bluuebunny/crossref_metadata_2025 huggingface dataset:
Triiodothyronine and amiodarone effects on β3‐adrenoceptor density and lipolytic response to the β3‐adrenergic agonist BRL 37344 in rat white adipocytes
Authors: Germack R. , Adli H. , Vassy R. , Perret GY
Published: August 2009

Summary—The β‐adrenergic effects of catecholamines are potentiated by thyroid hormones in adipose tissue. Amiodarone (AM) is structurally similar to thyroid hormones and was used to explore the mechanism of the triiodothyronine (T3) effect on β‐adrenergic receptors (β‐ARs) in adipose tissue. AM decreases the expression of some T3sensitive genes in various tissues and antagonizes the effect of T3on its nuclear receptors. In this study, the T3, AM and AM + T3effects on the β1‐ and β3‐AR density were assessed on rat white adipocytes by radioligand binding using [3H]CGP 12177 after characterization of these subtypes by displacement of [3H]CGP 12177 binding by isoproterenol, BRL 37344 and noradrenaline. BRL 37344 was used to study β3‐AR lipolysis. White adipocytes from hyperthyroid rats had increased responsiveness (Emax× 2) and sensitivity (+ 38%) to BRL 37344, while those given AM alone had decreased values. Moreover, AM antagonized the T3effect on lipolysis. The β1‐binding characteristics (receptor density [Bmax]: 45 ± 4 fmol/mg of proteins; dissociation factor [Kd]: 0.96 ± 0.10 nM) were not modified by either compound. Finally, T3significantly increased β3‐AR density (587 ± 69 versus 363 ± 25 fmol/mg of proteins) and Kd(38 ± 2 versus 23 ± 3 nM), while AM alone had no effect and did not antagonize the T3effect on β3‐AR number. In conclusion, the hyperthyroid state in the rat potentiated the lipolytic response of white adipocytes to a specific β3‐agonist and increased the β3‐AR density without changing in β1‐AR number and affinity. Furthermore, the lack of antagonism between AM and T3on β3‐AR expression suggests that T3does not work directly on the β3‐AR gene. Moreover, AM induced a functional tissular hypothyroid‐like effect and its antilipolytic effect probably occurred at a postreceptor level.
Effects of pentobarbital and etomidate on plasma catecholamine levels and spectral analysis of blood pressure and heart rate in dogs
Authors: Mazerolles M. , Senard JM , Verwaerde P. , Tran MA , Montastruc JL , Virenque C. , Montastruc P.
Published: August 2009

Summary— The present paper investigates the effects of two anæsthetic drugs (pentobarbital and etomidate) on both short‐term variabilities of systolic blood pressure (SBP) and heart rate (HR) using fast Fourier transformation and catecholamine plasma levels. HR and BP were continuously recorded through an arterial catheter and blood samples were taken from the jugular vein. Spectral analysis was performed first in the conscious state and six minutes after induction of anæsthesia on a series of 256 consecutive BP and HR values (Δt: 2 Hz). The area under the curve (AUC) was determined in the low‐frequency component of the SBP (LF: 40–150 mHz), in the high‐frequency band of HR (HF: respiratory frequency ± 50 mHz) and in the total frequency spectra. Results were normalized by calculation of the ratio between AUC of LF and HF and the total AUC of the corresponding spectrum (TS). Etomidate (2 mg/kg iv) induced a significant increase in TS and LF without changing the LF/TS ratio or the HR variability when compared with the awake period. Catecholamine plasma levels did not change. In contrast, pentobarbital (30 mg/kg iv) decreased the values of LF, HF, LF/TS and HF/TS and catecholamine plasma levels. These results suggest that pentobarbital decreases the activity of the two components of the autonomic nervous system whereas etomidate induces only minimal changes.
Absence of tolerance in duodenal ulcer patients treated for 28 days with a bedtime dose of roxatidine or ranitidine
Authors: Savarino V. , Mela GS , Zentilin P. , Cutela P. , Vigneri S. , Termini R. , Di Mario F. , Ferrana M. , Malesci A. , Belicchi M. , Celle G.
Published: August 2009

Summary—There is much experimental work on the occurrence of tolerance to the antisecretory effect of H2‐receptor antagonists in healthy subjects, while data on its development in patients with duodenal ulcer are poor and conflicting. Moreover, this phenomenon has not been studied previously with 24 h gastric pH‐metry in patients with active duodenal ulcer. For these reasons, we carried out a prospective pharmacodynamic investigation in 48 patients with endoscopically proven duodenal ulcer using the well‐established once daily dosing schedule of H2blockers. They were studied by means of 24 h continuous endoluminal pH‐metry which was performed before, on d1 and d28 after receiving an oral bedtime dose (2200 hours) of either roxatidine 150 mg or ranitidine 300 mg, given in randomized and single‐blind fashion. Eight patients did not complete the study for various reasons and 82% of ulcers healed after 4 weeks of therapy. Gastric pH was higher (P< 0.001) on d1 and d28 than basal values during all time periods, but the evening, with both H2blockers. There was no significant difference between pH values of d1 and d28 in any time interval with both roxatidine and ranitidine. There was also no difference in pharmacodynamic data between the two active treatments. We conclude that tolerance does not develop after 1 month's treatment with a bedtime dose of H2antagonist in patients with active duodenal ulcer and therefore data gathered on this phenomenon in healthy subjects are not applicable to ulcer patients.
Influence of lipophilicity on the diffusion of cephalosporins into the cerebrospinal fluid
Authors: Radouane A. , Péhourcq F. , Tramu G. , Creppy EE , Bannwarth B.
Published: August 2009

