bluuebunny/crossref_metadata_2025 huggingface dataset:
Plasma and cerebrospinal fluid concentrations of chlordiazepoxide and its metabolites in surgical patients
Authors: Stanski Donald R. , Greenblatt David J. , Selwyn Adrian , Shader Richard I. , Franke Kate , Koch-Weser Jan
Published: January 2016

Thirty otherwise healthy patients received a 100‐mg oral dose of chlordiazepoxide HCl just prior to surgical procedures using spinal anesthesia. Fourteen of these patients had also received 100 mg on the night before surgery. Simultaneous sampies of venous blood and cerebrospinal fluid (CSF) were taken immediately prior to injection of spinal anesthesia and were assayed for concentrations of chlordiazepoxide (CDX) and its major metabolite, desmethylchlordiazepoxide. Plasma concentrations of CDX ranged from 2.32 to 13.34 µg/ml. Simultaneous CSF concentrations were considerably lower, ranging from 0.04 to 0.34 µg/ml. Equilibration of CDX between plasma and the lumbar sampling site appeared to be complete within 2 hr of the most recent dose. After attainment of distribution equilibrium, simultaneous plasma and CSF concentrations of CDX were highly correlated (r = 0.76), with a mean CSF‐plasma concentration ratio of only 0.043 (range; 0.02 to 0.06). The limited passage of CDX into human CSF is probably due to extensive binding (0 plasma protein. Assuming that transfer of CDX from plasma to CSF is governed by passive diffusion, the extent of plasma protein binding of CDX in healthy individuals averages about 96%.
Clinical biostatistics; XXXVII. Demeaned errors, confidence games, nonplussed minuses, inefficient coefficients, and other statistical disruptions of scientific communication
Authors: Feinstein Alvan R.
Published: January 2016

After completing a research project, an investigator encounters several different challenges in the management of data. One of these challenges is in organizing and analyzing the information; another is in drawing conclusions; a third is in communicating the results.
Genetic study of amobarbital elimination based on its kinetics in twins
Authors: Endrenyi L. , Inaba T. , Kalow W.
Published: January 2016

Following the intravenous administration of }25 mg amobarbital sodium in 7 pairs (if dizygotic and 7 pairs of monozygotic twins, the time‐course of plasma concentrations was observed. The number of detectable compartments varied from subject to subject but was consistently} or 2 or 3 within a given individual. The terminal slope of the semilogarithmic concentration‐time plot (corresponding to biologic half‐life of 22.8 hr) did not represent the elimination rate constant even in persons with apparently single‐compartmental characteristics. The redistribution of amobarbital was rapid in comparison with its elimination. The rate of the latter (characterized by kel = 0.05} hr−1, plasma clearance = 37.7 ml/min} could be closely idelltified with the rate of metabolism. The twin data showed that genetic control was exerted on kinetic parameters characterizing the rate of amobarbital elimination and, therefore, the rate of its metabolism. Correlation analysis suggested that this control was independent of size factors, which were themselves substantially heritahle. The genetic analysis of twin data included, in addition to intraclass correlations and Holzinger's H factors, newly developed lower (and upper) bounds of the broad‐sense heritability. In pharmacogenetic studies, assessment (it model‐independent kinetic parameters, such as plasma clearance with or without adjustment for body weight, is recommended.
Absorption and metabolism of phenytoin from tablets and capsules
Authors: Smith Thomas C. , Kinkel Arlyn
Published: January 2016

Crossover studies were conducted to compare plasma levels of phenytoin and urinary throughput of the major metabolite, 5‐(p‐hydroxyphenyl)‐5‐phenylhydantoin (HPPH), after ingestion of single 250‐mg oral doses as tablets or as capsules. Plasma levels of phenytoin did not differ significantly for the 2 formulations except at 8 and 12 hr after ingestion of drug, when the mean values for the tablets were higher than for the capsules. The normalized area under the curve, however, did not differ significantly for either preparation, indicating that equivalent amounts of each preparation were absorbed. Urinary throughput of HPPH did not differ significantly between the 2 preparations. The results suggest that the 2 preparations provide equivalent therapeutic efFects.
Fenoprofen, aspirin, and gold induction in rheumatoid arthritis
Authors: Davis John D. , Turner Robert A. , Collins Ronald L. , Ruchte Inez R. , Kaufmann John S.
Published: January 2016

Fenoprofen calcium (2,400 mg/day) or aspirin (3,900 mg/day) was administered in double‐blind fashion to 20 rheumatoid patients during 6 months of gold induction therapy, and to 20 rheumatoid patiellts not receiving gold. Among both the gold‐treated and nongold‐treated patients, the fenoprofen and aspirin groups improved equally in all but one parameter of disease activity. Fenoprofen and aspirin did not differ significantly in the observed prevalences of abdominal discomfort, guaiac‐positive stools, or peptic ulcers. Aspirin was associated with significantly higher mean serum glutamic oxaloacetic transaminase (SGOT) levels than fenoprofen, but only among patients undergoing gold induction. Comparison of efficacy parameters between patients treated with gold and patients treated with oral drugs alone revealed significant differences famring gold.
Plasma adriamycin and daunorubicin levels by fluorescence and radioimmunoassay
Authors: Bachur Nicholas R. , Riggs Charles E. , Green Mark R. , Langone John J. , Van Vunakis Helen , Levine Lawrence
Published: January 2016

