bluuebunny/crossref_metadata_2025 huggingface dataset:
Comparative effects of mibefradil and other calcium antagonists on resistance arteries of different end organs
Authors: van der Lee Robin , Pfaffendorf Martin , van Zwieten Pieter A.
Published: August 2009

Abstract—The biphasic contractile responses of rat isolated mesenteric, renal, coronary and basilar small arteries to potassium‐induced depolarization were investigated. The tonic phase is assumed to be exclusively the result of L‐type calcium channel (LCC) activation, whereas in the generation of the phasic phase T‐type calcium channels (TCC) may be involved. In order to evaluate whether TCC blockade has any influence on depolarization‐induced contractions the effects of the LCC antagonists nifedipine, diltiazem and verapamil were compared with those of the combined L‐ and TCC antagonist mibefradil. Small arteries (size 393.6 ± 4.8 μm,n= 104) were dissected from the respective organs of male Wistar rats (300–350 g) and studied in an isometric wire myograph. The effects of increasing concentrations of the calcium antagonists on repetitive potassium‐induced contractions were quantified by means of cumulative concentration‐response curves. A comparison was made with mesenteric vessels of SHR and WKY for nifedipine and mibefradil. Nifedipine was the most potent compound in blocking both the phasic phase (reduction 66–77%) and the tonic phase (IC50= 1.1–5.4 nM). The effect of mibefradil on the phasic response was comparable to that of verapamil and diltiazem. With respect to the tonic response mibefradil was comparable to verapamil (IC50= 19.6–178.9 nM). These findings indicate that the TCC blockade does not contribute to the vasodilator effect of mibefradil under the conditions investigated.
Stimulation of aldosterone secretion by benzodiazepines in bovine adrenocortical cells
Authors: Kenyon Christopher J. , Thomson Ian , Fraser Robert
Published: August 2009

Abstract—Previous studies have indicated that peripheral benzodiazepine receptor (PBR) ligands inhibit aldosterone secretion in isolated adrenal zona glomerulosa cells although positive responses have been demonstrated in other steroidogenic tissues. In the present study, aldosterone secretion was measured in bovine cells after 6 days of primary culture. At this time, basal aldosterone secretion was very low and cells appeared less sensitive to the steroidogenic effects of extracellular [K+] (maximal response required K+ concentration > 32 mmol/L) but were sensitised to angiotensin II (maximal response achieved with 3 nM) when compared with previous studies with freshly isolated cells. Diazepam concentration in the range 0.1 nM to 1 μM increased basal aldosterone secretion, an effect which was not enhanced by pre‐treatment with diazepam. The effects were small compared with those of angiotensin II or K+. Over the same concentration range, diazepam also potentiated the stimulatory effects of sub‐maximally effective concentrations of angiotensin II. When cells were treated with high‐density lipoprotein (HDL‐3) as a source of cholesterol, diazepam and the PBR ligands Ro5‐4864 and PK11195 also stimulated aldosterone secretion at nanomolar concentrations. In addition, the conversion of added 11‐deoxycorticosterone (DOC) to aldosterone was increased by nanomolar concentrations of diazepam and Ro5‐4864 but inhibited by high micromolar concentrations of these drugs (100 μM). We conclude that adrenocortical responses to PBR ligands are complex. At high concentrations, inhibitory effects involving competition for steroidogenic enzymes and calcium channel blockage predominate. At low concentrations, an enhancement of basal, angiotensin‐II and cholesterol‐dependent aldosterone synthesis is revealed which may involve a PBR‐mediated mitochondrial uptake of cholesterol and DOC.
Pentoxifylline decreases neutrophil respiratory bursts in patients with stable angina
Authors: Kowalski Jan , Kosmider Maciej , Pasnik Jaroslaw , Zeman Krzysztof , Baj Zbigniew , Janiszewska‐Drobinska Beata , Czekalska Romana
Published: August 2009

Abstract— We estimated the effect of pentoxifylline (PTX) on the respiratory burst (examined by chemiluminescence method) of unprimed and primed neutrophils with tumor necrosis factor‐α (TNF‐α) in patients with stable angina pectoris. Chemiluminescence of non‐stimulated as well as formyl‐methionyl‐leucyl‐phenylalanine (fMLP) and phorbol myristate acetate (PMA) stimulated neutrophils was measured. We studied 45 patients with stable angina subjected to percutaneous transluminal coronary angioplasty (PTCA) procedure, who were randomly divided into two groups. The study group consisted of 24 patients who were administered pentoxifylline orally, and the control group consisted of 21 patients without pentoxifylline administration. Blood samples for examination were collected from the coronary sinus and peripheral vein just before the PTCA procedure. Pentoxifylline decreased the respiratory burst of non‐stimulated and fMLP‐stimulated neutrophils without affecting the chemiluminescence of PMA stimulated neutrophils. Moreover, pentoxifylline diminished the chemiluminescence non‐stimulated and stimulated by fMLP but not by PMA of TNF‐α primed neutrophils. We presume that administration of PTX in stable angina patients may have a beneficial effect.
The effect of lithium administration in animal models of depression: a short review
Authors: Redrobe John P. , Bourin Michel
Published: August 2009

