bluuebunny/crossref_metadata_2025 huggingface dataset:
Kinetics of intravenous and intramuscular morphine
Authors: Stanski Donald R. , Greenblatt David J. , Lowenstein Edward
Published: January 2016

The disposition of parenteral morphine was assessed in two pharmacokinetic studies. In Study 1, 10 mg of morphine sulfate was administered by intravenous (IV) infusion, intramuscular (1M) injection, or both, to 8 healthy young adult male volunteers. Plasma morphine concentrations were determined by radioimmunoassay in multiple blood samples drawn after each dose. Mean (±SE) kinetic parameters following IV morphine were: volume of distribution (Vd), 3.2 (±0.3) Llkg; elimination half‐life (t½β), 2.9 (±0.5) hr; clearance, 14.7 (±0.9) ml/min/kg; extraction ratio, 0.70 (±0.04). After IM morphine, peak plasma levels ranged from 51 to 62 ng/ml and were reached within 20 min of injection. The absorption half‐life averaged 7.7 (±1.6) min. Systemic availability was 100% complete. In study 2, 4 elderly male patients (61 to 80 yr of age) received 45 to 80 mg of morphine sulfate IV prior to operative repair of an abdominal aortic aneurysm. Morphine pharmacokinetics were determined as described above. Kinetic variables were: Vd, 4.7 (±0.2) L/kg; t½β 4.5 (±0.3) hr; clearance, 12.4 (±1.2) ml/min/kg; extraction ratio, 0.59 (±0.05). Both studies demonstrate that morphine distribution is rapid and extensive and its t½β relatively short. IM morphine is rapidly and completely absorbed.
Plasma codeine and morphine concentrations after therapeutic oral doses of codeine‐containing analgesics
Authors: Findlay John W. A. , Jones Evelyn C. , Butz Robert F. , Welch Richard M.
Published: January 2016

Plasma concentrations of codeine and morphine were determined by specific radioimmunoassays in healthy human subjects at various times following oral administration of analgesic preparations containing therapeutic doses of codeine phosphate. Following administration of codeine phosphate (60 mg) in combination with aspirin (650 mg) or acetaminophen (600 mg) to two separate groups, mean peak codeine plasma concentrations and β‐phase elimination half‐lives were 159 ng/ml and 2.9 hr or 138 ng/ml and 2.4 hr, respectively. Mean maximum concentrations of metabolically produced morphine were 6.8 nglml (aspirin‐codeine phosphate administration) and 7.4 ng/ml (acetaminophen‐codeine phosphate). Following drug administration, the mean ratio of the areas under the respective plasma concentration‐time curves for morphine and codeine was 0.095 for the aspirin‐codeine phosphate study and 0.12 for the acetaminophen‐codeine phosphate study. Thus, free morphine represented about 10% of the free codeine area in each case. These results support the hypothesis that metabolically produced morphine may influence or be responsible for the analgesic efficacy of codeine.
Long‐term oral bronchodilator therapy of asthma with pirbuterol
Authors: Burki N. K. , Diamond L.
Published: January 2016

We studied the effects of an oral β2 selective bronchodilator, pirbuterol, in 12 male asthmatic patients over periods ranging from 6 to 23 months (mean, 13.8). Each patient was evaluated initially by physical examination, urinalysis, blood analysis, and pulmonary function tests. Patients were examined at regular intervals thereafter. Patients remained off all bronchodilator therapy for 12 hr before each visit. Blood analysis, urinalysis, and pulmonary function tests were performed and the pulmonary function tests were repeated approximately 2 hr after an oral dose of pirbuterol. We found no significant changes in the baseline resistance or in the bronchodilator response to pirbuterol during the course of the study, but there was a significant decrease in the functional residual capacity (FRC). The reduction in FRC could be due to the prolonged reduction in airways resistance with continuous therapy. We found no increase in the bronchodilator response to pirbuterol during oral prednisone therapy. There were no significant changes in serum potassium. Side effects attributable to pirbuterol, nervousness and tremor, occurred in only 2 patients and were easily controlled.
Effect of intravenous thiamine on pralidoxime kinetics
Authors: Josselson John , Sidell Frederick R.
Published: January 2016

Subjects were given pralidoxime chloride (5 mg/kg, intravenously) alone and again while they were receiving an infusion of thiamine hydrochloride. After the addition of thiamine: (1) overall, the urinary excretion of oxime was the same but the amount excreted in the first three hours was smaller; (2) the plasma half‐life of oxime lengthened; (3) the plasma concentrations of oxime rose; and (4) the intercompartmental clearances and rate constant for elimination for oxime fell. These changes suggest that thiamine and oxime compete for a common renal secretory mechanism or that thiamine alters the membrane transport of oxime.
Hemodynamic effects of dopamine in patients with resistant congestive heart failure
Authors: Durairaj Sadayappa K. , Haywood L. Julian
Published: January 2016

