bluuebunny/crossref_metadata_2025 huggingface dataset:
Significance of error associated with use of the one‐compartment formula to calculate clearance of thirty‐eight drugs
Authors: Dvorchik Barry H. , Vesell Elliot S.
Published: January 2016

A survey of the literature was performed to gather information on the magnitude of the error introduced into calculating drug clearance by using a one‐compartment formula for drugs whose disposition follows multicompartment kinetics. Sufficient data to permit quantitation of this error were found for 38 drugs. The magnitude of the error varied widely depending on the initial distribution of the particular drug. Antipyrine and such commonly used drugs as amobarbital, chlordiazepoxide, nortriptyline, pentobarbital, phenytoin, sulfisoxazole, theophylline, tolbutamide, and warfarin had errors of 8% or less, thereby permitting utilization of the one‐compartment formula for determination of drug clearances without much loss of accuracy. However, 22 drugs exhibited errors ranging from 12% to 196%; for these drugs, the one‐compartment formula introduced considerable inaccuracy. The errors for diazepam, meperidine, and propranolol, when administered to patients with hepatic cirrhosis or to hypertensive patients, were 4%, 5%, and 6%, respectively, whereas in normal subjects the errors were 18%, 14%, and 2/%. Thus, the clinical status of the subject may influence the choice of the model used. On the basis of these data we conclude that for many commonly used drugs the one‐compartment formula is acceptable for determining drug clearance, loading dose, or maintenance dose.
Relation between plasma concentration of indomethacin and its effect on prostaglandin synthesis and platelet aggregation in man
Authors: Rane Anders , Oelz Oswald , Frolich Jürgen C. , Seyberth Hannsjørg W. , Sweetman Brian J. , Watson J. Throck , Wilkinson Grant R. , Oates John A.
Published: January 2016

The dose and plasma levels of indomethacin correlated with inhibition of prostaglandin synthesis as measured both by urinary excretion of the major metabolite of prostaglandin E2 (PGE‐M) and by the release of prostaglandin E drom thrombin‐stimulated platelets. Considerable intersubject variability was observed in the suppression of PGE‐M excretion. In some patients 37.5 mg indomethacin daily, usually considered subtherapeutic, caused suppression. Maximal suppression (>90%) occurred in some after a daily dose of 75 mg, whereas 150 mg was required to achieve this level of inhibition in others. Suppression of the excretion of PGE‐M by 60% occurred when the end of the dosage interval plasma levels of indomethacin were in the range 0.05 to 0.3 µg/ml, which implies that a somewhat higher average steady‐state concentration during the dosage interval was required to achieve this effect. A similar degree of inhibition of the release of PGE2 on thrombin‐stimulated platelets was associated with the same range of plasma levels. Upon discontinuation of the drug, the levels of indomethacin in plasma decreased exponentially; inhibition of the release of PGE2 from platelets by indomethacin declined linearly with time and in parallel with the logarithm of the diminishing plasma levels.
XLIV. A survey of the research architecture used for publications in general medical journals
Authors: Feinstein Alvan R.
Published: January 2016

A striking feature of modern medical education is the absence of instruction in the design and evaluation of clinical research. During pre‐clinical courses in microbiology, biochemistry, or physiology, a medical student may be exposed to the principles of laboratory experiments with animals, microbial organisms, or inanimate substances; but the student is seldom taught how to appraise investigations in which the data come from intact human beings.
Aspirin and aspirin‐caffeine in postpartum pain relief
Authors: Jain Adesh K. , McMahon F. Gilbert , Ryan Jerome R. , Unger Deanne , Richard Wilma
Published: January 2016

In two double‐blind, randomized, balanced, single oral dose studies with 140 women, a combination of 800 mg aspirin and 64 mg caffeine (aspirin‐caffeine) was compared to 650 mg aspirin and to placebo. In patients with moderate to severe uterine or episiotomy pain, there was greater analgesic response with active drugs when the initial pain intensity was more severe. In patients with severe episiotomy pain, aspirin‐caffeine was more effective than 650 mg aspirin (p < 0.05) at the second and third hours. There was no difference between analgesic effects of aspirin and aspirin‐caffeine in women with severe uterine pain.
The rate of development of new drugs in the United States, 1963 through 1975
Authors: Wardell William M. , Hassar Mohammed , Anavekar Sadanand N.
Published: January 2016

Information was obtained on 1,103 new chemical entities (NCEs) first tested in man from 1963 through mid‐1975 by 36 U.S.‐owned and 10 foreign‐owned pharmaceutical companies operating in the U.S. Of these NCEs, 1,029 reached the stage of IND filing. The portion of the U.S. industry responsible for the NCEs was relatively concentrated; 7 of the 36 companies accounted for half of the NCEs and 4 of these accounted for one‐third. Although the annual worldwide rate of testing of NCEs by U.S. companies appeared to rise and then fall from 1963 through 1966, since 1966 the rate has beenfairly constant. With time, however, a higher proportion of U.S.‐owned NCEs is being first studied in man abroad. The annual rate of IND filings for U.S.‐owned NCEs generally declined from 1965 to 1972, whereas the rate was fairly constant for foreign‐owned NCEs over the entire period. The overall success rate in drug development has been low; nearly 90% of the NCEs studied in man are dropped prior to NDA submission, but about 88% of the NDAs submitted are approved for market. The 1974–1975 data indicate that the mean durations of the IND and NDA phases were then 4 and 2 years, respectively. However, there were variations in the time required for NDA approval between different pharmacologic areas. The data described in this paper represent the first baselines against which future trends in the processes of drug development and approval can be measured.
Plasma protein binding and distribution characteristics of drugs as indices of their hemodialyzability
Authors: Gwilt Peter R. , Perrier Donald
Published: January 2016