Summary— The aim of this quantitative structure‐activity relationship (QSAR) study was to investigate the influence of lipophilicity on the diffusion of cephalosporins into the cerebrospinal fluid (CSF). The lipophilicity was expressed as the chromatographic capacity factor (log k'w) determined by high‐performance liquid chromatography in a reversed‐phase system. The penetration of eight cephalosporins into CSF was studied in male Wistar rats receiving the drugs intramuscularly (1.5 mg/kg). One hour after administration, CSF and blood samples were collected, and concentrations of free drug were measured in CSF (CCSF) and in plasma (CP). A significant parabolic relationship was sought between lipophilicity (log k'w) and the capacity of diffusion across the blood‐brain barrier expressed as log (CCSF/CP). The cephalosporins exhibiting a moderate lipophilicity diffused well into CSF. A pharmacokinetic study was performed at 1, 2 and 4 h after administration of three cephalosporins: cefazolin, ceftriaxone and cefsulodin. These compounds were choosen according to their lipophilicities (low, moderate and high values, respectively). The AUC0–4h for both free plasma (AUCP) and cerebrospinal fluid (AUCCSF) concentrations were determined. The AUCCSF/AUCP ratio presented a maximum value for a strongly albumin bound cephalosporin, ceftriaxone. In our experimental conditions, the ideal lipophilicity (log k'w) range for diffusion of cephalosporins from plasma into CSF was between 1.6 and 1.8.
The effect of the antimycotic itraconazole on the pharmacokinetics and pharmacodynamics of diazepam
Authors: Ahonen J. , Olkkola KT , Neuvonen PJ
Published: August 2009

Summary— The azole antimycotic itraconazole is a potent and relatively unspecific inhibitor of cytochrome P450 enzymes and has a potentially dangerous interaction with midazolam and triazolam. The possible interaction between itraconazole and diazepam was investigated in a double‐blind, randomized, cross‐over study. Ten healthy volunteers were given orally placebo or itraconazole 200 mg a day for 4 days. The challenge dose of 5 mg of diazepam was ingested on the fourth day, after which plasma samples were collected and psychomotor performance tests were carried out for 42 h. Despite a statistically significant small increase in the area under the plasma diazepam concentration‐time curve and the elimination half‐life of diazepam, there was no clinically significant interaction as determined by the psychomotor performance tests. The lack of significant first‐pass metabolism and the different metabolic pathways of diazepam explain the smaller interaction potential of diazepam compared with midazolam and triazolam. Diazepam, unlike midazolam and triazolam, can be prescribed in usual doses for patients receiving itraconazole and probably other inhibitors of P4503A4, at least when diazepam is used as single doses.
Circadian phase dependent pharmacokinetics of L‐dopa, its main metabolites (3‐OMD, HVA, DOPAC) and carbidopa in rats
Authors: Andre MH , Grignon S. , Bruguerolle B.
Published: August 2009

Summary— This study aims to evaluate whether or not the kinetics of L‐dopa, its main metabolites (3‐O‐methyldopa, 3‐OMD, homovanilic acid, HVA and 3,4‐dihydroxyphenylacetic acid, DOPAC) and carbidopa, vary according to the 24‐hour scale in rats. Four groups of seven adult male Wistar AF EOPS rats were used for these experiments; each group received L‐dopa (200 mg·kg−1 ip) and carbidopa (20 mg·kg−1 ip) at 1000, 1600, 2200 or 0400 hours. L‐dopa, 3‐OMD, DOPAC, HVA and carbidopa were simultaneously determined by specific ion‐pair reversed‐phase high performance liquid chromatography with electrochemical detection. A temporal variation of the kinetics of both L‐dopa and carbidopa was demonstrated with higher plasma clearance and lower area under concentration curve after the administration at 2200 hours. Moreover, a temporal variation of the metabolism of L‐dopa was indirectly documented by temporal variation in kinetics of 3‐OMD, DOPAC and HVA.
Salbutamol potentiates the relaxant effects of selective phosphodiesterase inhibitors on guinea pig isolated trachea
Authors: Planquois JM , Ruffin‐Morin Y. , Lagente V. , Payne AN , Dahl SG
Published: August 2009

Summary—The ability of low concentrations of salbutamol to potentiate the relaxant effects of the phosphodiesterase (PDE) inhibitors, rolipram, Ro 20–1724 (PDE type IV inhibitor), siguazodan and milrinone (PDE type III inhibitor) was studied on guinea pig isolated trachea. These PDE inhibitors were strong relaxants of guinea pig trachealis under basal tone, but had only a weak activity on tissues precontracted with histamine (10−5M). In both cases, PDE type IV inhibitors showed a relaxant effect composed of two phases. The first phase represented 20 and 40% and the second, 90 and 140%, respectively, of relaxation of basal tone and histamine‐induced tone. A second characteristic of PDE type IV inhibitors was the very fast and partially reversible relaxation observed at concentrations greater than 3 × 10−8M (for histamine‐induced tone) at the first addition of inhibitor, followed by a residual relaxant activity. The latter relaxant effect was stable at concentrations of 3 × 10−8‐10−5M and was equivalent to a 20% relaxation (for histamine‐induced tone). In the presence of low concentrations (10−9and 10−8M) of salbutamol, there was a significant concentration‐dependent potentiation of the effects of PDE inhibitors on trachea precontracted with histamine. Salbutamol, at a concentration of 10−9M, potentiated the effects of PDE inhibitors between 1.4‐ and 3.6‐fold. In the presence of salbutamol 10−8M, the potentiation was more marked for siguazodan (37.9‐fold), milrinone (11.0‐fold) and Ro 20–1724 (14.5‐fold) than for rolipram (4.3‐fold). These results suggest that low concentrations of salbutamol can potentiate the relaxant effects of both PDE type III and PDE type IV inhibitors. Thus, PDE type IV inhibitors, which have antiinflammatory properties, could also provide adequate bronchodilation when used in combination with lower than usual doses of β2‐agonists.
A randomized, double‐blind, multicentre controlled trial of ibuprofen versus acetaminophen and placebo for symptoms of acute otitis media in children
Authors: Bertin L. , Pons G. , D'Athis P. , Duhamel JF , Maudelonde C. , Lasfargues G. , Guillot M. , Marsac A. , Debregeas B. , Olive G.
Published: August 2009

