bluuebunny/crossref_metadata_2025 huggingface dataset:
A scale for assessing the severity of diseases and adverse drug reactions; Application to drug benefit and risk
Authors: Tallarida Ronald J. , Murray Rodney B. , Eiben Carl
Published: January 2016

Physicians were interviewed to assess their willingness to risk adverse drug reactions among patients. These untoward reactions were ranked according to severity and weighted against the primary illness being treated. A specially designed questionnaire in the form of a matrix was used. Severity was divided into seven classes denoted by progressively increasing numerical scores, W1 to Wτ, whose values could be calculated from analysis of the completed questionnaires. The questionnaires presented several cases, in each of which an illness of specified severity was to be treated with a drug whose untoward reactions differ in severity from that of the primary illness. Each case involved a different permutation of the severities. Analysis of the completed questionnaires yielded the mean values of the scores which were found to range from W1 = 1.00 (the mildest case) to Wτ = 817 (the most serious case). It is our opinion that this type of scale is preferable to nonnumerical descriptions of severity such as “mild” or “serious,” since, when combined with data on frequency of occurrence, a numerical scale permits a determination of expectation of both benefit and risk.
Once‐daily metoprolol in primary hypertension
Authors: Karlberg Bengt E. , Nilsson Ove , Tolagen Kerstin , Nitelius Eva , Waern Urban
Published: January 2016

The antihypertensive effect of the selective beta‐1‐adrenoceptor blocker, metoprolol, administered once daily was evaluated in 32 patients with primary hypertension. After a 4‐wk placebo period, the patients were treated with either 150 mg or 300 mg of metoprolol, once daily, for 8 wk. Initially and during the treatment periods blood was drawn for analysis of metoprolol in plasma, plasma renin activity (PRA), and electrolytes, and urine was collected for determination of the urinary aldosterone excretion. Metoprolol reduced the blood pressure measured up to 26 hr after the last dose. The percentage of responders to metoprolol (decrease of mean arterial pressure ≥10% over placebo) was 40% for patients on 150 mg and 71 % for patients on 300 mg. Except in the standing position, heart rates were reduced for 26 hr after a 150‐mg dose. There was a correlation between pretreatment PRA levels and antihypertensive effect of metoprolol in patients on 300 mg metoprolol but not in patients on 150 mg. Urinary aldosterone decreased equally during treatment in responders and nonresponders. Antihypertensive effects and side effects did not correlate with plasma metoprolol concentrations.
γ‐Carboxyglutamate excretion and warfarin therapy
Authors: Levy Robert J. , Lian Jane B.
Published: January 2016

The urinary excretion of γ‐carboxyglutamic acid (Gla), the amino acid involved in the vitamin K‐dependent calcium binding of prothrombin and clotting factors VII, IX, and X, was studied in warfarin‐anticoagulated patients. An isotope dilution procedure was developed for the measurement of free urinary Gla with the use of prior anion‐exchange chromatography to separate and concentrate the free Gla from whole urine and subsequent automated amino acid analysis. Eight subjects on stable warfarin anticoagulant therapy and 11 comparable control subjects with normal coagulation were examined. Urinary Gla excretion was reduced in patients on warfarin anticoagulant therapy (p = 0.001) and the urinary Gla level correlated (r = −0.73, p = 0.001) with plasma prothrombin time. It is concluded that decreased urinary Gla in warfarin‐treated patients is related to coagulation status and may be a clinically useful parameter.
Dose‐dependent prednisolone kinetics
Authors: Tanner Andrew , Bochner Felix , Caffin Janet , Halliday June , Powell Lawrie
Published: January 2016

Kinetic data for prednisolone and prednisone have been determined following oral administration of prednisolone over a dosage range of 5 to 200 mg in 43 subjects. Intravenous studies have been performed at 20 mg and 100 mg in 3 subjects. At all dosage levels the elimination t½β for prednisolone remained constant (t½β 3.5 ± 0.2 hr [20 mg], t½β 3.7 ± 0.1 hr [100 mg] mean ± SEM). For prednisolone, there was a linear relationship between dose and AUC0→∞ and Cmax up to a dose of 20 mg, but above this level AUC00→∞ and Cmax demonstrated a less rapid increase as the dose increased. The prednisone AUC0→∞. remained a constant proportion, 26 ± 2%, of the prednisolone AUC0→∞ at all dosage levels. Bioavailability of prednisolone was 98.5 ± 4%. There was a constant amount of prednisolone bound to cortisol‐binding globulin (CBG) (145 ± 16 ng/ml) and as a proportion of the remaining serum prednisolone, the free remained at 14 ±2% and non‐CBG protein‐bound prednisolone at 86 ± 2% over the whole dosage range. The intravenous studies demonstrated a significant difference in the volume of distribution of prednisolone as the dose changed from 20 mg (Vd 58 ±4 L) to 100 mg (Vd 90 ± 6 L). Since it has been demonstrated that bioavailability, serum protein binding, prednisone‐prednisolone interconversion, and t½β remained constant over this dosage range, the altered Vd may account for the nonlinear relationship between AUC and dose.
Adipose tissue blood flow and insulin disappearance from subcutaneous tissue
Authors: Kølendorf K. , Bojsen J. , Nielsen S. L.
Published: January 2016