Twelve patients with clinical and hemodynamic evidence of severe congestive heart failure, unresponsive to the usual therapy of salt restriction, oxygen, bed rest, digitalis, and massive doses of diuretics, were studied during a control period and after intravenous dopamine. Seven patients survived and 5 died with intractable failure and shock despite transiently improved hemodynamic indices. At control period and after optimal dose of dopamine, there were no significant changes in heart rate (HR) and mean systemic arterial pressure. The mean pulmonary artery (PA) und pulmonary capillary wedge (PCW) pressures decreased slightly. Cardiac index (CI), strake volume (SV), and strake work indices (SWI) rase (p < 0.005) from the control values of 1.4 ± 0.1, 15.3 ± 5, and 13.6 ± 1.7 to 2.2 ± 0.1,24.1 ± 4, and 24 ± 2.3, respectively; pulmonary arteriolar (PAR), total pulmonary vascular (TPVR), and systemic vascular (SVR) resistances fell (p < 0.01). Urine output increased from 13.5 ml/hr before to 58.2 ml/hr after dopamine (p < 0.005). After 24 and 48 hr of dopamine, in addition to the above hemodynamic changes, PA pressure fell from 38 ± 4 to 33 ± 3 and 28 ± 2, and PCW from 30 ± 2 to 24 ± 3 and 18 ± 3 (p < 0.05). Compared with nonsurvivors, survivors had significant decreases in PA and PCW pressures, PAR, and TPVR and an increase in SWI. These data indicate that dopamine is effective in some patients with refractive congestive heart failure associated witli acute oliguric renal failure and that the prognosis may be impraved.
Influence of corticosteroid on hexobarbital and tolbutamide disposition
Authors: Breimer D. D. , Zilly W. , Richter E.
Published: January 2016

The influence of 10 days' prednisone treatment on the disposition of hexobarbital and tolbutamide was studied in 7 healthy male volunteers. No significant changes in the pharmacokinetic parameters of the two drugs became apparent, which indicates that prednisone pretreatment does not affect their metabolic activities.
Effect of human growth hormone on amobarbital metabolism in children
Authors: Redmond Geoffrey P. , Bell Jennifer J. , Perel James M.
Published: January 2016

Drug metabolism changes during the course of growth and development. Hormones mediate somatic growth and may mediate other developmental changes. To determine the effect of human growth hormone (hGH) on human drug metabolism, 6 hGH‐deficient children were given single oral doses of amobarbital before and 6 wk after beginning hGH replacement therapy. Amobarbital was selected as a marker of hepatic microsomal oxidation. Half‐lives rose from 13.89 ± 2.78 hr to 22.75 ± 3.97 hr, volume of distribution was unchanged, and clearance fell from 62.2 ± 15.2 ml/kg/hr to 31.2 ± 11.4 ml/kg/hr. Results indicate that hGH slows the metabolism of amobarbital, probably through an effect on the hepatic microsomal drug‐oxidizing system.
Adrenoceptor blockade of the circulatory responses to intravenous isoproterenol
Authors: Richards D. A. , Prichard B. N. C. , Dobbs R. J.
Published: January 2016

Linear log dose response curves were constructed of isoproterenol induced increases in heart rate and reductions in diastolic blood pressure from 6 normal healthy men. After propranolol and labetalol, such curves were shifted to the right in a parallel manner indicative of antagonism at both beta‐1 and beta‐2 adrenoceptor sites. Log dose‐response curves of isoproterenol‐induced increases in cardiac output before and after the antagonists followed a similar pattern as those of increases in heart rate and were found to be predominantly related to the changes in heart rate. Estimates of relative poteney at beta‐1 and beta‐2 sites fell in the range 4 to 6: 1 propranolol: labetalol. Serial measurement of the immediate eirculatory changes induced by propranolol (0.125 mg/kg intravenously) and labetalol (1.0 mg/kg intravenously) showed that their effeets were dissimilar. Propranolol indueed heart rate‐related reductions in cardiac output together with a small elevation in diastolie pressure, whereas labetalol reduced systolic and diastolie pressure without reducing heart rate or cardiac output. As propranolol and labetalol have qualitatively similar beta antagonist properties, the differenees in circulatory effeets seem to be due to the additional alpha adrenoceptor antagonist property of labetalol not possessed by propranolol. Adding the alpha blocking drug phentolamine to both propranolol and labetalol did not appear to influence the circulatory responses indueed by isoproterenol.
Formation of a thiomethyl metabolite of phenacetin and acetaminophen in dogs and man
Authors: Klutch A. , Levin W. , Chang R. L. , Vane F. , Conney A. H.
Published: January 2016

Conjugates of 3‐methylthio‐4‐hydroxyactanilide were found in the urine of dogs and humans treated with phenacetin (4‐ethoxyacetanilide) or acetaminophen (4‐hydroxyacetanilide). About 1% to 3% of the administered dose was excreted as this thiomethyl metabolite after administration ofphenacetin or acetaminophen to dogs. An average of0.39% ofthe dose was excreted in the urine as 3‐methylthio‐4‐hydroxyacetanilide conjugates after administration of phenacetin to several subjects, and an average of 0.66% of the dose was excreted as this metabolite in the urine after administration of acetaminophen to humans. The possibility that the thiomethyl metabolite is derived from a mercapturic acid conjugate or an N‐hydroxy derivative of phenacetin or acetaminophen is discussed.
The interaction between indomethacin and probenecid; A clinical and pharmacokinetic study
Authors: Baber N. , Halliday L. , Sibeon R. , Littler T. , Orme M. L'E.
Published: January 2016