Summary— Two hundred and nineteen children (boys: 56%, girls: 44%) were included in a randomized, double‐blind, multicentre (4 centres) controlled trial designed to assess the efficacy and safety of ibuprofen (IBU) in the treatment of 1 to 6 year‐old children with otoscopically proven acute otitis media (AOM), either unilateral or bilateral. They randomly received 10 mg/kg IBU (n = 71), or acetaminophen (PARA) (n = 73) or placebo (PLA) (n = 75), orally, tid, for 48 hours. All received oral cefaclor (Alfatil®, Lilly, France) for seven days. They were evaluated before (D0) and at the end of treatment (D2). The main criterion of response was the aspect (landmarks and color) of the tympanic membrane assessed on a semi‐quantitative scale from 0 to 6. Other criteria, assessed on semi‐quantitative scales, included relief of pain (0 or 1), rectal temperature (0 to 2), and overall evaluation by parents of the improvement of quality of life on three items: appetite (0 to 2), sleep (0 to 2) and playing activity (0 to 2). The results at D2 were as follows: there was no significant difference between treatment groups as to the main criterion, but only a trend for IBU and PARA to do better than PLA but not for IBU to do better than PARA. From these data there is no argument to emphasize the utility of nonsteroidal anti‐inflammatory drugs (NSAIDs) in treating the inflammatory signs of the tympanic membrane in otitis. There was a statistically significant difference between treatment groups at D2 for pain, IBU being superior to PLA (P < 0.01): 7%, 10% and 25% of the children were still suffering at D2 in the IBU, PARA and PLA treatment groups, respectively. The difference between PARA and PLA for pain was not statistically significant. There was no significant difference between treatment groups for the other criteria. All treatments were well and equally tolerated. Although no significant difference was found between the treatment groups on the aspect of the tympanic membrane, the efficacy of IBU was evidenced on the relief of pain, the symptom that most disturbs the child.
Growth hormone therapy in elderly people: an age‐delaying drug?
Authors: Bouillanne O. , Rainfray M. , Tissandier O. , Nasr A. , Lahlou A. , Cnockaert X. , Piette F.
Published: August 2009

Summary— The aims of this review are to present a brief overview of growth hormone (GH) physiology and to summarize the studies of GH treatment in adults. Special attention has been paid to randomized controlled trials. Studies have revealed a partial deficiency of GH secretion in the elderly. GH secretion on the average declines by 14% with each decade in normal adults after 20 years of age. Aging has a central effect on the GH secretion and peripheric effect on insulin‐like growth factor 1 (IGF‐1) through changes in the body composition. GH administration may attenuate several important decrements in body composition and in function associated with aging. GH may also have very potent anabolic effects in surgical situations. Short‐term side‐effects of GH therapy include edema, carpal tunnel syndrome and arthralgia. A number of agents such as oral GH‐releasing peptides (GHRPs) increase GH secretion; they may be an alternative to GH treatment in the future. Further studies of GH replacement are needed, examining issues such as dosage, tolerance and efficacy before the widespread use of GH in the elderly is advocated.
5‐HTP induced diarrhea as a carcinoid syndrome model in mice?
Authors: Bourin M. , Hascoet M. , Deguiral P.
Published: August 2009

Summary—Serotonin (5‐HT) is present in the gastrointestinal tract and is probably one of the compounds responsible for diarrhea in patients presenting with carcinoid syndrome. Intraperitoneal administration of L‐5‐hydroxytryptophan (L‐5‐HTP) at doses of 25 to 100 mg/kg dramatically increase defecation in mice. In this new paradigm, counting fecal boli deposited is simple and the appraised or inhibition of diarrhea induced by ip 25 mg/kg of L‐5‐HTP is very clear, with a good reproducibility of scores. L‐5‐HTP needs to be metabolized into 5‐HT to be active; benserazide, an inhibitor of decarboxylase, antagonized the diarrhea induced by 5‐HT. Among the 5‐HT antagonists used in interaction with 5‐HT, only those of the 5‐HT3type (ondansetron, granisetron, tropisetron) and, to a lesser extent 5‐HT2type (ritanserin), decreased the diarrhea induced by 5‐HTP. The 5‐HT4receptor agonists from the benzamide family (metoclopramide and zacopride) increased defecation in mice but the effect failed to reach statistical significance.
β‐Adrenoceptor density in patients with left‐sided valvular regurgitation
Authors: Dzimiri N. , Moorji A.
Published: August 2009

Summary— Aortic regurgitation differs from mitral regurgitation in that it is a result of combined volume and pressure overload, while the latter represents an almost pure volume overload. In this study, we tested the possibility that these two forms of left ventricular volume overload exert different effects on β‐adrenoceptor density. Lymphocyte (n = 33) and myocardial (n = 22) β‐adrenoceptor densities were evaluated by [125I]‐iodocyanopindolol binding in volume‐overloaded patients with left heart valvular disease, compared with 31 healthy donor blood and 15 donor heart controls, made available as a result of failing to get matching recipient. The total lymphocyte (LC) β‐adrenoceptor density decreased from 43.4 ± 5.5 fmol mg−1 protein in controls to 9.2 ± 2.7 fmol (P < 0.001) in heart valvular patients. In the myocardial controls, the left ventricular (LV)‐receptor density was 126.7 ± 19.5 fmol; right ventricular (RV), 123.1 ± 14.6 fmol; left atrial (LA), 81.6 ± 10.5 fmol; and right atrial (RA), 108.1 ± 14.5 fmol mg−1 protein. Compared to this group, the total LV‐receptor density of the patients decreased by 63%, RV by 54%, LA by 31% and RA by 34%. The decrease in receptor density exhibited a positive correlation with increasing ejection fractions in both the left (r = 0.38) and right (r = 0.44) ventricles, indicating that the former was dependent on the extent of the disease. These changes were accompanied by a 44% increase in plasma epinephrine, 13% in norepinephrine and a 27% decrease in dopamine levels. Based on the predominant left ventricular volume overload classified as aortic regurgitation (AVR), mitral regurgitation (MVR) and mixed aortic and mitral regurgitation (MOL), the attenuation in myocardial‐receptor densities showed the following trend: MOL > MVR > AVR. The results show a global reduction in myocardial and LC β‐adrenoceptor density, which depends on the origin and the gravity of the LV volume overload.
Formulas and tables for the determination of sample sizes and power in clinical trials for testing differences in proportions for the matched pair design: a review
Authors: Sahai H. , Khurshid A.
Published: August 2009

