Authors: Gifford Ray W.
Published: January 2016

The Seventy‐eighth Annual Meeting of the Society will be held at the Fairmont Hotel in Dallas, Texas, on March 23, 24, and 25, 1977. Items of special interest are included here.
Differences between the effects of practolol and propranolol on the diastolic properties of the left ventricle
Authors: Sniderman Allan D. , Marpole Derek G. F. , Fallen Ernest L.
Published: January 2016

To elucidate the mechanism by which left ventricular end diastolic pressure (LVEDP) is reduced by practolol, ventricular volumes, hemodynamics, and diastolic elastic stiffness were determined before and 10 min after intravenous practolol (400 µg/kg) in 12 patients. Heart rate decreased in all patients after practolol (avg., −9/min, p < 0.02). There was an insignificant increase in stroke work index and decrease in cardiac index attributable to the fall in rate. Practolol did not change end diastolic volume or ejection fraction, but the average LVEDP fell from 21 to 15 mm Hg (p < 0.01) which was sustained even with atrial pacing to prepractolol heart rates. Diastolic elastic stiffness was also reduced after practolol (0.665 to 0.593, p < 0.0025). The data indicate that practolol exerts a negative chronotropic effect on the intact heart and, in contrast to other beta blockers such as propranolol, appears to decrease diastolic stiffness in the left ventricle.
Individualization of phenytoin dosage regimens
Authors: Ludden Thomas M. , Allen John P. , Valutsky William A. , Vicuna Ana V. , Nappi Jean M. , Hoffman Stephen F. , Wallace Jack E. , Lalka David , McNay John L.
Published: January 2016

Two methods for arriving at optimum, individual phenytoin dosage regimens have been evaluated in 12 patients. (1) Individual Michaelis‐Menten pharmacokinetic parameters for phenytoin were estimated from two reliable steady‐state phenytoin serum concentrations resulting from different daily doses: The observed steady‐state phenytoin serum levels obtained after 3 to 8 wk of compliance with dosage regimens calculated from the individual pharmacokinetic parameters agreed well with predicted levels (r = 0.824, p < 0.02). The average deviation between observed and predicted levels was 0.04 µg/ml (range, ±3.2 µg/ml). (2) A previously published nomogram for making adjustments in phenytoin dosage regimens: The serum phenytoin concentration actually expected from the dose indicated by the nomogram was calculated using individual pharmacokinetic parameters. The daily dose for one patient would have exceeded his estimated maximal rate of metabolism. The correlation between calculated and predicted phenytoin serum levels in the other 11 patients was weak but significant (r = 0.360, p < 0.05). The average deviation was −3 µg/ml (range, 3.9 to −11.3 µg/ml). It was concluded that the use of individual pharmacokinetic parameters is practical and is also superior to the nomogram.
Naproxen, aspirin, and codeine in postpartum uterine pain
Authors: Bloomfield Saul S. , Barden Tom P. , Mitchell Jeanette
Published: January 2016

The analgesic efficacy of oral naproxen and its sodium saft was compared with that of aspirin and codeine in two separate trials involving 140 and 90 patients, respectively, with postpartum uterine pain in a single‐dose, parallel, stratified, randomized, placebo‐controlled, double‐blind design. With 300 or 600 mg naproxen and with 275 mg naproxen sodium, significant analgesia, measured subjectively by pain intensity differences (PID), was prolonged at least 7 or 8 hr; onset tended to be delayed 2 hr or more. With 650 mg aspirin analgesia began within 1 hr and continued until the fifth hour, while with 60 mg codeine responses were indistinguishable fram placebo responses throughout the 8‐hr time course. Although time‐effect patterns with naproxen sodium and aspirin were different, summed analgesic effects (SPID) showed equal efficacy and superiority over placebo (p < 0.005). With each of the 2 doses of naproxen, SPID separation from placebo was comparable to that above (p < 0.02 and 0.005, respectively), but analgesic dose response, though measurable, was not significant. Side effects were not significant with any of the treatments. It appears that naproxen and naproxen sodium are analgesics with efficacy equal to aspirin and may prove to be rational substitutes for currently available analgesics in some painful states in which longer pain relief would be desireable.
Prolactin and psychophysiologic measures after single doses of thioridazine
Authors: Nikitopoulou Georgia , Thorner Michael , Crammer John , Lader Malcolm
Published: January 2016