The interaction between indomethacin and probenecid has been studied in 17 patients with rheumatoid arthritis with the use of a specific gas‐liquid chromatographie method for the assay of indomethacin in plasma and urine. Probenecid in a dose of 0.5 gm twice daily improved the therapeutic response to indomethacin administered in a dose of 25 mg 3 times daily for a 3‐wk period. There was an increase in the mean AUC of indomethacin in plasma from 2,553 ± 213 hr ng/ml to 4,181 ± 384 hr ng/ml when probenecid was given, but there was no change in the plasma half‐life of indomethacin. There was a reduction in the mean plasma clearance of indomethacinfrom 174 ± 21 m/lkg/hr to 107 ± 14 ml/kg/hr when probenecid was added to the indomethacin therapy and a decrease in the apparent volume of distributionfrom 0.927 ± 0.16 L/kg to 0.613 ± 0.13 L/kg. There was no change in the amount of free indomethacin excreted in the urine during probenecid therapy but there was a reduction in the urinary excretion of free plus glucuronide conjugate of indomethacinfrom 8,967 ± 867 µg/day to 4,760 ± 674 µg/day, with a fall in the mean renal clearance of indomethacin glucuronide from 271 ± 48 ml/min to 126 ± 57.0 ml/min. The changes in the plasma indomethacin concentration profile during probenecid therapy are due to a decrease in the nonrenal clearance of indomethacin possibly because of reduced biliary clearance.
Impaired absorption of desmethyldiazepam from clorazepate by magnesium aluminum hydroxide
Authors: Shader Richard I. , Georgotas Anastasios , Greenblatt David J. , Harmatz Jerold S. , Allen Marcia Divoll
Published: January 2016

Ten healthy volunteers ingested single 15‐mg doses of clorazepate dipotassium (CZP) with 60 ml of water, or with 60 ml of magnesium aluminum hydroxide (Maalox), on two occasions in a randomized, two‐way crossover study. Plasma concentrations of desmethyldiazepam (DMDZ) were determined in multiple sampies drawn during 48 hr after each dose. Mean kinetic variables for DMDZ in CZP‐water and CZP‐magnesium aluminum hydroxide treatment conditions, respectively, were: peak measured concentration, 273 and 188 ng/ml (p < 0.001); time of peak concentration, 1.8 and 2.8 hr after dose (p < 0.01); apparent absorption half‐life, 14.8 and 30.7 min (p < 0.02); area under the 48‐hr plasma concentration curve, 6,028 and 5,433 ng/ml · hr (p < 0.02). Self‐rated sensations offeeling “spacey,” “thinking slowed down,” and of generalized sedation, were reported with both treatment conditions, but these subjective effects occurred earlier and were more profound when CZP was taken with water as opposed to magnesium aluminum hydroxide. Thus administration of single doses of CZP with usual doses of a commonly prescribed antacid reduces the rate and extent of appearance in blood of DMDZ (the compound responsible for clinical activity) and attenuates self‐rated clinical effects.
Prediction of in vivo red cell/plasma Li+ ratios by in vitro methods
Authors: Pandey Ghanshyam N. , Baker Joyce , Chang Sidney , Davis John M.
Published: January 2016

Two incubation procedures were used for the determination, in vitro, of the steady‐state Li+ ratio between red cells and external media. The Li+ ratio in vitra determined prior to Li+ therapy correlates significantly with the subsequent ratio in vivo between red cells and plasma in patients treated with Li+. The Li+ ratio determined in vitro in patients during Li+ therapy was significantly higher than the value determined during the pretreatment, drug‐free period but correlated significantly with Li+ ratios in vivo. The in vitro procedure used thus could be applied in the prediction of the in vivo Li+ ratio, and possibly of the response to Li+, in patients before treatment is begun. It also could be used for studies on abnormalities and on the genetics of Li+ transport in affective illness.
Combined effects of fenmetozole and ethanol
Authors: Griffis Larry C. , Bright Thomas P. , Cerimele Benito J. , Forney Robert B.
Published: January 2016

Eight male subjects took none or 200 mg fenmetozole 1 hr before drinking a beverage containing none or 50 m/l70 kg ethanol. Tests designed to measure mental and motor performance were administered 2 hr after fenmetozole ingestion. Fenmetozole alone impaired standing steadiness but improved mental performance in one test. Fenmetozole did not antagonize the decrement in performance induced by this amount of ethanol. In combination, the subjective symptoms caused by fenmetozole were additive with those of ethanol.
Kinetics of acetaminophen absorption and gastric emptying in man
Authors: Clements J. A. , Heading R. C. , Nimmo W. S. , Prescott L. F.
Published: January 2016

Eight healthy male volunteers ingested an aqueous solution containing acetaminophen (20 mg/kg) and a nonabsorbable isotopic marker. The concentrations of unconjugated acetaminophen in samples of blood plasma taken at frequent intervals were measured by gas‐liquid chromatography. The data points followed a smooth curve in most cases and were fitted to the classical two‐compartment pharmacokinetic model to obtain KA, the apparent first‐order rate constant for absorption from the gastrointestinal tract. Gastric emptying was measured simultaneously from serial scintiscans of the subject's abdomen. The subjects were also studied after intramuscular injection of meperidine (150 mg) and pentazocine (60 mg) with and without naloxone (1.2 mg). The acetaminophen absorption curves and gastric emptying patterns were consistent with negligible absorption from the stomach. A new model is proposed in which the conventional single compartment used to represent the gastrointestinal tract is replaced by two compartments: one represents the stomach and the other the small intestine, from which absorption occurs rapidly. Pharmacokinetic analysis using this model showed good agreement in all cases, and provided an estimate of KA*, the first‐order rate constant for drug transfer from the intestinal lumen into the systemic circulation. The mean half‐time for transfer was 6.8 ± 0.9 min. As expected, KA* was greater than KG (the first‐order rate constant for gastric emptying), showing that gastric emptying was rate‐limiting in the absorption of acetaminophen. The value of KA* was greater than KA and the two were not related. The value of KA was not equal to KG in most studies because gastric emptying was not a single exponential process.
Metoclopramide in Parkinson's disease
Authors: Bateman D. N. , Kahn C. , Legg N. J. , Reid J. L.
Published: January 2016