Abstract—The aim of this short review was to collate the data involving the effects of lithium alone, or in combination, with antidepressant drugs in several animal models of depression. It has been shown that lithium administration reduced immobility in the mouse forced swimming test when given 30 min, but not 45 min, before testing. Further studies indicated that this activity was probably a result of an activity on serotonin (5‐HT) 1A and IB receptor subtypes. Lithium treatment has been shown to reverse helpless behaviour in the learned helplessness model of depression after chronic treatment (30 days), where lithium was administered in the drinking water. Further studies showed that acute (5 days) administration of lithium failed to reverse behavioural deficits. In the olfactory bulbectomised rat model of depression, several immunological and enzymatic functions have been shown to be altered and these changes are regularised by antidepressant treatment as well as lithium administration for 15 days. Hypokinesia (reduced locomotor activity) is a phenomenon observed following immobilisation stress in rats. This behavioural deficit was attenuated by lithium together with a wide range of antidepressant drugs used in the treatment of unipolar depression at non‐stimulant doses. In addition, a single administration of lithium slightly inhibited midbrain raphe lesion‐induced muricidal behaviour (25%); however, repeated treatment (5 days) significantly attenuated this behavioural deficit. Lithium treatment has also been shown to reverse behavioural and biochemical deficits induced by reserpine together with those induced by acute administration of single intracerebroventricular (i.e.v.) dose of the Na, K‐ATPase‐inhibiting compound, ouabain. Long‐term studies of lithium augmentation have not been performed, so that no clear recommendations for the duration of this therapy can be made. The points raised in this short review endorse the commencement of such studies.
Functional assessment of rat aorta after cold storage in different media
Authors: Stanke‐Labesque Françoise , Cracowski Jean‐Luc , Devillier Philippe , Caron Françoise , Bessard Germain
Published: August 2009

Abstract—Cold storage is frequently used to store isolated blood vessels for a limited period of time. However preservation of vascular smooth muscle and endothelial functions is time and medium‐dependent. The present study was designed to compare the reactivity of rat aorta before and after cold storage for 24 and 48 h in one of four different solutions consisting of Hepes‐buffered Krebs solution, Belzer solution, Krebs solution, and Eurocollins solution. Smooth muscle and endothelial functions of the rat aorta were assessed using in vitro isometric tension measurement. The results obtained for vessels preserved for 24 and 48 h were compared with those for vessels studied immediately after harvesting. Sensitivity and maximum contraction to KCl and norepinephrine were not altered in rat aorta preserved up to 48 h in Hepes‐Krebs and Belzer solutions. In contrast, the amplitude of contraction elicited by KCl was significantly reduced by 50% and 77% in aorta stored for 24 and 48 h in Krebs solution and by 77% and 96% in those stored in Eurocollins solutions. Similarly, the maximal contraction elicited by norepinephrine was significantly reduced by 60% and 45% in arteries stored for 24 and 48 h in Krebs solution and by 34% and 86% in those stored in Eurocollins solution. In contrast, cold storage in the different media did not alter the relaxations elicited by sodium nitroprusside and forskolin. The endothelium‐dependent relaxations in response to acetylcholine were not statistically modified after preservation up to 48 h in Hepes‐Krebs solution. In contrast, the maximal relaxations to acetylcholine were significantly decreased after storage for 24 and 48 h in Belzer, Krebs and Eurocollins solutions. These results suggest that among the four media studied, Hepes‐Krebs solution is the most suitable medium for the storage of blood vessels under hypothermic conditions.
Role of CYP3A in haloperidol N‐dealkylation and pharmacokinetics in rats
Authors: Watanabe Minoru , Tateishi Tomonori , Asoh Masako , Nakura Hironori , Tanaka Masami , Kumai Toshio , Kobayashi Shinichi
Published: August 2009