The dialysis clearance, plasma protein binding, and distribution (expressed as volume of distribution) characteristics of a drug were evaluated as predictive indices of the efficiency of hemodialysis in removing drug from the body. Dialysis clearance correlated poorly with the fraction of drug in the body removed by hemodialysis. The best predictive measure of hemodialysis efficiency was obtained by a nonlinear model relating the ratio of the percent of free drug in the plasma and the volume of distribution of the drug to the fraction removed. Knowledge of the binding and distribution characteristics of a drug provides insight into the diatyzability of a drug which in turn may assist in coming to decisions on the necessity of dose adjustments for patients on chronic hemodialysis and the rational use of hemodialysis in the treatment of drug intoxication.
Effect of benzopyranoperidine, a Δ‐9‐THC congener, on pain
Authors: Jochimsen Peter R. , Lawton Richard L. , VerSteeg Kyle , Noyes Russell
Published: January 2016

In a double‐blind, 5‐way crossover designed study, single doses of placebo, 2 doses of codeine sulfate (60 and 120 mg), and 2 doses of benzopyranoperidine (2 and 4 mg) were administered orally to 35 patients who required analgesics for chronic pain due to malignancies. Benropyranopyridine is an analogue of delta‐9‐tetrahydrocannabinol and was chosen on the basis of its sedative, hypnotic, and analgesic properties in animals. Pain relief scores indicated a degree of relief of clinical significance witn 120 mg of codeine but no consistent difference between placebo and any other active agent. On the basis of the data, benzopvranoperidine (2 or 4 mg) is not as effective as codeine (120 mg or 60 mg) and no more effective than placebo in relieving pain due to cancer; indeed, pain perception appeared to be augmented by both doses.
Effeets of folie aeid on phenytoin kineties in healthy subjeets
Authors: Furlanut M. , Benetello P. , Avogaro A. , Dainese R.
Published: January 2016

Phenytoin (DPH) disposition was studied in normal subjects before and after treatment with folic acid for 14 days. Our results suggest that folic acid lowers DPH serum levels without significantly modifying its bound fraction and inereases the rate of DPH and meta‐hydroxydiphenylhydantoin excretion in urine.
Effects of aging and liver disease on disposition of lorazepam
Authors: Kraus J. W. , Desmond P. V. , Marshall J. P. , Johnson R. F. , Schenker S. , Wilkinson G. R.
Published: January 2016

The disposition of lorazepam after intravenous administration (2 mg) was investigated in patients with alcoholic cirrhosis and acute viral hepatitis, and compared to that in normal subjects ranging in age from 15 to 73 yr. No statistically significant age‐dependent relationships in the drug's pharmacokinetic parameters were observed. Cirrhosis was associated with a doubling of the mean elimination half‐life (21.7 ± 7.6 to 41.2 ± 24.5 hr). This was due to a similar increase in the volume of distribution of lorazepam, caused by a reduction in the extent of the drug's plasma binding (88.6 ± 2.5 from 93.2 ± 1.8). No changes in systemic plasma clearance of either the unbound (about 11 ml/min/kg) or bound plus unbound (about 0.75 ml/min/kg) lorazepam, or urinary recovery of conjugated drug (about 50%) were detected. In contrast, there were no significant changes in the kinetics of lorazepam in the patients with acute viral hepatitis. Comparison of lorazepam's systemic plasma clearance in the liver disease patients in whom studies with antipyrine and chlordiazepoxide had also been performed indicated impairment in their values but this was not the case for lorazepam. It is concluded that the degree of impairment, if any, in the metabolism of lorazepam in patients with liver disease is considerably less than that of certain other drugs including related benzodiazepines. Aging also does not lead to alterations either in distribution or metabolism as have been observed with other benzodiazepines. It is speculated that these observations may reflect characteristics of the drugs associated with their metabolic fate, i.e., glucuronidation or oxidative biotransformation.
Protein binding of tolmetin
Authors: Selley M. L. , Madsen B. W. , Thomas J.
Published: January 2016

The protein binding of the new nonsteroidal anti‐inflammatory agent tolmetin to human serum albumin (HSA) and to the plasma of 8 healthy subjects was studied by equilibrium dialysis at 37° and pH 7.4 with 14C‐tolmetin. Over the total concentration (Ct) range 3.0 to 28.7 µg/ml (therapeutic range), the fraction oftolmetin unbound to 4% HSA was largely invariant at 0.3%. At 100 µg/ml the unboundfraction rose to 0.8 and at 434 µg/ml to 3.6%. Within the therapeutic concentration range, tolmetin binding to 0.4% HSA was reduced in accordance with the law of mass action and at Ct = 26.2 µg/ml, 10.5% was free. Analysis of the 0.4% HSA data showed tolmetin had 3 classes of binding sites (n1 = 1, Kt = 8.3 × 105 M−1; n2 = 4, K2 = 2.4 × 104 M−1; n3 = 44, K1 = 7.9 × 101 M−1). By studying the binding to 0.4% HSA at 23°, it was established that the free energy change in binding for the first two classes of sites was entirely entropic in nature. Albumin accounted for almost all the binding oftolmetin in human plasma. The effect of other drugs, the tolmetin metabolite McN 2987 (5‐p‐carboxybenzoyl‐l‐methylpyrrole‐2‐acetic acid), tryptophan, and oleic acid on tolmetin binding to 4% HSA was studied using ultrafiltration and 14C‐tolmetin. Aspirin and salicyclic acid decreased tolmetin binding and a combination of aspirin and salicylic acid exerted a synergistic displacing effect. Indomethacin and ibuprofen had no effect while phenylhbutazone and acetaminophen increased tolmetin binding slightly. Tolmetin binding was decreased slightly by McN 2987 and tryptophan and markedly increased by oleic acid. McN 2987 was not bound as extensively as tolmetin. Binding of 14C‐tolmetin to the plasma of 4 arthritic patients was studied by ultrafiltration and found to be less than to normal plasma and 4% HSA. Distribution of tolmetin in the whole blood of 8 healthy subjects using a centrifugation technique showed that the drug was not taken up by red blood cells at therapeutic concentrations.
Plasma levels of free and acid‐labile hydralazine: Effects of multiple dosing and of procainamide
Authors: Schneck Dennis W. , Sprouse Jeffrey S. , Miller Kenneth , Vary Jean E. , DeWitt Floyd O. , Hayes Arthur Hull
Published: January 2016

