bluuebunny/crossref_metadata_2025 huggingface dataset:
A method for the determination of amitriptyline and its metabolites nortriptyline, 10‐hydroxyamitriptyline, and 10‐hydroxynortriptyline in human plasma using stable isotope dilution and gas chromatography‐chemical ionization mass spectrometry (GC‐CIMS)
Authors: Garland W. A. , Muccino R. R. , Min B. H. , Cupano J. , Fann W. E.
Published: January 2016

A gas chromatography‐mass spectrometry (GC‐MS) method has been developed to measure amitriptyline and its metabolites nortriptyline, 10‐hydroxyamitriptyline, and 10‐hydroxynortriptyline in human plasma. Deuterated analogs of each compound were synthesized as internal standards. Isobutane was used as both gas chromatography (GC) carrier gas and chemical ionization (Cl) reagent gas. In order to obtain compounds with satisfactory GC and mass spectrometry (MS) properties, the two alcohol metabolites were dehydrated without loss of label during sample preparation. Selective ion monitoring of the MH+ ions of the protio‐ and deuterio‐ compounds gave ion ratios which were converted to plasma concentrations using standard curves. For amitriptyline and nortriptyline, which are assayed using multiple deuterated analogs as internal standards, the curves are straight lines. For 10‐hydroxyamitriptyline and 10‐hydroxynortriptyline, which are assayed using monodeuterated analogs as internal standards, the curves are nonlinear and are analyzed using an iterative computer procedure. Assay sensitivity is 0.5 ng/ml for amitriptyline, nortriptyline, and 10‐hydroxyamitriptyline and 1 ng/ml for 10‐hydroxynortriptyline. Assay precision and accuracy in terms of percent error are both < 5%. Following oral administration of a single 75‐mg dose of amitriptyline to two subjects, the mean plasma levels of amitriptyline, nortriptyline, 10‐hydroxyamitriptyline, conjugated 10‐hydroxyamitriptyline, 10‐hydroxynortriptyline, and conjugated 10‐hydroxynortriptyline were 36, 8, 10, 66, 16, and 46 ng/ml, respectively, at 2 hr after dosing and 3, 4, 0.5, 1, 6, and 17 ng/ml, respectively, at 72 hr after dosing. Analyses of plasma samples from 12 subjects who had been receiving 50 mg amitriptyline therapy three times a day for an average ±SD of 32 ± 5 days gave a mean concentration of 81 ± 40 ng/ml for amitriptyline, 71 ± 57 ng/ml for nortriptyline, 12 ± 5 ng/ml for 10‐hydroxyamitriptyline, 91 ± 30 ng/ml for conjugated 10‐hydroxyamitriptyline, 82 ± 27 ng/ml for 10‐hydroxynortriptyline, and 176 ± 64 ng/ml for conjugated 10‐hydroxynortriptyline.
Lorazepam kinetics in the elderly
Authors: Greenblatt David J. , Allen Marcia Divoll , Locniskar Ann , Harmatz Jerold S. , Shader Richard I.
Published: January 2016

Lorazepam is a 3‐hydroxy‐1,4‐benzodiazepine derivative biotransformed by glucuronide conjugation, followed by urinary excretion of the glucuronide metabolite. The kinetic properties of single 1.5‐ to 3.0‐mg doses of intravenous lorazepam were assessed in 15 healthy elderly subjects, 60 to 84 yr of age, and in 15 healthy young subjects, 19 to 38 yr of age. Volumes of distribution for lorazepam in the elderly group (mean, 0.99 1/kg), were slightly but significantly smaller than in the young group (1.11 1/kg), suggesting less extensive drug distribution in the elderly. Values of elimination half‐life (t½β) in the elderly (15.9 hr) did not differ significantly from those in the young group (14.1 hr), but total clearance in the elderly (0.77 ml/min/kg) was 22% less (p < 0.05) than in the young subjects (0.99 ml/min/kg). Age differences in lorazepam clearance were partly explained by more frequent cigarette smoking in the young subjects. Gender had no apparent relationship to kinetics. The rate and completeness of absorption of intramuscular (IM) and oral lorazepam was assessed in 10 of the elderly subjects. Deltoid 1M injection and oral administration of tablets in the fasting state led to rapid absorption of lorazepam into the systemic circulation. Peak plasma lorazepam concentrations were always reached within 2.5 hr, and values of absorption half‐life (t½α) did not exceed 45 min. Absorption of IM and oral lorazepam was 80% to 100% complete. Thus, the aging process is associated with small changes in the kinetics of lorazepam. IM and oral administration of lorazepam in elderly persons, as in the case of young individuals, leads to rapid and nearly complete absorption into the systemic circulation.
Absorption and excretion of tolmetin in arthritic patients
Authors: Grindel Joseph M. , Migdalof Bruce H. , Plostnieks Janis
Published: January 2016

The absorption, kinetics, biotransformation, and excretion of tolmetin and its metabolites were studied in patients with rheumatoid arthritis (RA) to evaluate the effects of the disease on tolmetin disposition. Five RA patients were stabilized on tolmetin sodium (300 mg, 4 times daily for 14 days) before receiving a single oral solution dose of tolmetin‐14C sodium (300 mg as the acid) on day 15. Tolmetin was rapidly and completely absorbed (peak time, 20 to 60 min) and eliminated rapidly from plasma with a biphasic decay curve (t½β ≅ 2.1 hr). MCPA, the oxidative metabolite, appeared more slowly (peak time, 40 to 90 min) but was eliminated rapidly in a biphasic manner (t½β ≅ 1.7 hr). The terminal elimination phases for both tolmetin and MCPA demonstrated a curvature which suggested possible nonlinearity in the kinetic disposition of the drug. There were no apparent effects of the disease on the kinetics of tolmetin or MCPA. Tolmetin, MCPA, and tolmetin glucuronide were recovered quantitatively in urine (0 to 72 hr) with most of the excretion occurring in the 0‐ to 24‐hr period. A significant increase, relative to data on normal subjects, in the renal clearance of both tolmetin and MCPA was noted. Concomitant increase in the apparent volume of distribution secondary to reported decreases in the plasma protein binding of tolmetin appeared to be the reason for increased renal clearance of tolmetin.
Responses to tyramine and norepinephrine after imipramine and trazodone
Authors: Larochelle Pierre , Hamet Pavel , Enjalbert Marc
Published: January 2016