Abstract—Haloperidol (HP), an antipsychotic drug, is N‐dealkylated hy cytochrome P450 (CYP) to 4‐fluorobenzoylpropionic acid (FBPA). The purpose of this study was to identify whether CYP3A metabolizes HP to FBPA in hepatic microsomes of rats and to investigate whether an inhibitor or an inducer of CYP3A affects HP pharmacokinetics in rats. The rate of FBPA formation was determined in hepatic microsomes from 8‐week‐old male Sprageue‐Dawley rats. Among several specific CYP isozyme inhibitors including troleandomycin (TAO). diethyldithiocarbamate. furafylline and quinine, only TAO showed marked inhibition of FBPA formation. Anti‐rat CYP3A serum inhibited FBPA formation by 76.4%, while other anti‐rat CYP sera (1A1. 1A2, 2B1, 2C11. 2E1) only slightly did. In a pharmacokinetic study, 8‐week‐old male Sprague‐Dawley rats were given 0.5 mg/kg HP intravenously after treatment with 100 mg/kg erythromycin, a CYP3A inhibitor, or 80 mg/kg dexamethasone. a CYP3A inducer, intraperitoneally once a day for 7 days or 2 days, respectively or untreated. HP half‐life was prolongated to 171% of the average control value by erythromycin and shortened to 49% of control by dexamethasone. HP clearance was reduced to 63% of control by erythromycin and was increased to 167% of control by dexamethasone. These results suggested that CYP3A mainly catalyzed HP to FBPA in rats, and the modification of this enzyme activity would affect the pharmacokinetics of HP.
Differential effects of pinacidil and levcromakalim on the contractions elicited electrically or by noradrenaline in the portal vein of the rabbit
Authors: Gojković‐Bukarica Ljiljana , Kažić Tomislav
Published: August 2009

Abstract— The present study was undertaken to examine the antivasoconstrictor effects of pinacidil and levcromakalim, two potassium channel openers (PCOs), on the isolated rabbit portal vein and to define the role for different subtypes of pre‐ and/or post‐synaptic K+ channels in the antivasoconstrictor action of the PCOs. The vein strips were contracted by electrical field stimulation (EFS) or by exogenous noradrenaline (NA). The results of this study showed that pinacidil produced a more potent inhibition of the neurogenic contractions (pD2 = 6.04 ± 0.05) than of contractions induced by exogenous NA (pD2 = 4.90 ± 0.10). Glibenclamide (1 μM), a selective blocker of adenosine triphosphate (ATP)‐sensitive K+ channels (KATP), did not affect the pinacidil‐induced inhibition of contractions evoked by exogenous NA. In contrast, glibenclamide (0.1–10 μM) significantly antagonized the effect of pinacidil on EFS evoked contractions in a noncompetitive manner. There was no difference between the inhibitory effects of levcromakalim on neurogenic contractions (pD2 = 7.58 ± 0.05) and contractions evoked by exogenous NA (pD2 = 7.64 ± 0.08). Glibenclamide (1 μM) antagonized in the same manner the levcromakalim‐induced inhibition of neurogenic contractions and contractions evoked by exogenous NA. Moreover, glibenclamide competitively antagonized the effect of levcromakalim on EFS induced contractions of the rabbit portal vein (pA2 = 6.40 ± 0.10). Charybdotoxin (0.4 μM) and apamin (0.1 μM) did not influence the inhibitory effects of pinacidil and levcromakalim, both on contractions evoked by EFS and contractions evoked by exogenous NA. These results suggest that the antivasoconstrictor effect of levcromakalim might be postsynaptic and associated with opening of the smooth muscle KATP channels. In contrast, it is hypothesized that the effect of pinacidil on neurogenic contractions is due to an interference with KATP channels in the neuromuscular synapse. It seems that the action of pinacidil on the NA contractions is mediated by another still undefined mechanisms of pinacidil.
Antagonism by pimozide of olanzapine‐induced hypothermia
Authors: Ninan Ipe , Kulkarni Shrinivas K.
Published: August 2009

Abstract—The atypical antipsychotic olanzapine (2.5–20 mg/kg) produced hypothermia in rats. The decrease in rectal temperature caused by olanzapine (2.5–20 mg/kg) was blocked by the selective dopamine D2receptor antagonist pimozide (0.5 and 1 mg/kg) but not by the dopamine D1receptor antagonist SCH 23390 (0.5 and 1 mg/kg). The dopamine D1/D2receptor agonist apomorphine (3 mg/kg) and the selective dopamine D2receptor agonist talipexole (0.5 mg/kg) produced hypothermia in rats. Olanzapine (10 and 20 mg/kg) significantly blocked hypothermia produced by both apomorphine and talipexole while the lower doses (2.5 and 5 mg/kg) of olanzapine failed to block it. The present results demonstrate that olanzapine behaves as a partial agonist at brain DA D2receptor populations involved in thermoregulation in the rat.
Pharmacological characterization of muscarinic receptors implicated in rabbit detrusor muscle contraction and activation of inositol phospholipid hydrolysis in rabbit detrusor and parotid gland
Authors: Barras Martine , Coste Annick , Eon Marie‐Thérèse , Guillot Etienne
Published: August 2009