In 38 adriamycin experiments and 4 daunorubicin experiments, radioimmunoassay readily and reproducibly detects and estimates these drugs alld immunologically similar metabolites in patients' plasma and urine to at least 120 hr after dosing without interference by concurrent medication. The plasma drug decay follows first‐order kinetics in a triphasic pattern. Radioimmunoassay and fluorescence assay show similar decay up to 4 hr but diverge at that point with the fluorescence assay yielding higher values. Pharmacokinetic differences are amplified in patients with liver dysfunction and may be caused by fluorescent drug metabolites not sensitive to radioimmunoassay or nonspecific fluorescent materials. The radioimmunoassay offers the capability to measure adriamycin and daunorubicin in clinical settings in which fluorescence assay is not available.
Depression of renal clearance of furosemide in man by azotemia
Authors: Rose H. Josephine , O'Malley Kevin , Pruitt Albert W.
Published: January 2016

The renal clearance of furosemide and tetraethylammonium (TEA) were compared in 10 patients with hypertensive nephropathy. BUN and creatinine ranges were 10 to 88 mg/dl and 0.9 to 3.8 mg/dl, respectively. Diuretics were discontinued 48 hr prior to the study, and 2 consecutive clearances (ml/min/1.73 m2BSA) of creatinine were performed. The patient then received a bolus followed by a constant infusion of furosemide‐14C and tetraethylammonium‐14C (analyzed by specijic methodology for plasma and urine), both in subpharmacologic doses. After 40‐min equilibration sequential 20‐min clearance periods were obtained. Both the clearance of furosemide (range 17 to 133) and TEA (range 99 to 443) correlated negatively with BUN and serum creatinine and positively with creatinine and urea clearances. Thus, by using a constant‐infusion technique we demonstrated that the renal clearance of furosemide is depressed by azotemia in man and that there was greater depression with furosemide than with TEA.
Plasma concentrations of 5‐(4‐hydroxyphenyl)‐5‐phenylhydantoin in phenytoin‐treated patients
Authors: Hoppel Charles , Garle Mats , Rane Anders , Sjöqvist Folke
Published: January 2016

A mass fragmentographic method was used to determine unconjugated and conjugated 5‐(4‐hydroxyphenyl)‐5‐phenylhydantoin (4‐OH‐DPH) in plasma of patients being treated with phenytoin (DPH). The plasma concentration of unconjugated 4‐OH‐DPH is stable at steady‐state for DPH and the level does not change during the dose interval. Most patients (82.5%) have plasma concentrations of unconjugated 4‐OH‐DPH between 0.04 and 0.2 µg/ml at concentrations of DPH between 5 and 30 µg/ml. Interindividual differences in the ratio between plasma concentration of unconjugated 4‐OH‐DPH and DPH were noted in a wide range of doses. Dosage adjustments of DPH in patients were not associated with major changes in the plasma level of unconjugated 4‐OH‐DPH. The plasma concentration of conjugated 4‐OH‐DPH also showed interindividual differences and varied between 1.2 and 4.5 µg/ml in patients with DPH concentrations between 5 and 30 µg/ml. The data are consistent with the concept of Michaelis‐Menten kinetics for DPH metabolism.
Influence of acute viral hepatitis on disposition and plasma binding of tolbutamide
Authors: Williams Roger L. , Blaschke Terrence F. , Meffin Peter J. , Melmon Kenneth L. , Rowland Malcolm
Published: January 2016

To study the influence of acute hepatic disease on the disposition of tolbutamide, we measured tolbutamide plasma protein binding and pharmacokinetic parameters after intravenous administration of the drug to 5 subjects during and after apparent recovery from acute viral hepatitis. Although during the acute phase of illness protein binding of the drug decreased in all, volume of distribution of tolbutamide (0.15 ± 0.03 L/kg) did not change. Clearance based on total concentration of tolbutamide in plasma increased in all subjects during the acute phase of study (26 ± 5.4 ml/hr/kg) in comparison to the recovery phase (18 ± 2.8 ml/hr/kg, p < 0.02). Protein binding decreased after unconjugated bilirubin was added to plasma from the recovery phase, but not to the extent observed during the acute phase of illness at comparable levels of bilirubin. Clearance based on unbound drug concentration, calculated by dividing the observed plasma clearance by the fraction of unbound drug in plasma, did not differ significantly between the 2 study phases (300 ± 47 and 260 ± 39 ml/hr/kg). These observations suggest that the increase in clearance based on total drug concentration in plasma during hepatitis can be attributed solely to decreased plasma binding. This decrease in binding may be attributed in part, but not entirely, to increased concentration of bilirubin during illness. The concentration of unbound drug in plasma at steady‐state is determined by the rate of drug administration and the clearance based on unbound drug. If this clearance does not change during hepatic disease, no dosage alterations for tolbutamide and other comparable drugs are necessary to maintain a constant concentration of unbound drug.
Aging and ethanol metabolism
Authors: Vestal Robert E. , McGuire Elizabeth A. , Tobin Jordan D. , Andres Reubin , Norris Arthur H. , Mezey Esteban
Published: January 2016

The effect of aging on the distribution and elimination of ethanol was studied in a group of 50 healthy subjects ranging in age from 21 to 81 yr (mean, 53.3). Ethanol was administered in a continuous 1‐hr infusion at a mean rate of 375 mg/m2 body surface area/min (equivalent to a mean dose of 0.57 gm/kg body weight). Serial blood samples for the determination of ethanol concentration were obtained at 15‐ to 30‐min intervals for up to 4 hr post irifusion. Ethanol elimination and distribution were evaluated with the aid of a two‐compartment model. Rates of ethanol elimination were not affected by age. Peak ethanol concentration in blood water at the end of the infusion period was correlated with age (r = 0.55, p ‐ 0.001). Lean body mass and total volume of distribution of the ethanol were negatively correlated with age. The smaller volume of distribution, in association with the decreased lean body mass, most likely explains the higher peak ethanol concentration found in the blood after administration of an ethanol dose on the basis of surface area in the old as compared with the young subjects. This study demonstrates that age‐related changes in body composition are important factors in the study of ethanol metabolism and its pharmacologic effects.
Efficacy and acceptability of different dosage schedules of clonidine
Authors: Jain Adesh K. , Ryan Jerome R. , Vargas Ramon , McMahon F. Gilbert
Published: January 2016