Trazodone is a new antidepressive with properties which differ from those of tricyclics. In animals, trazodone seems to be devoid of catecholamine potentiating action, which is thought to be responsible for the cardiotoxicity of this tricyclic. Our study was undertaken to determine the cardiovascular effects of trazodone in man, as indicated by responses to tyramine and norepinephrine. Six normal subjects received either imipramine (25 mg) 3 times a day or trazodone (50 mg) 3 times a day according to a double‐blind randomized cross‐over protocol with a placebo washout period. Each subject was tested on placebo after the first dose and after 1 wk of each drug. The responsiveness of blood pressure to tyramine differed after placebo and imipramine but not after placebo and trazodone. The responsiveness of blood pressure to norepinephrine was increased by imipramine and seemed to be depressed by trazodone after single doses and after 7 days of treatment. Except for one case of sinus bradycardia during norepinephrine infusion, no major side effects were noted during the study. Trazodone seems to have no effect on the blood pressure response to tyramine and presumably does not affect the uptake of tyramine into the adrenergic neuron, while decreased sensitivity to norepinephrine was indicated by the blood pressure response.
Effects of three antibiotics on theophylline kinetics
Authors: Pfeifer Henry J. , Greenblatt David J. , Friedman Paul
Published: January 2016

Nine healthy subjects received single doses of intravenous aminophylline (5 mg/kg) on four occasions separated by at least 1 wk. One trial was a control; the other three were performed during administration of therapeutic doses (250 mg every 6 hr) of tetracycline, erythromycin, and cephalexin. Theophylline concentrations in multiple plasma samples drawn during 24 hr after each dose were determined by high‐pressure liquid chromatography. Mean kinetic variables for theophylline during control, tetracycline, erythromycin, and cephalexin trials, respectively, were: volume of distribution, 0.57, 0.61, 0.63, and 0.62 1/kg; elimination half‐life (t½), 7.9, 9.2, 10.3, and 8.6 hr; total clearance, 0.90, 0.84, 0.78, and 0.89 ml/min/kg. In no case did differences between treatment conditions approach significance. Thus there is no consistent evidence of a kinetic interaction between theophylline and three commonly prescribed antibiotics.
Piperacillin kinetics
Authors: Batra Vijay K. , Morrison John A. , Lasseter Kenneth C. , Joy Vincent A.
Published: January 2016

Piperacillin was administered to normal, healthy volunteers by an intravenous infusion over 30 min at dosage regimens of 12 gm daily (4 gm every 8 hr) and 24 gm daily (6 gm every 6 hr) for 5 consecutive days. Mean peak serum level after 12 gm daily was 244 ± 24 (SE) βg/ml and after 24 gm daily, 353 ± 7 βg/ml. After infusion the serum level declined monoexponentially in most subjects. On the 12‐gm daily dosage mean values were 60 min for half‐life (t½), 16 1 for volume of distribution, 188 ml/minfor body clearance, and 139 ml/minfor renal clearance. The same values on day 4 were 47 min, 12 1, 181 ml/min, and 125 ml/min; the volume of distribution was lower than on day 1. On the 24‐gm daily dosage regimen, tlh was 60 min; volume of distribution, 16 1; body clearance, 183 ml/min; and renal clearance, 101 ml/min on day 1 compared to 68 min, 15 1, 148 ml/min, and 71 ml/min on day 4, the last 2 being significantly lower than on day 1. High renal clearance values were observed at low serum concentrations and vice versa, suggesting saturation of the tubular secretion process at high piperacillin concentrations in serum.
Hematologic perturbations associated with salicylate
Authors: Rothschild Bruce M.
Published: January 2016

Interactions of salicylates with the hematopoietic system are reviewed. Development of anemia is discussed with respect to fluid retention, gastrointestinal bleeding, and hemolytic anemia. Alterations in polymorphonuclear leukocyte and platelet function are evaluated. Interactions with anticoagulants and with the coagulation system are identified.
Plasma clearance of propranolol and sotalol and hepatic drug‐metabolizing enzyme activity
Authors: Sotaniemi Eero A. , Anttila Markku , Pelkonen R. Olavi , Járvensivu Pekka , Sundquist Hannu
Published: January 2016

The role of hepatic drug‐metabolizing enzyme activity for plasma propranolol and sotalol levels was investigated in 68 patients with hypertension or angina pectoris by comparing elimination rate with antipyrine kinetics and cytochrome P‐450 content in the liver. All subjects were resistant to or had hepatotoxic reaction to previous treatment. Plasma antipyrine clearance and cytochrome P‐450 content in biopsies were related to propranolol elimination from plasma, the best fit being obtained with the clearance values. Sotalol plasma clearance was not related to any indirect or direct reflector of the hepatic drug‐metabolizing enzyme system. The results demonstrate that plasma clearance of the short‐acting beta blocker, propranolol, depends on the activity of hepatic drug‐metabolizing enzyme system and indicates a trial with a drug such as sotalol which is not dependent on liver metabolizing capacity.
Intravenous phenobarbital therapy in barbiturate and other hypnosedative withdrawal reactions: A kinetic approach
Authors: Martin Peter R. , Kapur Bhushan M. , Whiteside Edwin A. , Sellers Edward M.
Published: January 2016