Abstract—In the present study, we evaluated the pharmacological characteristics of the functional muscarinic receptors implicated in rabbit detrusor contraction and coupled to inositol phospholipid turnover in rabbit detrusor and parotid gland. The selectivity of several muscarinic antagonists for detrusor vs. salivary gland muscarinic receptors was also examined. The affinities for the muscarinic m1‐, m2‐ and m3‐receptor subtypes were determined using membranes from human cloned receptors expressed in CHO‐K1 cells using [3H]‐N‐methyl scopolamine as a radioligand. Anti‐muscarinic activity was determined in isolated rabbit detrusor by measuring the displacement of the contractile response to carbachol, and in rabbit detrusor and rabbit parotid by measuring the displacement of inositol phospholipid hydrolysis (total inositol phosphate accumulation) to carbachol. A significant correlation was found between the potencies to antagonize carbachol‐induced rabbit detrusor contraction (pKB) and the affinities (pKi) for the m3‐receptor subtype (r = 0.93,P= 5 × 10−6). Lower, but significant, correlations [0.88 (P= 6.3 × 10−5), 0.72 (P= 4.6 × 10−3)] were obtained with m1‐ or m2‐receptor subtypes, respectively. Each muscarinic antagonist tested displayed similar potency to antagonize carbachol‐stimulated inositol phospholipid hydrolysis in rabbit detrusor and parotid (r = 0.96,P= 8 × 10−3). A significant correlation was found between the potencies to antagonize carbachol‐stimulated inositol phospholipid hydrolysis (pKB), determined in rabbit detrusor and rabbit parotid, and the affinities (pKi) for the m3‐receptor subtype [r = 0.96 (P= 0.01), 0.99 (P= 5 × 10−5), respectively] and for the m1‐receptor subtype [r = 0.98 (P= 3.5 × 10−3), 0.94 (P= 0.02), respectively] but not for the m2‐receptor subtype [r = 0.33, 0.57, ns, respectively]. In each in vitro assay, methoctramine (preferential M2 selective antagonist) and pirenzepine (preferential M1 selective antagonist) were slightly potent. We suggest that the muscarinic receptor implicated in the response to carbachol in rabbit detrusor and parotid gland corresponds to the M3‐subtype. None of the muscarinic antagonists studied in rabbit tissues displayed preferential affinity for the detrusor.
Stereospecific analysis of omeprazole supports artemisinin as a potent inducer of CYP2C19
Authors: Mihara Kazuo , Svensson Ulrika S.H. , Tybring Gunnel , Hai Trinh Ngoc , Bertilsson Leif , Ashton Michael
Published: August 2009

Abstract—The purpose of the study was to determine the enantiomer pharmacokinetics of omeprazole and 5‐hydroxy‐omeprazole before and after administration of the antimalarial artemisinin to confirm artemisinin's ability to induce CYP2C19. Nine healthy male Vietnamese subjects were given a single 20 mg dose of omeprazole orally 1 week before (day ‐ 7) artemisinin administration. Artemisinin was then given orally (500 mg) for 7 days (days 1–7). On days 1 and 7, a single 20 mg dose of omeprazole was coadministered with artemisinin. After a washout period of 6 days, a single 20 mg dose of omeprazole was again administered together with a single 500 mg of artemisinin (day 14). Stereoselective pharmacokinetics of omeprazole and 5‐hydroxyomeprazole was determined on days of omeprazole administration. Seven days of artemisinin administration significantly decreased the AUC of both omeprazole enantiomers (day 7), compared with day 1 (P< 0.001). All values were normalized after the washout period. Artemisinin increased the AUC ratio of R‐5‐hydroxyomeprazole/R‐omeprazole significantly (P< 0.01) on day 7. The AUC ratio of omeprazole sulphone/S‐omeprazole did not differ between study days. Artemisinin decreased the AUC of S‐omeprazole to the same extent as that of R‐omeprazole in extensive CYP2C19 metabolizers, suggesting that artemisinin induces a different enzyme in addition to CYP2C19. These results support and strengthen earlier findings that artemisinin induces CYP2C19 as well as at least one enzyme other than CYP3A4.
Chlorpromazine at comparatively low concentrations potentiates carbachol‐induced tonic contraction of ileal longitudinal smooth muscle of the guinea‐pig
Authors: Nasu Tetsuyuki , Ou Shuichi
Published: August 2009

Abstract—The neuroleptic phenothiazine derivative chlorpromazine (CPZ) at high concentration (1 × 10−5M) decreased either the phasic or tonic contraction in response to carbachol and the carbachol‐induced increase in [Ca2+]i in both phases in ileal muscle. In contrast, CPZ at low concentrations (8 × 10−7– 5 × 10−6M) decreased only the phasic contraction and potentiated the tonic contraction induced by carbachol. However, CPZ at these concentrations dose‐dependently decreased the carbachol‐induced increase in [Ca2+]i in both phases. These results suggested that CPZ dose‐dependently decreased the initial phasic contraction in response to carbachol by inhibition of Ca2+release from the intracellular storage sites. CPZ at low concentrations appears to increase Ca2+sensitivity to contractile proteins in the carbachol‐induced tonic phase. CPZ dose‐dependently reduced the 60 mM K+‐induced phasic and tonic responses and a concomitant decrease in [Ca2+]i in ileal muscle.
Immunosine (7‐thia‐8‐oxoguanosine) acts as a cofactor for proliferation of T cells
Authors: Čolić Miodrag , Jandrić Dušan , Gašić Sonja , Vučević Dragana , Popović Petar , Medić‐Mijačevic Ljubica , Rakić Ljubisav
Published: August 2009