The steady‐state plasma levels of unchanged free (H) and its ALC were measured in 6 normal volunteers—3 RA and 3 SA. All subjects received 25 mg H every 6 hr for a total of 12 doses; RA received an additional dose of 50 mg in a similar manner. Peak plasma levels offree H occurred at ½ to 1 hr following drug administration and declined with a t½ of 3.5 to 4.5 hr in both RA and SA. In contrast, ALC levels remained approximately constant over the 8‐hr sampling period. In the SA the mean steady‐state plasma concentration of ALC was 28% of the free H at the 25‐mg dose level. In the RA the percentages were 25 at the 25‐mg dose and 22 at the 50‐mg dose. These results indicate that under steady‐state conditions H is present predominantly in its free form. Administration of H (12 doses; 25 or 50 mg every 6 hr) with PA (every 3 or 4 hr) resulted in no alteration in the plasma levels of either H and its ALC or PA and its acetylated metabolite. This remained true when each phenotype was considered separately. The results from this portion of the study demonstrate that in normal subjects therapeutic plasma levels of neither PA nor H interfere with the acetylation of the other. Possible explanations for the lack of an interaction are presented.
Diazepam concentrations in parotid saliva, mixed saliva, and plasma
Authors: DiGregorio G. John , Piraino Anthony J. , Ruch Eileen
Published: January 2016

The concentration of diazepam in the plasma and saliva of 9 normal human subjects receiving a single oral dose of diazepam (10 mg) over an 8‐hr period was determined by gas‐liquid chromatography/electron capture analysis. In addition, the binding of diazepam to plasma protein in these subjects was determined using equilibrium dialysis at specific time intervals corresponding to periods of plasma and saliva collection. A linear relationship was found between diazepam concentration in plasma and that in both mixed and parotid saliva, over plasma concentrations ranging from 196 ± 16.4 to 74.8 ± 10.3 ng/ml. The elimination constants (−Ke) were 0.13, 0.17, 0.18 for diazepam disappearance from plasma, parotid saliva, and mixed saliva, respectively. The mean parotid concentration ratio was 0.035 and the mixed saliva/plasma diazepam concentration ratio was 0.029. These were not affected by variations in plasma diazepam levels. The percentage of the plasma diazepam concentration in both parotid saliva (3.5%) and mixed saliva (2.9%) was of the same order as the fraction of diazepam found to be free from plasma protein in these subjects (2.0% to 3.5%). The results indicate that there is no significant difference between parotid saliva and mixed saliva concentrations over a period of 8 hr after a single oral dose of diazepam. The results strongly suggest that the appearance of diazepam in saliva may provide an alternate, non invasive method of determining plasma diazepam levels.
Inhibition of propranolol metabolism by chlorpromazine
Authors: Vestal R. E. , Kornhauser D. M. , Hollifield John W. , Shand D. G.
Published: January 2016

The effects of chlorpromazine 50 mg 8‐hourly on the disposition and effectiveness of propranolol have been investigated in 5 subjects. Propranolol was given orally in a dose of 80 mg 8‐hourly and after 3 days H3‐propranolol was injected intravenously. Both native and H3‐drug were measured in serial blood samples, allowing calculation of intrinsic (oral) clearance and liver blood flow as well as the usual kinetic parameters. The study was repeated after 3 or 4 days of chlorpromazine treatment. Chlorpromazine consistently produced a reduction in intrinsic (oral) clearance from 4.30 ± 0.51 to 2.94 ± 0.16 (p < 0.01), indicative of inhibition of propranolol metabolism. This was associated in an increase in bioavailability from 25 ± 3 to 32 ± 4% (p < 0.005). As would be expected with a highly extracted drug, the change in systemic (intravenous) clearance was much less and was not significant. There were no changes in liver blood flow, volume of distribution, t½, or plasma binding of propranolol. Propranolol efficacy was determined in 3 subjects. In 2 of these plasma levels of propranolol were increased by chlorpromazine at the time of study and resulted in increased isoproterenol antagonism and lowered plasma renin activity. In the third subject plasma propranolol levels were only slightly elevated and no clear pharmacodynamic changes were detected. A sixth subject experienced postural hypotension and syncope following the first dose of chlorpromazine. It was unclear whether this was due to chlorpromazine alone or to an interaction with propranolol. We conclude that chlorpromazine can inhibit the metabolism of propranolol in man, thereby increasing propranolol efficacy.
Bromocriptine inhibits norepinephrine release
Authors: Ziegler M. G. , Lake C. R. , Williams A. C. , Teychenne P. F. , Shoulson I. , Steinsland O.
Published: January 2016