Phenobarbital (0.03 to 0.04 mg/kg/min) was infused intravenously in 7 patients with clinical hypnosedative withdrawal reactions until patients slept but were arousable. The infusion time to reach this clinical end point was 7.8 ± 1.1 hr (mean ± SEM), the total dose was 992 ± 144 mg, and the peak serum phenobarbital concentration was 26.1 ±5.1 µg/ml. A user of minimal hypnosedatives required 54% less phenobarbital and 65% lower concentration than any of the abusers to reach an equivalent state of intoxication. The mean serum half‐life (t½) was 57.5 ± 4.9 hr for hypnosedative abusers and 86 ± 3 hr for 8 normal volunteers (p < 0.001). Only the patient with the shortest t½ (36.4 hr) required oral phenobarbital supplements to prevent withdrawal symptoms. Dosage supplements required can be calculated from the postinfusion rate of fall of serum phenobarbital. Slow infusion of large amounts of phenobarbital provides a safe, efficacious single‐dose treatment.
XLIX. The basic data structures used in quantitative indexes
Authors: Feinstein Alvan R.
Published: January 2016

The domain of statistics is divided into two parts: descriptive and inferential. The inferential part contains the mathematical strategies that produce P values, confidence intervals, and other features of stochastic probability. The descriptive part is more mundane and often receives only cursory attention. In most textbooks and in classroom instruction, the descriptive features of statistics are usually taught rapidly as a necessary but relatively unimportant background for the inferential work. The means, proportions, rates, variances, distributions, correlation coefficients, and other descriptive statistical entities are generally presented as mere participants in the “important” inferential decisions that come later.
Estimation of kinetic parameters from a two‐point determination of the drug cumulation factor
Authors: Bjornsson Thorir D. , Shand David G.
Published: January 2016

A method is described which allows the calculation of kinetic parameters of drugs from two data points, involving a set of simple algebraic equations. This method is based on cumulation characteristics of drugs during multiple dosing. The necessary two blood samples are collected at the end of the first dosing interval and before a succeeding dose after steady state has been reached. The method is applicable for drugs which exhibit linear kinetic characteristics not subject to concentration or time‐dependent phenomena. The estimates of the kinetic parameters are associated with different ranges of possible errors, with total clearance being the most reliable estimate. The potential clinical utility of this method is discussed.
Multiple‐dose amikacin kinetics in pediatric oncology patients
Authors: Kramer William G. , Cleary Tom , Frankel Lawrence S. , Kohl Steve , Pickering Larry K.
Published: January 2016

Amikacin kinetics was studied in 8 pediatric oncology patients who received the drug by intravenous infusion over 30 or 60 min at a dose of 5 mg/kg every 6 or 8 hr. This regimen is recommended but, due to patient variability, patients should be monitored. Dosing intervals during 1 or 2 and 3 or 4 days of therapy were studied with serum samples collected before and at the end of the infusion and serially to the end of the dosing interval. The data appeared consistent with and were analyzed according to a l‐compartment model. An equation describing serum concentration with time for the multiple‐dose case was fit to each patient's multiple‐interval data with nonlinear regression. Half‐life averaged 1.2 hr, volume of distribution 0.24 l/kg, and total body clearance 109 ml/min/1.73 m2 or 2.51 ml/min/kg. The volume of distribution and the clearance are greater than reported for adults and probably account for the larger dose needed to achieve and maintain therapeutic levels. Although the total daily dose was greater than previously reported, there were no signs of toxicity, although therapeutic concentrations were maintained.
Effect of probenecid on cerebrospinal fluid methotrexate kinetics
Authors: Howell Stephen B. , Olshen Richard A. , Rice John A.
Published: January 2016

The effect of probenecid (PBC) on methotrexate (MTX) kinetics in the cerebrospinal fluid (CSF) and serum was studied in 4 patients on high‐dose MTX with leucovorin rescue to determine whether addition of PBC could prolong effective CSF MTX levels. Each patient received 2 courses of MTX, 1 with and 1 without PBC. PBC caused a 2.8 to 4.2‐fold increase in CSF MTX concentrations but failed to prolong the CSF half‐life (t½). PBC prolonged the initial MTX elimination tVi in the blood from 2.7 to 4.1 hr, but had little effect on subsequent t½is. No effect of MTX on PBC clearance was detected. Our data suggest that in man PBC in concentrations that were high enough to inhibit the renal clearance of MTX failed to alter the clearance of MTX from the CSF when both drugs were administered systemically.
Plasma theophylline levels after sustained‐release aminophylline
Authors: Trembath Peter W. , Boobis Susan W.
Published: January 2016

Healthy adult subjects were given oral sustained‐release (SR) aminophylline tablets 225 mg 12‐hourly (n =12) or 450 mg 12‐hourly (n = 6) for 5 doses, and all were given aminophylline 225 mg intravenously on a separate occasion to determine individual kinetic parameters. The mean plasma theophylline half‐life (t½) from the intravenous study was 5.8 hr (SD ± 1.9). During the 12 hr after the fifth dose of SR aminophylline, the maximum and minimum mean (SD) plasma theophylline levels were 9.7 (3.2) µg/ml and 4.9 (2.0) µg/ml for the 225‐mg dose, and 21.1 (2.2) µg/ml and 11.6 (4.4) µg/ml for the 450‐mg dose. Side effects were generally mild in the low‐dose study, but in the high‐dose study 3 subjects reported headache and 1 was withdrawn after 3 doses. Two subjects also noted nausea, and 3 reported insomnia and anxiety in the high‐dose study. It was concluded that there was a considerable range of doses needed to achieve adequate plasma levels, and that the formulation studied was capable of producing reasonably stable and satisfactory plasma theophylline levels once individual dose requirements had been established.
Hemodynamic effects of oxprenolol and propranolol in hypertension
Authors: Franciosa Joseph A. , Johnson Susan M. , Tobian Louis J.
Published: January 2016