Abstract—Immunosine (7‐thia‐8‐oxoguanosine) is a novel guanosine analogue showing immunostimulatory activity both in vivo and in vitro. This compound acts on different components of the immune system including B cells, natural killer (NK) cells and antigen‐presenting cells (APC). However, its influence on functions of T cells is poorly understood. In this work we studied the effect of immunosine on proliferation of total rat splenocytes and purified T cells triggered by different mitogens and the mechanisms involved. The results demonstrate that immunosine significantly stimulates proliferation of T cells. The effect was dose‐dependent and also depended on concentrations of specific stimulators. Maximal stimulation was seen using 250 μM immunosine. The stimulatory effect of immunosine on lymphocyte proliferation triggered by Concanavalin A (Con A) correlated with increased interleukin 2 (IL‐2) production and upregulation of the IL‐2 receptor α (IL‐2Rα) expression. The dependency of T‐cell proliferation on IL‐2/IL‐2R was confirmed using neutralizing anti‐IL‐2Rα monoclonal antibodies (mAbs). Higher concentrations of immunosine in the presence of optimal concentrations of Con A (5 μg/mL) inhibited proliferation of T cells. A similar stimulatory effect of immunosine on proliferation of purified T cells and IL‐2 production was observed using an anti‐T‐cell receptor (TCR) mAb and a combination of anti‐TCR mAb and IL‐2. However, the guanosine analogue did not significantly modulate proliferation of T cells triggered by IL‐2 alone. When the combination of phorbol myristate acetate (PMA) and ionomycin was used for T‐cell stimulation different results were obtained. Under lower cell stimulation immunosine significantly potentiated T‐cell proliferation, expression of IL‐2Rα and IL‐2 production. In the presence of suboptimal stimulation the compound stimulated T‐cell proliferation and IL‐2Rα expression, whereas under maximal stimulation an enhancing effect on IL‐2 production was seen. Since direct stimulatory effect of immunosine on T‐cell growth in culture was rather weak it can be postulated that the compound acts as a cofactor for T‐lymphocyte proliferation.
Low levels of lymphocyte MDR1 gene expression during early renal transplantation in patients treated with tacrolimus
Authors: Becquemont Laurent , Camus Maryse , Kriaa Faical , Barbu Véronique , Charpentier Bernard , Jaillon Patrice
Published: August 2009

Abstract— P‐glycoprotein (P‐gp) is a membrane efflux pump increasing the transport of drugs such as tacrolimus out of the cells. The aim of the study was to determine the kinetics of lymphocyte P‐gp expression in patients treated with tacrolimus during the first 3 months following renal transplantation. Lymphocyte MDR1 gene expression was measured by semi‐quantitative RT‐PCR a few hours before transplantation, 3 weeks and 3 months after the graft. Lymphocyte MDR1 gene expression was low in all the 10 patients compared to 10 healthy volunteers: 0.30 ± 0.07 arbitrary units (patients) vs. 1.74 ± 0. 55 (healthy volunteers) (P = 0.0002). MDR1 gene expression decreased among the patients during the study: 0.28 ± 0.12 (3 weeks later) and 0.12 ± 0.09 (3 months later) (P = 0.006). We can conclude that lymphocyte MDR1 gene expression among patients before renal transplantation is low and remains low during the first 3 months following the graft.
Gastroprotective effects of pantoprazole against experimental mucosal damage
Authors: Blandizzi Corrado , Natale Gianfranco , Gherardi Giorgio , Lazzeri Gloria , Marveggio Cristina , Colucci Rocchina , Carignani Diego , Del Tacca Mario
Published: August 2009

