bluuebunny/crossref_metadata_2025 huggingface dataset:
A stereochemical investigation of the cytotoxicity of mianserin metabolites in vitro.
Authors: Riley RJ , Lambert C , Kitteringham NR , Park BK
Published: July 2012

1. The metabolism of the enantiomers of mianserin to stable, chemically reactive and cytotoxic metabolites by human liver microsomes has been investigated in vitro. 2. Both enantiomers were metabolised to three major oxidation products: 8‐hydroxymianserin, desmethylmianserin and mianserin 2‐oxide. Hydroxylation occurred more readily with the S‐ enantiomer, whereas desmethylmianserin was always the major metabolite of the R‐enantiomer. 3. The generation of chemically reactive metabolites exhibited a marginal degree of stereoselectivity, as assessed by irreversible binding of drug to microsomal protein (S greater than or equal to R; P less than or equal to 0.05). 4. The formation of metabolites which were cytotoxic towards human mononuclear leucocytes was greater (P less than or equal to 0.001] for R(‐)‐ mianserin than for S(+)‐mianserin and showed a significant correlation with N‐demethylation (r = 0.84, P less than or equal to 0.01).
Unbound phenytoin plasma concentrations in patients comedicated with sodium valproate‐the predictive value of plasma albumin concentration.
Authors: Johnson GJ , Kilpatrick CJ , Bury RW , Fullinfaw RO , Moulds RF
Published: July 2012

1. Phenytoin protein binding in epileptic patients on phenytoin as monotherapy has been compared with protein binding in patients treated with both phenytoin and sodium valproate. In addition the relative value of assayed total phenytoin plasma concentrations and assayed unbound phenytoin plasma concentrations and the value of predicted unbound phenytoin plasma concentrations in predicting phenytoin toxicity has been assessed. 2. The mean phenytoin unbound fraction for patients taking sodium valproate (0.122) was significantly greater than for those on monotherapy (0.082). 3. There were six episodes of clinical toxicity. In five toxic episodes the assayed unbound phenytoin plasma concentration was a better reflection of toxicity than the assayed total phenytoin plasma concentration, and four of these occurred in patients on sodium valproate. 4. Unbound phenytoin plasma concentrations were predicted from a single regression equation correlating all assayed total phenytoin plasma concentrations with assayed unbound phenytoin plasma concentrations, from two separate regression equations for each group of patients, and from the correlation between phenytoin protein binding and plasma albumin concentration. 5. The unbound phenytoin plasma concentrations predicted from the two regression equations were statistically no less effective than the assayed unbound phenytoin plasma concentrations in assessing toxicity. 6. Despite a correlation between plasma albumin concentrations and phenytoin protein binding, the use of albumin concentrations in predicting unbound phenytoin plasma concentrations appeared to be of little additional benefit.
Effect of food on the absorption of vigabatrin.
Authors: Frisk‐Holmberg M , Kerth P , Meyer P
Published: July 2012

1. This study, involving eight healthy volunteers, revealed that food intake does not have a clinically significant effect on vigabatrin kinetics. 2. Kinetics of vigabatrin in the fasting state showed low inter‐individual variation. 3. The plasma concentration vs time profile followed a bi‐exponential decline with a terminal half‐life of 6.8 h and a relative bioavailability of 92% +/‐ 11%. 4. In the clinical setting, vigabatrin may be taken at times convenient for the patient.
Neuropathology of vigabatrin.
Authors: Graham D
Published: July 2012

1. Neuropathological changes in experimental animals have been observed with vigabatrin treatment in mice, rats and dogs. 2. These changes have comprised intramyelinic oedema which is reversible on cessation of treatment. 3. In human studies so far, no intramyelinic oedema has been noted. It is not clear whether humans will show the neurotoxicity observed in animals; close monitoring of patients is indicated.
Cerebrospinal fluid GABA and seizure control with vigabatrin.
Authors: Riekkinen PJ , Ylinen A , Halonen T , Sivenius J , Pitkanen A
Published: July 2012

1. To evaluate the relationship between the clinical response and enhancement of GABAergic neurotransmission, for 6 months we administered vigabatrin (gamma‐vinyl‐GABA, GVG) to 75 patients with complex partial epilepsy. Total GABA (TGABA), free GABA (FGABA), homocarnosine (HC), and GVG concentrations were measured in CSF of these patients before and during GVG treatment. 2. Over 50% reduction in seizures was found in 55% of the patients. Dose‐reduction resulted in a relapse, i.e. the return of seizures. 3. At baseline TGABA, FGABA, and HC did not differ in responders and nonresponders. After GVG treatment, the TGABA and HC levels were lower in nonresponders (P less than 0.001), but the GVG and FGABA levels did not differ. The GVG dose reduction resulted in a concomitant decrease in TGABA, FGABA, HC and GVG (P less than 0.001). 4. According to our results GVG is an effective anticonvulsant drug in complex partial seizures. In nonresponders the poor anticonvulsant response may be related to the lower elevation of the CSF markers of GABAergic neuronal activity in this group compared with the responders.
Vigabatrin in the treatment of epilepsy in children.
Authors: Livingston JH , Beaumont D , Arzimanoglou A , Aicardi J
Published: July 2012