The effect of metoclopramide given in a dose of 10 mg or 20 mg 3 times a day has been compared with placebo in a double‐blind randomized crossover study in 11 treated parkinsonian patients. Effects on blood pressure, parkinsonian symptoms and signs, and psychopathologic features were measured. There was no significant effect of metoclopramide at either dose level on parkinsonian symptoms and signs as assessed by a neurologist. Patients' self‐scored assessments indicated worsening of tremor at the higher metoclopramide dose (p < 0.025). Psychopathologic features and subjective symptoms were not significantly changed by metoclopramide (nausea was not a problem). Treatment with metoclopramide 30 mg daily was followed by a rise in supine (p < 0.05) and standing (p < 0.02) blood pressure in a subgroup of 5 patients who had postural falls in systolic blood pressure greater than 15 mm Hg when on placebo; no such effect was seen at the higher dose. In the group as a whole there was no drug effect on blood pressure taken supine, erect, or after exercise. Four of the patients expressed treatment preference; 2 were for placebo because of worsened tremor on metoclopramide and 2 for metoclopramide because of improvement in dyskinesia. These findings suggest that despite its dopamine‐blocking action metoclopramide is well tolerated in a dose of 10 mg 3 times a day by parkinsonian patients and might be safely used as an antiemetic without deterioration in function.
Alterations in state in apneic pre‐term infants receiving theophylline
Authors: Dietrich Jeanne , Krauss Alfred N. , Reidenberg Marcus , Drayer Dennis E. , Auld Peter A. M.
Published: January 2016

The present study is a report on 9 premature infants treated with aminophylline for relief of apnea. With serum theophylline levels of 2 to 10 µg/ml, all infants experienced significant decrease of apneic episodes in association with increased wakefulness and increased amounts of active (REM) sleep. These effects may occur independently, but it is possible that the alteration of sleep states may be partially responsible for the decrease in apneic episodes in these infants.
XLV. The purposes and functions of criteria
Authors: Feinstein Alvan R.
Published: January 2016

The word criteria and its singular, criterion, are additional entries in the list of terms that create ambiguity or confusion in modem clinical science. According to the definition in a conventional dictionary85, a criterion is a ‘standard, rule, or test by which something can be judged’. These three different nouns—the standard, the rule, and the test—refer to three distinct kinds of activity for the work that is done by criteria.
The drug lag revisited: Comparison by therapeutic area of patterns of drugs marketed in the United States and Great Britain from 1972 through 1976
Authors: Wardell William M.
Published: January 2016

This study describes rates and patterns of new drug introductions in the U.S. and Britain from January, 1972, through December, 1976, updating an earlier study that described the patterns over the previous decade. This comparative international approach enables overall effects of different regulatory, industrial, and other types of changes in drug research and development in the two countries to be evaluated. Numerical differences persisted. In the 1972 to 1976 period, 82 new drugs appeared for the first time in either country. Only 29% of these became mutually available in both countries, 2.4 times as many becoming available first in Britain as in the U.S. Of the 71% that became exclusively available, 2.6 times as many became available in Britain as in the U.S. More important than numerical data are clinical implications of differences between the countries. The largest differences have narrowed since the previous study, but important categories in which the U.S. still lagged behind Britain in December, 1976, included cardiovascular drugs, peptic ulcer drugs, and central nervous system drugs‐including therapies for depression, epilepsy, and migraine. Several factors contributed to the narrowing of U.S.‐British therapeutic differences, including more realistic regulatory practices and higher quality clinical studies in the U.S., more conservative practices in Britain, attention drawn by previous studies to anachronisms in the U.S., and industrial changes such as more efficient penetration of the U.S. market by foreign firms. It is difficult to determine the relative contribution of each of these factors to the narrowing of the international difference.
Antihypertensive responses to spironolactone in normal renin hypertension
Authors: Ogilvie Richard I. , Piafsky Kenneth M. , Ruedy John
Published: January 2016

The antihypertensive effect of spironolactone was studied in 20 patients with essential hypertension and normal stimulated peripheral renin activity (PRA). Single‐blind 8‐wk treatment periods of placebo, 100, 200, and 400 mg spironolactone were used in consecutive order. Average supine and erect blood pressures were lower than placebo values at the end of each treatment. A prominent orthostatic effect was observed. Changes in blood pressure were not related to changes in body weight, PRA, or blood urea nitrogen. A larger proportion (50%) of patients had a more normal erect diastolic pressure at the end of 400 mg/day than at the end of 100 mg/day (20%), but the response to 400 mg/day could not be predicted from the responses to lower doses. Larger doses of spironolactone were predictably associated with rises in serum potassium, PRA, and aldosterone excretion. Adverse effects were absent during therapy with 100 mg/day but were frequent during 200–400 mg/day. Although there are no apparent advantages in increasing spironolactone from 100 to 200 mg/day in this group of patients with normal renin hypertension, increasing the dose to 400 mg/day resulted in better blood pressure control with more frequent adverse effects.
Effect of trimazosin on hemodynamics in chronic heart failure
Authors: Orlando Joan R. , Danahy Daniel T. , Lurie Mark , Aronow Wilbert S.
Published: January 2016