Oxprenolol is a β‐adrenergic blocker with intrinsic sympathomimetic activity. Such drugs are not currently available in the United States, although they have the advantage of less negative inotropic effect than the available propranolol. In 18 patients with mild essential hypertension, oxprenolol (9 patients) or propranolol (9 patients) was added to thiazide in random double‐blind fashion and continued for 7 wk during which supine heart rate, blood pressure, and noninvasively measured cardiac output (by CO2 rebreathing) were determined weekly. With thiazide dosage constant throughout, maximal dose titration to 386.6 ± 52.1 (SEM) mg/day of oxprenolol and 360.0 ± 45.4 mg/day of propranolol was achieved over the first 5 wk. Blood pressure fell with both (141.8 ± 4.8/96.0 ± 2.3 to 128.0 ± 5.1187.2 ± 1.1 mm Hg on oxprenolol, p < 0.01; 150.8 ± 5.5/98.0 ± 1.7 to 129.9 ± 5.5/86.8 ± 3.4 mm Hg on propranolol, p < 0.01). Cardiac output fell from 6.85 ± 0.63 to 5.77 ± 0.45 l/min (p < 0.01) on oxprenolol, and from 6.79 ± 0.61 to 5.37 ± 0.37 Umin (p < 0.02) on propranolol. Oxprenolol reduced heart rate from 76.4 ± 2.0 to 65.6 ± 2.1 beatslmin (p < 0.001) and it fell from 82.0 ± 3.8 to 65.3 ± 3.7 beatslmin (p < 0.001) with propranolol; the fall in heart rate was less but not significantly so for oxprenolol (−14.2 ± 1.8% and −19.8 ± 2.8%, p < 0.1). Thus oxprenolol is equivalent to propranolol in antihypertensive action; minor hemodynamic differences between the two drugs might reflect intrinsic sympathomimetic activity of oxprenolol. Oxprenolol should be considered as an alternative to propranolol.
Kinetics of pamatolol, a cardioselective beta adrenoreceptor blocker
Authors: Carruthers S. George , Pentikainen Pertti , Hosier James P. , Azarnoff Daniel L.
Published: January 2016

The systemic bioavailability, elimination half‐life (t½), and plasma concentration‐response relationships of pamatolol, a relatively cardioselective beta adrenoceptor blocker, have been measured in healthy subjects. Pamatolol is rapidly and completely absorbed after ora! dosing. Elimination t½ ranged from 2.9 to 4.6 hr after oral doses and from 2.2 to 5.6 hr after intravenous doses. There was a clear relationship between log plasma pamatolol concentration and sympathetic blockade assessed by reduction of exercise heart rate. Concentration‐response curves were essentially identical after oral and intravenous doses. There is no evidence of a first‐pass effect, nor is there any evidence of metabolite activity.
Regional effects of propranolol on intraventricular conduction in coronary artery disease
Authors: Wiener Isaac , Mindich Bruce , DiStefano Douglas , Kupersmith Joel
Published: January 2016

In canines, propranolol slows conduction in acutely ischemic, but not in normal tissues. To determine propranolol effects on conduction in patients with coronary artery disease, we studied 7 patients after left anterior descending coronary artery bypass graft surgery. Bipolar electrodes were placed in the atrium, left ventricle (in the left anterior descending distribution), and right ventricle. On postoperative day 7, 3 mg propranolol were given intravenously. At a constant atrially paced rate, conduction intervals were measured from the earliest onset of the QRS in 3 simultaneously recorded surface electrocardiogram (ECG) leads to the major deflection of the electrogram recorded from each ventricle. Ten minutes after injection, conduction in the left ventricle was slowed by 4 ± 0.3 msec (10 ± 0.9%) and in the right ventricle by 0.4 ± 0.3 msec (1 ± 0.9%). QRS duration changed −1 msec (−0.8%). Stimulus to Q, a measure of propranol effect on A‐V conduction, changed 16 ± 2%. The difference in propranolol effects on left and right ventricles was significant (p < 0.001). We suggest that in patients with coronary artery disease (1) propranolol has local anesthetic effects in slowing conduction; (2) the effects of propranolol vary with the region of ventricular myocardium; and (3) propranolol slows conduction more in the left than right ventricle. This difference may be due to potentiation of drug effects in left ventricular tissue that is abnormal due to chronic coronary artery disease.
Rectal bioavailability of lidocaine in man: Partial avoidance of “first‐pass” metabolism
Authors: de Boer A. G. , Breimer D. D. , Mattie H. , Pronk J. , Gubbens-Stibbe J. M.
Published: January 2016