The disappearance rate of labeled insulin from subcutaneous tissue has shown wide variation, even using labeled insulin with biological properties identical to that of the unlabeled insulin. The aim of this study is to evaluate the influence of adipose tissue blood flow (ATBF) on the disappearance rate of soluble 131I‐labeled insulin from an injected depot subcutaneously in the frontal femoral region of 10 insulin‐treated diabetics. Changes in ATBF were induced by leg exercise on a bicycle ergometer in an upright position, by dynamic arm exercise in a supine position, and by local heating and cooling. The mean resting ATBF of the diabetics was 5.3 ±3.1 (ml · min−1 · 100 gm−1) and 6.7 ± 6.0 of the control subjects, difference (ns). Bicycling increased ATBF in 5 patients from 3.0 ± 0.7 to 7.7 ± 1.1, the disappearance constant (k) value of insulin from 0.484 ± 0.201 (min−1 · 10−2)to 0.937 ± 0.306, and the amount of insulin absorbed per hr from 24.7 ± 9.1% to 42.3 ± 10.5% (p < 0.05). Local cooling decreased ATBF in 6 diabetics from 6.6 ± 3.9 to 2.4 ± 1.1, the k value of insulin from 0.685 ± 0.163 to 0.362 ± 0.158, and the absorbed amount from 33.7 ± 3.9% to 17.4 ± 6.9% (p < 0.02). Dynamic arm exercise and local heating increased the ATBF, insulin disappearance, and absorbed amount of insulin. The skin and subcutaneous temperatures did not show any significant changes, except during local cooling and the subsequent local heating (p < 0.02). There was a correlation between ATBF and insulin absorbed per hr (r = 0.969, p < 0.001), which indicates that changes in subcutaneous tissue blood flow in the anterior thigh induce changes in insulin absorption from the injection site and might be of clinical importance.
Invited remarks
Authors: Hamilton Michael T.
Published: January 2016

As an ethicist, I am strongly in support of clinical trials, double blind, randomized, and with data‐monitoring committees whenever appropriate. I am also in favor of having ethicists and other representati ves of the public on the policy and protocol review boards of clinical trials. We bring a different perspecti ve from that of physicians and other health professionals, and, since ultimately both public funding and medical research policy are subject to public judgment acting through state and federal legislatures and also through the courts, our presence, though troublesome at times, enables the public better to trust and support national ventures in medical research. These arguments for the presence of nonmedical members on clinical trial boards are of a political nature, and the following are moral considerations.
Responses
Authors: Canner Paul L.
Published: January 2016

Dr. Klimt and Dr. Stamler both made brief mention of the fact that in closing out a study we may wish to consider setting up a mechanism for long‐term follow‐up of the patients to determine cause of death or more rarely for certain nonfatal end points beyond the end of the study proper. I would like to expand briefly on these comments and pose two questions. First, under what circumstances is such long‐term follow‐up warranted? And second, what means are available for accomplishing this task? With regard to the first question, we can all think of a number of reasons why it might be desirable to carry out such a long‐term follow‐up program, particularly if a study terminates with a conclusion that one or more of the treatment regimens are both effective and safe. One would like to be able to determine whether the beneficial effects of the treatments continue to hold up over the next 5 or 10 years and whether there are any latent carcinogenic or other adverse effects of the treatment. It does not seem quite so clear whether such long‐term follow‐up is warranted for treatments found by the trial to be ineffective and/or unsafe. A case might be made for follow‐up for latent carcinogenic effects even in instances such as this. I would be interested in any comments that the participants or anyone in the audience may have concerning this issue.
Patient recruitment: Problems and soluti
Authors: Prout Thaddeus
Published: January 2016

The goal of this session is to illustrate not only some of the problems but also some of the solutions to patient recruitment. The rapporteur for this session is Barbara Hawkins of the Coordinating Center Models Project at the University of Maryland. It was Harold Roth of the National Institute of Arthritis, Metabolism, and Digestive Diseases who first suggested the need for a rapporteur for these sessions. I misunderstood hirn, thinking he had said “raconteur,” and I invited Barbara to entertain us with some lively stories to lighten the program. Unfortunately, Barbara will not be telling us any stories today, but she did tell me one to pass on to you.
LRC Coronary Prevention Trial: Baltimore
Authors: Benedict G. William
Published: January 2016

Intense, initial efforts tu enroll 250 individuals in the Coronary Prevention Trial at Johns Hopkins University Hospital through referrals from private physicians and from commercial laboratories were largely unsuccessful. Not until a mass‐screening effort was initiated in the community were we able to contact sufficient numbers of potential study candidates. The time needed to acquire the trial candidates was 2.5 times as long as our original estimate, and 35,000 individuals were tested in the process.
Aspects of clinic monitoring in large‐scale multiclinic trials
Authors: Mowery Richard L. , Williams O. Dale
Published: January 2016

Monitaring the implementation of large‐scale studies and the adherence of clinical centers to a common protocol should be an integral part of the study design and a primary responsibility of the coordinating center for the study. There are four basic concepts in external clinic monitoring: (1) the maintenance of open lines of communication between alt study facilities, (2) “responsibility and accountability” for study implementation and for the integrity of the data, (3) evaluation of clinic operations, and (4) analysis of data quality. A monitoring scheme consisting of regular telephone calts to the screening centers, periodic visits to the screening centers, and continuing review of the data coltected can be effectively used by the coordinating center.
External monitoring in multiclinic trials: Applications from ophthalmologic studies
Authors: Ferris Frederick L. , Ederer Fred
Published: January 2016