1. This study presents the results of the preliminary screening of vigabatrin as add‐on therapy in an open, non‐controlled multicentre study in children with refractory epilepsy. 2. There were 135 children, with an age range of 2 months‐12 years. Main seizure type was partial in 42%, generalized in 29%, Lennox‐Gastaut syndrome in 19% and West syndrome in 10%. 3. Vigabatrin was added onto current antiepileptic treatment in an initially recommended dose of 40‐80 mg kg‐1 day‐1. However, the doses were frequently increased when tolerance allowed it, and the final mean dose used was 87 mg kg‐1 day‐1 (27‐600). 4. A 75% to 100% reduction in seizure frequency was observed in 25% of patients (11 patients became seizure free) and 50 to 75% decrease in a further 13%. Efficacy was better in partial seizures, with good to excellent results in 49% of patients. The use of high doses, above 100 mg kg‐1 day, was not associated with greater efficacy in this preliminary study. 5. No side effects were reported in 79% of patients. Agitation and insomnia were observed in 8.8% and somnolence in 6%. Other adverse events included ataxia (2.2%), nausea (2.2%) and increased appetite (1%). A moderate and transient decrease in haemoglobin was reported in six patients from the same centre; these patients were all receiving very high doses of vigabatrin (250 to 600 mg kg‐1 day‐1). 6. Vigabatrin thus appears to be a safe antiepileptic drug that may be effective in the treatment of severe epilepsy in children.
Effects of xamoterol on sodium excretion in volunteers.
Authors: Zech PY , Pozet N , Day MA , Snow HM , Madonna O , Hadj‐Aissa A
Published: July 2012

Xamoterol has been shown to reduce the frequency of oedema and lung crepitations in heart failure. We examined its effects on blood pressure and renal function in healthy volunteers. Systolic blood pressure rose, sodium and chloride excretion increased and there was a strong correlation in individual subjects between rises in systolic blood pressure and in sodium excretion. Although no changes in glomerular filtration rates were seen, changes sufficient to explain the observed rise in sodium excretion are well within the experimental error of this study. Xamoterol may increase sodium excretion by an action on renal haemodynamics.
The renal effects of atrial natriuretic peptide in man are not attenuated by (+)‐sulpiride.
Authors: Freestone S. , MacDonald TM , Jeffrey RF , Brown J. , Lee MR
Published: July 2012

1. Human alpha atrial natriuretic peptide (ANP) was infused intravenously for 1 h in eight healthy salt‐replete men on two occasions, with and without pretreatment with (+)‐sulpiride. 2. ANP increased sodium excretion and urine flow rate but did not alter blood pressure or plasma renin activity. 3. (+)‐sulpiride had no significant effect on baseline creatinine clearance, sodium excretion or urine flow rate and did not alter the increases in these parameters with ANP. 4. It is unlikely that the renal effects of ANP are mediated by dopamine DA1‐receptors in man.
Effect of the combination of alinidine and other anti‐anginal drugs on heart rate and blood pressure in healthy volunteers.
Authors: Harron DW , Deering AH , Scott M. , McMahon M. , Shanks RG
Published: July 2012

1. Heart rate and blood pressure changes following the administration of alinidine 30 mg alone and in combination with atenolol 25 mg, nifedipine retard 20 mg and glyceryl trinitrate 500 micrograms were investigated in three groups of six healthy male volunteers. 2. Concomitant administration of alinidine and atenolol reduced (P less than 0.05) supine, standing and exercise heart rate when compared with alinidine alone. The maximum reduction in exercise heart rate was 116 +/‐ 2.4 beats min‐1 for the combination vs 129.0 +/‐ 3.1 beats min‐1 for alinidine alone. 3. Supine (3, 4, 8 h) and standing (2 h) systolic BP were also reduced (P less than 0.05) with the alinidine and atenolol combination compared with alinidine alone. Little change occurred in diastolic blood pressure. 4. Alinidine and nifedipine in combination reduced (P less than 0.05) the nifedipine induced increase in heart rate in the supine (2, 4 h) and standing (4 h) position and following exercise (2, 4 h). No further decreases in systolic and diastolic blood pressure occurred with the combination. 5. Alinidine administered 2 h before a glyceryl trinitrate challenge reduced (P less than 0.05) the glyceryl trinitrate induced increase in standing heart rate at all time intervals (1 to 6 min); the maximum reduction occurred at 3 min (105.0 +/‐ 4.3 (glyceryl trinitrate) vs 86.8 +/‐ 6.7 beats min‐1 (combination]. Systolic blood pressure was further reduced at all time intervals with glyceryl trinitrate taken in the presence of alinidine.(ABSTRACT TRUNCATED AT 250 WORDS)
Beta‐adrenoceptors and human skeletal muscle characterisation of receptor subtype and effect of age.
Authors: Elfellah MS , Dalling R. , Kantola IM , Reid JL
Published: July 2012

1. Rectus abdominis muscle biopsies were obtained from 28 patients undergoing abdominal surgery. In membranes prepared from these biopsies beta‐adrenoceptor binding was examined. The apparent affinity (KD) and the density (Bmax) of the receptors for the radioligand (−)− [125I]cyanopindolol were 28.5 +/‐ 2.7 (pM) and 25.9 +/‐ 2.1 (fmol mg‐1 protein) (mean +/‐ s.e. mean) respectively. In forceps biopsies from vastus lateralis muscle from four healthy volunteers the values for KD and Bmax were 22.5 +/‐ 4.4 (pM) and 16.4 +/‐ 2.2 (fmol mg‐1 protein). The binding characteristics for the radioligand were similar in the biopsies from the two muscle sites. 2. Inhibition of the radioligand binding by the selective beta 2‐adrenoceptor antagonist ICI 118551 (KI = 117 +/‐ 45 nM) and selective beta 1‐adrenoceptor antagonist metoprolol (KI = 15229 +/‐ 5046 nM) suggests the dominance of beta 2‐ adrenoceptor subtype in human skeletal muscle. 3. There were no significant differences in the skeletal muscle beta‐adrenoceptor densities or affinities between the young and older patients.
The pharmacokinetics of caffeine and its dimethylxanthine metabolites in patients with chronic liver disease.
Authors: Scott NR , Stambuk D. , Chakraborty J. , Marks V. , Morgan MY
Published: July 2012