It is often speculated that after rectal administration drugs will enter the systemic circulation without first passing through the liver, because at least the lower hemorrhoidal veins are not connected to the portal system. To test this hypothesis, the systemic availability of the high‐clearance drug lidocaine was investigated in 6 healthy subjects following administration of 200 mg intravenous, 300 mg oral, and 300 mg rectal lidocaine in a balanced crossover design. Plasma and whole blood concentrations of lidocaine were measured by capillary gas chromatography. The mean rectal systemic availability was higher than the oral: 63% vs 31% (whole blood) and 71% vs 34% (plasma). The elimination half‐lifes (t½e1s) lidocaine were about the same intravenously and orally, whereas these were slightly longer after rectal administration. The oral and rectal investigations were repeated in the same panel of volunteers about 6 mo later. The mean rectal systemic availability, based on plasma concentrations, was then 67% vs 27% orally. Intraindividual variability was rather small, indicating that oral and rectal bioavailability of lidocaine is reproducible in individuals. An equation was derived for the calculation of the fraction of the dose given rectally that bypasses the liver after absorption which is slightly more than half the dose, assuming that dose is 100% absorbed. This investigation indicates that in principle it is possible to avoid, at least partly, drug loss caused by “first‐pass” metabolism by giving the drug rectally.
Screening methods using sulfamethazine for determining acetylator phenotype
Authors: du Souich Patrick , McLean Allan J. , Stoeckel Klaus , Ohlendorf Dieter , Gibaldi Milo
Published: January 2016

Analysis of sulfamethazine (SMZ) kinetics in man has revealed complexities including wide intersubject variability. In our study, an attempt was made to assess the potential influence of changes in nonmetabolic parameters (absorption and urinary elimination rate constants) on the markers of acetylation capacity normally used in clinical screening procedures to determine phenotype. Seven normal subjects were classified as slow (SA) or fast acetylators (FA) according to their metabolic rate constant for SMZ (Km), plasma SMZ half‐life, and percentage of N‐acetyl SMZ in a 6‐hr blood sample (PI6), a 5‐ to 6‐hr urine collection (UI6), or a 6‐hr total urine collection (UI6). Computer simulations were applied to baseline SMZ kinetic data from these subjects, varying nonmetabolic kinetic parameters over experimentally defined ranges singly, or in parallel with 1 or more of the other parameters. The simulations indicate that all the usual phenotyping procedures were sensitive to changes in absorption and urinary elimination rate constants. While these predictions require experimental confirmation, results show that the PI6 method is least sensitive to such changes, suggesting this method may minimize errors in phenotyping screening.
Highly Water‐Soluble Cyclopentadienyl and Indenyl Molybdenum(II) Complexes – Second Generation of Molybdenum‐Based Cytotoxic Agents
Authors: Mrózek Ondřej , Šebestová Lucie , Vinklárek Jaromír , Řezáčová Martina , Eisner Aleš , Růžičková Zdeňka , Honzíček Jan
Published: January 2016

A series of the cyclopentadienyl and indenyl molybdenum compounds bearing alkylammonium functions [(η5‐Cp′)Mo(CO)2(N,NL)][BF4]2 were synthesized and characterized by analytical and spectroscopic methods. The structures of [{η5‐C5H4CH2CH2NH(CH2)5}Mo(CO)2(4,7‐Ph2‐phen)][BF4]2 (4,7‐Ph2‐phen = 4,7‐diphenyl‐1,10‐phenanthroline) and [(η5‐C9H6CH2CH2NHMe2)Mo(CO)2(phen)][BF4]2 (phen = 1,10‐phenanthroline) were determined by X‐ray crystallography. All of the synthesized compounds exhibit high activity against the human leukemia cell lines MOLT‐4 and HL‐60. They are approximately one order of magnitude more active than cisplatin. This study has proven that the modification of the outer coordination sphere of molybdenum complexes has a strong impact on their activity and may be successfully used for the design of new highly cytotoxic active species.
Good Things in Store!
Authors: Hindson Karen
Published: January 2016

Editor Karen Hindson presents the changes that have been taking place in EurJIC and its sister journals and gives a preview of what is to come in 2016.
Deep Eutectic Solvents: The Organic Reaction Medium of the Century
Authors: Alonso Diego A. , Baeza Alejandro , Chinchilla Rafael , Guillena Gabriela , Pastor Isidro M. , Ramón Diego J.
Published: January 2016

This microreview summarizes the use of deep eutectic solvents (DESs) and related melts in organic synthesis. Solvents of this type combine the great advantages of other proposed environmentally benign alternative solvents, such as low toxicity, high availability, low inflammability, high recyclability, low volatility, and low price, avoiding many disadvantages of the more modern media. The fact that many of the components of these mixtures come directly from nature assures their biodegradability and renewability. The classification and distribution of the reactions into different sections in this microreview, as well as the emphasis paid to their scope, easily allow a general reader to understand the actual state of the art and the great opportunities opened, not only for academic purposes but also for industry.
Room‐Temperature Phosphorescence of Crystalline 1,4‐Bis(aroyl)‐2,5‐dibromobenzenes
Authors: Shimizu Masaki , Kimura Akinori , Sakaguchi Hiroshi
Published: January 2016

There is a growing interest in metal‐free organic luminophores that exhibit phosphorescence at room temperature. We report herein that 1,4‐bis(aroyl)‐2,5‐dibromobenzenes serve as a new class of such luminophores. The bis(aroyl)benzene derivatives were not emissive either in solution or in a doped polymer thin film. In contrast, crystals of bis(aroyl)benzenes showed photoluminescence under ambient conditions, which was subsequently confirmed as phosphorescence with a luminescence lifetime measurement. The emission color ranged from blue to green, depending on the nature of the aroyl groups, and the luminescent quantum yields were 0.05–0.18 at room temperature and 0.38–0.67 at 77 K. In each crystal, several intermolecular interactions such as C=O···H, Br···Br, C=O···Br, F···F, S···H, and MeO···H were observed, which contributed to the restriction of intramolecular motions, thereby diminishing the nonradiative decay process from the triplet excited states.
Lacosamide inhibits calcitonin gene‐related peptide production and release at trigeminal level in the rat
Authors: Greco M.C. , Capuano A. , Navarra P. , Tringali G.
Published: January 2016

Background

Several classes of drugs are effective in prevention and treatment of migraine, although they may differ among each other in their mode of action and in indications. One such class is represented by antiepileptics. Lacosamide is an approved antiepileptic drug that also shows antinociceptive activity in animal models, including analgesic efficacy in central and trigeminal pain. Calcitonin gene‐related peptide (CGRP) is considered the main neuro‐mediator of trigeminal signalling, playing an essential role in headache, migraine in particular. Here, we investigated the effects of lacosamide on CGRP signalling in both in vitro and ex vivo/vitro models in the rat.