The editing of data by the statistical center is only one element in assuring data quality in multiclinic trials. Our experience in assuring the quality of the visual acuity measurement in multiclinic trials of eye disease illustrates the need for a more comprehensive approach. The visual acuity measurement is influenced by a number of physical variables and by possible personal biases on the part of both patient and examiner. Although a detailed “cookbook” protocol was written in an attempt to assure uniformity of equipment and procedures and to minimize personal biases, we found in our visits to the clinics that each protocol element was violated by at least one clinic. To prevent these problems, a central clinic‐monitoring system similar to that used in the Lipid Research Clinic Program was instituted. Our experience in monitoring multiclinic trials leads us to the foltowing conclusions: First, responsibility for a comprehensive program of data quality assurance should be vested in a central authority. Second, a clinic coordinator at each clinic with detailed knowledge of alt aspects of clinic performance and with responsibility for monitoring adherence to the protocol is an important element in this comprehensive program. Third, much of the work essential to adequate quality assurance should be done before the study starts. This includes training and certification of personnel and pretesting of procedures and data forms. In long‐term studies, because of the turnover in clinic personnel, training and certification must be an ongoing process. Fourth, there must be continual communication, both by telephone and in person, between the central monitoring group and the clinic. As part of this communication, there should be routine and systematic examination of all aspects of clinic performance.
Retrieving information on clinical trial methodology
Authors: Schoolman Harold M.
Published: January 2016

Evidence derived from several simple searches of the literature suggests that one interested in identifying papers whieh discuss the methodologies of clinical trials will have reasonable success. However, the retrieval of a meaningful methodologic discussion of any actual trial is unlikely because very little of this information has been published. Some suggestions to remedy this deficiency are given.
Diazoxide infusion in severe hypertension and hypertensive crisis
Authors: Thien Theo A. , Huysmans Frans T. M. , Gerlag Paul G. G. , Koene Robert A. P. , Wijdeveld Paul G. A. B.
Published: January 2016

Prompted by reports of hypotension with myocardial ischemia after bolus injection, we restudied the efficacy of diazoxide infusion (5 mg/kg, rate, 15 mg/min) in 35 hypertensive patients. In 20 patients with chronic hypertension, mean arterial pressure of 138 mm Hg was 110 (after 30 min) and 121 (after 8 hr). In 15 patients with hypertensive crisis, there was a fall from 159 to 126 (in 30 min) and 133 mm Hg (after 8 hr), similar to findings in 12 patients with hypertensive crisis treated with a 300‐mg bolus injection (159, 130, 140 mm Hg). In the latter, the maximal systolic blood pressure decrease was greater (56 mm Hg, reached in 4 min) than in the 15 patients with hypertensive crisis treated by slow infusion (38 mm Hg in 28 min). Thus, infusion of diazoxide causes a gradual decline of blood pressure and is, in contrast to current opinion, also an effective treatment in hypertensive crisis.
Effect of magnesium trisilicate on nitrofurantoin absorption
Authors: Naggar Viviane F. , Khalil Said A.
Published: January 2016

In vitro adsorption studies revealed that for an identical initial concentration of nitrofurantoin, magnesium trisilicate exhibited the greatest adsorptive capacity with bismuth oxycarbonate, talc, kaolin, and magnesium oxide exhibiting intermediate adsorptive powers, while aluminum hydroxide and calcium carbonate exhibited low or no adsorption properties. Trials to elute the drug with acidic or alkaline solution were unsuccessful. The in vivo absorption characteristics of nitrofurantoin and nitrofurantoin‐magnesium trisilicate combination were evaluated in 6 healthy males. Administration of magnesium trisilicate with nitrofurantoin reduced the rate and extent of its excretion reflecting decrease in both rate and extent of absorption. The time during which the drug concentration in the urine was above the minimum effective concentration of 32 µg/ml was also significantly reduced after administration of the antacid.
Disopyramide kinetics in patients with acute myocardial infarction
Authors: Ilett Kenneth F. , Madsen Barry W. , Woods James D.
Published: January 2016

The kinetic behavior of disopyramide was studied in 20 patients with supected myocardial infarction: in 13 of these, the diagnosis was subsequently confirmed. All received a 400‐mg oral loading dose of disopyramide base followed by an oral maintenance regimen of either 100 or 200 mg 4 times daily. The elimination half‐life (t½β) was longer (p < 0.05) in patients with confirmed infarction than in patients with unconfirmed infarction [38.0 ± 3.7 hr (mean ± SEM) compared to 24.3 ± 0.8 hr, and 21.2 ± 2.1 hr compared to 7.2 ± 2.4 hr for the 100‐ and 200‐mg maintenance dose regimens, respectively]. The t½β was dose dependent for infarct and noninfarct patients. Two of the patients with confirmed infarction failed to reach trough plasma levels equal to or exceeding the lower end of the manufacturer's recommended therapeutic range (3.3 µg/ml) during the study. For the remaining 11 patients the time taken to achieve trough plasma levels of 3.3 µg/ml varied from 18 to 170 hr; hence plasma disopyramide concentration in these patients was suboptimal at a time when the risk of arrhythmias is high. Modification of existing oral loading dose regimens is therefore required for optimization of oral disopyramide therapy.
Plasma chlorpromazine concentrations in children with behavioral disorders and mental illness
Authors: Rivera-Calimlim L. , Griesbach P. H. , Perlmutter R.
Published: January 2016

Plasma chlorpromazine (CPZ) levels were studied in children 8 to 15 yr of age who were receiving CPZ for mental disorders. The results showed that children need larger doses of CPZ than adults to attain comparable plasma concentrations. The apparent therapeutic plasma concentration in children (40 to 80 ng/ml) is lower than that reported for adults (50 to 300 ng/ml). In the children studied, the plasma concentrations declined despite maintained dosage, possibly because of autoinduction of CPZ metabolism. Doses of 6 to 11 mg/kg body‐weight, and even as much as 850 mg /day, were tolerated without significant side effects when administered in divided doses 3 or 4 times a day, while doses of less than 6 mglkglday frequently failed to produce the desired plasma CPZ levels.
XLVIII. Efficacy of different research structures in preventing bias in the analysis of causation
Authors: Feinstein Alvan R.
Published: January 2016