Abstract—The present study investigated the gastroprotective effects of the proton pump inhibitor pantoprazole on gastric mucosal damage induced by ethanol‐HCI in rats. Omeprazole was used as reference drug. The morphometric analysis of gastric histological sections revealed that pantoprazole and omeprazole dose‐dependently prevented the necrotic mucosal injury evoked by ethanol‐HCI (ED50= 14.1 and 21.6 μmol/kg. respectively). These effects were associated with a marked increment of Alcian blue recovery from gastric bound mucus (ED50=18.8 and 29.3 μmol/kg, respectively). In addition, both pantoprazole and omeprazole inhibited gastric acid secretion in pylorus‐ligated rats (ED50= 1.5 and 3.3 μmol/kg, respectively). Further experiments indicated that the protective effects of pantoprazole were not modified byL‐365,260 (a gastrin receptor antagonist), suramin (a drug able to interfere with endogenous growth factors), NG‐nilro‐L‐arginine (an inhibitor of nitric oxide synthase) or systemic ablation of capsaicin‐sensitive sensory nerves, whereas they were partly blocked by indomethacin (an inhibitor of prostaglandin synthesis) and fully prevented by N‐ethylmaleimide (a potent blocker of sulfhydryl compounds). The present data provide histomorphometric evidence that: 1) pantoprazole is endowed with gastroprotective properties and is more active than omeprazole in preventing the necrotic mucosal damage induced by ethanol‐HCl; 2) according to the rank order of ED50values, the protective effects of both drugs appear to depend mainly on the enhancement of the gastric mucosal barrier rather than on the inhibition of acid secretion; 3) an increased production of prostaglandins, as well as an increased availability of sulfhydryl radicals at the level of the gastric mucosa may account for the gastroprotective effects of pantoprazole.
Frequency‐independent blockade of cardiac Na+channels by riluzole: comparison with established anticonvulsants and class I anti‐arrhythmics
Authors: Mestre Michel , Djellas Yasmine , Carriot Thierry , Cavero Icilio
Published: August 2009

Abstract—The Na+channel blocking activity and the antiarrhythmic effects of riluzole, and established anticonvulsants (lamotrigine and lifarizine) and class 1 antiarrhythmics (lidocaine, flecainide and disopyramide) were studied under in vitro and in vivo conditions. Guinea‐pig cardiac Purkinje fibres were superfused with Tyrode solution and electrically driven for recording action potentials with intracellular microelectrodes. In these preparations paced at 1 Hz, all compounds tested produced concentration‐dependent (0.3–100 μM) reductions in the maximum rate of depolarization of the action potential (Vmax). For riluzole, phenytoin and carbamazepine this effect was frequency‐independent (0.5–6 Hz) but for lamotrigine, lifarizine, lidocaine, flecainide and disopyramide it was frequency‐dependent. In anaesthetized rats, riluzole, in contrast to flecainide, did not delay the appearance of aconitine‐induced arrhythmias. Riluzole (0.3‐3.9 mg/kg, i.v.) also lacked notable cardiac electrophysiological effects in anaesthetized dogs. At an i.v. dose of 3.0 mg/kg riluzole failed to restore a normal sinus rhythm in conscious dogs with polymorphic arrhythmias produced by ligation of the left anterior descending coronary artery 24 h earlier. These results indicate that riluzole, phenytoin and carbamazepine, unlike lamotrigine, lifarizine and flecainide, block cardiac Na+channels in a frequency‐independent manner. This property may account for the lack of antiarrhythmic activity of riluzole, phenytoin and carbamazepine in animal models of arrhythmias that respond to class I antiarrhythmic drugs. It may also account for the clinical observation that riluzole does not seem to cause the unfavourable electrocardiographic changes characteristic of drugs that block cardiac Na+channels in a frequency‐dependent manner.
Influence of low temperature on bronchodilatation induced by terbutaline administered by metered dose or dry powder inhalers in asthmatics
Authors: Ramón Mercedes , Juan Gustavo , Ciscar Miguel Angel , Martí‐Bonmatí Ezequiel , Morcillo Esteban J. , Marín Julio
Published: August 2009

Abstract— Low temperatures may affect dose delivery efficacy and clinical effectiveness of medication aerosols. In this study we examine the effect of cold ambient temperature on the bronchodilatation produced by terbutaline delivered from a chlorofluorocarbon pressurized metered dose inhaler (pMDl) compared to a multi‐dose dry powder inhaler (DPI). Fourteen stable asthmatics were studied on two consecutive days. On day 1, after measuring FEV1 at room temperature (22 °C), each patient was randomized to receive 500 μg of terbutaline delivered from pMDI or DPI stored for 24 h at 22 °C with FEV1 recorded 20 min post‐dose; then, patients were placed in a chamber at − 10 °C, and after obtaining FEV1, each patient received 500 μg of terbutaline delivered from pMDI or DPI (same formulation as previously administered) stored for 24 h at − 10 °C, and FEV1 was obtained 20 min post‐dose. On day 2, a similar protocol was followed but each patient received terbutaline as the alternative to the formulation administered on day 1. Pairwise comparisons of the FEV1 (% predicted) values obtained on day 1 and day 2 at 22 °C and − 10 °C (pre‐dose) showed no significant differences. Similar bronchodilatations were observed for terbutaline DPI administration at 22 °C and − 10 °C (24.85 ± 11.72 and 20.08 ± 6.27 % increase of FEV1; P>0.05). By contrast, the bronchodilatation obtained for terbutaline pMDI at 22 °C (21.07 ± 8.55% increase in FEV1) was not reproduced at − 10 °C (0.72 ± 2.84%; P < 0.05 from 22 °C). In five asthmatics a cumulative dose‐response curve for terbutaline pMDI was obtained. This part of the study showed that a higher dose of terbutaline pMDI was necessary at − 10 °C to obtain a bronchodilator response (10.04 ± 6.75% increase of FEV1 after 2 000 μg) that remained lower than the bronchodilatation for 500 μg terbutaline pMDI at − 10 °C. In conclusion, the clinical effectiveness of terbutaline delivered from chlorofluorocarbon pMDIs is compromised by cold storage while DPIs are not affected.
Pharmacokinetics of sustained and immediate release formulations of indapamide after single and repeated oral administration in healthy volunteers
Authors: Schiavi Pierre , Jochemsen Roeline , Guez David
Published: August 2009