Methods

We assessed: (1) CGRP released from brainstem explants at baseline or after pharmacological challenges; and (2) CGRP levels in brain areas after in vivo treatments with test drugs.

Results

We found that: (1) lacosamide inhibits CGRP release from brainstem explants under basal conditions as well as after stimulation by 56 mM KCl, 10 μM veratridine or 1 μM capsaicin; and (2) the i.p. administration of nitroglycerine produces an increase in CGRP levels in the brainstem and trigeminal ganglia, which is inhibited by a pre‐treatment with lacosamide.

Conclusions

These findings provide preliminary evidence suggesting that lacosamide is able to control pain transmission under conditions affecting the trigeminal system, such as migraine.
Fire resistance of geopolymer concrete produced from Elazığ ferrochrome slag
Authors: Türkmen İbrahim , Karakoç Mehmet Burhan , Kantarcı Fatih , Maraş Müslüm Murat , Demirboğa Ramazan
Published: January 2016

This paper presents the effect of elevated temperatures up to 700 °C on compressive strength and water absorption of two alkali‐activated aluminosilicate composites (one of them is river sand aggregate geopolymer concrete; the other one is crushed sand aggregate geopolymer concrete) and ordinary Portland cement based concretes. To obtain binding geopolymer material, Elazığ ferrochrome slag was ground as fine as cement, and then it was alkali activated with chemical (NaOH and Na2SiO3). Geopolymer concrete samples were produced by mixing this binding geopolymer material with aggregates. At each target temperature, concrete samples were exposed to fire for the duration of 1 h. Fire resistance and water absorption of geopolymer and ordinary Portland cement concrete samples were determined experimentally. Experimental results indicated that compressive strength of geopolymer concrete samples increased at 100 °C and 300 °C temperatures when compared with unexposed samples. In geopolymer concrete samples, the highest compressive strength was obtained from river aggregates ones at 300 °C with 37.06 MPa. Water absorption of geopolymer concrete samples increased at 700 °C temperature when compared with unexposed samples. However, a slight decrease in water absorption of concrete samples was observed up to 300 °C when compared with unexposed samples. SEM and X‐ray diffraction tests were also carried out to investigate microstructure and mineralogical changes during thermal exposure. Copyright © 2016 John Wiley & Sons, Ltd.
Genetics‐based dynamic systems model of canopy photosynthesis: the key to improve light and resource use efficiencies for crops
Authors: Song Qingfeng , Chu Chengcai , Parry Martin A. J. , Zhu Xin‐Guang
Published: January 2016

Improving canopy photosynthetic light use efficiency instead of leaf photosynthesis holds great potential to catalyze the next “green revolution”. However, leaves in a canopy experience different biochemical limitations due to the heterogeneities of microclimates and also physiological parameters. Mechanistic dynamic systems models of canopy photosynthesis are now available which can be used to design the optimal canopy architectural and physiological parameters to maximize CO2 uptake. Rapid development of modern crop genetics research now makes it possible to link such canopy models with genetic variations of crops to develop genetics‐based dynamic systems models of canopy photosynthesis. Such models can guide marker‐assisted breeding or genomic selection or engineering of crops to enhance light and nitrogen use efficiencies for different regions under future climate change scenarios.
Disciplinary Literacy Through the Lens of the Next Generation Science Standards
Authors: Houseal Ana , Gillis Victoria , Helmsing Mark , Hutchison Linda
Published: January 2016

The current discussion among adolescent literacy researchers describes two positions at either end of a continuum: a generalist content area reading approach and a disciplinary literacy approach. Within the field, there are misunderstandings about the disciplinary literacy approach and claims that adolescents are ill suited to the kinds of thinking advocated by disciplinary literacy scholars. This article explores disciplinary literacy through the lens of the Next Generation Science Standards (NGSS) and argues that requirements for discipline‐appropriate literacy abilities are already embedded in national standards for English language arts, mathematics, science, and social studies. We explore the practices and cross‐cutting concepts described in the NGSS and provide examples of discipline‐appropriate thinking associated with selected practices and concepts.
A review on carrier systems for bone morphogenetic protein‐2
Authors: Agrawal Vishal , Sinha Mukty
Published: January 2016

Bone morphogenetic protein‐2 (BMP‐2) has unique bone regeneration property. The powerful osteoinductive nature makes it considered as second line of therapy in nonunion bone defect. A large number of carriers and delivery systems made up of different materials have been investigated for controlled and sustained release of BMP‐2. The delivery systems are in the form of hydrogel, microsphere, nanoparticles, and fibers. The carriers used for the delivery are made up of metals, ceramics, polymers, and composites. Implantation of these protein‐loaded carrier leads to cell adhesion, degradation which eventually releases the drug/protein at site specific. But, problems like ectopic growth, lesser protein delivery, inactivation of the protein are reported in the available carrier systems. Therefore, it is need of an hour to modify the available carrier systems as well as explore other biomaterials with desired properties. In this review, all the reported carrier systems made of metals, ceramics, polymers, composites are evaluated in terms of their processing conditions, loading capacity and release pattern of BMP‐2. Along with these biomaterials, the attempts of protein modification by adding some functional group to BMP‐2 or extracting functional peptides from the protein to achieve the desired effect, is also evaluated. © 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 105B: 904–925, 2017.
Non‐viral approaches for direct conversion into mesenchymal cell types: Potential application in tissue engineering
Authors: Lee Eun‐Seo , Kim Seung Hyun L. , Lee Hwajin , Hwang Nathaniel S.
Published: January 2016