Bromocriptine is a dopamine agonist that induces postural hypotension and can be used as an antihypertensive. The drug inhibits release of norepinephrine (NE) from an isolated artery by stimulating presynaptic receptors. In normotensive subjects it lowers both plasma and cerebrospinal fluid (CSF) levels of NE by 50% and lowers blood pressure moderately in standing subjects and slightly in recumbent subjects. Through central and peripheral mechanisms, bromocriptine inhibits sympathetic nervous discharge of NE.
Furosemide‐induced adverse reactions in cirrhosis of the liver
Authors: Naranjo Claudio A. , Pontigo Erika , Valdenegro Carmen , González Guillermo , Ruiz Inés , Busto Usoa
Published: January 2016

Furosemide is frequently used for ascites and causes adverse reactions (AR). In an intensive prospective drug monitoring study of 1,920 patients, 172 (8.9%) had cirrhosis of the liver and received furosemide. Mean age was 53 years, and 66.3% were male; and 87% had alcoholic cirrhosis. Eighty‐eight (51.2%) had 221 events that by consensus of the monitoring team and attending physicians were either definitely or probably related to furosemide. No AR was fatal but 24% of patients had severe reactions. Almost all reactions were dose‐related (96%). The most common were electrolyte disturbances (23.3% of patients) and volume depletion (14%). Furosemide‐induced coma occurred in 20 (11.6%) patients and was more frequent in patients with prior hepatic encephalopathy (p < 0.0005). Higher total doses (p < 0.001), hyperbilirubinemia (p < 0.05), prolonged prothrombin time (p < 0.02), and longer hospital stay (p < 0.001) were associated with higher frequencies of AR to furosemide. The frequency of hypokalemia did not decrease when potassium chloride or potassium‐sparing diuretics were added to furosemide therapy. Frequdncy of AR did not correlate with age, sex, renal impairment, serum albumin, transaminase, or alkaline phosphatase.
Blood collection techniques, heparin and quinidine protein binding
Authors: Kessler Kenneth M. , Leech Robin C. , Spann James F.
Published: January 2016

With the use of glass syringes without heparin and all glass equipment, the percent of unbound quinidine was measured by ultrafiltration and a double‐extraction assay method after addition of 2 µg/ml of quinidine sulfate. Compared to the all‐glass method, collection of blood using Vacutainers resulted in an erroneous and variable decrease in quinidine binding related to blood to rubber‐stopper contact. With glass, the unbound quinidine fraction was (mean ± standard error) 10 ± 1% in 10 normal volunteers, 8.5 ± 1.5% in 10 patients with congestive heart failure, and 11 ± 2% in 11 patients with chronic renal failure (although in 8 of the latter 11 patients the percent of unbound quinidine was 4 or more standard errors from the mean of the normal group). During cardiac catheterization, patients had markedly elevated unbound quinidine fractions: 24 ± 2% (p < 0.001). This abnormality coincided with the addition of heparin in vivo and was less apparent after the addition of up to 10 U/ml of heparin in vitro (120% and 29% increase in unbound quinidine fractions, respectively). Quinidine binding should be measured with all glass or equivalent equipment.
Kinetics of cis‐dichlorodiammineplatinum
Authors: Gormley Paul E. , Bull Joan M. , LeRoy Andre F. , Cysyk Richard
Published: January 2016

The cancer chemotherapeutic cis‐dichlorodiammineplatinum (cis‐DDP) was administered to 8 patients (1‐hr intravenous infusion) at a dose of 70 mg/m2. Plasma and urine concentrations of platinum were determined by flame less atomic absorption spectrometry. Measured plasma platinum concentrations revealed a biphasic clearance of platinum with half‐life values of 23 min and 67 hr. Platinum values obtained 3 wk after the infusion indicated that a third excretory phase might be present. Urinary measurements showed 17 ± 2.7% of the administered dose excreted in the first 4 hr and 23 ± 3.9% excreted in the first 24 hr. Renal excretion appears to be predominantly by glomerular filtration. Non‐protein‐bound plasma platinum values were calculated and the non‐protein‐bound platinum was found to be rapidly and biphasically cleared from the plasma with half‐life values of 8 to 10 min and 40 to 45 min.
The biologic half‐life of heparin
Authors: McAvoy Thomas J.
Published: January 2016

Half‐lives (t½s) varying from 23 min to 2.48 hr have been reported for heparin. It is shown that much of the discrepancy between authors can be attributed to methods used to analyze data. It is suggested that three terms should be carefully used, the t½ of bioassayed heparin concentration, the t½ of the extension of the clotting time, and the t½ of the clotting time to differentiate among the various methods of analyzing the raw data.
Opioids: Similarity between evaluations of subjective effects and animal self‐administration results
Authors: Griffiths Roland R. , Balster Robert L.
Published: January 2016

Abuse potential studies of 33 morphine‐like analgesics were compared in humans and monkeys. The results of intravenous self‐administration studies in rhesus monkeys were correlated with measures of morphine‐like signs, symptoms, and subjective effects in ex‐addicts. Each set of data was assigned to a position in a 3 × 3 contingency table dependent upon whether the results were yes, no, or equivocal. Of the 33 drugs, 29 were given identical classifications in both the human and animal test procedures. This good concordance between the human and animal results further validates each procedure and suggests the possibility that both the human and animal procedures are measuring a common underlying pharmacological property which relates to abuse potential of drugs.
Recruitment for the National Cooperative Gallstone Study
Authors: Croke Gloria
Published: January 2016