In 12 hospitalized patients with hypertension, clonidine 3 times a day led to better control of blood pressure than did the same total dose administered once daily. Compared to the uniform control of blood pressure on divided dose regimen, the single daily 8 p.m. dose led to wider fluctuations and inadequate control 18 hr after dosing. However, 10 of the 12 patients preferred the single daily dose at 8:00 p.m. to the divided dose regimen because of no drowsiness during the day. In 2 patients administration of clonidine twice daily resulted in better control of blood pressure than that du ring the single or thrice‐daily dose regimens. Since there appeared to be a correlation between the dose and the duration of adequate blood pressure control, administration of clonidine twice a day with a larger dose at bedtime and a sm aller dose before noon could limit unwanted drowsiness and combine the convenience of less frequent dosing with superior blood pressure control.
Effect of triamterene on potassium excretion in cirrhotic patients receiving furosemide
Authors: Thompson Eugene J. , Torres Esther , Grosberg Saul J. , Martinez-Maldonado Manuel
Published: January 2016

In a three‐way erossover study, 23 patients with hepatic cirrhosis, ascites, and dependent edema received 40 mg/day of furosemide alone and combined with triamterene 50 mg/day and triamterine 100 mg/day. Baseline potassium exeretion did not increase when furosemide was given alone, but potassium excretion fell when 50 mg or 100 mg of triamterene was also given. Both doses of triamterene augmented the natriuretic effect of furosemide.
Studies on digitalis; X. Digitoxin metabolites in human myocardium and relationship between myocardial and serum concentrations of digitoxin in patients on maintenance treatment
Authors: Storstein Liv
Published: January 2016

The levels of digitoxin and cardioactive metabolites were measured in 42 atrial biopsies with a 86Rb method mod(fiedfor analysis of myocardial sampies. The mean value was 91.0 ng/gm wet weight (SD 54.4). Myocardial and serum concentrations were compared in 23 patients; there was no significant correlation. The ratio of total drug concentration in myocardium and serum ranged from 1 to 38 with a mean value of 5.4. Calculated from the free drug concentrations, the mean myocardial serum ratio was 200, which reflects the high affinity of digitoxin and cardioactive metabolites to the myocardium. The metabolic pattern of cardioactive and inactive metabolites (conjugates with glucuronic and sulfuric acid) was studied in autopsy samples from left ventricular myocardium from 7 patients. Significant differences between the myocardial and serum patterns of cardioactive and inactive metabolites were demonstrated. The myocardium contained less unchanged digitoxin (25.7%) and more hydrolyzed (55.4%) and conjugated (54.1%) metabolites than serum (57.6%, 31.0%, and 33.1%, respeetively). Hydroxylated metabolites in myocardium (15.8%) were not significantly changed compared to serum (10.0%).
Naloxone‐precipitated withdrawal: A method for rapid induction onto naltrexone
Authors: Resnick Richard B. , Kestenbaum Richard S. , Washton Arnold , Poole Doris
Published: January 2016

We examined naloxone‐precipitated withdrawal as a meansfor rapid opiate detoxification and induction onto naltrexone, In 29 patients dependent on methadone (5 to 20 mg/day), abstinence was precipitated by an injection qf naloxone. Repeated injections of naloxone were given subsequently until symptoms of abstinence were no longer induced. Successive injections induced less intense withdrawal assessed by vital signs and ratings on abstinence scales. The most rapid procedure consisted of 1.2 mg naloxone every 30 min for 3 to 6 hr, followed by hourly increasing doses of naltrexone. This procedure allowed transition from opiate dependence to naltrexone maintenance (50 to 100 mg/day) within 48 hr. The results are consistent with assumptions that antagonists actively displace opiates from receptor sites.
Disposition of diazepam and its major metabolite desmethyldiazepam in patients with liver disease
Authors: Klotz U. , Antonin K. H. , Brügel H. , Bieck P. R.
Published: January 2016

In six patients with cirrhosis and five patients with fibrosis of the liver elimination of diazepam (D) was compared after single and subchronic dosage. The pharmacokinetics of the major metabolite desmethyldiazepam (DD) was investigated infour healthy individuals and four patients with hepatic dysfunction and compared to its parent compound D. In the initial study, 11 patients with liver disease (cirrhosis and fibrosis) had a longer half‐life (T½(β)) of99.2 ± 23.2 hr after a single intravenous bolus of 0.1 mg/kg of D than to age‐matched normal subjects (46.6 ± 14.2). After subchronic treatment with 10 mg of D for 7 days T½(β) was prolonged only slightly (p = 0.043) in these patients (107.6 ± 25.1 hr). Neither total plasma clearance (Cl) nor the apparent volume of distribution (Vdss or VdCl) showed significant changes. After intravenous injection of DD (0.1 mg/kg) plasma levels declined in the same biexponential manner as after D. The cross‐over study in the four normal subjects demonstrated that DD was eliminated much more slowly than D. Whereas for D, T½(β) and Cl were 32.6 ± 11.3 hr and 32.3 ± 11.0 ml/min, respectively, the corresponding values for DD were 50.9 ± 6.2 hr and 11.3 ± 3.1 ml/min. The accumulation (if DD after multiple dosage could be explained by the fact that it is formedfaster from D than it is eliminated. In four patients with liver disease the elimination (if D and the elimination (if DD were altered. In these patients T½(β) for DD was prolonged (p = 0.015) to 108.2 ± 40.3 hr. This prolongation was caused by a decrease in Cl of 4.6 ± 1.1 ml/min, (p = 0.003) whereas Vd(Cl) did not change significantly. This indicates that at least two steps in diazepam metabolism are impaired in patients with liver disease.
Studies on digitalis; XI. Digitoxin metabolism in patients with impaired renal function
Authors: Storstein Liv
Published: January 2016