Acquiring adequate number of cells is one of the crucial factors to apply tissue engineering strategies in order to recover critical‐sized defects. While the reprogramming technology used for inducing pluripotent stem cells (iPSCs) opened up a direct path for generating pluripotent stem cells, a direct conversion strategy may provide another possibility to obtain desired cells for tissue engineering. In order to convert a somatic cell into any other cell type, diverse approaches have been investigated. Conspicuously, in contrast to traditional viral transduction method, non‐viral delivery of conversion factors has the merit of lowering immune responses and provides safer genetic manipulation, thus revolutionizing the generation of directly converted cells and its application in therapeutics. In addition, applying various microenvironmental modulations have potential to ameliorate the conversion of somatic cells into different lineages. In this review, we discuss the recent progress in direct conversion technologies, specifically focusing on generating mesenchymal cell types. © 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 104B: 686–697, 2016.
Rolled knitted scaffolds based onPLA‐pluronic copolymers for anterior cruciate ligament reinforcement: A step by step conception
Authors: Pinese Coline , Leroy Adrien , Nottelet Benjamin , Gagnieu Christian , Coudane Jean , Garric Xavier
Published: January 2016

The aim of this study was to prepare a new knitted scaffold from PLA‐Pluronic block copolymers for anterior cruciate ligament reconstruction. The impact of sterilization methods (beta‐ray and gamma‐ray sterilization) on copolymers was first evaluated in order to take into account the possible damages due to the sterilization process. Beta‐ray radiation did not significantly change mechanical properties in contrast to gamma‐ray sterilization. It was shown that ACL cells proliferate onto these copolymers, demonstrating their cytocompatibility. Thirdly, in order to study the influence of shaping on mechanical properties, several shapes were created with copolymers yarns: braids, ropes and linear or rolled knitted scaffolds. The rolled knitted scaffold presented interesting mechanical characteristics, similar to native anterior cruciate ligament (ACL) with a 67 MPa Young's Modulus and a stress at failure of 22.5 MPa. These findings suggest that this three dimensional rolled knitted scaffold meet the mechanical properties of ligament tissues and could be suitable as a scaffold for ligament reconstruction. © 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 105B: 735–743, 2017.
The CREB Transcription Factor Controls Transcriptional Activity of the Human RIC8B Gene
Authors: Maureira Alejandro , Sánchez Rodolfo , Valenzuela Nicole , Torrejón Marcela , Hinrichs María V. , Olate Juan , Gutiérrez José L.
Published: January 2016

Proper regulation of gene expression is essential for normal development, cellular growth, and differentiation. Differential expression profiles of mRNA coding for vertebrate Ric‐8B during embryo and adult stages have been observed. In addition, Ric‐8B is expressed in few cerebral nuclei subareas. These facts point to a dynamic control of RIC8B gene expression. In order to understand the transcriptional regulation of this gene, we searched for cis‐elements in the sequence of the human RIC8B promoter region, identifying binding sites for the basic/leucine zipper (bZip) CREB transcription factor family (CRE sites) and C/EBP transcription factor family (C/EBP sites). CRE sites were found clustered near the transcription start site, while the C/EBP sites were found clustered at around 300 bp upstream the CRE sites. Here, we demonstrate the ability of CREB1 and C/EBPβ to bind their respective elements identified in the RIC8B promoter. Comparative protein‐DNA interaction analyses revealed only the proximal elements as high affinity sites for CREB1 and only the distal elements as high affinity sites for C/EBPβ. Chromatin immunoprecipitation analyses, carried out using a human neuroblastoma cell line, confirmed the preferential association of CREB to the proximal region of the RIC8B promoter. By performing luciferase reporter assays, we found the CRE sites as the most relevant elements for its transcriptional activity. Taken together, these data show the existence of functional CREB and C/EBP binding sites in the human RIC8B gene promoter, a particular distribution of these sites and demonstrate a relevant role of CREB in stimulating transcriptional activity of this gene. J. Cell. Biochem. 117: 1797–1805, 2016. © 2016 Wiley Periodicals, Inc.
Dexamethasone‐Induced Skeletal Muscle Atrophy Increases O‐GlcNAcylation in C2C12 Cells
Authors: Massaccesi Luca , Goi Giancarlo , Tringali Cristina , Barassi Alessandra , Venerando Bruno , Papini Nadia
Published: January 2016