The National Cooperative Gallstone Study (NCGS) recruitment experience is reported, and the factors determining recruitment performance at a center are evaluated. Recruitment performance was grouped into four major areas: coordinating center, protocol, patient population, and treatment center. At the treatment centers, no relationship was found between performance and the prior experience of the clinic staff in clinical trials or expertise in gallstone research, lack of instituttonal support was not initially apparent, and ancillary studies did not appear to stimulate performance. Neither the population density nor the annual rate of cholecystectomy were predictive of the monthly rate of patient randomization. After the initial biopsy study and in the major study, changes in eligibility criteria and procedural requirements were followed by an augmented randomization rate. No significant correlation was found between the rating given to a center at the time of selection and the subsequent randomization rate. In conclusion, the criteria used by the NCGS for treatment center selection were inadequate to predict subsequent performance.
Ethical considerations in clinical trials
Authors: Levine Robert J. , Lebacqz Karen
Published: January 2016

The ethical norms established in various codes and regulations are inadequate to resolve some of the ethical problems presented by clinical trials. They are stated too vaguely to provide unequivocal answers to many specific questions. In order to remedy this situation, many commentators have proposed the development of more specific and complex regulations. We propose that a more fruitful approach would be to examine the ethical principles underlying the norms and to apply these principles to the specific problems. We apply this approach to two questions: (1) ls it ethical to select subjects for a randomized clinical trial (RCT) exclusively from Veterans Administration (VA) hospitals? (2) In the conduct of a RCT is it necessary to disclose the fact that therapy will he determined by chance? We conclude that problems of justice arise not only hecause of the vulnerability of patients in VA hospitals hut also hecause of the loss of the physician‐patient relationship in an RCT. However, the use of patients in a VA hospital is not always unjust; in most cases such use can he made more just through various modifications in design. We also conclude that the gact of randomization should be disclosed in any situation in which it might materialiy affect the prospective subject's decision, and that the values and preferences of the subjects should he taken into account in determining what information might be material. This work is only a preliminary step toward analyzing ethical issues in clinical trials. While some would challenge our conclusions, we hope that our methods will facilitate clarity about the loeus of disagreement in current controversies and about the value questions that must be answered in order to set an ethical context for the conduct of clinical trials.
Acute hemodynamic effects and cardioselectivity of acebutolol, practolol, and propranolol
Authors: Wollam Gary L. , Cody Robert J. , Tarazi Robert C. , Bravo Emmanuel L.
Published: January 2016

The relative cardioselectivity of acebutolol in man was studied by comparing its hemodynamic effects with those of two other β‐blockers—propranolol, a nonselective β‐blocker, and practolol, a cardioselective β‐blocker. Hemodynamic studies (Cardio‐Green) were performed on hypertensive patients before and after intravenous administration of acebutolol 1 mg/kg (9 patients), practolol 50 mg (8 patients), and propranolol 10 mg (21 patients). The hemodynamic changes after acebutolol were similar to those obtained with practolol but not as striking as those with propranolol. Acebutolol did not differ significantly from practolol with respect to effects on heart rate (HR), mean arterial pressure, cardiac output, and total peripheral resistance (TPR). Propranolol led to a greater reduction in HR (p < 0.001) and a larger increase in TPR (p < 0.025) than acebutolol; there was no significant difference between the 2 in their effects, on arterial pressure and cardiac output. The relative cardioselectivity of these 3 drugs was further investigated by comparing the degree of blockade of chronotropic and diastolic blood pressure (DPB) responses to isoproterenol (0.03 µg/kg/min). In terms of cardiac β‐blockade, acebutolol was more effective than practolol and approximately equipotent to propranolol in blocking the chronotropic response to isoproterenol; it induced significantly less blockade of the DBP decrease with isoproterenol than propranolol but more than practolol. The data suggest that acebutolol induces a greater effect on cardiac β‐receptors (β1) than on arteriolar receptors (β2) and is relatively more cardioselective than propranolol but less so than practolol.
Disposition of chlordiazepoxide: Sex differences and effects of oral contraceptives
Authors: Roberts Roderick K. , Desmond Paul V. , Wilkinson Grant R. , Schenker Steven
Published: January 2016

There is considerable interspecies and interdrug variability in the effect of sex differences and oral contraceptive (OC) steroids on hepatic drug elimination. Their influence on the disposition of chlordiazepoxide has been studied in 11 healthy young men (29 ± 5 yr), 11 healthy young women (28 ± 5 yr), and 7 healthy women receiving OC steroids (27 ± 2 yr) for more than 6 months. The elimination half‐life (t½β) was longer (from 14.8 ± 5.9 hr to 8.9 ± 2.5 hr) and protein binding less (95.5 ± 1.4% and 97.0 ± 1.2%) in women than in men. Weight‐normalized plasma clearances of total drug did not differ, but the clearance of unbound drug was significantly less in women (8.7 ± 5.0 ml/min/kg) than in men (15.6 ± 5.3 ml/min/kg). Women on OC steroids had a lower plasma binding (from 93.6 ± 1.5% to 95.5 ± 1.4%) and a higher volume of distribution (from 0.62 ± 0.23 1/kg to 0.40 ± 0.14 1/kg) than women not on OC steroids. The elimination t½ was longer (from 24.3 ± 12 hr to 14.8 ± 5.9 hr) and the clearance of unbound drug lower (from 5.7 ± 3.0 ml/min/kg to 8.7 ± 5.0 ml/min/kg) in women on OC steroids than in those not using them, but these differences were not statistically significant.
Chlordiazepoxide and oxazepam disposition in cirrhosis
Authors: Sellers Edward M. , Greenblatt David J. , Giles H. G. , Naranjo Claudio A. , Kaplan H. , MacLeod S. M.
Published: January 2016