Summary— This paper is a compendium of exact and asymptotic formulas and tables for calculating the sample size in a clinical trial for a matched‐pair design involving a dichotomous outcome. Formulas for calculating power given the sample size are also given.
Inhibitory effects of okadaic acid on rat uterine contractile responses to different spasmogens
Authors: Arteche ME , Ausina P. , Delgado J. , Fernandez JJ , Norte M. , Candenas ML , Martín JD
Published: August 2009

Summary— In the present study, we examined the effects of okadaic acid, a selective inhibitor of type 1 and 2A protein phosphatases, on the mechanical responses evoked by oxytocin, K+‐ and Na+‐modified solutions and ouabain in estrogen‐primed rat myometrium. Oxytocin elicited a rapid, phasic contraction followed by rhythmic oscillations. The phasic response was partially resistant to the absence of external Ca2+. Okadaic acid (1 μM) and the L‐type calcium channel blocker nifedipine (1 μM) abolished the oscillatory component and reduced the initial, phasic response to about 80% of the control response. High K+ (60 mM) solution, ouabain (1 mM), K+‐free medium and low Na+ (25 mM) solution induced extracellular Ca2+‐dependent biphasic responses composed by an early rapid (KCl, ouabain and K+‐free solution) or slower developed (25 mM Na+ solution) phasic contraction followed by a sustained increase in tension. Okadaic acid and nifedipine, alone or in combination, abolished or decreased similarly the contractile response evoked by these stimulants. The okadaic acid‐ and nifedipine‐insensitive responses to ouabain, K+‐free and low Na+ solution were enhanced by increasing the extracellular concentration of Ca2+ in the medium and were inhibited in a dose‐dependent manner by amiloride (0.05–0.5 mM). These data suggest that, in estrogen‐primed rat uterus, dephosphorylating mechanisms by OA‐sensitive protein phosphatases play an important role in regulating myometrial contractions elicited by Ca2+ entry through voltage‐sensitive Ca2+ channels.
Effects of K+channel inhibitors and antagonists on NS‐004 evoked relaxations in guinea‐pig isolated trachea
Authors: Lawson K. , Barras M. , Armstrong JM , Hicks PE
Published: August 2009

Summary—The smooth muscle relaxant responses to NS‐004, an activator of charybdotoxin‐sensitive, large conductance Ca2+‐dependent K+channels (BKCa) were studied on the basal spontaneous tone in guinea‐pig trachea in vitro. The sensitivity of these responses to a range of K+channel inhibitors and antagonists were also evaluated. NS‐004 (0.1–30 μM) evoked concentration‐related relaxations (pIC505.48 ± 0.13) on the spontaneous tone in guinea‐pig tracheal rings, suspended in Krebs bicarbonate solution, with a maximum response not different to that to aminophylline (1 μM). Charybdotoxin (0.03 and 0.1 μM) or iberiotoxin (0.1 μM) significantly displaced the NS‐004 concentration‐response curve to the right of control with no change in maximum response. In contrast, glibenclamide (1.0 μM), apamin (0.1 μM) and dofetilide (1.0 μM) each failed to modify the responses to NS‐004 on spontaneous tone in guinea‐pig trachea. These results suggest that relaxations in guinea‐pig tracheal smooth muscle to the substituted benzimidazolone, NS‐004, involve the activation of BKCachannels.
Pharmacokinetics and pharmacodynamics of two oral forms of cefuroxime axetil
Authors: Garraffo R. , Drugeon HB , Chiche D.
Published: August 2009

Summary— Cefuroxime axetil is a cefuroxime ester that can be administered by mouth. Two dosage forms (tablets and granules) have been developed for oral administration. We evaluated the pharmacokinetics and pharmacodynamics of these forms in an open cross‐over study involving 12 healthy volunteers receiving single doses of 250 mg. The bioavailability of the two forms was different, the observed peak concentration and time‐concentration curve values of the tablet form being, respectively, 39 and 27% higher than those of the granule form. However, ex vivo studies of serum bactericidal activity against Streptococcus pneumoniae showed no significant differences between the two formulations. This is in keeping with the fact that the bactericidal activity of samples from only six subjects gave evaluable data for Haemophilus influenzae; although small differences were found between the two formulations, further investigations are required. The pharmacodynamic approach is becoming an essential element in determining the equivalence of antibiotic dosage forms.
Nimodipine improves kainic acid induced neurotoxicity in cerebellar granular cell culture: a double‐blind dose‐response study
Authors: Gepdiremen A. , Sönmez S. , Batat İ , Eşrefoǧlu M. , Düzenli S. , Süleyman H.
Published: August 2009