The metabolic pattern of cardioactive and conjugated digitoxin metabolites was studied in 10 uremic patients on maintenance treatment with digitoxin 24 hr after the last dose (mean dose, 0.060 mg/day). Urine was collected over 24 hr. The mean serum digitoxin level was 9.4 ng/ml, and urine level was 6.8 ng/ml. The metabolic pattern of cardioactive metabolites was studied in 5 patients on hemodialysis. Their mean serum digitoxin level was 6.3 ng/ml and urine level was 7.3 ng/ml, on a digitoxin dose of 0.072 mg/day. Unchanged digitoxin was the main cardioactive substance present in both serum and urine of uremic patients. Uremic patients had significantly less unchanged digitoxin and had more hydroxylated (DG‐3) and hydroxylated and hydrolyzed (DG‐2, DG‐1, and DG‐0) metabolites than control patients. The extent of conjugation was the same in the two groups. Our data suggest that uremic patients produce more digitoxose than control patients and that digitoxin elimination is more rapid in uremic patients. The altered pattern of digitoxin metabolites is most consistent with uremia‐induced changes in hydroxylation and hydrolysis. The hemodialysis group had a pattern of digitoxin and cardioactive metabolites similar to control patients, indicating that patients on hemodialysis differ from other uremic patients with respect to digitoxin metabolism.
Clinical and cardiovascular effects of alpha methyldopa in combination with decarboxylase inhibitors
Authors: Kersting F. , Reid J. L. , Dollery C. T.
Published: January 2016

The peripheral decarboxylase inhibitor carbidopa, given (100 mg/day) for 6 wk in a double‐blind trial, lowered supine diastolic pressure of 10 patients with essential hypertension treated with alpha methyldopa by a small (6 mm Hg) but significant (p < 0.05) amount. Large doses ofbenserazide (1.5 gm) did not modify the hypotensive effect of 1.0 gm of alpha methyldopa in untreated hypertension but significantly reduced the central nervous side effects of sedation and dry mouth. These studies indicate that extensive peripheral decarboxylation is not necessary for alpha methyldopa to lower blood pressure and would be compatible with the central nervous site of hypotensive action of this drug.
Aminopyrine metabolism in the presence of hyperbilirubinemia due to cholestasis or hepatocellular disease; Combined use of laboratory tests to study disease‐induced alterations in drug disposition
Authors: Hepner Gershon W. , Vesell Elliot S.
Published: January 2016

Hepatocellular diseases, such as hepatitis, cirrhosis, or hepatic neoplasm, are associated with impaired metabolism of certain drugs, including aminopyrine, whereas cholestasis produced variable effects on aminopyrine metabolism. Reasons for the variable effects of cholestasis on hepatic aminopyrine metabolism were sought by performing in patients with hyperbilirubinemia the aminopyrine breath test (ABT), which consists of measurement of 14CO2 in breath 2 hr after oral administration of [14C]aminopyrine. Hyperbilirubinemia (total serum bilirubin <1.2 mg/lOO ml) in these patients was due to hepatocellular disease or cholestasis. The ABT, defined as the percentage of the administered dose of 14C excreted in breath for 2 hr after [14C]aminopyrine administration, was 6.2 ± 0.8% (mean ± SD) in 107 control patients with normal t9tal serum bilirubin. The ABT was severely abnormal (<3.1 %) in 54 of 77 hyperbilirubinemic patients (70%) with hepatocellular disease and normal (>4.5 %) in only 5 of these patients (6%). In contrast, the ABT was severely abnormal in only 1 of 40 cases of cholestasis with hyperbilirubinemia and normal in 70% of these patients. Thus, aminopyrine metabolism is normal in most cases of hyperbilirubinemia due to cholestasis and is only rarely severely abnormal in these patients. On the other hand, severe abnormality in aminopyrine metabolism occurs in the majority of patients with hyperbilirubinemia due to hepatocellular disease. It therefore appears that the ABT may be useful in hyperbilirubinemia to distinguish patients with hyperbilirubinemia due to cholestasis from most patients with hyperbilirubinemia due to hepatocellular disease.
Interindividual differences in the effect of drugs on bilirubin plasma binding in newborn infants and in adults
Authors: Øie Svein , Levy Gerhard
Published: January 2016

The nonprotein‐bound fraction of bilirubin was determined in undiluted plasma or serum from healthy adult volunteers and newborn irifants after addition of unconjugated bilirubin, 12 mg/100 ml. There were significant interindividual differences (2‐fold in 13 adults, 2.6‐fold in 9 full‐term newborn infants) in the free fraction value. Sulfisoxazole, salicylic acid, and salicyluric acid had a pronounced displacing effect on bilirubin in the 10 to 30 mg/100 ml drug concentration range. Aspirin had only a small effect at concentrations below 20 mg/100 ml. There was a very strong correlation between the free fraction value of bilirubin in individual samples of drug‐free plasma and in the same plasmas after addition of anyone of the 4 drugs studied. This shows that the relative increase of the free fraction of bilirubin induced by anyone of the drugs was essentially the same but that the absolute increase varied greatly between subjects. It may be possible, therefore, to predict quantitatively the bilirubin‐displacing effect of drugs in individual patients before drug administration by determining the free fraction of bilirubin in a plasma or serum sample obtained prior to initiation of drug therapy.
Oral and intravenous propranolol during exercise
Authors: Sutton John R. , Hughson Richard L. , McDonald Rodney , Powles A. C. Peter , Jones Norman L. , Fitzgerald J. Desmond
Published: January 2016