When disease impairs clearance of drugs, multiple‐dose therapy may result in cumulation. The disposition of chlordiazepoxide (CDX), 50 mg infused intravenously over 10 min, was studied in 14 normal subjects and in 11 patients with biopsy‐proven cirrhosis. In the normal subjects, mean (±SE) kinetic parameters were: t½β, 10.0 (±0.9) hr; Vd, 0.38 (±0.04) 1/kg; clearance, 0.54 (±0.13) ml/min/kg. Clearance of total drug correlated inversely with serum albumin concentration in normal subjects (r = −0.63). Values in cirrhotic patients were: t½β, 34.9 (±8.7) hr; Vd, 0.34 (±0.024) 1/kg; and clearance, 0.185 (±0.034) ml/min/kg. Desmethylchlordiazepoxide (DMCDX), the major metabolite of CDX, appeared in blood of cirrhotic patients less rapidly than in normal subjects. Severity of liver disease did not indicate the impairment of CDX clearance. In 5 of the same cirrhotic patients, mean tVifîfor oxazepam (7.1 ± 1.0 hr) was 27% longer than in control subjects (5.6 ± 0.7 hr); the difference is not significant. On kinetic grounds oxazepam may be preferable to chlordiazepoxide in cirrhotic patients since its elimination kinetics are not greatly altered in cirrhosis.
Effect of furosemide on plasma concentration and β‐blockade by propranolol
Authors: Chiariello Massimo , Volpe Massimo , Rengo Franco , Trimarco Bruno , Violini Roberto , Ricciardelli Bruno , Condorelli Mario
Published: January 2016

Although propranolol and furosemide are used together for hypertension, the effects of furosemide on plasma levels and β‐blocking action of propranolol are not known. Ten healthy subjects received propranolol 40 mg orally; the mean plasma propranolol levels in 60, 90, 180, and 300 min were 85 ± 16, 90 ± 7, 82 ± 8, and 58 ± 8 ng/ml. Propranolol was then given together with furosemide (25 mg orally) and the propranolol blood level was measured. Mean propranolol plasma levels were 106 ± 11 ng/ml at 60 min, 120 ± 12 ng/ml at 90 min (p < 0.01), 102 ± 8 ng/ml at 180 min (p < 0.05), and 78 ± 8 ng/ml at 300 min (p < 0.01). Six additional subjects were given an infusion of 1 µg/min isoproterenol increased by 0.5 µg/min every 2 min until the heart rate rose by 25% after oral administration of furosemide 25 mg. This procedure was repeated after propranolol (40 mg orally) and propranolol with furosemide (25 mg orally). The amount of isoproterenol which raised the heart rate by 25% was 2.6 ± 0.3 µg after furosemide alone and 17.7 ± 2 µg after propranolol (p < 0.01). After propranolol with furosemide the dose of isoproterenol required to elevate heart rate by 25% was 109 ± 15 µg (p < 0.001).
Effects of nefopam on visual tracking
Authors: Belleville Jon P. , Dorey Fred , Bellvllle J. Weldon
Published: January 2016

The effects of 2 doses of nefopam, d‐amphetamine, pentazocine, and placebo were studied in healthy male sleep‐deprived volunteers to determine whether the drugs improved or impaired coordination and whether they induced subjective effects. A critical tracking task was used to study hand‐eye coordination. D‐amphetamine, 10 mg orally, significantly improved tracking performance and made subjects feel better able to perform tasks but more anxious. It also made them feel more alert, steady, sociable, and strong. Pentazocine, 45 mg intramuscularly, caused deterioration in tracking performance and was followed by reports of depression, gloominess, dreaminess, nausea, and injection site pain. There was no significant change in tracking performance or subjective effects after both doses of nefopam and placebo.
Tobramycin pharmacokinetics in morbidly obese patients
Authors: Blouin Robert A. , Mann Henry J. , Griffen Ward O. , Bauer Larry A. , Record Kenneth E.
Published: January 2016

Tobramycin kinetics were examined in 9 morbidly obese women following a single intavenous (120 mg) bolus. After the injection, serum elimination conformed to a 2‐compartment open model with a and β t½s of 0.285 and 2.1 hr. The volume of distribution (Varea) was determined to be 0.44 l/kg ideal body weight (IBW) and 0.20 l/kg total body weight (TBW). To normalize Varea to 0.26 l/kg, 58% of the patients’ adipose weight (TBW — IBW) must also be taken into account.
Effects of beta blockade with acebutolol on hypertension, hemodynamics, and fluid volume
Authors: Dreslinski Gerald R. , Aristimuno Gerardo G. , Messerli Franz H. , Suarez Daniel H. , Frohlich Edward D.
Published: January 2016

Eleven patients with essential hypertension were treated with the beta adrenergic blocker, acebutolol. Clinical, systemic, and regional hemodynamic and biochemical studies were performed before and after 4 wk of acebutolol therapy (average dose, 1,200 mg/day.) In 4 patients there was a reduction in mean arterial pressure ≥10 mm Hg; there was none in the remainder. Regardless of the blood pressure response, the renin secretory index did not change. Although cardiac output did not change, renal blood flow fell (p < 0.005) without relation to response of arterial pressure. Supine heart rate decreased (p < 0.05), so also the responses to upright tilt (p < 0.01) and isometric exercise (p < 0.02). These results demonstrate that in those patients with a hypotensive response to acebutolol, the clinical effect was not related to reduced cardiac output or plasma renin activity, further adding to confusion on the mechanism of the lowering of elevated blood pressure by beta adrenergic blockade.
Verapamil in atrial fibrillation and atrial flutter
Authors: Aronow Wilbert S. , Landa Daniel , Plasencia Gilbert , Wong Raymond , Karlsberg Ronald P. , Ferlinz Jack
Published: January 2016