Six normal men ingested thioridazine, high and low doses, and placebo on three occasions. Their plasma and urinary thioridazine and mesoridazine plus sulforidazine were measured over 5 hr, together with their plasma prolactin, and a battery of psychophysiologic variables. Drowsiness and EEG changes correlated highly with rise in prolactin, but not with drug plasma concentrations. Finger tremor increased, and some psychologic tests were impaired by thioridazine; other psychologic tests, the auditory‐evoked response, and palmar skin conductance were unaffected and showed no relationship to drug or prolactin levels. This suggests that plasma prolactin may be a useful indicator of some aspects of the individual's response to a psychotropic drug, and possibly a better guide to the selection of a suitable drug and its appropriate dose in clinical practice than the measurement of plasma concentrations oi the drug itself.
Pharmacokinetics of chlorpromazine after single and chronic dosage
Authors: Dahl Svein G. , Strandjord Roald E.
Published: January 2016

Plasma concentrations of chlorpromazine and its sulfoxide were measured after single intramuscular, single oral, and multiple oral doses of chlorpromazine. In four out of nine patients, intramuscular doses gave stable chlorpromazine plasma levels which were maintained for 12 hr or longer. Chlorpromazine sulfoxide was found in plasma from all patients after oral doses but not after intramuscular doses, which indicates that sulfoxidation took place presystemically. The biologic availability of single oral doses relative to single intramuscular doses ranged from 10 to 69%, and was on average 32%. After 33 days of oral dosing, the plasma levels of chlorpromazine were on average 37% lower than might have been predicted from the single oral dose curves. This was not due to decreased biologic t½ of chlorpromazine, but apparently to a decrease in the biologic availability by oral administration, possibly by increased presystemic metabolism.
Variations in the bioavailability of thiazinamium methylsulfate
Authors: Jonkman Jan H. G. , Van Bork L. E. , Wijsbeek Jaap , De Zeeuw Rokus A. , Orie N. G. M.
Published: January 2016

Bioavailability after oral administration of the anticholinergic drug thiazinamium methylsulfate (Multergan), a phenothiazine derivative with a quaternary ammonium group in the moleeule, has been studied in patients and volunteers by measuring the drug concentrations in plasma or the excretion of the parent drug in urine. The relative bioavailability as compared to intramuscular injection seems to be of the order of 10%. Much more of the drug is absorbed, however, but is metabolized during the first liver passage. Moreover, there seems to be a substantial interindividual variation in the bioavailability of the drug. Studies in a group of eight volunteers showed that there is also a substantial intraindividual variation, but its magnitude is smalter than that of the interindividual variation.
Dose‐ranging trial of N‐acetylprocainamide in patients with premature ventricular contractions
Authors: Atkinson Arthur J. , Lee Woong-Ku , Quinn Michael L. , Kushner William , Nevin Mary Jane , Strong John M.
Published: January 2016

Ten patients with chronic premature ventricular contractions (PVCs) received short‐term oral therapy with N‐acetylprocainamide (NAPA) to determine its antiarrhythmic efficacy and side effects under the conditions of a placebo‐controlled, dose‐ranging trial. NAPA was effective in suppressing PVCs in 8 patients but caused a paradoxical increase in PVC frequency in one. Results were equivocal in the remaining patient because PVCs did not recur when NAPA therapy was withdrawn. Mean NAPA plasma levels as high as 41.1 µg/ml did not have untoward hypotensive or myocardial depressant effects, as judged by electrocardiographic and systolic time intervals. There was, infact, a consistent reduction in PEP/LVET ratio, indicating that NAPA increases the force of myocardial contraction. The mean NAPA elimination half‐life of 10.9 hr was longer than the 6.2 hr half‐life reported for normal subjects, but its prolongation was predictably correlated with reductions in creatinine clearance. Gastrointestinal side effects experienced by 3 patients and insomnia noted by 2 patients are similar to known adverse reactions to procainamide.
Development of a radioimmunoassay for theophylline; Application to studies in premature infants
Authors: Neese Allen L. , Soyka Lester F.
Published: January 2016