1. Serum and salivary concentrations of caffeine (1,3,7‐ trimethylxanthine) and its dimethylxanthine metabolites were measured in 10 healthy control subjects and in 19 patients with cirrhosis, for up to 96 h following a 400 mg oral caffeine load. 2. Serum and salivary caffeine concentrations correlated significantly (r = 0.954; P less than 0.001) and no significant differences were observed in the pharmacokinetic data derived from the respective concentration‐time curves. 3. In the control subjects, basal salivary caffeine concentrations did not exceed 0.4 mg l‐1. The median (range) basal salivary caffeine concentrations in patients with compensated cirrhosis (n = 10), 0.2 (0‐0.7) mg l‐1 and decompensated cirrhosis (n = 9), 0.7 (0‐5.8) mg l‐1, were not significantly different from control values, although three patients with decompensated cirrhosis had basal salivary caffeine values above 2.0 mg l‐1. 4. In the patients with compensated cirrhosis, the median peak salivary caffeine concentration, 10.9 (8.2‐ 16.5) mg l‐1 was significantly greater than in controls, 7.1 (4.7‐11.8) mg l‐1 (P less than 0.01) and the median apparent volume of distribution was significantly reduced, 0.38 (0.19‐0.49) vs 0.41 (0.23‐ 0.63) l kg‐1 (P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)
The effect of carbamazepine on valproic acid disposition in adult volunteers.
Authors: Panesar SK , Orr JM , Farrell K. , Burton RW , Kassahun K. , Abbott FS
Published: July 2012

1. Pharmacokinetic parameters for valproic acid (VPA) were determined before and following 2 weeks of carbamazepine (CBZ) administration in five healthy male volunteers. Mean VPA dosage was 16.4 mg kg‐1 day‐1. CBZ dosage was started at 100 mg twice daily and increased after 1 week to a total daily dose of 300 mg. 2. After CBZ administration, mean VPA plasma clearance increased from 0.90 +/‐ 0.18 s.d. to 1.26 +/‐ 0.24 l h‐ 1 (P less than 0.05) as did clearance of free VPA (20.8 +/‐ 7.6 to 37.0 +/‐ 13.6 l h‐1). Mean VPA elimination rate constant increased from 0.051 +/‐ 0.011 to 0.067 +/‐ 0.011 h‐1 (P less than 0.05) after CBZ administration. 3. Mean area under the serum concentration vs time curve decreased from 675.0 +/‐ 130.5 to 475.7 +/‐ 75.7 mg l‐1 h (P less than 0.05) after CBZ administration. Mean serum VPA half‐life decreased from 14.0 +/‐ 2.4 to 10.6 +/‐ 1.4 h (P less than 0.05). Mean serum VPA trough concentrations decreased from 44.0 +/‐ 16.7 to 27.0 +/‐ 10.4 micrograms ml‐1 (P less than 0.05). 4. A significant change was not observed in the mean VPA volume of distribution after CBZ coadministration suggesting that enzyme induction rather than a competition for plasma protein binding sites was involved in this interaction. 5. Despite the increased clearance of VPA, the urinary recovery of VPA or conjugate did not increase after CBZ administration.
The need for reassessment of digoxin prescribing for the elderly.
Authors: Nolan L. , Kenny R. , O'Malley K.
Published: July 2012

1. The prevalence and circumstance of digoxin prescribing was assessed in five private nursing homes. 2. Forty‐one patients (21% residents) were taking digoxin. 3. Seventeen patients were in atrial fibrillation and the remainder in sinus rhythm. The ventricular rate exceeded 100 beats min‐1 in eight of the 17 patients in atrial fibrillation. 4. Thirty‐seven patients were prescribed 0.0625 mg digoxin daily and serum digoxin concentrations were subtherapeutic in 20 of 32 patients in whom concentrations were measured. 5. These data indicate a need for more careful review of the need for maintenance digoxin and illustrate the inappropriateness of routinely prescribing very low doses in all elderly patients.
A double‐blind randomized cross‐over study of the efficacy and tolerability of nifedipine and nitrendipine in the treatment of mild to moderate hypertension.
Authors: Heagerty AM , Swales JD
Published: July 2012

1. In order to examine whether nitrendipine was superior to slow release nifedipine as monotherapy in the treatment of mild to moderate essential hypertension, the two agents were administered to 22 patients in a double‐blind randomized cross‐over study, incorporating low and titrated dose regimes. 2. Six patients failed to complete the study because of vasodilator side‐effects such as headache, flushing and ankle swelling. Three were taking nitrendipine and three took nifedipine and all withdrawals occurred at the introduction of the drug. 3. Both agents reduced blood pressure in the 16 patients who completed the study, and neither agent was superior to the other; mean blood pressure after the placebo phase was 177 +/‐ 5.5/100 +/‐ 2.6 mm Hg supine and 175 +/‐ 5.3/113 +/‐ 2.4 mm Hg standing. At the end of therapy with nifedipine pressures were 160 +/‐ 4.0/91 +/‐ 3.0 mm Hg supine and 158 +/‐ 4.6/103 +/‐ 2.7 mm Hg standing. After 8 weeks treatment with nitrendipine blood pressures were 162 +/‐ 4.4/90 +/‐ 2.9 mm Hg supine and 161 +/‐ 6.2/104 +/‐ 2.7 mm Hg standing. Comparisons of these attained blood pressures on both agents showed no statistically significant differences. 4. Nitrendipine did not appear to be effective on a once daily basis.
Variable metabolism of pinacidil: lack of correlation with the debrisoquine and trimethylamine C‐ and N‐oxidative polymorphisms.
Authors: Ayesh R. , Al‐Waiz M. , McBurney A. , Mitchell SC , Idle J.R. , Ward JW , Smith RL
Published: July 2012