The intrinsic sinoatrial (SA) rate at rest and during exercise was measured in 5 normal male subjects after prolonged oral and acute intravenous administration of propranolol and atropine. At rest, the intrinsic SA rate was similar after both oral and intravenous propranolol. At the higher levels of power output on a cycle ergometer, cardiac rate was slower after oral than after intravenous propranolol. When the intravenous study was repeated with the use of an additional dose of propranolol, cardiac rate was lower at comparable levels of power output, but not as low as that after oral propranolol. Differences in responses were interpreted as reflecting varying degrees of beta blockade, the most complete being that after prolonged oral propranolol administration of 320 mg daily. The intravenous dose of propranolol usually used to obtain the “pharmacologically isolated heart” at rest is too small to induce full beta blockade in exercise.
Kinetics of hydralazine elimination
Authors: Talseth Tore
Published: January 2016

Hydralazine was given orally in single doses of 10, 25, and 50 mg to 2 slow‐acetylating subjects, while 2 rapid‐acetylating subjects also received 100‐ and 150‐mg doses on different occasions. Administration of the 50‐mg dose to the subjects who were slow acetylators and the 150‐mg dose to those who were rapid acetylators caused a disproportionately large increase in the amount of unchanged drug appearing in the systemic circulation as judged from the increases in the ratios of areas under concentration‐time curves (AUC) to dose. A modification of the gas‐liquid chromatographic hydralazine assay allowed the simultaneous determination of hydralazine and its acetylated metabolite, 3‐methyl‐s‐triazolo‐3,4,a‐phthalazine (MTP), in serum. It was found that the disproportionately large increases in the AUC/dose ratio of hydralazine upon intake of 50 or 150‐mg doses by the slow and rapid‐acetylating subjects, respectively, were paralleled by a decrease in the ratio AUCMTP/AUChydralazine during a 6‐hr observation period. It is concluded that the acetylation of hydralazine in man is a capacity‐limited process.
Disposition of pirprofen, a new anti‐inflammatory drug
Authors: Luders Richard C. , Maggio-Cavaliere M. Beth , Egger Hanspeter , HTL Chemiker , Gum Oren B. , Resnick Oscar , Bartlett M. Fred , Gaito Michael J. , Soo Alexander , Li Carina
Published: January 2016

Plasma and urine concentrations of 2‐(3‐chloro‐4[3‐pyrrolinyl]phenyl) propionic acid, pirprofen, a new nonsteroidal anti‐inflammatory compound, are described for normal male volunteers receiving one or more doses of the drug. Orally administered pirprofen is rapidly and almost completely absorbed from the gastrointestinal tract, resulting in maximum plasma levels in 1 to 2 hr. Mean peak levels are 23 µg/ml after an oral pirprofen dose of 200 mg; lower doses give proportionally lower levels. Administration 1 hr after a meal slightly delays the peak plasma level, but the extent of absorption is not affected significantly. Administration of pirprofen, 150 mg, 4 times daily, or 200 mg, 3 times daily, results in nearly identical plasma levels at steady‐state. Pirprofen has an apparent elimination half‐life of about 7 hr. The results obtained from a 200‐mg pirprofen‐14C dose indicate that excretion of the drug occurs primarily by the renal route in the form of metabolites and is essentially complete within 24 hr. In urine, less than 5% of the administered dose is accounted for as unchanged drug.
Cumulation of N‐acetylprocainamide, an active metabolite of procainamide, in patients with impaired renal function
Authors: Drayer Dennis E. , Lowenthal David T. , Woosley Raymond L. , Nies Alan S. , Schwartz Allan , Reidenberg Marcus M.
Published: January 2016

N‐Acetylprocainamide (NAPA) accumulated in the plasma of 6 cardiac patients with renal failure taking procainamide chronically for therapy (4 were undergoing hemodialysis) and contributed to the therapeutic and toxic effects of the procainamide. NAPA plasma levels ranged from 14.0 to 28.0 µg/ml 3 hr after a dose of procainamide which is well above the 3‐hr NAPA plasma levels of nonazotemic cardiac patients (range 1.9 to 6.3 µg/ml; p = 0.002) on larger doses of procainamide. There was almost no decline in NAPA plasma levels on interdialysis days. In one of the patients with renal failure NAPA was still present 15 days (13.8 µg/ml) and 38 days (0.9 µg/ml) after procainamide was stopped, indicating a half‐life of several days. Measurement of procainamide plasma concentrations by the usual fluorometric or colorimetric methods does not detect NAPA. Since NAPA accumulates in patients with impaired renal function, the concentrations of both this active metabolite and procainamide should be determined in these patients if drug level monitoring is to be helpful.
Phenytoin in the treatment of diabetic symmetrical polyneuropathy
Authors: Saudek Christopher D. , Werns Steven , Reidenberg Marcus M.
Published: January 2016

The efficacy of phenytoin in the treatment of the symptoms of diabetic symmetrical polyneuropathy has been tested in a double‐blind, crossover study. Symptoms were evaluated daily by linear analogue self‐assessment, while contral of blood glucose and plasma phenytoin level were monitored on a weekly basis. There was no significant improvement in symptoms on phenytoin, whether analyzed in aggregate, as pain alone, or on the last 3 days of each treatment week. Blood glucose, however, was elevated in diabetic patients taking phenytoin, and the incidence of undesirable side effects was increased. lt is concluded that phenytoin has no role in the treatment of diabetic symmetrical polyneuropathy.
Biliary disposition of adriamycin
Authors: Riggs Charles E. , Benjamin Robert S. , Serpick Arthur A. , Bachur Nicholas R.
Published: January 2016