The effect of the oral vasodilator trimazosin on hemodynamics in 16 patients with chronic left ventricular failure was compared with placebo in a double‐blind, randomized study. Eight patients received trimazosin 100 to 300 mg, and 8 received placebo. Over the 6‐hr period after medication trimazosin caused no significant change in heart rate, stroke work index, or pulmonary vascular resistance, but there were significant reductions in mean arterial pressure (p < 0.05), mean right atrial pressure (p < 0.01), mean pulmonary artery pressure (p < 0.01), mean pulmonary capillary wedge pressure (p < 0.01), and systemic vascular resistance (p < 0.01), and significant increases in stroke index (p < 0.05) and cardiac index (p < 0.05). None of 8 patients improved after placebo, whereas 5 of 8 patients (63%) had a good or excellent hemodynamic response after trimazosin (p = 0.006). Four of 4 patients who received 300 mg of trimazosin had a good or excellent response. Trimazosin is a long‐acting orally effective vasodilator which improves ventricular function in patients with left ventricular failure.
Distinctive patterns of amobarbital metabolites
Authors: Kalow W. , Tang B. K. , Kadar D. , Inaba T.
Published: January 2016

This paper establishes that the relative proportion of amobarbital metabolites in urine is highly variable from person to person and that observations of plasma half‐life give no indication of this variability, but it shows that a valid estimate of a given person's metabolite pattern can be obtained by studying a single urine specimen in the postdistributive phase. The two metabolites which were measured in urine accounted on the average of 9 subjects for 80% ± 3% of the dose with a range from 66% to 94%. The two metabolites were the well known 3′‐hydroxyamobarbital (COH) as a product of side chain hydroxylation and N‐β‐D‐glucopyranosyl amobarbital (N‐glu), a glucose conjugate which at some earlier time had been mistaken for an N‐hydroxylation product. Among 129 volunteer subjects, the metabolite ratio N‐glu/COH showed a median value of about 0.5 with a range from 0 to 2.8. A virtual absence of N‐glu was observed in one of the 129 subjects and confirmed by a second administration of amobarbital 3 mo later. Of the 14 subjects with predominant N‐glu excretion 4 were of Chinese origin, while there were 6 Chinese among the 115 other subjects (p < 0.02).
Transplacental passage of diazepam during labor: Influence of uterine contractions
Authors: Haram Kjell , Bakke Olav M. , Johannessen Kristina H. , Lund Tjøstolv
Published: January 2016

The rate of transplacental passage of diazepam (DZ) has been studied in 33 cases of cephalic presentation where operative forceps delivery was indicated by intrauterine hypoxia or by prolonged second stage of labor. The drug (30 mg) was injected intravenously immediately before delivery either during uterine contractions (Group I) or in the relaxation period (Group II) according to a randomized protocol. As judged by the concentration in the newborn and the child/mother concentration ratio at 2 hr after delivery, and the concentration on the second day, the fetal exposure to the drug was probably less when the injection was timed to coincide with uterine contractions. In the group of patients given the drug in the relaxation period, the injection‐delivery (I‐D) interval was up to 305 sec, and the 2‐hr child/mother concentration ratio was close to unity in some cases. It therefore appears that the transplacental passage of DZ is rapid when the high initial concentrations in the maternal circulation coincide with favorable conditions for transfer in the relaxation period. Although sleep was induced by the injection of DZ in all of the mothers, the amounts of drug transferred during the short I‐D intervals in the present study did not exert deleterious effects on the newborn infants.
Diazepam absorption: Effect of antacids and food
Authors: Greenblatt David J. , Allen Marcia Divoll , MacLaughlin Dean S. , Harmatz Jerold S. , Shader Richard I.
Published: January 2016

Nine healthy fasting volunteers received 5 mg of diazepam orally with 60 ml of water, 60 ml of magnesium aluminum hydroxide mixture (Maalox), or 60 ml of aluminum hydroxide trisilicate mixture (Gelusil) in a randomized, single‐dose, three‐way crossover study. Plasma concentrations of diazepam and its major metabolite (desmethyldiazepam) in multiple samples drawn during 48 hr after each dose were determined by electron‐capture gas‐liquid chromatography. Compared with the water treatment condition, administration of diazepam with each antacid yielded lower peak plasma concentrations which were attained later after the dose, longer lag times prior to the start of absorption, and prolongation of the absorption half‐life. Completeness of diazepam absorption, judged by the area under the 48‐hr plasma concentration curve (AUC‐48), was not influenced. In a second study, 6 of the subjects took diazepam after a standard breakfast. Diazepam absorption was slowed to an even greater extent than in the diazepam‐antacid treatment conditions. However, AUC‐48 averaged 26% more in the diazepam‐food condition than with the diazepam water condition suggestive of enhanced absorption. Under the conditions of this study, coadministration of diazepam with antacids or a standard meal reduces the rate of absorption but does not reduce extent of absorption.
Potential anticoagulant drug interactions in ambulatory patients
Authors: Hull J. Heyward , Murray William J. , Brown H. Shelton , Williams Benjamin O. , Chi Shelly L. , Koch Gary G.
Published: January 2016

Computer‐generated prescription drug purchase records for ambulatory patients receiving oral anticoagulants (OAC) were studied for concomitant use of other drugs which have been reported to induce clinically significant interactions. One third of 479 patients taking OAC were exposed to a potentially interacting drug at some time during this 6‐month period. The percentage of patients with drug interaction exposure correlated directly with total drug use (p < 0.0005). There were no significant differences when interaction exposure rates were compared in the cases of single: multiple pharmacy and single: multiple physician‐patient groups. Warfarin was the most common anticoagulant (>95%) and barbiturates the most common interacting drug.
Lidocaine and its active metabolites
Authors: Narang Prem K. , Crouthamel William G. , Carliner Nathan H. , Fisher Michael L.
Published: January 2016