A characteristic of scientific method and scientific thinking is the “dissection” of a general phenomenon into its component parts and mechanisms. For example, almost everyone knows that carbohydrates are ultimately metabolized by the human body into carbon dioxide and water. In the science of biochemistry, however, the pathway between input and output is dissected into many intermediate steps, which include the Krebs cycle, a variety of enzyme systems, and numerous intermediate chemical substances.
Kinetics of intravenous melphalan
Authors: Alberts David S. , Chang Sai Y. , Chen H.-S. George , Moon Thomas E. , Evans Thomas L. , Furner Raymond L. , Himmelstein Kenneth , Gross Joseph F.
Published: January 2016

We have studied the disposition and elimination of melphalan after intravenous administration in 9 patients with cancer. High‐pressure liquid chromatography and 14C‐melphalan were used to assay drug concentration in plasma and urine. Composite plasma t½β was 7.7 ± 3.3 and t½β was 108 ± 20.8 min for 8 of the patients. The mean 24‐hr urinary excretion of melphalan was 13.0 ± 5.4% of the administered dose. In 2 patients, 80% to 100% of the measured 14C counts in plasma and urine samples at each study interval, up to 24 hr after drug administration, could be accounted for by the sum of parent compound, monohydroxy and dihydroxy products, and methanol nonextractable radioactivity (i.e., protein‐bound activity). These data and evidence of rapid disappearance from plasma at 37° in vitro suggest that spontaneous degradation, and not enzymatic metabolism, is the major determinant of the t½β of melphalan in vivo.
Effects of equiblocking doses of nadolol and propranolol on left ventricular performance
Authors: Le Winter Martin M. , Curtis Guy P. , Engler Robert L. , Shabetai Ralph , Verba John
Published: January 2016

Nadolol, a recently developed noncardioselective β‐adrenergic blocker, has the potential advantages of a longer oral half‐life (t½) than propranolol and, in animal studies, markedly fewer direct myocardial depressant effects. Neither the relative intravenous potency of nadolol and propranolol nor the comparative effects of the 2 drugs on left ventricular performance has been studied in man. We compared equiblocking intravenous doses of nadolol and propranolol in 10 subjects with ischemic wall‐motion disorders. Nadolol was on the average 6.2 times as potent on a milligram‐for‐milligram basis. Both drugs decreased resting heart rate (p < 0.02) and produced small rises in both mean pulmonary artery (p < 0.03) and mean pulmonary artery wedge (p < 0.03) pressures without significantly reducing the cardiac output. Both drugs also produced depression of the radionuclide ejection fraction (p < 0.002). There were no significant differences between the effects of the 2 drugs on any of the aforementioned variables. Thus, the effects of nadolol on left ventricular performances are similar to those of propranolol. Because of its long oral t½, nadolol may prove to be a clinically useful drug.
A radioreceptor assay for propranolol
Authors: Bilezikian John P. , Gammon Donald E. , Rochester Carolyn Lee , Shand David G.
Published: January 2016

A radioreceptor assay for the measurement of propranolol levels in human subjects is described. The assay is based upon competition between the radiolabeled β‐adrenergic inhibitor [125I]iodohydroxybenzylpindolol and propranolol for specific beta receptor sites in turkey erythrocyte plasma membranes. The radioreceptor assay is extremely sensitive, specific, and technically adaptable to processing clinical samples. Propranolol in serum is quantitatively extracted into ethyl acetate and, after the organic phase is reduced to dryness, reconstituted in aqueous assay buffer. Propranolol levels as low as 0.25 to 0.5 ng/ml can be detected and maximal sensitivity occurs at a concentration of 2.4 ± 0.2 ng/ml. The assay demonstrates specificity for biologically active metabolites of propranolol as well and therefore, with modifications, has the potential of providing a composite index of circulating β‐adrenergic inhibitory activity. Nonactive propranolol metabolites, d‐isomers, and the catecholamines do not significantly interfere in the assay. Thirty clinical samples containing a wide spectrum of propranolol concentrations were analyzed by radioreceptor assay and then compared with values obtained by high‐pressure liquid chromatography (HPLC) or by radioimmunoassay. The coefficients of correlation, r, between the radioreceptor assay and these other two methods were +0.91 and +0.85, respectively (p < 0.01). These observations establish the characteristics and the clinical feasibility of the radioreceptor assay for propranolol and suggest that it will be useful in further elucidating the kinetics of propranolol in human subjects.
Reduced β‐adrenoceptor sensitivity in the elderly
Authors: Vestal Robert E. , Wood Alastair J. J. , Shand David G.
Published: January 2016

The effect of age on sensitivity to both isoproterenol and propranolol has been investigated in 27 male volunteers aged 21 to 73 yr. The dose of isoproterenol (given as a rapid intravenous injection) required to increase the resting heart rate by 25 bpm (I25) increased with age. The I25 was repeated during an intravenous infusion of propranolol and the dose ratio (I25 after propranolol divided by the control I25) determined. This was related to the concentration of free propranolol in plasma. It was found that the effectiveness of any given free concentration diminished progressively with age. These data are consistent with a diminished responsiveness of the β‐adrenoceptor to both agonist and antagonist drugs with advancing years.
Inter‐ and intrasubject variation in diazepam free fraction
Authors: Abel J. G. , Sellers E. M. , Naranjo C. A. , Shaw J. , Kadar D. , Rornach M. K.
Published: January 2016