Summary—The neuroprotective role of nimodipine was tested in kainic acid (50 and 100 μM) induced neurotoxicity in cerebellar granular cell cultures of 4 to 7 day‐old rat pups. Nimodipine was applied in 50, 100 and 200 μM concentrations. Kainate, in either dose, induced cerebellar granular cell death in respect to controls and the results were statistically significant (P= 0.000 for both doses). However, kainic acid in 100 μM concentration led to higher rates of cell death than 50 μM (P= 0.017). The neuroprotective role of nimodipine in kainate induced neurotoxicity was dose dependent. Kainate toxicity in 50 μM concentration was blocked by 50 and 100 μM nimodipine concentrations (P= 0.006 andP= 0.002, respectively) while 200 μM nimodipine was found ineffective. The most effective nimodipine dose for 100 μM kainic acid neurotoxicity was 200 μM (P= 0.000) while 50 and 100 μM concentrations of nimodipine were found ineffective. In this study, we have proven the dose‐dependent neuroprotective role of nimodipine in kainate induced neurotoxicity in cerebellar granular cell cultures of rat pups.
Pharmacokinetics of intrarectal nalbuphine in children undergoing general anaesthesia
Authors: Bessard G. , Alibeu JP , Cartal M. , Nicolle E. , Debeauvais F Serre , Devillier P.
Published: August 2009

Summary— The pharmacokinetics of nalbuphine (0.3 mg/kg) administered by the rectal route were studied in ten children undergoing general anaesthesia for minor surgery. Blood sampling was carried out for 8 h after rectal administration and plasma drug concentrations were measured by high performance liquid chromatography using electrochemical detection after an optimized solid‐phase extraction procedure. The mean time to achieve the maximum plasma concentration (Cmax = 24 ± 15 ng/mL) was 25 ± 11 min and the elimination half‐life was 2.7 ± 0.7 h. The coefficients of variation for Cmax and the concentration‐time curve (AUC) were 62 and 68%, respectively. Although rectal absorption is considered irregular, the large intersubject variability is also explainable by a variable hepatic bypass for a drug, like nalbuphine, that undergoes extensive first‐pass metabolism. No problem of analgesic efficacy or of local tolerance was reported. In conclusion, the rectal route of administration provides a rapid and reliable absorption of nalbuphine.
Cholinesterase activity in pig airways and epithelial cells
Authors: Taisne C. , Norel X. , Walch L. , Labat C. , Verriest C. , Mazmanian GM , Brink C.
Published: August 2009

Summary— Acetylcholinesterase (AChE, EC 3.1.1.7) and butyrylcholinesterase (BChE, EC 3.1.1.8) activities were detected in bronchial and bronchial epithelial cell homogenates of the pig. In the bronchial homogenates, the maximal upstroke velocity (Vmax) of AChE and the maximal velocity after second substrate fixation (Vss) of BChE were 5.70 ± 0.46 and 7.87 ± 0.81 mU/mg protein, respectively. In the epithelial cell homogenates, a smaller amount of cholinesterase (ChE) was found: Vmax was 0.62 ± 0.29 and Vss was 1.56 ± 0.33 mU/mg protein for AChE and BChE, respectively. AChE activity was increased by 21 ± 5% in the bronchial homogenates and by 54 ± 14% in the epithelial cell homogenates, when intact bronchial segments were incubated with a cyclooxygenase inhibitor, indomethacin (INDO). These results suggest that prostanoids may be involved in the regulation of AChE activity in pig airways.
Comparative inotropic effect of calcium, endothelin‐1, and forskolin on ferret papillary muscles during acidosis
Authors: Ishiguro Y. , Morgan JP
Published: August 2009

Summary— Acidosis affects multiple steps in the excitation‐contraction coupling pathway of myocardium, producing decreased calcium sensitivity of myofibrils and modification of the function of the sarcoplasmic reticulum. Our aim was to evaluate the effectiveness of three different classes of inotropic agents under acidotic conditions: 1) forskolin, an adenylate cyclase activator that enhances cellular cyclic AMP concentrations, 2) elevated extracellular Ca2+ and 3) endothelin‐1, an activator of the inositol triphosphate, diacylglycerol pathway. Ferret papillary muscles were mounted in organ baths containing normal physiological solution (pH = 7.4). After baseline tension was measured, the muscles were bathed in an acidotic solution (pH = 6.98) that decreased tension to 40% of the control; subsequently, the muscles were washed with normal physiological solution until they returned to baseline. Each inotropic agent was added to the bathing solution in a concentration sufficient to increase tension by 40% above the baseline. Then the solution was made acidotic (pH = 6.98) in the continuous presence of that concentration of inotropic agent and the resultant steady‐state developed tension measured. The increases in tension induced by each inotropic agent at normal pH were adjusted to be similar; in contrast, the response to each drug in acidosis was significantly different. Under acidotic conditions, endothelin‐1 was the most effective inotropic agent in restoring the depressed developed tension. This was possibly due to enhancement of the myofilament sensitivity to Ca2+, which was more effective than increasing [Ca2+]i through elevating extracellular Ca2+ or the addition of forskolin which increased [Ca2+]i but desensitized the myofilaments to Ca2+.
Involvement of a CCK‐dependent capsaicin‐sensitive afferent pathway in the inhibitory effect of pinaverium bromide on the colonic motor response to eating in rats
Authors: Fioramonti J. , Christen MO , Dupre I. , Bueno L.
Published: August 2009

Summary— The effects of pinaverium bromide on the stimulation of colonic motility induced by meal and cholecystokinin (CCK) were investigated in rats chronically fitted with intraparietal electrodes on the proximal colon and previously treated or not by capsaicin. Pinaverium bromide inhibited in a dose‐related manner (2–50 mg/kg, per os) the increase in colonic spike burst frequency induced by a 3 g meal or CCK‐8 (2 μg/kg, iv). The CCK‐A and CCK‐B antagonists, devazepide and L 365260 (100 μg/kg, ip), respectively, inhibited the postprandial colonic motor response while only L 365260 reduced the CCK‐induced stimulation. The effects of pinaverium bromide and CCK antagonists were not observed in capsaicin‐treated animals. Moreover, CCK‐8 (2 μg/kg, iv) did not stimulate colonic motility after capsaicin treatment. The inhibition of postprandial colonic motility by pinaverium bromide, given orally at therapeutic doses, involves a CCK‐dependent pathway which requires the integrity of capsaicin‐sensitive afferents.
Clinical electrophysiologic effects of a single high oral dose of amiodarone
Authors: Deharo JC , Durand A. , Macaluso G. , Malaterre H. , Le Tallec L. , Panagides D. , Bory M. , Djiane P.
Published: August 2009