A patient with a choledochal T tube and normal liver function received adriamycin as therapy for abdominal histiocytic lymphoma. Plasma, urine, and bile sampIes were collected after drug administration, Adriamycin and its metabolites were extracted from the sampIes and separated by thin‐layer chromatography. The pharmacokinetics of adriamycin and metabolites in plasma and urine resembled those of previous patients, with a plasma elimination half‐life for adriamycin of 25.2 hr. Bile contained adriamycin and 11 metabolites, 4 of which were not present in plasma or urine, Forty‐one percent of the administered dose of adriamycin appeared in the bile in 7 days; of this amount, 42% was adriamycin, 22% was adriamycinol, the major metabolite, and 36% was other metabolites. Hepatic clearances of adriamycin and odriamycinol showed early, rapid removal of drug by the liver, with subsequent slowing of removal rate as plasma drug concentration declined. Adriamycin was more efficiently cleared than adriamycinol by both liver and kidney, Disease states which impair the capacity of the liver to excrete adriamycin may result in prolonged, high drug levels and increased toxicity,
Effects of delta‐9‐tetrahydrocannabinol on drug distribution and metabolism Antipyrine, pentobarbital, and ethanol
Authors: Benowitz Neal L. , Jones Reese T.
Published: January 2016

Delta‐9‐tetrahydrocannabinol (THC) has been reported to inhibit drug metabolism in animals. Twenty‐two hospitalized healthy volunteer subjects received THC, 60 to ISO mg/day in divided doses for 14 days. Body weight increased and plasma proteins decreased in all subjects, which is consistent with previously reported plasma volume expansion. Total bilirubin was significantly lower, while other liver function tests remained normal. A within‐subject comparison of the pharmacokinetics of antipyrine, pentobarbital, or ethanol given before, during, and after THC was performed. Antipyrine plasma half‐life increased during THC in 5 of 6 subjects‐mean, 7.9 hr ± 3.3 (SD) to 9.6 ± 3.S. Pentobarbital half‐life increased in 7 of S subjects‐mean, 16.9 hr ± 2.0 to 20.S ± 4.2. Blood ethanol disappearance rate decreased in 7 of S subjects from a mean of 0.26 mg/JOO ml/min ± 0.05 to 0.23 ± 0.07. The effect ofTHC on disappearance rate of these drugs appeared to be due to a combination of: (1) increased distribution volume, due in part to expansion of extracellular fluid volume noted during THC ingestion, and (2) diminished metabolic clearance. THC also delayed absorption of pentobarbital and ethanol in several subjects. This is consistent with THC effects of slowing intestinal motility in animals. The effects of THC on absorption and drug elimination must be considered in evaluating interactions with other drugs.
Drug interactions and multiple drug administration
Authors: May Franklin E. , Stewart Ronald B. , Cluff Leighton E.
Published: January 2016

Effects of multiple drug administration on adverse drug reactions were studied in 10,518 patients hospitalized on a general medical service during a five‐year period. Nine index drug groups, including analgesic, antacid, antiarrhythmic, antimicrobic, anticoagulant, antihypertensive, anti‐inflammatory, diuretic, and sedative‐tranquilizer drugs, were selected for study. The average number of adverse drug reactions for the anticoagulant and antihypertensive drug groups was higher (p < 0.05) than for all other drug groups when classified by the number of drugs being taken concurrently (i.e., 0 to 5, 6 to 10, etc.). The rate of reaction for anticoagulant and antihypertensive drug groups was higher (p < 0.001) than the rate for other drug groups studied. These data suggest a higher risk of adverse drug reactions for patients receiving multiple drugs. The increased risk may result from drug interactions.
Comparison of trimazosin and methyldopa in hypertension
Authors: Aronow Wilbert S. , Tobis Jonathan , Hughes David , Siegel Jack , Easthope John
Published: January 2016

Eighteen patients with hypertension participated in a double‐blind, randomized study to evaluate the effect of trimazosin, methyldopa, and placebo on supine and standing blood pressure and heart rate. Of 6 patients on methyldopa, one developed drug fever (and was dropped from the study) and one developed impotence. None of 6 patients on trimazosin and none of 6 patients on placebo developed any adverse effects. The mean supine blood pressure on 900 mg trimazosin daily was 17.0/12.8 mm Hg lower than that on the first placebo trial (p < 0.01) and 17.0/12.1 mm Hg lower than that on the second placebo trial (p < 0.01). The mean supine blood pressure on 2,250 mg methyldopa daily was 17.8/12.4 mm Hg lower than that on the first placebo trial (p < O.OJ) and 16.8/13.0 mm Hg lower than that on the second placebo trial (p < 0.01). The mean supine blood pressure was not significantly affected by placebo. Trimazosin, 900 mg daily, and methyldopa, 2,250 mg daily, were equally effective in lowering supine and standing systolic and diastolic blood pressure and did not affect supine or standing heart rate.
Trials with an adenosine analogue as antianginal medication
Authors: Irshad Fauzia , Dagenais Gilles R. , Fedor Edward J. , Cavanaugh John H.
Published: January 2016

The potential antianginal effects of orally administered ethyl‐adenosine‐5‐carboxylate hydrochloride (EACH) were assessed in 9 patients with stable angina pectoris who underwent two standardized exercise tests for 3 consecutive days. The first daily exercise performed after placebo revealed no daily variation. The second test was preceded by placebo, 26 mg EACH or 33 mg EACH administered in a double‐blind fashion with the use of crossover design. After the completion of the study in the first 6 patients, the 33‐mg dose of EACH had to be discontinued because 3 patients had severe angina and another one had nausea and diffuse numbness after this dose. In the remaining 3 patients, a 6‐mg dose of EACH was used instead of 33 mg, after which the study was terminated because no difference could be determined. EACH, 26‐mg and 6‐mg, had no significant effect on resting and exercise heart rate, on blood pressure, on onset or duration of angina and positive‐exercise electrocardiogram, or on exercise duration. Our study revealed that EACH had no potential antianginal effect and that at a dosage of 33 mg it may induce angina.
Activation of monooxygenases in human liver by 7,8‐benzoflavone
Authors: Kapitulnik J. , Poppers P. J. , Buening M. K. , Fortner J. G. , Conney A. H.
Published: January 2016