Abstract— The pharmacokinetics of a 2.5 mg immediate release (IR) formulation of indapamide was compared to a 1.5 mg sustained release (SR) formulation of indapamide after single and repeated oral administration dose using double blind randomised cross‐over studies. In the first study, 12 subjects received a single dose of each treatment: IR fasted, SR fasted or with food. In the second study one tablet of either formulation was administered daily for one week at breakfast. In each study, blood samples were collected pre dose (Cmin) and up to 120 h after the last dose. Urine was collected over the dosing interval (24 h). Following a single oral administration the SR formulation had a lower dose‐normalised Cmax compared to the IR formulation (17.6 ± 6.3 vs. 39.3 ± 11.0 ng.mL−1, respectively), a much longer tmax (12.3 ± 0.4 vs. 0.8 ± 0.3 h) and a greater t75 (15.3 ± 6.1 vs. 1.8 ± 1.4 h) but there were no differences in dose‐normalised AUC (559 ± 125 and 564 ± 146 ng.h.mL−1) nor in t1/2zvalues (14.8 ± 2.8 vs. 18.4 ± 13.4 h). The SR formulation clearly demonstrated sustained release characteristics as compared to the IR formulation. Food co‐administration had no effect on dose‐normalised AUC for the SR formulation. After repeated administration, steady‐state was achieved by day 5. The absorption rate of the SR formulation was lower and the 24 h peak‐to‐trough fluctuation was 4‐fold lower compared to the IR formulation. After dose correction there was no change in AUC, (726 ± 207 and 690 ± 183 ng.mL −1.h for SR and IR, respectively). The elimination parameters (t1/2z, AeT and CLr) remained unchanged. The SR formulation showed sustained release of indapamide with a reduction in peak concentration, while steady‐state level was not affected by formulations. The two formulations have the same bioavailability.
Lubeluzole‐induced prolongation of cardiac action potential in rabbit Purkinje fibres
Authors: Grand Bruno Le , Dordain‐Maffre Myriam , John Gareth W.
Published: August 2009

Abstract—Lubeluzole, a novel neuroprotective compound, has been associated with cases of QT interval prolongation but its effects on the cardiac action potential have not been described to date. Thus, the electrophysiological effects of lubeluzole were studied in rabbit isolated Purkinje fibres. The results demonstrate that lubeluzole (0.001‐1 μM) concentration‐dependently lengthened action potential duration at 50% and 90% of repolarization (APD50and APD90) without significantly modifying other parameters. Furthermore, APD lengthening induced by lubeluzole was not significantly decreased by reducing the basic cycle length (from 3 000 to 1 000 ms). The results demonstrate that lubeluzole potently and concentration‐dependently increases APD from 0.01 μM, consistent with class III‐type antiarrhythmic actions, which is likely to underlie QT interval prolongation induced by the drug.
Combination treatment for chronic hepatitis C: what is the role of ribavirin?
Authors: Souvignet Claude , Zarski Jean‐Pierre
Published: August 2009

Abstract— Ribavirin in combination with interferon‐α2b is the new standard for chronic hepatitis C (CHC) treatment. Although usually considered as an antiviral compound, this guanosine analogue shows some additional effects on the immune system that could largely contribute to its clinical efficacy in CHC. Numerous in vitro experiments demonstrate that ribavirin has a selective down‐regulatory effect on TH2 cytokine release with, in some cases, a concomitant TH1 cytokine up‐regulation. In vivo, combination treatment of CHC patients was shown to induce a predominant TH1 response in isolated PBMCs, but also a reduction of peripheral TH2 response. Considering that: 1) a strong CD(4) + helper T‐cell response is associated with viral clearance in acutely infected patients; 2) a weak T‐cell response to the viral antigens is common in chronic infected patients; 3) responding patients to combination treatment (but not non‐responding patients) altered their cytokine profile under treatment, either to express IFN‐γ or to reduce pro‐inflammatory mediators; it is highly presumed that ribavirine participates to restore an efficient T‐cell response and to reduce the non‐specific inflammatory cytolytic activity during CHC combination treatment.
Additivity of bupivacaine and morphine for peripheral analgesia in rats
Authors: Fletcher Dominique , Gentili Marc , Mazoit Jean‐Xavier , Samii Kamran
Published: August 2009