The use of theophylline in premature infants has necessitated the development of an assay applicable to samples under 0.1 ml. To accomplish this we have developed a radioimmunoassay for theophylline. The antiserum to theophylline has been characterized and found to be highly specific for theophylline and sensitive to 2 ng. The affinity of our antibody and the titer developed in the goat allowed the assay to be performed routinely with the use of a plasma sample size of only 2 to 5 µl. Theophylline levels of 6 to 20 µg/ml were found 2 hr after maintenance doses of aminophylline, 4 mg/kg per rectum in 12 premature infants. Terminal serum half‐lives ranged from 12 to 54 hr.
An outbreak of digoxin intoxication
Authors: Danon Abraham , Horowitz Jacob , Ben-Zvi Zvi , Kaplanski Jacob , Glick Seymour
Published: January 2016

An outbreak of digoxin intoxication brought about by an unannounced change affecting bioavailability by a manufacturer is reported. Public health implications are discussed.
Safety of single large oral doses of guanethidine
Authors: Walter Inge E. , Nies Alan S.
Published: January 2016

The cardiovascular effects of single 100‐mg doses of guanethidine were assessed in hypertensive patients by measurement of arterial pressure, heart rate, and systolic time intervals. In the 3‐hr period following a dose there was no evidence of an inotropic effect. Therefore, large doses of guanethidine as required for the guanethidine loading regimen would seem to be safe even in patients in whom inotropic effects of released catecholamines would be contraindicated.
Cardiovascular effects of total hip placement in man; With observations on the effects of methyl methacrylate on the isolated rabbit heart
Authors: Wong K. C. , Martin Wayne E. , Kennedy William F. , Akamatsu Toshio J. , Convery Robert F. , Shaw Curtis L.
Published: January 2016

The cardiovascular effects of total hip placement were evaluated in 10 surgical patients, aged 55 to 82, while receiving fluroxene‐N20‐02 anesthesia. The anesthetic regimen caused mild cardiovascular depression. The placement of the acrylic cement into the acetabulum and femoral shaft also induced mild cardiovascular depression, but these changes were not significant at p < 0.05. In one 67‐yr‐old woman, there were significant reductions of cardiac output and stroke volume 2 min after the insertion of acrylic into the femoral shaft, despite careful replacement of intravascular loss and careful anesthetic management. Methylmethacrylate (1 × 10−6 to 1 × 10−4, v/v) was administered to 24 isolated perfused rabbits hearts. These concentrations of methylmethacrylate are of the same order as measurable blood levels in surgical patients. There was a dose‐dependent depression of left ventricular dP/dt correlated with a depression of the spontaneous heart rate. When the bradycardia was prevented by electrically pacing the hearts or the administration of atropine, the depressed dP /dt rose to control levels. Reduction in myocardial temperature and heart rate by means of reduction in perfusate temperature of the isolated hearts reduced the myocardial depressant effect of methylmethacrylate.
Antibiotic‐associated colitis
Authors: Miller Russell R. , Jick Hershel
Published: January 2016

Among 26,294 hospitalized patients monitored by the Boston Collaborative Drug Surveillance Program (BCDSP), 8,948 (34%) received at least one antibiotic, and none were diagnosed as having drug‐induced colitis due to in‐hospital antibiotic exposure. Seven patients who had taken antibiotics as outpatients, however, were admitted with antibiotic‐associated colitis. Six of these patients had taken lincomycin prior to the onset of symptoms; one had taken ampicillin. Six of the patients were hospitalized at a New Zealand hospital and one at a hospital in Canada. The give patients with lincomycin‐associated colitis at the New Zealand hospital were admitted over an 11‐month period. Severe colitis due to antibiotics has been a rare event in the BCDSP experience, especially in the United States.
Enhancement by food of canrenone bioavailability from spironolactone
Authors: Melander A. , Danielson K. , Seherstén B. , Thulin T. , Wåhlin E.
Published: January 2016

The influence of food intake on the bioavailabiliry of canrenone, the major and active metabolite of spironolactone, was explored in 8 healthy male volunteers. Spironolactone was administered as a single oral dose of 100 mg, both in the fasting state and together wirh a srandardized breakfast. Numerous venous blood sampies were raken from 30 min to 96 hr after ingestion of the drug, and the plasma concentrations of eanrenone were determined by speetrofluorometry. The results indicxate that more eanrenone enters the general circulation when spironolactone is ingested together with a meal.
XL. Stochastic significance, consistency, apposite data, and some other remedies for the intellectual pollutants of statistical vocabulary
Authors: Feinstein Alvan R.
Published: January 2016