It has been shown that the antiarrhythmic and toxic effects of lidocaine may be in part dependent on its two active metabolites, monoethylglycylxylidide (MEGX) and glycylxylidide (GX), Presently available gas liquid chromatographic analytic methods require long and tedious steps or sophisticated equipment such as gas liquid chromatography‐mass spectrometry. The assay method reported here with the use of high‐performance liquid chromotography is rapid and allows accurate, precise determination of lidocaine, MEGX, and GX in biologic fluids. On the 3 patients studied extensively with the use of this assay, one patient had MEGX concentrations almost twice those of lidocaine. At 83% lidocaine potency, the contribution of MEGX in this patient was about 1.5 times that of lidocaine. The second patient studied on two consecutive days had a 20% increase in serum lidocaine concentration and an equivalent decrease in MEGX concentration on the second day. In the third patient lidocaine was stopped with a resulting half‐life of 3.8 hr, which is consistent with previously reported values for patients on long‐term lidocaine infusion. Urinary excretion of lidocaine and its metabolites is in agreement with previous work. These data suggest that much information still remains to be learned about the active metabolites of lidocaine as well as of lidocaine.
Physostigmine for cardiac and neurologic manifestations of phenothiazine poisoning
Authors: Weisdorf Daniel , Kramer Jeffrey , Goldbarg Alberto , Klawans Harold L.
Published: January 2016

Psychotropic drugs such as the phenothiazine neuroleptics and tricyclic antidepressants are known to cause electrocardiographic abnormalities as well as a central anticholinergic syndrome. Physostigmine is known to reverse the central muscarinic anticholinergic manifestations by inhibition of the enzyme cholinesterase. An unusual case of trifluoperazine overdose, in which the patient presented with cardiac arrhythmias and a central anticholinergic syndrome, is presented. Treatment with physostigmine reversed the central anticholinergic syndrome as well as the electrocardiographic abnormalities. Effects of phenothiazines on altering cardiac status are also discussed.
Naproxen‐probenecid interaction
Authors: Runkel R. , Mroszczak E. , Chaplin M. , Sevelius H. , Segre E.
Published: January 2016

Probenecid induced major alterations in the half‐life. renal clearance, and metabolism of naproxen. In 6 healthy subjects who received 500‐mg single oral doses of naproxen alone and (following two days of probenecid loading) with 500 mg of probenecid 4 times a day, there was an increase in naproxen plasma half‐life from the normal 14 to 37 hr. Twenty‐four hour naproxen plasma levels were doubled by probenecid. but the rate and extent of absorption were not affected. In an 8‐day chronic administration experiment (250 mg twice daily). naproxen steady‐state plasma levels measured before the morning dose were increased 50% by coadministration of 500 mg probenecid twice daily. The major probenecid effects on naproxen metabolism were a 66% reduction of the naproxen conjugates excreted in the urine and an increase in urinary 6‐0‐desmethyl naproxen. The renal clearance of unchanged naproxen was markedly depressed. We conclude that probenecid retards naproxen plasma clearance by inhibiting naproxen glucuronide formation and renal clearance of naproxen. The renal clearance effect is the result of the blocking of tubular secretion of organic anions by probenecid. Inhibition of conjugate formation by probenecid may be the result of successful competition for conjugative processes since a large percentage of both drugs are cleared from the plasma by conjugation. Because of this interaction, patients who receive naproxen and probenecid in combination will have higher steady‐state plasma levels of naproxen and form more of the 6‐0‐desmethyl metabolite than when probenecid is not used.
A message from the President—Come to Kansas City March 21–23, 1979
Authors: McMahon F. Gilbert
Published: January 2016

Once again it is time to make arrangements to attend the Annual Meeting of the American Society for Clinical Pharmacology and Therapeutics, our eightieth, at the Crown Center Hotel, March 21 to 23, 1979. The format of this year's meeting has been modified and we hope you will like the changes. The scientific program will begin Wednesday afternoon with a plenary session during which Dr. Richard M. Weinshilboum will deliver the first Rawls‐Palmer Progress in Medicine Lecture. There will be no Society luncheon, but on Thursday evening after the business meeting and social hour we will gather for the USV Presidential Awards Dinner. Your President will review the “Highlights of the Year,” and Dr. Kenneth G. Kohlstaedt will be honored as the first recipient of the Henry W. Elliott Distinguished Service Award. The Twenty‐fifth Oscar B. Hunter Memorial Award in Therapeutics will be given to Dr. Ray Gifford, everybody's friend and teacher in hypertension. You won't want to miss his acceptance address.
Metoprolol with and without chlorthalidone in hypertension
Authors: Kubik Michael , Kendall Martin , Ebbutt Alan , John Vivian
Published: January 2016

After a control period on a placebo, 45 patients with mild to moderate hypertension were treated with metoprolol, 100 mg twice daily alone and in free combination with chlorthalidone 50 mg daily using a double‐blind crossover technique. The β‐blocker alone induced a significant fall in blood pressure; the diastolic pressure was reduced to 100 mg Hg or less in 37 of the 45 patients and to 95 mm Hg or less in 19 patients. The addition of chlorthalidone enhanced the antihypertensive effect so that in 33 patients diastolic pressure fell to 95 mm Hg or less. The drugs were well tolerated even by a small number of patients with chronic bronchitis and diabetes mellitus. None of the patients developed cardiac failure. Adding a diuretic caused a small reduction in serum potassium concentrations, and the relevance of this observation is discussed.
Effect of naproxen on the steady‐state serum concentration and anticoagulant activity of warfarin
Authors: Jain Adesh , McMahon F. Gilbert , Slattery John T. , Levy Gerhard
Published: January 2016