1. The urinary excretion of pinacidil and its N‐oxide in man was found to vary over a five‐fold range. 2. Studies in individuals with inherited deficiencies for C‐hydroxylation (debrisoquine type) and trimethylamine N‐oxidation showed that the N‐oxidation of pinacidil did not co‐segregate with these oxidative polymorphisms. 3. It is concluded that the variable N‐oxidation of pinacidil is most likely to be due to variations in the activity of the P‐450 isozymes rather than in the microsomal flavoprotein containing mixed‐function amine oxidase of Ziegler which is considered to be responsible for the N‐oxidation of trimethylamine.
Genetically‐determined interaction between propafenone and low dose quinidine: role of active metabolites in modulating net drug effect.
Authors: Funck‐Brentano C. , Kroemer HK , Pavlou H. , Woosley RL , Roden DM
Published: July 2012

1. Quinidine is a potent inhibitor of the genetically‐determined debrisoquine 4‐hydroxylation. Oxidation reactions of several other drugs, including the 5‐hydroxylation of the new antiarrhythmic drug propafenone, depend on the isozyme responsible for debrisoquine 4‐ hydroxylation. 2. The effect of quinidine on the debrisoquine phenotype‐ dependent 5‐hydroxylation and the pharmacological activity of propafenone was studied in seven ‘extensive’ metabolizers and two ‘poor’ metabolizers of the drug receiving propafenone for the treatment of ventricular arrhythmias. 3. In patients with the extensive metabolizer phenotype, quinidine increased mean steady‐state plasma propafenone concentrations more than two fold, from 408 +/‐ 351 (mean +/‐ s.d.) to 1096 +/‐ 644 ng ml‐1 (P less than 0.001), decreased 5‐ hydroxypropafenone concentrations from 242 +/‐ 196 to 125 +/‐ 97 ng ml‐ 1 (P less than 0.02) and reduced propafenone oral clearance by 58 +/‐ 23%. 4. Despite these changes in plasma concentrations, electrocardiographic intervals and arrhythmia frequency were unaltered by quinidine coadministration, indicating that 5‐hydroxypropafenone contributes to the pharmacologic effects of propafenone therapy in extensive metabolizers. 5. In contrasts, plasma concentrations of propafenone and 5‐hydroxypropafenone remained unchanged in the two patients with the poor metabolizer phenotype. 6. Biotransformation of substrates for the debrisoquine pathway can be markedly perturbed by even low doses of quinidine; interindividual variability in drug interactions may have a genetic component.
Stereoselective binding of propranolol in the elderly.
Authors: Colangelo P. , Chandler M. , Blouin R. , McNamara P.
Published: July 2012

The influence of age on the stereoselective serum protein binding of propranolol was investigated. Serum was obtained from 10 young (mean age 23 +/‐ 2 years) and ten elderly (mean age 68 +/‐ 2 years) healthy male volunteers. The free fraction of propranolol (fu) was measured by equilibrium dialysis, using tritium labeled (+/‐)‐ and (−)−propranolol. The fu values were 0.159 +/‐ 0.049 and 0.148 +/‐ 0.028 (+/‐), 0.135 +/‐ 0.041 and 0.136 +/‐ 0.04 (‐), 0.174 +/‐ 0.056 and 0.161 +/‐ 0.028 (+) in the young and elderly subjects, respectively. Serum alpha 1‐acid glycoprotein (AAG) concentrations were 81.4 +/‐ 33.0 and 81.0 +/‐ 21.6 mg 100 ml‐1 in young and elderly respectively (P greater than 0.05). Variability in AAG concentration accounted for most of the observed intersubject variability in the binding of both propranolol isomers. The stereoselective binding of propranolol does not appear to be affected by age.
Histamine N‐methyl transferase: inhibition by drugs.
Authors: Pacifici GM , Donatelli P. , Giuliani L.
Published: July 2012

1. Histamine N‐methyl transferase activity was measured in samples of human liver, brain, kidney, lung and intestinal mucosa. The mean (+/‐ s.d.) rate (nmol min‐1 mg‐1 protein) of histamine N‐methylation was 1.78 +/‐ 0.59 (liver, n = 60), 1.15 +/‐ 0.38 (renal cortex, n = 8), 0.79 +/‐ 0.14 (renal medulla, n = 8), 0.35 +/‐ 0.08 (lung, n = 20), 0.47 +/‐ 0.18 (human intestine, n = 30) and 0.29 +/‐ 0.14 (brain, n = 13). 2. Inhibition of histamine N‐methyl transferase by 15 drugs was investigated in human liver. The IC50 for the various drugs ranged over three orders of magnitude; chloroquine was the most potent inhibitor. 3. The average IC50 values for chloroquine were 12.6, 22.0, 19.0, 21.6 microM in liver, renal cortex, brain and colon, respectively. These values are lower than the Michaelis‐Menten constant for histamine N‐ methyltransferase in liver (43.8 microM) and kidney (45.5 microM). Chloroquine carried a mixed non‐competitive inhibition of hepatic histamine N‐methyl transferase. Some side‐effects of chloroquine may be explained by inhibition of histamine N‐methyl transferase.
Plasma morphine‐3‐glucuronide, morphine‐6‐glucuronide and morphine concentrations in patients receiving long‐term epidural morphine.
Authors: Schneider JJ , Ravenscroft PJ , Cavenagh JD , Brown AM , Bradley JP
Published: July 2012

Plasma morphine concentrations were measured in five cancer patients receiving long‐term epidural morphine administration. Peak concentrations were observed within 1 h of dosage and concentrations then declined biexponentially. Plasma morphine‐3‐glucuronide (M3G) and morphine‐6‐glucuronide (M6G) concentrations were measured in two patients and plasma M3G concentrations were observed to be much higher than plasma M6G and morphine concentrations. Peak plasma M6G concentrations occurred within 1.0 h of dosing and plasma M6G concentrations then remained higher than plasma morphine concentrations.
The effect of genetically engineered glucagon on glucose recovery after hypoglycaemia in man.
Authors: Hvidberg A. , Jorgensen S. , Hilsted J.
Published: July 2012