A double‐blind, randomized study was performed to compare the efficacy of intravenous verapamil with saline in 28 patients with a rapid ventricular rate and atrial fibrillation or atrial flutter. Conversion of atrial fibrillation to sinus rhythm occurred in none of 14 patients after saline and in 3 of 20 patients (15%) 7 to 160 min after verapamil. The ventricular rate in atrial fibrillation was slowed ≥15% in 2 of 14 patients (14%) by saline, in 17 of 20 patients (85%) by 1 dose of verapamil (p < 0.001), and in 19 of 20 patients (95%) by 1 or 2 doses of verapamil (p < 0.001). Conversion of atrial flutter to sinus rhythm occurred in none of 4 patients after saline and in 1 of 7 patients (14%) 105 min after verapamil. The ventricular rate in atrial flutter was slowed &15% in none of 4 patients by saline, in 4 of 7 patients (57%) by 1 dose of verapamil, and in 7 of 7 patients (100%) by 1 or 2 doses of verapamil (p < 0.001).
N‐Acetylprocainamide pharmacokinetics in functionally anephric patients before and after perturbation by hemodialysis
Authors: Stec G. Paul , Atkinson Arthur J. , Nevin Mary Jane , Thenot Jean-Paul , Ruo Tsuen I. , Gibson Thomas P. , Ivanovich Peter , del Greco Francesco
Published: January 2016

NAPA pharmacokinetics were studied in 6 functionally anephric patients. Distribution and nonrenal elimination of this drug were found to be the same as in individuals with normal renal function but renal clearance was reduced, resulting in a mean elimination t½ of 41.9 hr (6.2 hr in normal subjects). Renal clearance of NAPA correlated well with ClCr. Dialysis removed NAPA from both red blood cells and plasma and increased ClTapproximately fourfold. Dialysis itself resulted in a 77% reduction in Cls that limited the total amount of NAPA removed by this procedure. This reduction in Cls was sustained for at least 3 hr after dialysis and attenuated rebound in plasma NAPA concentrations.
Plasma renin concentration and phenobarbital levels in patients with epilepsy
Authors: Booker Harold E. , Goodfriend Theodore L. , Tewksbury Duane A.
Published: January 2016

Plasma renin activity, renin concentration, and renin substrate were measured in patients on long‐term anticonvulsant medication. An inverse correlation was observed between phenobarbital levels and renin activity or concentration. There was a positive correlation between phenobarbital and renin substrate. Since elevation of renin substrate should have resulted in increased renin activity, it is possible that phenobarbital exerts 2 effects on the renin system: induction of renin substrate synthesis and suppression of renin release.
Oral melphalan kinetics
Authors: Alberts David S. , Chang Sai Y. , Chen H.-S. George , Evans Thomas L. , Moon Thomas E.
Published: January 2016

The systemic availability of melphalan after oral administration is not well known. Most patients are put on a fixed oral dosage regimen. We have studied the disposition of melphalan in 14 patients after single oral doses. Five were also studied after receiving the same dose intravenously. Oral melphalan had a mean plasma terminal phase half‐life (t½) of 90 ±17 min. The mean area under the plasma concentration: time curve (CXT) was 53 ± 33 µg · min/ml. Urinary excretion of oral melphalan averaged 10.9 ± 4.9% during the first 24 hr. The CXT ratio (oral: intravenous) for the 5 patients studied after both oral and intravenous melphalan (0.6 mg/kg) ranged between 0.25 and 0.89 and averaged 0.56. After oral dosing in 14 fasting patients, the time at which melphalan first appeared in the plasma varied between 15 min and 6 hr. In a myeloma patient who took oral melphalan, no melphalan was found in plasma or urine up to 24 hr. Some instances of failure of tumor response to oral melphalan may be due to inadequate bioavailability rather than inherent tumor resistance.
A method for studying drug metabolism in populations: Racial differences in amobarbital metabolism
Authors: Kalow W. , Tang B. K. , Kadar D. , Endrenyi L. , Chan F.-Y.
Published: January 2016

The two main metabolites of amobarbital excreted in urine are 3′‐hydroxyamobarbital (C‐OH) and 1‐(β‐D‐glucopyranosyl) amobarbital (N‐glu). When testing the metabolite ratio in small single samples of urine, it was found that the urine in a Caucasian population contained about one‐third glucose conjugation and two‐thirds hydroxylation product, while an Oriental population excreted both metabolites in equal proportion. Attempts to learn the causes for the different metabolite ratios led to an investigation of metabolite concentrations in urine. The sums of the 2 metabolite concentrations were the same in both populations. The average urinary concentration of C‐OH was greater in Caucasians than in Orientals, no matter how the data were expressed; the reverse was true for the N‐glu metabolite. C‐OH data was scattered more widely among Orientals than Caucasians; this might indicate bimodality of the distribution curves. There also was a trend toward more N‐glu metabolite in urine of females than of males. Measuring the metabolite/creatinine ratios narrowed the distribution range of the data, particularly after correction for sex difference in creatinine, but population differences were not changed. Expected relationships between metabolite content of urine, sampling times, and plasma half‐life (t½) were established by calculation. A Caucasian female with no capacity for N‐glucosidation was found during the first part of this population survey.16 An Oriental male with only trace capacity for amobarbital hydroxylation was found in the second part.
Effect of marihuana on cardiorespiratory responses to submaximal exercise
Authors: Avakian Edward V. , Horvath Steven M. , Michael Ernest D. , Jacobs Samuel
Published: January 2016