Summary— Several recent reports have described the antiarrhythmic effects of a single high oral dose of amiodarone but clinical electrophysiologic effects have not been reported. The present study was performed to assess electrophysiologic effects in 12 patients. After baseline electrophysiologic studies (EPS) patients were administered a single oral dose of 30 mg/kg of amiodarone. EPS was repeated 7.5 ± 0.5 hours later. Plasma levels of amiodarone and its metabolite desethylamiodarone were determined at the time of the second EPS. Holter monitoring was performed for 24 hours after amiodarone administration. Amiodarone significantly increased the following parameters: corrected QT interval (+4.5%), functional refractory period of the right atrium (+7%); AH interval (+12.3%), effective refractory period of the atrioventricular node (+18.5%), and cycle length of Wenckebach block (+8.4%). These effects were not correlated with plasma levels of amiodarone and desethylamiodarone. Holter monitoring detected no significant bradycardia or arrhythmia. These findings indicate that the effects of a single high oral dose of amiodarone are the same as those known to be induced by acute intravenous administration.
Clinical trial registries and ethics review boards: the results of a survey by the FICHTRE project
Authors: Boissel JP , Haugh MC
Published: August 2009

Summary— Clinical trial registries could make an important contribution to research by playing a role in the avoidance of trial duplication as well as serving as a source of information on the existence of clinical trials for those wishing to perform overviews. In order to fulfil their role efficiently, these registries should contain information about all trials. However, resources of existing registries are not exhaustive. Currently, all protocols for clinical trials must be submitted to an ethics review board for approval — thus these boards could provide an invaluable source of information about what trials are being performed. One of the objectives of our project was to assess the attitudes of the ethics review boards (ERBs) to providing this type of information to clinical trial registries. We received 115 replies from 281 questionnaires sent to ERBs in seven European countries. More than 70% replied that they would be willing to communicate information about the trials they review, and there seemed to be general agreement that clinical trial registries should be funded and supported by governments. Although ERBs could provide a useful source of information, only an official body such as the Ministry of Health or a drug regulatory body could establish and run a clinical trials registry efficiently.
Role of paraventricular and dorsomedial nuclei of the hypothalamus and central nucleus of the amygdala on muscimol‐induced cardiovascular responses
Authors: Gören Z. , Asian N. , Berkman K. , Şan T. , Sule O. , Onat F.
Published: August 2009

Summary—Gamma‐aminobutyric acid (GABA) plays an important role in the central control of cardiovascular functions. Previous evidence indicates that a tonically active GABAergic system exists in forebrain structures. The purpose of this study was to examine the role of the unilateral lesion of the central nucleus of amygdala, paraventricular or dorsomedial nuclei of the hypothalamus on muscimol‐induced cardiovascular responses. Electrolytic ablation of nuclei was made by a monopolar isolated electrode under a stereotaxic instrument, 3–5 days before the experiments. Effects of intracerebroventricular injections of muscimol were investigated in intact, lesioned and sham‐lesioned rats. On the day of the experiments, blood pressure and heart rate recordings were carried out in male Sprague‐Dawley conscious rats. Muscimol produced decreases in arterial blood pressure and heart rate. The hypotensive effect of muscimol was completely inhibited in rats with dorsomedial nucleus lesions, whereas the bradycardic effect was partially prevented. The results indicate that the dorsomedial nucleus of the hypothalamus plays an important role on muscimol‐induced blood pressure and heart rate responses.
In vitro calcium antagonistic and antioxidant effects of Org 13061 and its enantiomers, new potential antiatherosclerotic compounds
Authors: Beaughard M. , Chevalier A. , Dureng G. , Leboeuf J. , Massingham R. , Mazur A. , Rayssiguier Y. , Winslow E.
Published: August 2009

Summary— The calcium antagonistic and antioxidant properties of a new potential antiatherosclerotic agent. Org 13061 were compared with those of its (–) and (+) enantiomers (Org 13471 and Org 13581) in vitro and with appropriate reference drugs. Org 13061 antagonized contractions induced by potassium in rabbit aortic rings with an IC50 value of 0.50 μM and reduced the maximum rate of phase 0 depolarization (Vmax) of the ‘slow’ calcium‐mediated transmembrane action potentials in cardiac tissue (IC25 = 0.82 μM). Similarly to reference drugs, Org 13061 was more selective in reducing vascular compared to cardiac contraction. In concentrations overlapping those exerting vasorelaxant actions. Org 13061 inhibited copper ion‐induced human low density lipoprotein (LDL) peroxidation (0.1–1 μM) and inhibited lipid accumulation by rat aortic smooth muscle cells in culture (1–3 μM). Higher concentrations (3 μM) modestly inhibited proliferation of these cells. The (–) enantiomer was ten times more potent than the (+) enantiomer as a vasorelaxant but was equipotent in inhibiting lipid accumulation and LDL peroxidation (eg, lag phase of conjugated dienes formation increased by 29 and 61 min and by 22 and 56 min in response to 0.3 and 1 μM (–) and (+) enantiomers, respectively). The antioxidant probucol was approximately three times more potent than Org 13061 in inhibiting lipid accumulation but was 30 times less potent in antagonizing LDL peroxidation. The classical calcium channel blocking agents were totally ineffective on lipid accumulation (1–10 μM), whereas human LDL peroxidation was slightly reduced by nifedipine (0.1–3 μM) but unaltered by diltiazem (0.1–30 μM) and verapamil (0.1–3 μM). In conclusion, the racemic Org 13061 selectively blocks voltage‐operated calcium channels (VOCs) in concentrations that also exert marked antioxidant activity. The (–) enantiomer is largely responsible for calcium channel block but as antioxidants, the enantiomers are equipotent. This mixed pharmacological profile of Org 13061, not shared by known calcium channel blocking agents, may be potentially useful in the treatment of atherosclerosis.
Synergistic actions of pentobarbital and dihydropyridine Ca2+ antagonists on guinea pig isolated thoracic aorta†
Authors: Inami T. , Nakano J. , Kizawa Y. , Kotake H. , Nakajima Y. , Kusama T. , Murakami H.
Published: August 2009