To compare the effect on glucose recovery after insulin‐induced hypoglycaemia of intramuscular genetically engineered glucagon, intramuscular glucagon from pancreatic extraction and intravenous glucose, we examined 10 healthy subjects during blockage of glucose counterregulation with somatostatin, propranolol and phentolamine. Each subject was studied on three separate occasions. Thirty min after a bolus injection of 0.075 iu soluble insulin per kilogram body weight the subjects received one of the following treatments: 1 mg glucagon from pancreatic extraction intramuscularly; 1 mg genetically engineered glucagon intramuscularly; and 25 g glucose intravenously, respectively. The two glucagon preparations induced an equally rapid increase in plasma glucose. This was due to an abrupt (within 4 min) and equal increase in glucose appearance rate. The increases in both plasma glucose and in glucose appearance rate were far more protracted after i.m. glucagon than after i.v. glucose. These results suggest that genetically engineered glucagon and glucagon from pancreatic extraction have a similar effect on hepatic glucose production rate. Due to the protracted effect of intramuscular glucagon, a combined treatment consisting of both intravenous glucose and intramuscular glucagon may be more effective in the treatment of hypoglycaemia than any of these given alone.
Effect of 3 weeks treatment with yohimbine on salivary secretion in healthy volunteers and in depressed patients treated with tricyclic antidepressants.
Authors: Bagheri H. , Schmitt L. , Berlan M. , Montastruc JL
Published: July 2012

The effect of yohimbine treatment (4 mg three times daily) for 3 weeks on salivary secretion was investigated. In healthy volunteers, acute administration of yohimbine increased salivary volume within 1 h to a similar extent before and at the end of the treatment period. In depressed patients treated with tricyclic antidepressants (and exhibiting a reduced salivary flow), yohimbine also acutely increased salivary volume. In contrast, the alpha 2‐adrenoceptor antagonist failed to modify resting values measured in the morning (i.e. 10 and 14 h after the last administration in healthy volunteers and depressed patients respectively). This result indicates that alpha 2‐adrenoceptor antagonists may have a potential therapeutic use in the treatment of dry mouth caused by tricyclic antidepressant drugs.
An investigation into the effect of tenidap sodium on the pharmacokinetics of a combined oral contraceptive.
Authors: Coates PE , Mesure R
Published: July 2012

1. The effects of tenidap sodium and placebo on the pharmacokinetics of a combined oral contraceptive (Microgynon 30) were evaluated in 18 healthy premenopausal women in a double‐blind, cross‐over study lasting two menstrual cycles. 2. Tenidap (120 mg day‐1) or placebo was given for 11 days, starting within 4 days of menstruation and Microgynon 30, containing levonorgestrel (150 micrograms) and ethinyloestradiol (30 micrograms), was administered on day 10 of tenidap therapy. 3. The mean maximum plasma levonorgestrel concentrations (Cmax), time to Cmax (tmax) and area under the plasma time‐concentration curves (AUC(0,t)) did not differ between subjects given tenidap or placebo. The Cmax, tmax and AUC(0,t) values for ethinyloestradiol did not differ between tenidap and placebo recipients. Only the ethinyloestradiol Cmax showed a significant difference (P = 0.02) between menstrual cycles 1 and 2 (252.9 pg ml‐1 and 271.3 pg ml‐1, respectively). 4. Co‐administration of tenidap and Microgynon 30 was well tolerated and no subject withdrew from the study because of side‐effects. There were no side‐effects considered to be related to tenidap and no clinically significant laboratory abnormalities were considered to be related to treatment. 5. The results of the study suggest that the pharmacokinetics of the oestrogen and progestin components of the oral contraceptive Microgynon 30 are unlikely to be affected by concomitant administration of tenidap.
The effect of tenidap on the anti‐hypertensive efficacy of ACE inhibitors in patients treated for mild to moderate hypertension.
Authors: Rapeport WG , Grimwood VC , Hosie J , Sloan PM , Korlipara K , Silvert BD , James I , Mechie GL , Anderton JL
Published: July 2012

1. A randomised, placebo controlled, double‐blind, parallel group study was conducted to assess the effect of tenidap sodium, a novel cytokine modulating drug, on the stable hypotensive response to the angiotension converting enzyme (ACE) inhibitor enalapril in subjects with mild to moderate, uncomplicated, essential hypertension. 2. Twenty‐four male and female hypertensives, aged 33‐77 years, received either 120 mg tenidap sodium or matched placebo daily for 22 days concomitantly with enalapril. 3. Mean endpoint supine and standing, systolic and diastolic pressures remained within 10% of baseline in each treatment group. However, the endpoint values were marginally above baseline during double‐blind treatment with tenidap and marginally below baseline in the group receiving placebo. The increases in supine and standing systolic pressures in the tenidap group differed significantly from the changes in the placebo group. There were no significant differences between groups in changes in pulse rate. 4. Gastrointestinal side effects of mild to moderate severity attributed to treatment with tenidap were experienced by five subjects, one of whom was withdrawn during the third week of treatment. One subject receiving placebo was withdrawn because of a moderate headache attributed to study treatment. 5. The results of this study suggest that treatment with tenidap may interfere with the anti‐hypertensive efficacy of ACE inhibitors. It is recommended that blood pressure should be monitored when tenidap is administered concomitantly with an ACE inhibitor.
Lack of photosensitising potential of tenidap, a novel anti‐rheumatic agent.
Authors: Ferguson J , Leeming MR
Published: July 2012