Six male chronic marihuana (MH) users exercised on a bicycle ergometer for 15 min at ∼ 50% Vo2max under 3 conditions: (1) not smoking (control), (2) after smoking MH containing 7.5 mg (−) delta‐9‐tetrahydrocannabinol, and (3) after smoking placebo marihuana (PL). The MH was administered double‐blind in a counterbalanced repeated‐measures design. Heart rates (HRs), arterial blood pressures (BPs), pulmonary ventilation (VE), and oxygen uptake (Vo2) were measured during exercise and 15 min recovery. PL had no effect on any of the physiologic variables. Smoking MH had no effect on systolic blood pressure (SBP), diastolic blood pressure (DBP), VE, or Vo2. but did induce a marked increase in heart rate which persisted throughout exercise and recovery periods, averaging 34% higher than control values at rest, 18% higher during exercise, and up to 50% higher during recovery. MH smoking increased the product of HR × SBP in all circumstances.
Glucagon therapeutics: Dawn of a new era for diabetes care
Authors: Davidson Jaime A. , Holland William L. , Roth Michael G. , Wang May‐yun , Lee Young , Yu Xinxin , McCorkle Sara K. , Scherer Philipp E. , Unger Roger H.
Published: January 2016

Although insulin monotherapy prevents death from ketoacidosis, it does not prevent either the hyperglycemic surges or the hypoglycemic plunges of glucose levels that plague the majority of patients with type 1 diabetes. However, significant improvements have occurred with the combination of continuous insulin delivery matched by continuous glucose monitoring, but the technology is not available for all patients, requires extensive education, is expensive and moreover, while much better than standard care, it almost never reduces haemoglobin A1c (HbA1c) to below 6%. This may indicate that an improved diabetes therapy involving antagonism of glucagon action will for the first time control glucose levels to normal and eradicate the long‐term complications of diabetes. Although one can never predict that results in animals will be reproduced in humans, the available evidence suggests that patients with type 1 and type 2 diabetes may expect far superior control of the metabolic abnormalities without the need for significant monitoring of glucose, a very important but expensive part of any insulin regimen.
Coumarin‐Phosphine‐Based Smart Probes for Tracking Biologically Relevant Metal Complexes: From Theoretical to Biological Investigations
Authors: Dondaine Lucile , Escudero Daniel , Ali Moussa , Richard Philippe , Denat Franck , Bettaieb Ali , Le Gendre Pierre , Paul Catherine , Jacquemin Denis , Goze Christine , Bodio Ewen
Published: January 2016

Ten metal‐based complexes and associated ligands have been synthesized and characterized. One of the metal ligands is a coumarin‐phosphine derivative, which displays tunable fluorescence properties. The fluorescence is quenched in the case of the free ligand and ruthenium and osmium complexes, whereas it is strong for the gold complexes and phosphonium derivatives. These trends were rationalized by theoretical calculations, which revealed non‐radiative channels involving a dark state for the free ligands that is lower in energy than the emissive state and is responsible for the quenching of fluorescence. For the RuII and OsII complexes, other non‐radiative channels involving the manifold of singlet and triplet excited states may play a role. The anti‐proliferative properties of all the compounds were evaluated in cancer cell lines (SW480, HCT116, MDA‐MB‐231 and MCF‐7); higher IC50 values were obtained for gold(I) complexes, with the free ligands being only weakly cytotoxic.
Pressure and shear stress caused by raindrop impact at the soil surface: Scaling laws depending on the water depth
Authors: Nouhou Bako Amina , Darboux Frédéric , James François , Josserand Christophe , Lucas Carine
Published: January 2016

Raindrop impact is an important process in soil erosion. Through its pressure and shear stress, raindrop impact causes a significant detachment of the soil material, making this material available for transport by sheet flow. Thanks to the accurate Navier–Stokes equations solver Gerris, we simulate the impact of a single raindrop of diameter D, at terminal velocity, on water layers of different thickness h:
,
, D, 2D, in order to study pressures and shear stresses involved in raindrop erosion. These complex numerical simulations help in understanding precisely the dynamics of the raindrop impact, quantifying in particular the pressure and the shear stress fields. A detailed analysis of these fields is performed and self‐similar structures are identified for the pressure and the shear stress on the soil surface. The evolution of these self‐similar structures are investigated as the aspect ratio h/D varies. We find that the pressure and the shear stress have a specific dependence on the ratio between the drop diameter and the water layer thickness, and that the scaling laws recently proposed in fluid mechanics are also applicable to raindrops, paving the road to obtain effective models of soil erosion by raindrops. In particular, we obtain a scaling law formula for the dependence of the maximum shear stress on the soil on the water depth, a quantity that is crucial for quantifying erosion materials. Copyright © 2016 John Wiley & Sons, Ltd.
Social Competence at the Playground: Preschoolers During Recess
Authors: Veiga Guida , de Leng Wendy , Cachucho Ricardo , Ketelaar Lizet , Kok Joost N. , Knobbe Arno , Neto Carlos , Rieffe Carolien
Published: January 2016

Social interactions at the playground have been represented as a rich learning opportunity to hone and master social skills at preschool years. Specifically, all forms of social play (fantasy, role, exercise or rough‐and‐tumble) have been related to children's social competence. The main goal of this study was to examine whether it is a certain kind of social play which facilitates the development of social competence, or if it is just the opportunity for interacting during recess that provides children with an optimal environment for social learning. A total of 73 preschoolers (4–6 years old) were videotaped at the school's playground. Teachers provided assessments of children's social competence. Children's interactions at the playground were assessed through an innovative measuring method, based on radio‐frequency identification devices. The results showed a positive association between exercise play and children's social competence. In contrast with the literature, both forms of pretend play, fantasy and role play were unrelated to children's social competence. Smaller peer groups and longer interactions also demonstrated a positive association with these preschoolers' social competence. The study shows the importance of outdoor physical play for preschoolers' social success. Moreover, the study suggests that the environment in which children play has an important effect on the adaptive nature of their play. Copyright © 2016 John Wiley & Sons, Ltd.