The purpose of this investigation was to determine whether the anti‐inflammatory drug naproxen interacts with warfarin during prolonged administration of both drugs. Healthy adults received oral doses of warfarin daily for 26 days. Naproxen, 375 mg twice daily, was given from the eleventh through the twentieth days. Naproxen administration had no apparent effect on the steady‐state concentrations of free and total (free and protein‐bound) warfarin in serum, despite a small but statistically significant increase of the warfarin‐free fraction in serum. There was no apparent difference between the prothrombin times (at a constant daily dose of warfarin) observed before, during, and after administration of naproxen.
Placental passage of oxazepam and its metabolism in mother and newborn
Authors: Tomson G. , Lunell N.-O. , Sundwall A. , Rane A.
Published: January 2016

The transfer across the placenta and the maternal and neonatal kinetics of oxazepam and its conjugate were studied in 12 patients and their newborns. A single oral dose of 25 mg was given to the women 40 min to 23 hr before delivery. The concentration of oxazepam and oxazepam conjugate was determined by electron capture gas chromatography. Oxazepam was readily absorbed and peak plasma concentrations were in the same range as those in healthy males and nonpregnant females given the same dose. When meperidine was given within one hour of oxazepam the absorption was delayed without a change in bioavailability. The elimination half‐lives (t½) ranged from 5 to 8 hr, which is shorter than reported for nonpregnant subjects. The t½s of conjugates were in the same range as those of oxazepam. Oxazepam was found in the umbilical vein of all patients. The concentrations of the oxazepam conjugate were lower (in three cases unmeasurable) than those of oxazepam. The ratio between umbilical/maternal vein oxazepam concentrations reached a value of about 1.35 and remained constant beyond a dose‐delivery time of 3 hr. The corresponding ratios of the conjugate were lower. The t½ of oxazepam was 3‐ to 4‐fold as long (mean 21.9 hr) in the newborns as in the mothers (mean 6.5 hr). In three newborns the plasma concentration of oxazepam conjugate rose during the first 6 to 10 hr of extrauterine life, which indicates that the newborn is able to conjugate oxazepam. The Apgar score values were normal in all newborns.
Stimulatory effect of brussels sprouts and cabbage on human drug metabolism
Authors: Pantuck E. J. , Pantuck C. B. , Garland W. A. , Min B. H. , Wattenberg L. W. , Anderson K. E. , Kappas A. , Conney A. H.
Published: January 2016

Ten healthy volunteers were fed (1) a control diet for 10 days, (2) the same control diet for 3 additional days and a brussels sprouts and cabbage‐containing diet for the next 7 days, and (3) the control diet for the 10 subsequent days. Antipyrine and phenacetin were administered orally before breakfast on days 7 and 10, respectively, of each dietary regimen. During the test diet period the mean plasma half‐life of antipyrine decreased 13% and the mean metabolic clearance rate increased 11%. While small, these changes were statistically significant, indicating a stimulatory effect of cabbage and brussels sprouts on antipyrine metabolism. The values returned to control levels during the second control diet period. During the test diet period the mean plasma concentration of phenacetin was decreased by 34% to 67% at each time interval from 0.5 to 7 hr after phenacetin administration, and the mean plasma concentration of total (conjugated plus unconjugated) N‐acetyl‐p‐aminophenol (APAP), phenacetin's major metabolite, was increased from 0.5 to 3 hr after phenacetin administration. The concentrations of phenacetin and APAP returned toward control values during the second control diet period. The mean plasma half‐life of phenacetin was not influenced by the dietary changes. These results suggest that the test diet enhanced the metabolism of phenacetin in the gastrointestinal tract and/or during its first pass through the liver. Feeding the test diet increased the mean ratio of conjugated APAP to unconjugated APAP observed in plasma at each time interval from 0.5 to 7 hr after phenacetin administration, suggesting that the diet enhanced the conjugation of APAP.
Effect of alpha‐methyldopa on cardiac output in hypertension
Authors: Safar M. E. , London G. M. , Levenson J. A. , Kheder M. A. , Aboras N. E. , Simon A. Ch.
Published: January 2016

Hemodynamic and blood volume changes, systolic time intervals, and baroreflex mechanisms were studied in 20 patients with hypertension after methyldopa (12 ± 0.9 mg/kg/day). The drug was administered orally during 7 days' hospitalization on a normal sodium diet (110 mEq/day). There was a fall in blood pressure and in total peripheral resistance, without significant change in cardiac index, heart rate, and stroke index. There were increases in plasma and blood volume (p < 0.05) but no change in cardiopulmonary blood volume or systolic time intervals. The unchanged heart rate was associated with an increased sensitivity (p <0.05) of the baroreflex mechanisms. The study supports the view that the unchanged cardiac output after methyldopa is related to important changes in control of cardiac output, including redistribution of blood volume and modifications in baroreflex mechanisms.
Smoking and warfarin disposition
Authors: Bachmann Kenneth , Shapiro Ronald , Fulton Robert , Carroll F. Thomas , Sullivan Timothy J.
Published: January 2016

Nine cigarette smokers ingested an average daily 0.032 mglkg dose of sodium warfarin for 2 wk while continuing to smoke and for an additional 2 wk after having abstained from cigarette smoking for a month washout phase. Steady‐state plasma levels of warfarin, clearances, t½, apparent volumes of distribution, steady‐state prothrombin times, and plasma thiocyanate levels were measured during both the smoking and nonsmoking phases. During the nonsmoking phase there was a 13% increase in average steady‐state warfarin level and a 13% decrease in warfarin clearance rate. There also was a 23% increase in warfarin t½ and an 11% increase in the apparent volume of distribution. Prothrombin time did not change. Thiocyanate levels were 3 to 4 times as high during the smoking than the nonsmoking phase. It appears that cigarette smoking does affect warfarin clearance, t½, and apparent volume of distribution, though the net effect on warfarin's pharmacodynamic activity is negligible, at least at doses which are ineffective therapeutically.
Binding of imipramine to plasma proteins: Effect of hyperlipoproteinemia
Authors: Danon Abraham , Chen Zehava
Published: January 2016