1. The potential of orally administered tenidap sodium, a novel anti‐ rheumatic agent under investigation for the treatment of rheumatoid arthritis and osteoarthritis, to cause phototoxic reactions was investigated. 2. Twenty‐four healthy volunteers entered a randomised, double‐blind study in which they received tenidap sodium 40 mg or 120 mg or placebo daily for 7 days. The minimal erythema dose was determined using wavelengths of 305‐460 nm for 3 days prior to drug administration and on the last 3 days of dosing. Appropriate clinical and laboratory tests were performed before, during and after the dosing period. 3. Tenidap did not have a statistically significant effect on immediate or delayed photosensitivity. No drug‐related side effects were reported and there were no clinically significant adverse findings from the laboratory tests. 4. At the dosage and duration of tenidap sodium used, a photosensitising potential has not been demonstrated.
Analogous effects of recombinant human full‐length amelogenin expressed by Pichia pastoris yeast and enamel matrix derivative in vitro
Authors: Cheng L. , Lin Z. K. , Shu R. , Liu D. L. , Zhang X. L. , Liu B. , Wang J. , Tian L.
Published: July 2012

Objectives

Amelogenins are proposed to be responsible for enamel matrix derivative (EMD)‐induced periodontal regeneration; however, heterogeneity of amelogenins makes it challenging to purify the full‐length proteins. This study has been carried out to express and purify a recombinant full‐length human amelogenin protein (rHhAm175) in the eukaryotic yeast Pichia pastoris, and further compare biological responses of human periodontal ligament fibroblasts (PDLFs) to rHhAm175 and porcine EMD (pEMD).

Materials and methods

Human cDNA encoding a 175‐amino acid amelogenin was subcloned into the pPIC3.5K vector. The rHhAm175 expressed in P. pastoris GS115 (Mut+) was purified and characterized. We examined cell attachment, migration and proliferation responses of human PDLFs to rHhAm175 and pEMD respectively, and characterized associated changes of proliferation‐related intracellular signalling molecules, including extracellular signal response kinase (ERK) and Akt kinases/protein kinase B (Akt/PKB) kinases.

Results

The purified rHhAm175 was confirmed to be molecular mass 22 021.13 Da, phosphorylated human amelogenin, and alone significantly promoted proliferation and migration of human PDLFs to an extent comparable to that of pEMD. Cell attachment was increased over the first 60 min incubation with rHhAm175 or pEMD. Both rHhAm175 and pEMD induced PDLF mitogenesis via extracellular signal response kinase (ERK1/2), but not by Akt kinases/protein kinase B (Akt/PKB).

Conclusions

rHhAm175 modulated cell activities of human PDLFs, to a comparable extent as porcine EMD. These data suggest that rHhAm175 might be used to induce periodontal tissue regeneration.
From brain to bridge: masticatory function and dental implants
Authors: Trulsson M. , van der Bilt A. , Carlsson G. E. , Gotfredsen K. , Larsson P. , Müller F. , Sessle B. J. , Svensson P.
Published: July 2012

Masticatory function is an important aspect of oral health, and oral rehabilitation should aim to maintain or restore adequate function. The present qualitative review is the joint effort of a group of clinicians and researchers with experiences ranging from basic and clinical oral neuroscience to management of patients with dental implants. The aim is to provide a short summary for the clinician of the many aspects related to masticatory function (including quality of life) and rehabilitation with dental implants. While there are many reviews on the tissue responses to dental implants and technical aspects, the functional aspects have received relatively little focus.
Risk for Developmental Coordination Disorder Correlates with Gestational Age at Birth
Authors: Zhu Jin Liang , Olsen Jørn , Olesen Annette W.
Published: July 2012

Background:  Studies suggest that children born very preterm have a high risk of developmental coordination disorder (DCD). We examined the relation between the larger spectrum of gestational age at birth and the risk of DCD.

Methods:  We used the 7‐year follow‐up data from 22898 singletons in the Danish National Birth Cohort. We calculated a total score from the Developmental Coordination Disorder Questionnaire (DCDQ), incorporated in the 7‐year follow‐up, and defined children with a score of 46 or below as having probable DCD. Information on gestational age was obtained from the Medical Birth Register.

Results:  Gestational age at birth was inversely associated with the risk of DCD; a decline in gestational age by a week was associated with a 19% [95% confidence interval 14%, 25%] increased risk of DCD screening positive among children delivered before 40 weeks. No significant increased risk of DCD was seen for children born post‐term.

Conclusion:  Our data indicate that short gestational age at birth in a range up to gestational week 37 is related to an increased risk of DCD.
In vitro miconazole susceptibility of meticillin‐resistant Staphylococcus pseudintermedius and Staphylococcus aureus
Authors: Weese J. Scott , Walker Meagan , Lowe Terri
Published: July 2012

Background –  The emergence and dissemination of meticillin‐resistant staphylococci has created significant treatment challenges in veterinary medicine and increased interest in topical therapy for superficial infections. Concern has been expressed regarding the use of some topical antimicrobials in animals because of the potential for emergence of resistance, and additional options are required. Miconazole has limited antibacterial properties that include antistaphylococcal activity.

Hypothesis/Objectives –  The objective of this study was to assess the in vitro susceptibility of Staphylococcus pseudintermedius and Staphylococcus aureus to miconazole.

Methods –  In vitro susceptibility of 112 meticillin‐resistant S. pseudintermedius (MRSP), 53 meticillin‐resistant S. aureus (MRSA) and 37 meticillin‐susceptible S. pseudintermedius (MSSP) to miconazole was assessed using agar dilution.

Results –  The minimal inhibitory concentration (MIC) range, MIC50 and MIC90 for MRSP were 1–8, 2 and 4 μg/mL, respectively. Corresponding results for MRSA were 1–8, 2 and 6 μg/mL, and for MSSP 1–4, 2 and 2 μg/mL. The MIC for MSSP was a significantly lower MIC than that for both MRSP (P = 0.006) and MRSA (P < 0.001), while the MIC for MRSP was significantly lower than that for MRSA (P = 0.001).