Summary— In order to elucidate the mechanism(s) behind the interactions between barbiturates and Ca2+ antagonists, the effects of pentobarbital combined with three structurally diverse types of Ca2+ antagonist on CaCl2‐induced contractile responses of the guinea pig thoracic aorta in Ca2+‐free and 40 mM K+ medium and the effects of pentobarbital on Ca2+ antagonist binding to guinea pig aortic membranes were investigated. The dihydropyridine derivatives isradipine (10−10–10−8 M) and nifedipine (10−10–10−8 M) inhibited CaCl2‐induced contractions concentration‐dependently. Treatment with both pentobarbital (10−4 M) and dihydropyridine Ca2+ antagonists (10−9 M) shifted the CaCl2 concentration‐response curves to the right significantly compared with those after treatment with the Ca2+ antagonists and pentobarbital alone. However, no synergistic effects of pentobarbital (10−4 M) with other types of Ca2+ antagonist (verapamil (10−7 M) and diltiazem (10−6 M)) were observed. The binding of [3H]isradipine (2 × 10−9 M) to guinea pig aortic membranes was increased significantly by simultaneous pentobarbital treatment, but no such effect was observed with [3H]verapamil (10−8 M) or [3H]diltiazem (2 × 10−8 M). These findings suggest that the synergistic contractile effects of pentobarbital and dihydropyridines were, in part, due to enhancement of dihydropyridine binding to guinea pig aortic membranes (L‐type Ca2+ channels) by pentobarbital and that the interactions between pentobarbital and Ca2+ antagonists may be structurally specific.
Trolox‐derivative antioxidant protects against methanol‐induced damage
Authors: Skrzydlewska E. , Farbiszewski R.
Published: August 2009

Summary— This paper reports data on the effect of a new antioxidant, U‐83836E, on the lipid peroxidation and antioxidant status of liver, red blood cells (RBCs) and blood serum of rats intoxicated with methanol (3.0 g/kg body weight). Methanol administration slightly increased the levels of peroxidation products in the liver, and markedly increased them in RBCs and serum. In contrast, glutathione‐peroxidase, glutathione‐reductase activity, reduced glutathione concentration and total antioxidant status were decreased. The use of U‐83836E, containing a trolox ring, appeared to be beneficial in reducing lipid peroxidation products and in partially in preventing the decrease in glutathione and antioxidant enzymes induced by methanol in liver and serum. These results show that antioxidant U‐83836E may partially prevent methanol toxicity.
Effects of lorazepam on film‐induced differentiated emotions in healthy volunteers
Authors: Garcia C. , Philippot P. , Lacarelle B. , Valli M. , Rimé B. , Bruguerolle B. , Blin O.
Published: August 2009

Summary— We studied the effects of lorazepam, a benzodiazepine, on differentiated emotions in healthy volunteers. In order to induce differentiated emotions, film excerpts were selected on the basis of the type of emotion they induced (fear, anger and for affective tone neutral film). For 6 days (D1 to D6), ten healthy volunteers received lorazepam (1 mg bid) or placebo in a randomized cross‐over double‐blind trial. During each treatment period, emotional induction occurred on D4, D5 and D6. One film excerpt (fear, anger or neutral) was presented each morning after relaxation. Evaluation was performed before and after each emotional induction and included questionnaires (Differential Emotions Scale and physical activation visual analog scales), and neurophysiological parameters (systolic and diastolic blood pressure, heart rate and norepinephrine levels). Globally, the film excerpts induced the predicted emotions. An analysis of variance was undertaken and revealed a significant effect of lorazepam versus placebo. On the Differential Emotions Scale and during fear induction, lorazepam induced a significantly higher increase in fear, anxiety and disgust emotions than placebo, whereas no effect was observed after anger induction. Lorazepam also induced a significantly higher increase in diastolic and systolic blood pressure with no change in heart rate, and physical activation items (“tears” and “faster breathing”) without no significant change in norepinephrine. In conclusion, our results are consistent with an overall increase in emotional reactivity with lorazepam (1 mg bid) as compared to placebo. The pertinence of film‐induced differentiated emotions has to be confirmed for clinical pharmacological use.
Dynamics of the cationic and secretory responses to A‐4166 in perifused pancreatic islets
Authors: Jijakli H , Ulusoy S , Malaisse WJ
Published: August 2009

Summary— The dynamics of the cationic and secretory response to A‐4166, a hypoglycemic meglitinide analogue, was investigated in rat islets prelabelled with either 86Rb or 45Ca and placed in a perifusion system. In the absence of D‐glucose, A‐4166 (10 μM) provoked an immediate, sustained and rapidly reversible inhibition of 86Rb outflow, this contrasting with a short‐lived stimulation of insulin release. In the presence of 6 mM D‐glucose, A‐4166 provoked a rapid, sustained and rapidly reversible stimulation of both insulin release and 45Ca efflux. The latter cationic response was suppressed in the absence of extracellular Ca2+, in which case A‐4166 even caused a modest decrease in effluent radioactivity.