The extent of intersubject variation in diazepam free fraction was measured in fasting plasma of 74 unrelated subjects. Free fraction differences between subjects were significant and ranged from 0.97% to 1.99%. Diazepam free fraction in 29 males was normally distributed about a mean of 1.25% (range, 1.05% to 1.47%), but the distribution in females was skewed to higher free fractions and 40% had values above the highest in males. Albumin concentration (r = −0.27, p < 0.002) and age (r = 0.44, p < 0.001) only accounted for a small part of the variation. Within‐pair variances were not greater in 11 dizygotic than in 18 monozygotic twin pairs, indicating a greater contribution of environmental than of genetic factors to diazepam binding. The prehemodialysis free fractions of diazepam in 9 uremic patients ranged from 3.44% to 9.69%, and decreased (p < 0.005) in 7 after 6 hr of hemodialysis. In 10 subjects determination of intrasubject variation in diazepam free fraction between 14‐hr fasting and 2‐hr postprandial plasma samples indicated that because subjects differ in their pattern of change in free fraction (p < 0.001), the overall decrease in mean free fraction did not achieve statistical significance (p = 0.10). The mean relative percent change in free fraction within subjects after feeding was 15.2%.
Techniques for plasma protein binding of demethylchlorimipramine
Authors: Bertilsson Leif , Braithwaite Robin , Tybring Gunnel , Garle Mats , Borgå Olof
Published: January 2016

The cerebrospinal fluid (CSF) and plasma levels of demethylchlorimipramine (DMC1) were determined during treatment of depression or obsessive‐compulsive disorders with chlorimipramine. In 18 patients the mean CSF/plasma ratio of DMCI was 2.6% ± 0.7 SD with fourfold variation (1.1% to 4.0%). In spite of this variation, the levels in CSF and plasma at steady state correlated closely (r = 0.91; p < 0.001). With equilibrium dialysis for the determination of the protein binding of DMCI, a much higher free fraction was found in patients (8.0 ± 1.6%) and in control subjects (8.2 ± 1.4%). It was shown that part of the plasma binding capacity was lost during the incubation. Results obtained by ultrafiltration (3.9 ± 1.0% unbound drug) were closer to the in vivo results, but this method also had disadvantages; much of the drug was absorbed on the ultrafiltration dialysis membrane. Our results suggest that there is a need for care in the selection of a technique for studies of drug protein binding.
Intraindividual variation in drug disposition
Authors: Alvares A. P. , Kappas A. , Eiseman J. L. , Anderson K. E. , Pantuck C. B. , Pantuck E. J. , Hsiao K.-C. , Garland W. A. , Conney A. H.
Published: January 2016

Large interindividual differences occur in the in vivo metabolism of drugs due to genetic and environmental factors. Our studies show that intraindividual variabilities in rates of metabolism are relatively low for antipyrine and phenylbutazone, which are drugs that are primarily metabolized by the liver and have low hepatic extractions; whereas in the case of phenacetin, a drug that undergoes extensive metabolism in the gastrointestinal tract or during its first pass through the liver, or both, intraindividual variations in plasma half‐lifes and areas under the plasma concentration‐time curves are of much greater magnitude. In our studies, no effort was made to control the lifestyles of our subjects. The variations in rates of drug metabolism did not result from assay procedures, since there was little variation in measured concentrations when the drugs were added to plasma and assayed on multiple occasions. Intraindividual variation occurring in subjects given the drug on 5 different occasions may be due to changes in the external environment or changes in internal physiologic parameters or both. Our studies confirm the usefulness of antipyrine as a test drug in studying drug metabolism in man and also demonstrate that the antipyrine test may be able to detect those subjects whose environments are perturbed by unidentified factors.
Hydrochlorothiazide‐induced sympathetic hyperactivity in hypertensive patients
Authors: Lake C. Raymond , Ziegler Michael G. , Coleman Michael D. , Kopin Irwin J.
Published: January 2016

Hydrochlorothiazide‐induced diuresis and natriuresis is considered to be responsible for the antihypertensive effect of this drug. After short‐term treatment there is decreased cardiac output and increased peripheral resistance which we have found to be attended by increased plasma norepinephrine (NE) levels. After longer treatment cardiac output returns to normal and peripheral resistance declines. At this time, plasma NE levels remain elevated, indicating that peripheral resistance reduction is not a consequence of a reduction of the elevated level of sympathetic activity. These results provide a rationale for the combined use of diuretics and drugs which diminish noradrenergic activity in the treatment of hypertension.
Effects in normal subjects of long‐term administration of azosemide
Authors: Brater Craig , Anderson Shirley , Muckleroy Carolyn
Published: January 2016

Azosemide is a new loop diuretic which has been shown to affect solute transport proximal to the diluting segment. We assessed the effects of chronic administration of azosemide in normal subjects on low and normal salt diets. In both, there was compensatory renin release and aldosterone secretion, but the subjects on the low sodium diet developed striking hyperuricemia and metabolic alkalosis and were symptomatic, whereas those on the normal diet compensated to the extent that there were only minor changes.
Haloperidol‐induced syndrome of inappropriate secretion of antidiuretic hormone
Authors: Peck Valerie , Shenkman Louis
Published: January 2016