A statistician who wants to do serious work in matters of clinical medicine becomes confronted by a complex, sometimes formidable, professional vocabulary. The vocabulary contains the multitude of words—arising from all their Greek, Latin, and other etymologic sources—that are needed to label the diverse anatomic, pathologic, physiologic, biochemical, microbial, pharmacologic, and other entities that constitute the contents of clinical medicine. A physician learns most of this vast vocabulary during the first two years of medical school, but thereafter must constantly augment and occasionally replace the basic terms as new ones emerge from subsequent experience, technology, ideas, and research.
Linear dose response and quantitative attenuation by potassium of the inotropic action of acetylstrophanthidin
Authors: Lee Garrett , Zefis Robert , Mason Dean T.
Published: January 2016

To evaluate the nature of the inotropic dose response of digitalis and to determine the effects of potassiwn on this response, isometrically contracting isolated supported right ventricular cat papillary muscles were studied relative to their peak tension and peak dT/dt increases to physiologic cumulative doses of acetylstrophanthidin (ACS) in different extracellular potassium coneentrations in the muscle bath. The inotropic dose response to ACS was observed to be linear in cumulative glycoside concentrations ranging from 0.40 to 4.23 × 10−7 M ACS in 3.5 mM K+ medium and also from 1.22 to 7.47 × 10−7 M ACS in 7.0 mM K+ medium. The influence of potassium alterations in the muscle bath from the low to the high K+ concentrations prior to ACS resulted in marked attenuation of the positive inotropic property of ACS. From these data, it is concluded that the dose inotropic response of digitalis is linear, with small doses producing proportionally the same effects as larger doses, and that extracellular potassium markedly influences this linear dose response such that higher K+ concentrations considerably attenuate the positive inotropic response of digitalis.
Physiologic disposition of nabilone, a cannabinol derivative, in man
Authors: Rubin Alan , Lemberger Louis , Warrick Patricia , Crabtree Ross E. , Sullivan Hugh , Rowe Howard , Obermeyer Boyd D.
Published: January 2016

Nabilone is a cannabinoid that is being evaluated in man as a potentially useful psychoactive drug. We found that nabilone was readily absorbed from the human gastrointestinal tract when administered orally as a coprecipitate with polyvinyl‐pyrrolidone. The absorbed drug disappearedfrom plasma rather rapidly (half‐life, approximately 2 hr), evidently due to extensive tissue distribution and rapid metabolism. The metabolites of nabilone persist in plasma for extended periods (half‐life of total radioactivity exceeds 20 hr). Circulating metabolites include isomeric carbinols formed by reduction of the ketone in the 9‐position of nabilone. Nabilone is eliminated in feces (about 65% of dose) and urine (20%). The excretory products in urine have not been identified, but metabolites that are labile to hydrolysis by β‐glucuronidase or sulfatase do not appear to be formed in signijicant amounts. A metabolite of nabilone in fixes has been identified as a diol formed by reduction of the 9‐keto group plus oxidation at the penultimate carbon of the dimethylheptyl side chain. The long duration of action of nabilone in the face of rapid and extensive metabolic elimination suggests that the pharmacologic effects, at least in part, may be exerted by one or more active metabolites.
Methadone maintenance: Effect of urinary pH on renal clearance in chronic high and low doses
Authors: Bellward Gail D. , Warren P. M. , Howald W. , Axelson James E. , Abbott Frank S.
Published: January 2016

The subjects were 12 male patients stabilized on methadone for many months or years. A comparison was made of the plasma levels and renal clearance of methadone between patients on “high” doses (80 to 110 mg/day) and those on “low” doses (15 to 40 mg/day). A general trend to higher renal clearance was seen in the “high”‐dose group, but on more detailed examination there was a direct correlation only when the patients were categorized by urinary pH. At low pHs, there was nearly a 3‐fold increase in renal clearance which was associated with a decreased major metabolite to methadone ratio. No evidence for a difference in rate of metabolism between the two groups was found nor were there differences in hepatic function. It was concluded that urinary pH was a major factor in renal clearance of methadone.
Continuous sampling as a pharmacokinetic tool
Authors: Vogelstein Bert , Kowarski A. Avinoam , Lietman Paul S.
Published: January 2016