These findings support the view that A‐4166 acts mainly in the islet B‐cell by closing ATP‐responsive K+ channels, leading to subsequent depolarization of the plasma membrane and gating of voltage‐sensitive Ca2+ channels. Independently of the latter effect, A‐4166 may also affect the intracellular distribution of Ca2+ ions. The present data further indicate that A‐4166 belongs to those hypoglycemic agents that cause rapidly reversible changes in cationic and secretory events, at variance with highly potent sulfonylureas such as glibenclamide or glimepiride.
NG‐Nitro‐L‐arginine methyl ester: a muscarinic receptor antagonist?
Authors: Hellmich B , Gyermek L
Published: August 2009

Summary— The effect of the nitric oxide synthase inhibitor NG‐Nitro‐L‐arginine methyl ester (L‐NAME) towards muscarinic receptors was studied in vitro and in vivo. L‐NAME displaced the antimuscarinic ligand [3H]quinuclidinyl benzilate (3H]QNB) from its specific binding sites in rat cerebral cortex and cerebellum homogenates with a more than 10,000 fold lower affinity than atropine, pirenzepine and AFDX 116. Data for L‐NAME binding were best fit according to a two‐site model (Kd 7.2 nM and 3,000 nM) in the rat cerebellum, whereas in rat cortex a one‐site model (Kd 1670 nM) was superior. In anesthetized rats and rabbits L‐NAME (7.5–185 μmol/kg) attenuated a hypotensive response to Acetyl β‐methyl‐choline (Ac β‐Me Ch)(6.25 nmol/kg) in a dose related fashion, but this effect was negligible as compared to that of atropine (8.8 and 17.7 nmol/kg). Furthermore, the effect of L‐NAME was not specifically antimuscarinic since its attenuating effect against ATP‐ or histamine‐induced responses was not statistically different from that of Ac β‐Me Ch. A vagus stimulation induced bradycardia was entirely uninfluenced by L‐NAME (37 μmol/kg). In isolated bladder experiments (rabbit) we demonstrated a complete lack of efficacy of L‐NAME against Ac β‐Me Ch induced contractions. In the pithed rat preparation L‐NAME was ineffective against the McN‐A‐343 induced pressor responses. In summary, we demonstrated that the nitric oxide synthase inhibitor L‐NAME shows very weak affinity at M1‐ and M2‐receptors in the rat brain in vitro, but appears to have no significant antimuscarinic properties against M1‐, M2‐ and M3‐receptor mediated effects in rats and rabbits in vivo.
The effects of ryanodine on calcium uptake by the sarcoplasmic reticulum of ischemic and reperfused rat myocardium
Authors: Mubagwa K , Kaplan P , Flameng W
Published: August 2009

Summary— The effects of ischemia and reperfusion on sarcoplasmic reticulum (SR) calcium uptake were measured in crude heart homogenates of rats and were compared to published results for rabbit hearts. Isolated rat hearts (n = 5 in each group) were Langendorff‐perfused at 37 °C and were either kept normally perfused (control group), or submitted to 15 min normothermic ischemia (ischemic group), or reperfused for 10 min after 15 min ischemia (reperfused group). Mechanical function recovered to 50–60% of control after 10 min reperfusion following ischemia. Ca uptake (control Vmax; 23.0 ± 2.20 nmol·min−1·mg of protein−1) decreased during ischemia (Vmax: 15.7 ± 1.60 nmol·min−1·mg−1) but recovered to control level on reperfusion (Vmax: 20.8 ± 2.02 nmol·min−1·mg−1). An increased Ca uptake was obtained when the measurements were carried out in the presence of ryanodine (430 μM) to block Ca leakage through SR Ca‐release channels. The relative magnitude of ryanodine effect in the ischemic myocardium (increase: 77.2 ± 18.20%) was more marked than in control (32.0 ± 8.22%) or reperfused myocardium (39.0 ± 10.66%). This result is different from that of rabbit myocardium where similar ryanodine effect is present in all groups (56.7 ± 13.76%, 50.0 ± 13.56% and 54.2 ± 6.88% in control, ischemic and reperfused hearts, respectively) and suggests that a component of cytosolic Ca overload via SR Ca‐release channels is present during ischemia in rat, but not in rabbit myocardium.
Coronary effects of exogenous and endogenous bradykinin in conscious dogs
Authors: Puybasset L , Giudicelli JF , Berdeaux A
Published: August 2009

Summary—The effects of intravenous (iv) bolus administrations of bradykinin (0.1–1 μg·kg−1) on large and small coronary arteries were investigated in seven chronically instrumented conscious dogs. Bradykinin dose‐dependently increased heart rate, left ventricular dP/dt max, coronary blood flow and coronary artery diameter and decreased aortic pressure. Subchronic inhibition of the nitric oxide synthase (NOS) pathway (Nω‐nitro‐L‐arginine, 20 mg·kg−1·d−1during 7 days) attenuated the systemic and coronary effects of bradykinin. HOE 140, a specific bradykinin B2receptor antagonist, administered at a dose (30 μg/kg) sufficient to completely inhibit the systemic and coronary effects of exogenous bradykinin (1 μg/kg, iv bolus), had no effect on baseline systemic and coronary hemodynamic parameters. HOE 140 had also no effect on the flow‐dependent increase in large coronary artery diameter and on the relationship between flow debt and flow repayment volumes observed during myocardial reactive hyperemia. This lack of effect of HOE 140 persisted when experiments were repeated after NOS inhibition. We conclude that (a) exogenous bradykinin dilates large and small coronary arteries through a partially NO‐mediated mechanism, and (b) endogenous bradykinin plays no role in the control of arterial pressure, heart rate, LV dP/dt max, basal and flow‐stimulated coronary hemodynamics, both in control conditions and after subchronic inhibition of NOS in the conscious dog.