Several psychotropic drugs have been associated with the syndrome of inappropriate secretion of antidiuretic hormone (SIADH). We report here a patient who on two occasions developed clinically significant hyponatremia while receiving the antipsychotic drug, haloperidol. The criteria for the syndrome of inappropriate secretion of ADH were fulfilled and other causes of SIADH were excluded. We documented inability in this patient to excrete a water load while on haloperidol and normal ability in its absence. This case therefore illustrates SIADH due to haloperidol.
Effect of age and Billroth gastrectomy on absorption of desmethyldiazepam from clorazepate
Authors: Ochs Hermann R. , Greenblatt David J. , Allen Marcia Divoll , Harmatz Jerold S. , Shader Richard I. , Bodem Gunther
Published: January 2016

The effect of age and Billroth gastrectomy on absorption of desmethyldiazepam (DMDZ) from a single 20‐mg oral dose of its precursor, clorazepate (CZP) dipotassium, was assessed in 24 males. Six were healthy young controls (mean age, 24), 8 were elderly controls (mean age, 66.5 yr) with no gastrointestinal disease, and 10 were patients (mean age, 56) who had undergone Billroth gastrectomy at least 2 yr before. Absent or impaired gastric acid secretion was documented in 6 of the 10 postgastrectomy patients. Weight‐normalized area under the 48‐hr serum DMDZ concentration curve (WtN‐AUC‐48) among elderly controls (mean, 324 units) and gastrectomy patients (401 units) were similar and significantly less than those in young controls (603 units). Peak serum DMDZ concentrations in elderly controls and gastrectomy patients (185 and 216 ng/ml, respectively) were also lower and reached later after the dose (2.2 and 2.3 hr) than in young controls (371 ng/ml; 1.1 hr). Age per se rather than gastrectomy or acid secretion status explained by far most of the overall variability in WtN‐AUC‐48 and peak DMDZ concentration. Thus normal gastric acidity is not essential for absorption of CZP‐derived DMDZ. The appearance of DMDZ in the systemic circulation is reduced in elderly males, irrespective of surgery or gastric acid secretion. This could be explained by age‐related reduction in conversion of CZP to DMDZ or by more extensive distribution of DMDZ in the elderly.
Reduced renovascular resistance by clonidine
Authors: Cohen Irving M. , O'Connor Daniel T. , Preston Richard A. , Stone Richard A.
Published: January 2016

The antihypertensive effect of clonidine has been attributed to acute inhibition of sympathetic outflow from the central nervous system. This conclusion is derived from experiments with single doses of clonidine. The mechanism of the long‐term blood pressure‐lowering effect of clonidine has been less well characterized. Antihypertensive therapy may alter renal hemodynamics and these changes may ultimately affect systemic blood pressure. We studied the effect of long‐term clonidine therapy on intrarenal hemodynamics, the renin‐angiotensin system, and selected indices of sympathetic nervous system activity in 13 patients with essential hypertension to further elucidate its action. Long‐term clonidine therapy resulted in decreased MAP and RVR associated with the suppression of supine but not upright PRA. RPF, RBF, FF, and WBV did not change. UKA, an index of the putative vasodilating renal kallikrein‐kinin system, was also not changed. Our findings suggest a role for PRA in modulating RVR during long‐term clonidine therapy. This was associated with the reduction observed in MAP.
Debrisoquin hydroxylation polymorphism among Ghanaians and Caucasians
Authors: Woolhouse N. M. , Andoh B. , Mahgoub A. , Sloan T. P. , Idle J. R. , Smith R. L.
Published: January 2016

The alicyclic and aromatic hydroxylation of debrisoquin was studied in Ghanaians. As in a previously studied Caucasian population, the alicyclic 4‐hydroxylation of debrisoquin in Ghanaians was polymorphic. Three phenotypes were observed: homozygous extensive metabolizers (58%), heterozygous extensive metabolizers (36%), and homozygous poor metabolizers (6%). In contrast, British Caucasians are primarily monomorphic extensive metabolizers (92%) and homozygous poor metabolizers comprise 8% of the population. Urinary recovery of the drug and its hydroxylated metabolites was significantly less in the Ghanaian subjects. In both Ghanaian and British populations, aromatic hydroxylation producing 5‐, 6‐, 7ȁ0, and 8‐hydroxydebrisoquin was shown to parallel the alicyclic 4‐hydroxylation of debrisoquin, and thus to be controlled by the same gene locus. Debrisoquin is advocated as a tool for uncovering polymorphism in drug oxidation and its interethnic variations.
Interindividual variation in kinetics of infused epinephrine
Authors: FitzGerald Garret A. , Hossmann Volker , Hamilton Carlene A. , Reid John L. , Davies Donald S. , Dollery Colin T.
Published: January 2016

1‐Norepinephrine was infused continuously for 10 hr into 5 normotensive, male laboratory subjects (mean age, 32.4 ± 1.9 yr) at a mean rate of 0.06 µg/kg/min. Mean plasma norepinephrine (NE) rose from the preinfusion level of 0.19 ± 0.02 µ/l to a steady state level of 1.22 ± 0.29 µ/l. The mean increase in blood pressure was 21.8 ± 0.9 mm Hg systolic and 14.1 ± 1.0 mm Hg diastolic. The mean depression in heart rate was 12.7 ± 1.7 beats/min. The clearance of norepinephrine ranged front 27.9 to 100.0 ml/kg/min (mean, 58.0 ± 13.8) and was little influenced by acute hemodynamic changes. The volume of distribution ranged widely (0.09 to 0.40 Mkg), the mean value being 13.51 1. The mean norepinephrine half‐life was brief, ranging from 1.45 to 2.9 min (mean, 2.09 ± 0.34 min). There was no evidence of a slowly accumulating high‐capacity low‐affinity pool of norepinephrine. These results support the use of plasma norepinephrine as an index of sympathetic activity within an individual but not its validity in interindividual comparisons.
Amantadine kinetics in healthy young subjects after long‐term dosing
Authors: Aoki Fred Y. , Sitar Daniel S. , Ogilvie Richard I.
Published: January 2016