The binding of imipramine to plasma proteins was studied by equilibrium gel filtration. Imipramine was highly bound to lipoproteins as well as to other plasma proteins. The binding to the lipoproteins was higher in hyperlipoproteinemic patients than in normal subjects and correlated well with both plasma cholesterol and triglyceride levels. The overall percent binding of imipramine was also higher in hyperlipoproteinemic patients than in normal subjects. It is concluded that the varying degree of binding of imipramine to plasma proteins as a result of varying lipoprotein concentrations, as well as the special nature of the binding to lipoproteins, may be of kinetic and possibly clinical significance in hyperlipoproteinemic individuals.
Effect of indomethacin on salt and water homeostasis
Authors: Brater D. Craig
Published: January 2016

The effects of indomethacin‐induced prostaglandin inhibition on sodium and chloride homeostasis in normal man were assessed. Seven normal subjects were on a 150‐mEq sodium diet for 3 days prior to receiving indomethacin or no drug. Indomethacin decreased fractional excretions of sodium and chloride without affecting fractional excretion of potassium, creatinine clearance, or percent fractional reabsorption of free water. Cumulative sodium excretion at 8 hr fell from 49.8 ± 7.2 to 16.1 ± 4.8 mEq (p < 0.005) after indomethacin. Chloride fell at 8 hr from 49.7 ± 6.4 to 21.3 ± 5.1 mEq (p < 0.005). Urinary volume and osmolal clearance decreased in similar magnitudes such that free water reabsorption was not changed by indomethacin. This study showed that indomethacin decreased renal sodium and chloride excretion, implying that endogenous prostaglandins may be modulators of renal sodium excretion.
Urinary excretion of D‐glucaric acid by severely burned patients
Authors: Ciaccio Edward I. , Fruncillo Richard J.
Published: January 2016

The 24‐hr excretion of urinary D‐glucaric acid (VGA) has been measured in 5 seriously burned adults and compared with 6 healthy adults. In the burn patients mean VGA was 14.4 ± 5.4 (±SD) µmoles/day and 28.7 ± 6.5 pmoleslday in controls (p < 0.002). In a 6‐year‐old female, VGA was also found to be very low. In a seventh burn patient, an adult male taking 20 mg of fluphenazine until his injury, his VGA was still in the normal range (29 µmoles/day) on the day of admission but descended to 21 µmoles/day at 2 days, to 16 at 4 days, and to 13 at 6 days. Treatment with fiuphenazine was then reinstituted and on the tenth day VGA was 28 µmoles/day, indicating that after thermal injury VGA can respond to drugs. Although the inference has not been proved that decreased VGA corresponds to a decreased activity of drug metabolism, there is evidence of a strong correlation between increased VGA and increased drug metabolism. A decrease of VGA in disorders that generally lower metabolic activity supports a possible correlation in severe burns. If drug metabolism activity is lowered in the seriously burned patient, drug overdose may well result from the usual clinical doses.
Chloroquine serum concentration and side effects: Evidence for dose‐dependent kinetics
Authors: Frisk-Holmberg Marianne , Bergkvist Yngve , Domeij-Nyberg Britta , Hellström Laila , Jansson Folke
Published: January 2016

Serum concentrations of chloroquine were determined fluorometrically in 100 rheumatoid patients who had been treated with 0.25 gm daily for at least 2 mo. The total dose varied between 3.7 and 400 gm. No patient received more than 75 gm annually. In 15% of the patients side effects were noted. There was a relationship between serum concentrations and side effects but not with the total dose administered. Chloroquine displayed dose‐dependent kinetics, which may indicate that close monitoring of serum concentrations is an aid to the safe and rational use of the drug.
Kinetics and absolute bioavailability of atenolol
Authors: Mason William D. , Winer Nathaniel , Kochak Gregory , Cohen Irving , Bell Robert
Published: January 2016

Twelve healthy volunteers received four single doses of atenolol (25‐, 25‐, and 100‐mg oral solutions and a 50‐mg intravenous infusion), each dose separated by at least one week. Blood and urine assayed for atenolol by a high pressure liquid chromatography (HPLC) method. Kinetic analysis of the intravenous data indicates a three‐compartment model with elimination from the central compartment. The mean ( ± SD) terminal elimination half‐life is 6.06 ± 2.02 hr, the mean volume of the central compartment is 0.173 L/kg, and 94.1 ± 8.0% of the intravenous dose is excreted in the urine. The mean value of the plasma clearance is 10.7 ± 1.27 L/hr and of the renal plasma clearance, 10.4 ± 1.14 L/hr. The mean absolute bioavailability for the 25‐, 25‐, and 100‐mg oral doses is 0.52 ± 0.18, 0.54 ± 0.12, and 0.58 ± 0.16, respectively. The maximum plasma concentration varies as a linear function of dose. Time to mean maximum plasma concentration (3.0 hr) and the time for half of the bioavailable dose to be absorbed (2.0 hr) do not differ significantly with dose. The mean renal plasma clearance after oral doses (9.49 ± 1.6 L/hr) is in the same range as renal clearance after intravenous doses.