Conclusions and clinical importance –  These in vitro data suggest that miconazole could be a useful therapeutic option for superficial infections caused by meticillin‐susceptible and meticillin‐resistant staphylococci, but proper clinical investigation is required.
Donor race and outcomes in kidney transplant recipients
Authors: Molnar Miklos Z. , Kovesdy Csaba P. , Bunnapradist Suphamai , Streja Elani , Krishnan Mahesh , Mucsi Istvan , Norris Keith C. , Kalantar‐Zadeh Kamyar
Published: July 2012

Background

African Americans are at greater risk to reach end‐stage renal disease and this risk may carry over in a kidney transplant recipient after kidney transplantation.

Methods

Linking the five‐yr patient data of a large dialysis organization to the
Scientific Registry of Transplant Recipients, we identified 13 692 hemodialysis patients who underwent first kidney transplantation. Mortality or graft failure and delayed graft function risks were estimated by Cox's regression (hazard ratio [HR] and 95% confidence interval) and logistic regression, respectively.

Results

Patients were 48 ± 14 yr old and included 39% women and 26% patients with diabetes. After adjusting for several relevant clinical and transplant‐related variables, African American donor race was associated with higher all‐cause mortality, with HR of 1.39 (1.09–1.78) for all‐cause mortality, 1.80 (1.17–2.76) for cardiovascular mortality, 1.30 (1.03–1.64) for death‐censored graft loss and 1.31 (1.10–1.57) for combined outcome over the six‐yr observation period. In the non‐African American recipient subcohort, but not in the African American recipient subcohort, African American donor race was associated with higher risk of death‐censored graft loss (2.24 [1.44–3.49]) in our fully adjusted model.

Conclusions

African American donor race was associated with increased all‐cause and cardiovascular mortality and graft loss.
Foraging across ecosystems: diet diversity and social foraging spanning aquatic and terrestrial ecosystems by an invertebrate
Authors: Laidre Mark E.
Published: July 2012

Ecosystems are fundamentally connected to one another, although empirical documentation of the links between them, especially the links between marine and terrestrial ecosystems, has been limited. This study examined the foraging behavior and ecology of an understudied invertebrate, the hermit crab Coenobita compressus, which is remarkably abundant at the nexus of marine, terrestrial, and freshwater ecosystems. Data collected between 2008 and 2011 in the Osa Peninsula of Costa Rica revealed that C. compressus plays a generalist scavenger role across ecosystems. Beach almond fruits (Terminalia catappa) were a staple of the crabs’ diet, but the crabs also commonly consumed a variety of other fruit species and various parts of plants (nuts, seeds, flowers, husk, stems, buds) as well as algae, fungus, animal feces, and the carcasses of insects, jellyfish, conspecifics, other crustacean species, freshwater and saltwater fish, sea turtles (eggs and adults), and mammals. The crabs fed on these resources in prominent social aggregations, also forming such aggregations as they exchanged the aquatically derived gastropod shells that they use as homes while roaming the land. The size of the crabs’ aggregations around plant versus animal resources and around terrestrial versus aquatic resources did not differ, underscoring the species’ generalist foraging behavior. Broadly, these results suggest that C. compressus has one of the most diverse diets of any crustacean and plays a critical role in recycling organic matter and nutrients. This species might also mediate the passage of resources across different ecosystems, although further research is needed to explore this possibility.
Hyper‐eosinophilia in granular acute B‐cell lymphoblastic leukemia with myeloid antigen expression
Authors: Kobayashi Daisuke , Kogawa Kazuhiro , Imai Kohsuke , Tanaka Toshio , Sada Akiko , Nonoyama Shigeaki
Published: July 2012

Acute lymphoblastic leukemia with eosinophilia (ALLEo) is a rare but a distinctive clinical entity. Clinical features of idiopathic hyper‐eosinophilic syndrome (HES) can be seen in patients with ALLEo. We report a 10‐year‐old girl, in whom HES was initially suspected but further investigation confirmed the diagnosis of acute B‐cell lymphoblastic leukemia with myeloid antigen expression. Clinical response to chemotherapy was excellent with achievement of complete remission for 4 years. Serum interleukin‐3 and ‐5 were elevated at presentation and normalized with disappearance of eosinophilia after induction therapy, supporting the reactive nature of eosinophilia in ALLEo. Hematologic malignancy should be considered in patients with hyper‐eosinophilia, before attributing it to HES.
Acute disseminated encephalomyelitis following 2009 H1N1 influenza vaccine
Authors: Fujii Katsunori , Suyama Maiko , Chiba Koki , Okunushi Tomoko , Oikawa Junko , Kohno Yoichi
Published: July 2012

Acute disseminated encephalomyelitis (ADEM) is an immune‐mediated inflammatory disorder of the central nervous system. We describe a previously healthy 2‐year‐old boy with ADEM, who exhibited high fever, lethargy, and recurrent seizures at 25 days after H1N1 influenza vaccination. To our knowledge, there has been only one report of ADEM following the 2009 H1N1 influenza vaccine, although such vaccination is accompanied with optic neuritis apart from this case. Thus, this is the first case of ADEM without optic neuritis, following the 2009 H1N1 influenza vaccination. Although vaccine‐associated ADEM remains rare, the increasing number of influenza vaccinations might increase the incidence of ADEM. We still need to pay attention to the occurrence of ADEM and treat patients with steroid therapy.
Nephrotic syndrome complicated by renal and cerebral infarctions in a 14‐year‐old girl
Authors: Sugimoto Keisuke , Iba Yoshinori , Fujita Shinsuke , Sakata Naoki , Okada Mitsuru , Takemura Tsukasa
Published: July 2012