Skeletal muscle atrophy is a well‐known adverse effect of chronic treatment with glucocorticoids and it also occurs when stress conditions such as sepsis and cachexia increase the release of endogenous glucocorticoids. Although the mechanisms of action of these hormones have been elucidated, the possible molecular mechanisms causing atrophy are not yet fully understood. The involvement of the O‐GlcNAcylation process has recently been reported in disuse atrophy. O‐GlcNAcylation, a regulatory post‐translational modification of nuclear and cytoplasmic proteins consists in the attachment of O‐GlcNAc residues on cell proteins and is regulated by two enzymes: O‐GlcNAc‐transferase (OGT) and O‐GlcNAcase (OGA). O‐GlcNAcylation plays a crucial role in many cellular processes and it seems to be related to skeletal muscle physiological function. The aim of this study is to investigate the involvement of O‐GlcNAcylation in glucocorticoid‐induced atrophy by using an “in vitro” model, achieved by treatment of C2C12 with 10 μM dexamethasone for 48 h. In atrophic condition, we observed that O‐GlcNAc levels in cell proteins increased and concomitantly protein phosphorylation on serine and threonine residues decreased. Analysis of OGA expression at mRNA and protein levels showed a reduction in this enzyme in atrophic myotubes, whereas no significant changes of OGT expression were found. Furthermore, inhibition of OGA activity by Thiamet G induced atrophy marker expression. Our current findings suggest that O‐GlcNAcylation is involved in dexamethasone‐induced atrophy. In particular, we propose that the decrease in OGA content causes an excessive and mostly durable level of O‐GlcNAc residues on sarcomeric proteins that might modify their function and stability. J. Cell. Biochem. 117: 1833–1842, 2016. © 2016 Wiley Periodicals, Inc.
Cell‐Autonomous Brown‐Like Adipogenesis of Preadipocytes From Retinoblastoma Haploinsufficient Mice
Authors: Petrov Petar D. , Palou Andreu , Bonet M. Luisa , Ribot Joan
Published: January 2016

Mechanisms behind the emergence of brown adipocyte‐like (brite or beige) adipocytes within white adipose tissue (WAT) are of interest. Retinoblastoma protein gene (Rb) haploinsufficiency associates in mice with improved metabolic regulation linked to a greater capacity for fatty acid oxidation and thermogenesis in WAT. We aimed to explain a feasible mechanism of WAT‐to‐BAT remodeling in this model. Differentiated primary adipocytes and Sca1‐positive preadipocytes derived from adipose depots of Rb+/− mice and wild‐type siblings were compared. Primary white Rb+/− adipocytes displayed under basal conditions increased glucose uptake and an enhanced expression of brown adipocyte‐related genes (Pparg, Ppargc1a, Ppargc1b, Prdm16, Cpt1b) but not of purported beige/brite transcriptional markers (Cd137, Tmem26, Tbx1, Slc27a1, Hoxc9, Shox2). Lack of induction of beige markers phenocopied results in WAT of adult Rb+/− mice. Flow cytometry analysis evidenced an increased number of preadipocytes in WAT depots of Rb+/− mice. Sca1+ preadipocytes from WAT of Rb+/− mice displayed increased gene expression of several transcription factors common to the brown and beige adipogenic programs (Prdm16, Pparg, Ppargc1a) and of receptors of bone morphogenetic proteins (BMPs); however, among the recently proposed beige markers, only Tbx1 was upregulated. Adult Rb+/− mice had increased circulating levels of BMP7. These results indicate that preadipose cells resident in WAT depots of Rb+/− mice retain an increased capacity for brown‐like adipogenesis that appears to be different from beige adipogenesis, and suggest that the contribution of these precursors to the Rb+/− adipose phenotype is driven, at least in part, by interaction with BMP7 pathways. J. Cell. Physiol. 231: 1941–1952, 2016. © 2016 Wiley Periodicals, Inc.
Increased expression of H19/miR‐675 is associated with a low fat‐free mass index in patients with COPD
Authors: Lewis Amy , Lee Jen Y. , Donaldson Anna V. , Natanek S. Amanda , Vaidyanathan Srividya , Man William D.‐C. , Hopkinson Nicholas S. , Sayer Avan A. , Patel Harnish P. , Cooper Cyrus , Syddall Holly , Polkey Michael I. , Kemp Paul R.
Published: January 2016

Background

Loss of muscle mass and strength is a significant comorbidity in patients with chronic obstructive pulmonary disease (COPD) that limits their quality of life and has prognostic implications but does not affect everyone equally. To identify mechanisms that may contribute to the susceptibility to a low muscle mass, we investigated microRNA (miRNA) expression, methylation status, and regeneration in quadriceps muscle from COPD patients and the effect of miRNAs on myoblast proliferation in vitro. The relationships of miRNA expression with muscle mass and strength was also determined in a group of healthy older men.

Methods

We identified miRNAs associated with a low fat‐free mass (FFM) phenotype in a small group of patients with COPD using a PCR screen of 750 miRNAs. The expression of two differentially expressed miRNAs (miR‐675 and miR‐519a) was determined in an expanded group of COPD patients and their associations with FFM and strength identified. The association of these miRNAs with FFM and strength was also explored in a group of healthy community‐dwelling older men. As the expression of the miRNAs associated with FFM could be regulated by methylation, the relative methylation of the H19 ICR was determined. Furthermore, the proportion of myofibres with centralized nuclei, as a marker of muscle regeneration, in the muscle of COPD patients was identified by immunofluorescence.

Results

Imprinted miRNAs (miR‐675 and from a cluster, C19MC which includes miR‐519a) were differentially expressed in the quadriceps of patients with a low fat‐free mass index (FFMI) compared to those with a normal FFMI. In larger cohorts, miR‐675 and its host gene (H19) were higher in patients with a low FFMI and strength. The association of miR‐519a expression with FFMI was present in male patients with severe COPD. Similar associations of miR expression with lean mass and strength were not observed in healthy community dwelling older men participating in the Hertfordshire Sarcopenia Study. Relative methylation of the H19 ICR was reduced in COPD patients with muscle weakness but was not associated with FFM. In vitro, miR‐675 inhibited myoblast proliferation and patients with a low FFMI had fewer centralized nuclei suggesting miR‐675 represses regeneration.

Conclusions

The data suggest that increased expression of miR‐675/H19 and altered methylation of the H19 imprinting control region are associated with a low FFMI in patients with COPD but not in healthy community dwelling older men suggesting that epigenetic control of this loci may contribute to a susceptibility to a low FFMI.