Addition of 10‐4 M 7,8‐benzojlavone to homogenates of human liver samples obtained by autopsy or surgical biopsy increased the rate of benzo [a] pyrene hydroxylation up to II‐fold. 7,8‐Benzojlavone also increased the rates of hydroxylation of zoxazolamine and antipyrine at 10‐4 M but inhibited these reactions at 10‐6 M. The effects of 7,8‐benzojlavone on the hydroxylation of benzo[a]pyrene and zoxazolamine in microsomes from human liver were similar to those in homogenates. Addition of 7,8‐benzojlavone to homogenates of surgical biopsy samples of human liver had little or no effect on the rates of oxidative metabolism of 7‐ethoxycoumarin, coumarin, and hexobarbital. Marked individuality for the activating and inhibiting effects of 7,8‐benzojlavone was observed in different liver samples. This individuality may result both from the presence of multiple monooxygenases in varying amounts and proportions in the different liver samples and from a selective effect of 7,8‐benzojlavone on certain of the monooxygenases.
Clinical biostatistics
Authors: Feinstein Alvan R.
Published: January 2016

In the exchange that occurs when clinicians and statisticians collaborate to conduct a research project, the statistician is regularly asked for a great deal of mathematical activity. If the project is being planned prolectively, one of his assignments is to determine “sample size” by estimating how many patients will be needed for the research to attain stochastic significance.17 If the project is a clinical trial, the statistician is asked to prepare a suitable arrangement and schedule for the randomized allocation of the compared treatments. After the research data have been collected (or if he is first consulted after the data are already available), the statistician is customarily given the job of performing a suitable “statistical analysis”. For this job, he usually develops ways of sorting the data to display the results in various tables or graphs, and he then administers the statistical ritual used for testing the “significance” of what has been found.
Commentary
Authors: Bennett William M. , McDonald Walter J. , Kuehnel Edward , Hartnett Michael N. , Porter George A.
Published: January 2016

To ascertain whether diuretics have an antihypertensive effect independent of natriuresis, 12 stable patients on maintenance hemodialysis underwent a crossover evaluation with hydrochlorothiazide, 50 mg daily, metolazone, 5 mg daily, or placebo in 4‐wk treatment periods for 6 mo. Compliance was assured by pill counts and serum drug concentrations. All patients had daily urine < 100 mi. Pre‐ and postdialysis blood pressure, body weight, plasma volume, and plasma renin activity were monitored. Over the 6‐mo study period there were no statistically significant changes in any parameter related to diuretic therapy. It is concluded that afunctioning kidney with the ability to respond to diuretics with a natriuresis is necessary for the antihypertensive action of diuretics. Direct vascular effects of diuretics to lower peripheral resistance could not be demonstrated in this unique patient population.
Plasma protein binding of basic drugs
Authors: Piafsky Kenneth M. , Borga Olof
Published: January 2016

The protein binding of two basic drugs, alprenolol and imipramine, and the acidic drug, naproxen, was determined in plasma obtained from 23 healthy subjects. A 2jold variation was found between individuals in the free fraction of the two bases, while the range was even greater with naproxen. The free fraction correlated with the plasma concentration of ai‐acid glycoprotein for alprenolol (r = ‐0.75, p < 0.001) and imipramine (r = ‐0.78, p < 0.001), while there was no correlation for naproxen (r = 0.24, p > 0.1). This confirms recent experiments which showed that isolated ai‐acid glycoprotein avidly bound both alprenolol and imipramine. Drug binding, however, did not correlate with albumin concentration, although experiments with isolated albumin demonstrated its unusually high affinity for naproxen.
Tolerance to marijuana: Heart rate and subjective “high”
Authors: Nowlan Robert , Cohen Sidney
Published: January 2016

In a 94‐day supervised study of 30 subjects smoking marijuana. with drug‐free periods interspersed. mean heart rate and subjective "high" decreased over the smoking period. Light smokers had greater chronotropic and subjective effects than heavy smokers. but both demonstrated evidence of tolerance. Cumulation and minor withdrawal effects were noted.
Oxidative drug metabolism and inducibility by phenobarbital in sickle cell anemia
Authors: Anderson K. E. , Peterson C. M. , Alvares A. P. , Kappas A.
Published: January 2016

The plasma elimination rates of antipyrine and phenylbutazone were studied in 8 patients with sickle cell anemia. The mean antipyrine half‐life (t½) in plasma was not significantly different in the sickle cell patients ( 12.0 ± 3.0 hr) than in a control group of 20 normal subjects (12.7 ± 0.9 hr). For phenylbutazone the mean tV2 was shorter in the sickle cell patients (2.1 ± 0.1 days) than in normal subjects (3.3 ± 0.2 days, p < 0.001); both mean apparent volume of distribution (aVD) and mean metabolic clearance rate (MCR) for this drug were significantly higher in the sickle cell group, which suggests increased extravascular distribution as well as more rapid hepatic metabolism. After administration of phenobarbital (2 to 3 mg/kg daily for 2 wk) consistent increases in rates of antipyrine and phenylbutazone metabolism were observed in 6 sickle cell anemia patients, which were comparable to those observed in 5 normal subjects. Two other patients who were taking drugs (methyltestosterone, isoniazid) known to alter cytochrome P‐450 function did not respond typically. Our results suggest that cytochrome P‐450 function and sensitivity to phenobarbital induction are unimpaired in most sickle cell anemia patients. Since uptake of heme into hepatocytes is probably increased in this disorder, this suggests that an adapative response develops during long‐term hemolysis such that heme biosynthesis and formation of microsomal cytochromes are not repressed.
Effects of environmental chemicals on the genetic regulation of microsomal enzyme systems
Authors: Nebert Daniel W. , Levitt Roy C. , Orlando Michael M. , Felton James S.
Published: January 2016