We investigated the disposition of amantadine in 13 healthy, young adults after long‐term dosage. Doses of 25, 100, or 150 mg, randomly allocated, were taken at 12‐hr intervals in syrup for 31 doses. A l‐compartment open model and complete bioavailability were assumed. Absorption rate was variable with peak concentrations in plasma occurring at 1 to 12 hr. Since the calculated area under the plasma concentration against time curve was proportional to it, relative bioavailability was independent of dose at steady state. As the dose increased, the apparent volume of distribution decreased. Intra^#x2010; and intersubject variations in trough plasma drug concentrations at steady state were less than triple for equivalent doses. Elimination of drug from plasma was consistent with a first‐order process. Plasma half‐Iifes (t½s) ranged from 10.2 to 31.4 hr and were independent of dose or creatinine clearance. The ratio of renal drug clearance to creatinine clearance ranged from 1.26 to 14.97, suggesting substantial renal tubular secretion. The median ratio of plasma drug clearance to renal drug clearance approached unity.
Gestational age and indomethacin elimination in the neonate
Authors: Evans M. A. , Bhat R. , Vidyasagar D. , Vadapalli M. , Fisher E. , Hastreiter A.
Published: January 2016

The disposition of oral indomethacin was studied in 9 premature infants with significant patent ductus arteriosus (sPDA) with birth weights ranging from 800 to 1,960 gm and gestational ages of 28 to 36 wk. Peak plasma concentrations in most of the subjects were not observed until 3 to 4 hr after administration and ranged from 0.027 to 0.31 µg/ml. Plasma half‐life (t½) of indomethacin ranged from 11 to 20 hr and correlated with gestational age. Plasma protein binding studies, in samples from the premature infant using radiolabeled indomethacin, showed no difference in binding from values obtained with adult plasma (>98%). Absorption of orally administered indomethacin appears to be incomplete and plasma clearance much longer than in the adult.
Photolysis of Isoelectronic Ruthenium Nitrosyl and Diazonium Complexes in Frozen PVC Matrices: Retention of Dinitrogen on Ruthenium Following Photochemical Phenyl Radical Loss
Authors: Thornley Wyatt A. , Bitterwolf Thomas E.
Published: January 2016

Photolysis of RuCl3(η1‐NO)(PPh3)2 in poly(vinyl chloride) (PVC) matrices at 85 K results in reversible linkage isomerism of the nitrosyl ligand to form the isonitrosyl complex RuCl3(η1‐ON)(PPh3)2. Metal‐to‐ligand charge‐transfer (MLCT) excitation of the isoelectronic phenylazo complex, RuCl3(η1‐N2Ph)(PPh3)2, has previously been shown to result in generation of the phenyl radical, presumably through decomposition a photogenerated diazenyl radical. Examination of this photolysis in a PVC matrix at cryogenic temperatures has permitted direct observation of an isotopically sensitive product band that may be assigned to a 17‐electron ruthenium dinitrogen species, suggesting that this photochemical decomposition does not proceed through formation of a diazenyl intermediate but through homolytic cleavage of the parent diazonium complex to give the phenyl radical and the 17‐electron RuCl3(η1‐N2)(PPh3)2.
Preparation, Characterization, Electrochemistry, and Infrared Spectro­electrochemistry of Ruthenium ­Nitrosyl Porphyrins Containing η1‐O‐Bonded Axial Carboxylates
Authors: Awasabisah Dennis , Xu Nan , Gautam Krishna P. Sharmah , Powell Douglas R. , Shaw Michael J. , Richter‐Addo George B.
Published: January 2016

The synthesis, characterization and redox behavior of eight low‐spin nitrosyl carboxylate compounds (por)Ru(NO)[η1‐OC(=O)R] [por = T(p‐OMe)PP: R = Me (1), iPr (2), tBu (3), p‐C6H4NO2 (4), Fc (5), CF3 (8); por = TTP: R = Fc (6)] and [T(p‐OMe)PP]Ru(NO)(OC6HF4) (7) are reported. The compounds are moderately stable in air as solids. Their IR (KBr) spectroscopic data show υNO's in the 1839–1861 cm–1 range. The X‐ray crystal structures of compounds 1, 2, 5–7, and 8 have been determined, and reveal linear RuNO linkages for these formally {RuNO}6 complexes. The redox behavior of the compounds at a Pt working electrode were studied in CH2Cl2 with NBu4PF6 as supporting electrolyte. The compounds display reversible first oxidations. IR spectroelectrochemistry of compounds 1–4, 7 and 8 revealed porphyrin‐centered oxidations, whereas the ferrocenylcarboxylate compounds revealed first oxidations at the ferrocenyl moiety followed by second oxidations at the porphyrin macrocycles. Reductions of these compounds are accompanied by loss of the axial ligands.
Relay selection in mixed RF/FSO system over generalized channel fading
Authors: Sharma Nikhil , Bansal Ankur , Garg Parul
Published: January 2016