Continuous sampling (CS) of blood through a nonthrombogenic catheter is presented as a tool for determining various pharmacokinetic parameters after a single injection ofa drug. In addition to defining many of the usual parameters used in pharmacokinetic analyses, CS provides an accurate and direct determination of the total area under the plasma concentration curve. The theoretic background underlying the CS method is derived, and a practical [ormulation for its use in a clinical setting is described. The aminoglycoside antibiotic, amikacin, was chosen to exemplify the use ofthis technique. The drug was administered to 6 children, and CS was used to define plasma and single organ (kidney) clearance, volume of distribution, half‐life during the final elimination phase, the shape of the plasma concentration curve, and the exponential factorization of this curve for multicompartmental analysis. The CS method has several theoretical and practical advantages over the usual technique of intermittent blood sampling; such as accuracy in the determination of the plasma concentration‐time curve integral, relative model independence, requirement for few samples, and ease in obtaining samples.
Effects of morphine on reflex arteriolar constriction induced in man by hypercapnia
Authors: Zelis Robert , Flaim Stephen F. , Eiseie John H.
Published: January 2016

Since morphine alters ventilatory drive during chemoreceptor stimulation, we have examined whether it produces a similar resetting of the hypercapnia‐induced arteriolar constrictor rejiex. In 11 normal subjects, forearm blood jiow (FBF) was measured plethysmographically and forearm vascular resistance (FVR) was calculated before and during hypercapnia induced by a rebreathing technique. An increase in arterial carbon dioxide tension (P aC02) (16.8 ± 1.1 mm Hg) increased FVR by 30.5 ± 4.8 mm Hg/ml/min . 100 ml (55.1 ± 5.1 to 85.6 ± 9.0). Fifteen minutes after intravenous administration of 15 mg ofmorphine sulfate (MS), a similar increase in P aC02 (/6.6 ± 1.2 mm Hg) caused an increase in FVR of 16.7 ± 3.9 mm Hg/ml/min . 100 ml (34.1 ± 4.1 to 50.8 ± 6.7). The change in FVR with CO2during MS was less than that before MS (p < 0.02). When the sequential response patterns to CO2 challenge were determined, it was found that, prior to MS, the FVR increase occurred as a late response to hypercapnia, but after MS the late increase in FVR did not occur and in several subjects there was a general tendency toward net vasodilation. An MS‐induced resetting of the constrictor rejiex mechansim to CO2 must therefore have tended to unmask the direct dilator properties of the CO2. Such a dilation caused by hypercapnia and unopposed by the normal rejiex mechanism may partially explain the hypotensive effect of MS when administered to susceptible patients with CO2 retention . The attenuated chemoreceptor rejiex‐induced arteriolar constriction due to CO2 stimulation may also explain the withdrawal of alpha adrenergic tone which occurs when MS is given to normal subjects. This alteration in the chemoreceptor rejiex mechanism may occur at the level of the central nervous system since naloxone effectively restored the rejiex response to normal.
Kinetics of primidone metabolism and excretion in children
Authors: Kauffman Ralph E. , Habersang Rolf , Lansky Lester
Published: January 2016

The metabolism and excretion of orally administered primidone was studied in 12 children, aged 7 to 14 yr during long‐term dosing. Plasma concentrations ofprimidone (Pr) peaked at 4 to 6 hr and declined exponentially from 6 to 24 hr, with half‐life (t½) values ranging from 4.5 to 11 hr. A mean of 92% (72% to 123%) of the administered dose was recovered within 24 hr from the urine as Pr and its metabolites. Of the total Pr daily dose, 42.3% (15.2% to 65.9%) was recovered as unchanged drug, 45.2% (16.3% to 65.3%) as phenylethylmalonamide (PEMA), and 4.9% (1.1% to 8.0%) as phenobarbital (Pb). The mean rate constant for conversion of Pr to PEMA (K J was 0.0424 hr‐1, for conversion of Pr to Pb (Kz) was 0.0045 hr:', and for excretion of unchanged Pr (K3) was 0.0389 hr‐1 Of the Pb excreted, 43% (13% to 100%) was unchanged, 15% (0% to 27%) was unconjugated p‐OH Pb, 20% (0% to 44%) was conjugated p‐OH Pb, and 22% (0% to 33%) was conjugated 3,4‐0H Pb.,appears to be an important determinant of the steady‐state plasma concentration of Pb, but interindividual differences in Kz have little influence on the overall rate constant [or elimination of Pr.
Adjustment of lithium dose during lithiumchlorothiazide therapy
Authors: Himmelhoch Jonathan M. , Poust Rolland I. , MaIlinger Alan G. , Hanin Israel , Neil John F.
Published: January 2016