Venous thrombosis is a well‐known complication of nephrotic syndrome (NS), while arterial thrombosis is rare. We know of no reports of children with this complication. Here we report a case of 14‐year‐old girl with NS, who complicated with renal and cerebral infarctions resulting from arterial thrombosis. Urinary examination showed heavy proteinuria. She had intravascular dehydration. Serum albumin was 0.9 g/dL. Contrast‐enhanced computed tomography (CT) showed a low‐attenuation area in the right kidney. Decreased blood flow in the right middle cerebral artery was observed on MRA and also on multi‐detector‐row head CT. Urokinase and heparin were given. Cerebral infarction was treated neuroprotectively by i.v. infusion of edaravone. Comprehensive assessment of intravascular dehydration and the coagulation–fibrinolysis system is needed to guide decisions concerning prophylactic anticoagulation therapy. Better understanding of NS and its risks, as well as the necessity of drug therapy, may help teenagers to accept and cooperate with treatment.
Sex differences in fear memory and extinction of mice with forebrain‐specific disruption of the mineralocorticoid receptor
Authors: ter Horst J. P. , Carobrez A. P. , van der Mark M. H. , de Kloet E. R. , Oitzl M. S.
Published: July 2012

Previous studies showed that the mineralocorticoid receptor (MR) is needed for behavioral flexibility in a fear conditioning paradigm. Female mice with forebrain‐specific deletion of the MR gene (MRCaMKCre) were unable to show extinction of contextual fear, and could not discriminate between cue and context fear unlike control mice. In the present study, male and female (MRCaMKCre) mice and control littermates were used to study sex‐specific fear conditioning, memory performance and extinction. The fear conditioning paradigm assessed both context‐ and cue‐related fear within one experimental procedure. We observed that at the end of the conditioning all mice acquired the fear‐motivated response. During the first minutes of the memory test, both male and female MRCaMKCre mice remembered and feared the context more than the control mice. Furthermore, female MRCaMKCre mice were not able to extinguish this memory even on the second day of memory testing. The female mutants also could not discriminate between cue (more freezing) and context periods (less freezing). In contrast, male MRCaMKCre mice and the controls showed extinction and were capable to discriminate, although the MRCaMKCre mice needed more time before they started extinction. These findings further support the relevance of MR for behavioral flexibility and extinction of fear‐motivated behavior. In conclusion, the loss of MR in the forebrain results in large differences in emotional and cognitive behaviors between female and male mice, which suggests a role of this receptor in the female prevalence of stress‐ and anxiety‐regulated disorders.
Bursting as a source of non‐linear determinism in the firing patterns of nigral dopamine neurons
Authors: Jeong Jaeseung , Shi Wei‐Xing , Hoffman Ralph , Oh Jihoon , Gore John C. , Bunney Benjamin S. , Peterson Bradley S.
Published: July 2012

Nigral dopamine (DA) neurons in vivo exhibit complex firing patterns consisting of tonic single‐spikes and phasic bursts that encode information for certain types of reward‐related learning and behavior. Non‐linear dynamical analysis has previously demonstrated the presence of a non‐linear deterministic structure in complex firing patterns of DA neurons, yet the origin of this non‐linear determinism remains unknown. In this study, we hypothesized that bursting activity is the primary source of non‐linear determinism in the firing patterns of DA neurons. To test this hypothesis, we investigated the dimension complexity of inter‐spike interval data recorded in vivo from bursting and non‐bursting DA neurons in the chloral hydrate‐anesthetized rat substantia nigra. We found that bursting DA neurons exhibited non‐linear determinism in their firing patterns, whereas non‐bursting DA neurons showed truly stochastic firing patterns. Determinism was also detected in the isolated burst and inter‐burst interval data extracted from firing patterns of bursting neurons. Moreover, less bursting DA neurons in halothane‐anesthetized rats exhibited higher dimensional spiking dynamics than do more bursting DA neurons in chloral hydrate‐anesthetized rats. These results strongly indicate that bursting activity is the main source of low‐dimensional, non‐linear determinism in the firing patterns of DA neurons. This finding furthermore suggests that bursts are the likely carriers of meaningful information in the firing activities of DA neurons.
Mediators of the shame‐guilt‐psychological adjustment relationship
Authors: LYNCH JOHN S. , HILL ERIC D. , NAGOSHI JULIE L. , NAGOSHI CRAIG T.
Published: July 2012

Lynch, J. S., Hill, E. D., Nagoshi, J. L. & Nagoshi, C. T. Mediators of the shame‐guilt‐psychological adjustment relationship. Scandinavian Journal of Psychology 53, 437–443.

A college student sample (109 women, 90 men) was administered measures of psychological adjustment, shame, guilt, personal fear of invalidity, and aspects of empathy, including personal distress in emergencies and fantasy involvement. Consistent with previous studies, shame but not guilt was significantly positively correlated with poor psychological adjustment. Path analyses with bootstrapped mediation tests indicated that the shame‐adjustment relationship was significantly mediated by fear of invalidity, personal distress, and fantasy involvement. A novel finding was that the relationship between guilt and maladjustment was significantly mediated by proneness to fantasy. The findings are discussed in terms of an integrated theory of the shame‐fear/distress‐maladjustment relationship as a framework for understanding the maladaptive, individualistic shame experience.
PROFIT‐ENHANCING KNOW‐HOW DISCLOSURE: A STRATEGIC VIEW*
Authors: MATSUSHIMA NORIAKI , OGAWA SUSUMU
Published: July 2012

In this paper, we provide a theoretical framework to show a new insight into know‐how disclosure related to production technologies. An incumbent firm that can disclose its cost‐reducing know‐how and several new entrants exist. If the incumbent firm discloses its know‐how, all entrants learn it, and their production costs decrease. Under some conditions, through the disclosure, the incumbent firm can achieve a higher profit. We discuss several extensions of the basic framework.
THE (HIDDEN) COST OF EMPLOYER PARKING POLICIES*
Authors: Van Ommeren Jos , Wentink Derk
Published: July 2012

It has been argued that distortionary tax policies, which stipulate that employer parking is not taxed as a benefit in kind, as well as minimum parking requirements induce welfare losses. Using Dutch data, we show that current tax policies induce welfare losses of about 10% of employer parking resource costs. Hypothetical minimum parking requirements for employers, at levels currently applied in the United States, induce an additional deadweight loss of 18% of employer parking resource costs.