In this paper, a relay selection‐based amplify‐and‐forward (AF) with mixed radio frequency/free space optical (RF/FSO) system is proposed. We have considered two relay selection schemes namely max‐select, distributed switch and stay (DSS) and compared their performance when all relays are active. The AF‐based relay employs (1) full‐channel state information relaying (amplification gain dependent on instantaneous signal‐to‐noise ratio of source‐relay link) (2) semi‐blind relaying (fixed amplification gain) for the amplification purpose. The selected AF relay converts the received RF signal into an optical signal using the subcarrier intensity modulation scheme. The RF link is subject to a generalised η − μ distribution, while the channel for free space optical link is modelled as gamma–gamma distributed along with pointing errors. Novel analytical expressions for the probability density function, cumulative distribution function and the moment generating function of the equivalent signal‐to‐noise ratio is derived. Capitalising on these channel statistics, we provide the closed form expressions of the outage probability for different relay selection schemes. Copyright © 2016 John Wiley & Sons, Ltd.
Activity, balance, learning, and exposure (ABLE): a new intervention for fear of falling
Authors: Wetherell Julie Loebach , Johnson Kristen , Chang Douglas , Ward Samuel R. , Bower Emily S. , Merz Caroline , Petkus Andrew J.
Published: January 2016

Objective

Fear of falling is an important problem among older adults, even those with relatively low rates of objective fall risk, who are often overlooked as targets for intervention.

Method

We developed and pilot tested a new intervention, Activity, Balance, Learning, and Exposure (ABLE), in a sample of 10 older adults with excessive fear of falling. The ABLE intervention integrates exposure therapy and cognitive restructuring with a home safety evaluation and an exercise program and is conducted in the home. In this pilot project, ABLE was jointly conducted by a physical therapist and a psychologist with expertise in geriatric anxiety disorders.

Results

The intervention was feasible and acceptable and resulted in decreases in fear and activity avoidance for most participants. One participant experienced an injurious fall.

Discussion

We learned a number of important lessons resulting in modifications to the inclusion criteria, assessments, and intervention over the course of this pilot study. Results suggest that ABLE has promise for treating excessive fear of falling in the elderly and support testing the intervention in a larger randomized trial. Copyright © 2016 John Wiley & Sons, Ltd.
Print‐Based Texts
Authors: Blasingame James
Published: January 2016

This column provides reviews of adolescent and adult literature and provides a valuable resource for literature selection in‐ and outside the classroom
GRP78 Interacting Partner Bag5 Responds to ER Stress and Protects Cardiomyocytes From ER Stress‐Induced Apoptosis
Authors: Gupta Manish K. , Tahrir Farzaneh G. , Knezevic Tijana , White Martyn K. , Gordon Jennifer , Cheung Joseph Y. , Khalili Kamel , Feldman Arthur M.
Published: January 2016

Bag5 is a member of the BAG family of molecular chaperone regulators and is unusual in that it consists of five BAG domains, which function as modulators of chaperone activity. Bag family proteins play a key role in cellular as well as in cardiac function and their differential expression is reported in heart failure. In this study, we examined the importance of a Bag family member protein, Bag5, in cardiomyocytes during endoplasmic reticulum (ER) stress. We found that expression of Bag5 in cardiomyocytes is significantly increased with the induction of ER stress in a time dependent manner. We have taken gain‐in and loss‐of functional approaches to characterize Bag5 protein function in cardiomyocytes. Adenoviral mediated expression of Bag5 significantly decreased cell death as well as improved cellular viability in ER stress. Along with this, ER stress‐induced CHOP protein expression is significantly decreased in cells that overexpress Bag5. Conversely, we found that siRNA‐mediated knockdown of Bag5 caused cell death, increased cytotoxicity, and decreased cellular viability in cardiomyocytes. Mechanistically, we found that Bag5 protein expression is significantly increased in the ER during ER stress and that this in turn modulates GRP78 protein stability and reduces ER stress. This study suggests that Bag5 is an important regulator of ER function and so could be exploited as a tool to improve cardiomyocyte function under stress conditions. J. Cell. Biochem. 117: 1813–1821, 2016. © 2016 Wiley Periodicals, Inc.
Light/Dark Environmental Cycle Imposes a Daily Profile in the Expression of microRNAs in Rat CD133+ Cells
Authors: Marçola Marina , Lopes‐Ramos Camila M. , Pereira Eliana P. , Cecon Erika , Fernandes Pedro A. , Tamura Eduardo K. , Camargo Anamaria A. , Parmigiani Raphael B. , Markus Regina P.
Published: January 2016

The phenotype of primary cells in culture varies according to the donor environmental condition. We recently showed that the time of the day imposes a molecular program linked to the inflammatory response that is heritable in culture. Here we investigated whether microRNAs (miRNAs) would show differential expression according to the time when cells were obtained, namely daytime or nighttime. Cells obtained from explants of cremaster muscle and cultivated until confluence (∼20 days) presented high CD133 expression. Global miRNA expression analysis was performed through deep sequencing in order to compare both cultured cells. A total of 504 mature miRNAs were identified, with a specific miRNA signature being associated to the light versus dark phase of a circadian cycle. miR‐1249 and miR‐129‐2‐3p were highly expressed in daytime cells, while miR‐182, miR‐96‐5p, miR‐146a‐3p, miR‐146a‐5p, and miR‐223‐3p were highly expressed in nighttime cells. Nighttime cells are regulated for programs involved in cell processes and development, as well as in the inflammation, cell differentiation and maturation; while daytime cells express miRNAs that control stemness and cytoskeleton remodeling. In summary, the time of the day imposes a differential profile regarding to miRNA signature on CD133+ cells in culture. Understanding this daily profile in the phenotype of cultured cells is highly relevant for clinical outputs, including cellular therapy approaches. J. Cell. Physiol. 231: 1953–1963, 2016. © 2016 Wiley Periodicals, Inc.