There has been a long‐held belief that lithium salts cannot be used in the presence of thiazide diuretics. Recently, however, thiazldes have been demonstrated to be not only safe, but actually indicated in two situations in which lithium salts are used. The first is in the treatment of lithium‐induced nephrogenic diabetes insipidus and the second is in severe manic depressive illness in whicli high doses of lithium do not produce therapeutic serum or intraerythrocytic lithium concentrations . This new information now makes it possible for some manic depressive patients with serious medical illnesses (such as hypertension or congestive heart failure), in whom thiazide diuretics are routinely used, to be treated cautiously with lithium carbonate. This paper analyzes data from 13 patients taking lithium carbonate and varying doses of chlorothiazide in order to indicate the approximate magnitude of down ward adjustment of daily lithium dose which the clinician must make to safely give 500, 750, and 1,000 mg/day of chlorothiaride.
Effects of actodigin on the heart
Authors: Cagin Norman A. , Naidu Sriramalu , Arvan Steven , Goldman Isa , Somberg John , Levitt Barrie
Published: January 2016

Actodigin is a new semisynthetic cardiac glycoside reported to have a rapid onset and brief duration of action in dogs. Five patients with congestive heart failure in normal sinus rhythm were given incremental doses of actodigin. Overall, there was no significant change in heart rate, aortic or pulmonary artery pressure, systemic vascular resistance, cardiac index, and stroke volume. This lack of response to actodigin is consistent with previous reports of acute administration of other cardiac glycosides. Four patients with atrial fibrillation and a rapid ventricular rate were given similar doses of actodigin. The ventricular rate was readily controlled. After drug administration was stopped, the ventricular rate quickly returned toward predrug levels. Thus, the rapid onset and brief duration of action of actodigin may be useful in the initial management of atrial fibrillation.
Pathophysiologic and pharmacokinetic determinants of the antihypertensive response to propranolol
Authors: Esler Murray , Zweifler Andrew , Randall Otelio , DeQuattro Vincent
Published: January 2016

The tendency for patients with essential hypertension to differ markedly in antihypertensive response to propranolol could arise from pathophysiologic or pharmacokinetic differences between them. This possibility was investigated in 23 men with mild to moderately severe essential hypertension. At each of three propranolol doses, 40 mg, 80 mg, and 320 mg daily, approximately a 20‐fold range in steady‐state plasma propranolol concentrations was observed. Clinical response however was unrelated to plasma propranolol: oral dose ratio, since patients with higher plasma levels were less sensitive to the existing plasma drug concentration. When falls in blood pressure and plasma propranolol concentration were compared overall, a biphasic dose‐response relationship was noted, with a first component at plasma propranolol concentrations of 3 to 30 ng Iml and a second at concentrations above 30 ng Iml. Only patients with increased sympathetic nervous system activity and high plasma renin activity (PRA) had substantial falls in pressure at propranolol levels of 3 to 30 nglml. Cardiac beta adrenergic receptor blockade, not suppression of PRA, seemed to be the antihypertenisve mechanism. This relation of pretreatment sympathetic nervous activity and PRA to antihypertensive response existed only at lower plasma propranolol concentrations. With a propranolol dose of 320 mg daily, both plasma norepinephrine concentration and PRA were unrelated to the clinical response.
Effect of phenobarbital on the disposition of intravenous theophylline
Authors: Piafsky Kenneth M. , Sitar Daniel S. , Ogilvie Richard I.
Published: January 2016

The disposition of intravenous doses of theophylline was determined in normal male subjects before and after treatment with phenobarbital for 2 wk. Although there was some variation in disposition of the 2 drugs, there were no significant effects of phenobarbital on theophylline kinetics. We conclude that theophylline dosage need not be altered during concomitant administration of phenobarbital.
Effects of halofenate and probenecid on serum lipids and uric acid in hyperlipidemic, hyperuricemic adults
Authors: Bassett David R. , Mikkelsen William M. , Buckingham Robert B. , Block Walter D. , Sidiq Mohammed , Shakibai Ali , DiGaetano Ralph , Liou Ling-ling
Published: January 2016