The cytochrome P‐450‐‐mediated monooxygenase system, embedded in the endoplasmic reticulum of cell membranes, which metabolizes many hydrophobic environmental chemicals is involved in the metabolic potentiation and/or detoxification of many drugs and environmental pollutants. Examples of the interaction of such environmental chemicals with the genetic regulatory system controlling monooxygenase activity are presented, as well as the manner in which this interaction may be affected by genetic differences in susceptibility to drug toxicity and lead to chemically induced teratogenesis, mutagenesis, and carcinogenesis. Among the chemicals under study in this context were polycyclic hydrocarbons, halogenated hydrocarbons (Arochlor 1254, lindane, kepone), 2‐acetylaminojiuorene, and acetaminophen in inbred strains of mice and in genetic crosses. Only a very small number of genes was found to have a profound injiuence on an individual's increased susceptibility to cancer, mutation, and toxicity produced by different environmental chemicals. MUltiphasic response curves are predicted to occur with a given dosage of chemical causing different levels of toxicity in different individuals, depending upon the genetic predisposition of each individual. For example, cancer, chemical mutagenesis, hepatic necrosis, survival time, aplastic anemia, and possibly birth defects can vary among siblings in the same family because a relatively small number of genes regulates the differences in drug metabolism.
A self‐adjusting randomization plan for allocation of patients into two treatment groups
Authors: Nordle Orjan , Brantmark Bo
Published: January 2016

This paper presents a self‐adjusting randomization plan which is thought to be useful in controlled stratified randomized clinical trials. The method assures an optimal balance of treatments within each subgroup of patients. An imbalance caused by a high number of dropouts in one treatment group will be counteracted by the self‐adjusting nature of the method. The method has been tested in computer‐simulated trials and has been shown to produce better results than conventional plans for stratified randomized clinical trials. The method does not involve any complicated calculations and its use in a running clinical trial has shown that it is easy to handle
Propranolol serum levels during twenty‐four hours
Authors: Vervloet E. , Pluym B. F. M. , Cilissen J. , Kahlen K. , Merkus F. W. H. M.
Published: January 2016

Propranolol serum levels during a 24‐hr period were determined every 2 hr in 9 hospitalized patients with angina pectoris after oral administration of 40 mg of propranolol 3 times a day. After the first, second, and third tablets the mean maximum serum propranolol concentrations averaged 118 ± 71 ng Iml, 134 ± 97 ng/ml, and 118 ± 94 ng/ml and the mean minimum concentrations averaged 21 ± 18 nglml, 45 ± 25 ng/ml, and 54 ± 34 nglml (±SD), respectively. These data show a very wide inter‐ and intraindividual variation in serum propranolol levels. No relationship was found between serum level and blood pressure or dose (related to body weight).
Hemodynamic effects of trimazosin in patients with left ventricular failure
Authors: Franciosa Joseph A. , Cohn Jay N.
Published: January 2016

Trimazosin is a new quinazoline derivative vasodilator previously thought to act primarily on resistance vessels. Vasodilators characteristically improve hemodynamics in patients with left ventricular failure. Trimazosin in single oral doses of 100 to 300 mg was given to 6 patients with class III–IV congestive heart failure due to ischemic or primary cardiomyopathy and hemodynamics were monitored for 4 hr. Onset of action was apparent at 1 hr, with peak effects occurring at 1 to 3 hr and significant effects persisting at 4 hr. At peak, mean systemic arterial pressurefell from 91.2 ± 4.8 (SEM) to 82.5 ± 2.5 mm Hg (p < 0.05), heart rate was unchanged, and cardiac index (by dye dilution] was up to 2.12 ± 0.27 from 1.76 ± 0.33 L/min/m2 (NS). Right heart pressures (by Swan‐Ganz catheterization) were reduced, right atrial, 11.3 ± 2.1 to 8.7 ± 1.6 mm Hg (p < 0.02), mean pulmonary arterial pressure, 40.7 ± 4.6 to 33.8 ± 4.8 mm Hg (p < 0.01), and pulmonary arterial wedge, 30.7 ± 4.5 to 23.8 ± 5.0 mm Hg (p < 0.01). Forearm venous capacitance, by occlusion plethysmography, increased from 0.83 ± 0.18 ml/100 gm to 1.12 ± 0.22 ml/100 gm after trimazosin (p < 0.01). Trimazosin is an orally effective vasodilator that acts on both resistance and capacitance vessels in patients with congestive heart failure.
Binding of quinidine to plasma proteins in normal subjects and in patients with hyperlipoproteinemias
Authors: Kates Robert E. , Sokoloski Theodore D. , Comstock Thomas J.
Published: January 2016

Quinidine in the plasma binds to the various lipoproteins as well as to albumin. With the use of computer simulations the effect of varying the serum level of each of the lipoproteins as weil as albumin was examined. The results suggested that the overall binding of quinidine is relatively insensitive to changes in any one serum pro tein provided the others are present in normal concentrations. Evaluation of the degree of protein binding of quinidine in plasma from normal subjects and patients with types IV and IIa hyperlipoproteinemias supported the computer predictions. The degree of pro tein binding in plasma from normal subjeets and patients with types IV and IIa hyperlipoproteinemias were 71.2% ± 11.4%, 75.9% ± 8.7%, and 69.9% ± 15.0%, respectively. The quinidine bin ding in plasma of patients with hyperlipoproteinemias did not differ statistically from that in the normal subjects.