The effect of halofenate was compared with that of probenecid in overweight patients with hyperlipidemia and hyperuricemia. Halofenate induced a prompt and sustained lowering ( 12.7%) of serum triglycerides, but probenecid induced no change in serum triglycerides. Both drugs promptly induced reductions (32%) of serum uric acid. Halofenate induced a 13.3 % increase in serum lactic dehydrogenase. Both drugs induced mild but significant decreases in hemoglobin and in serum albumin, but the between‐group differences were not significant. When the effects of the two drugs were divided into subgroups below and above the baseline median value for serum triglycerides, cholesterol, uric acid, and percent ideal body weight, a differential effect on serum triglycerides was noted when serum uric acid and percent ideal body weight were taken as the segregating variables. There was a greater serum triglyceride decline after halofenate in the high‐weight group than in the lower‐weight group (‐25.5% vs +2.7%), and a greater serum triglyceride decline in the high uric acid group than in the lower uric acid group (‐22 .6% vs ‐2.4%). The divergent behavior in regard to initial percent ideal body weight and uric acid level may account for the greater halofenate‐induced reductions in serum triglycerides reported by others. In the halofenate group, there was a significant correlation between percent change in triglycerides and percent calories from alcohol. Further study of these responses may provide increased understanding of halofenate action and of the pathogenesis of some types of hyperlipidemia.
Commentary
Authors: Isbell Harris
Published: January 2016

The Twenty‐third Oscar B. Hunter Memorial Award in Therapeutics Lecture
Pharmacokinetics of bendroflumethiazide
Authors: Beermann Bjorn , Grind Margaretha Groschinsky , Lindstrom Bjorn
Published: January 2016

Bendrojlumethiazide (bft) , 10 mg, was administered orally to 9 healthy volunteers. The concentrations of the diuretic in plasma and urine were determined by gas‐liquid chromatography (GLC). Peak plasma levels (86 ± 18 ng/ml) of bft were reached at 2 ± 0.4 hr. The concentration declined with a mean tlh of 3.0 hr. The apparent volume of distribution averaged 1.48 Llkg. The major part of the drug was eliminated via nonrenal mechanisms, the nonrenal clearance being estimated to 269 ± 77 mllmin and renal clearance to 105 ± 24 mllmin. Urinary recovery of the thiazide averaged 30%.
Effects of probenecid on furosemide kinetics and natriuresis in man
Authors: Honari Jamshid , Blair Andrew D. , Cutler Ralph E.
Published: January 2016

Furosemide kinetics were studied in 4 normal subjects after single intravenous injections (1 mg/kg). One experiment was done after pretreatment with probenecid. The apparent volume offurosemide distribution was unchanged after probenecid (10.9 L). The mean plasma clearance fell from 155 to 85 mllmin and the mean plasma t½ rose from 36 to 61 min. Renal clearance of furosemide fell below 50% of control after probenecid, but the kidney remained the main route of its excretion (75% of the dose appeared in the urine). In another experiment in 4 subjects an infusion of furosemide was sustained following a loading dose to maintain a constant plasma level. After a control period, probenecid was given orally. This resulted in a decrease in renal excretion of furosemide with a simultaneous rise in its plasma concentration. Despite the rising plasma furosemide concentration, however, there was a diminution in both urine flow and the excreted fraction of filtered sodium, which suggested some reduction of diuretic action. In doses commonly used, probenecid reduces renal elimination of furosemide in man with only a mild impairment of its diuretic activity. This suggests that furosemide is eliminated predominantly by way of proximal tubular secretion and that tubular rather than plasma concentration is the main determinant of its diuretic effect.
Prediction of the lithium ratio in man by means of an in vitro test
Authors: Rybakowski Janusz , Frazer Alan , Mendels Joseph , Ramsey T. Alan
Published: January 2016

The movement of the lithium ion (Li+) across the membrane of intact erythrocytes incubated in vitro was assessed under two different experimental conditions in which such transfer occurred primarily due to the activity of a lithium‐sodium countertransport system. The 13 subjects on whom the in vitro procedures were done subsequently received lithium carbonate for 14 to 56 days, and the extent of accumulation of Li+ by erythrocytes in vivo was measured. While both in vitro procedures yielded data that correlated with the extent of accumulation of Li+ by erythrocytes in vivo, a system measuring the efflux of Li+ from Li+‐loaded cells produced a much higher correlation (0.976). The magnitude of this correlation suggests that this in vitro system can be used for further investigations into the relevance of the erythrocyte accumulation of Li+ to the pathogenesis and treatment of affective disorders.