Abstract—Infiltration of the surgical wound is a classical technique for post‐operative analgesia. Recent studies have suggested that local anaesthetic may be combined with other drugs such as opioids. This study has evaluated, in rat, the infiltration with morphine, bupivacaine and their combination. In all groups, the two hind paws were injected with carrageenin. The left hind paw was used as control. The vocalisation threshold to paw pressure (VTPP) of both hind paws was evaluated 2 h after induction of carrageenin inflammation (baseline value), then every lOmin until the return to baseline value after injection of analgesic drugs. The development of oedema was evaluated in both hind paws by measurement of paw circumference (PC) before, then after, carrageenin injection. All analgesic drugs were injected in the right inflamed paw diluted in 0.2 mL of normal saline. The analgesic effect of bupivacaine (0.1, 0.25 and 0.5%), morphine (25, 50 and 100 μg) and their combination (bupivacaine 0.1%/morphine 20 μg, bupivacaine 0.2%/morphine 40 μg and bupivacaine 0.4 %/morphine 80 μg) was tested. The effect of naloxone on morphine induced analgesia was tested. The interaction between bupivacaine and morphine was evaluated with an isobolographic analysis. Bupivacaine produced a dose‐dependent antinociceptive effect. Morphine infiltration produced a peripheral, dose‐dependent analgesic effect antagonised by naloxone. This analgesic effect of morphine was associated with an anti‐inflammatory effect. The isobolographic analysis revealed only additivity between bupivacaine and morphine. The infiltration with morphine offers a peripheral analgesic effect which is additive with the effect of bupivacaine. An anti‐inflammatory effect of morphine participates in this peripheral analgesic effect.
Direct vascular actions of methyclothiazide and indapamide in aorta of spontaneously hypertensive rats
Authors: Colas Bouchra , Slama Michel , Masson Henri , Colas Jean‐Laurent , Collin Thibault , Arnould Marie‐Luce , Hary Lionel , Safar Michel , Andrejak Michel
Published: August 2009

Abstract— In vitro experiments were designed to assess the inhibitory effect of the thiazide diuretics methyclothiazide (MCTZ), the hydrochlorothiazide (HCTZ), and the thiazide‐related diuretic indapamide (IND) on contractile responses to norepinephrine (NE) and arginine vasopressin (AVP) of aortic rings from spontaneously hypertensive rats (SHR) and normotensive Wistar Kyoto rats (WKY). Changes in the tension of aortic ring preparations were measured isometrically. MCTZ (10−4M) induced endothelium‐dependent inhibition of the vasoconstrictor responses to NE and AVP only in aortas from SHR, and the maximal vasoconstrictive effect of NE and AVP was decreased by 59 ± 11% and 32.3 ± 13%, respectively. Indapamide (10−4M) also induced endothelium‐dependent inhibition of the contractile response to AVP in aortic rings from SHR, and the maximal vasoconstrictive effect of AVP was decreased by 33 ± 5%. In contrast, HCTZ did not inhibit the contractile response to either NE or AVP, even at the highest concentration. This study provides evidence that methyclothiazide and indapamide inhibit the contractile response induced by norepinephrine and/or arginine vasopressin on SHR aortic preparations via an endothelium‐dependent mechanism.
Amiloride‐sensitive pressure‐induced myogenic contraction in rat cerebral artery
Authors: Oyabe Akihiro , Masumoto Naohiro , Ueta Kiichiro , Nakayama Koichi
Published: August 2009

Abstract—The inhibitory action of amiloride on the pressure‐induced contraction was assessed in isolated rat cerebral artery. The artery was mounted in an arteriograph, and the change in intracellular Ca2+concentration ([Ca2+]i) and vessel diameter were simultaneously measured. The contractile response elicited by intraluminal pressurization was independent of endothelium, i.e. myogenic in nature, and abolished by nicardipine, a Ca2+antagonist or by removal of extracellular Ca2+, and was potentiated by 25 mM KCl. Cyclopiazonic acid and thapsigargin, inhibitors of the Ca2+‐ATPase pump of the sarcoplasmic reticulum, and a protein kinase C inhibitor calphostin C did not suppress the pressure‐induced contraction. Amiloride, a putative stretch‐activated cation channel blocker, attenuated with an IC50(50% inhibitory concentration) of about 3 μM the increase in [Ca2+]iand contractile activity in response to pressure, whereas the drug showed no apparent effect on the contraction produced by high KCl or 9,11‐dideoxy‐11α,9α‐epoxymethano prostaglandin F2α, (U46619). Furthermore, amiloride (100 μM) did not significantly affect intracellular pH in the artery. In spite of its multiple pharmacological actions, it seems possible that amiloride is a useful alternative tool at the cellular or tissue level to study the mechanotransduction mechanisms involved in the pressure‐induced contraction in rat cerebral artery.
Temperature‐dependent basal tone in isolated human saphenous veins: implication of TP‐receptors
Authors: Simonet Serge , Bonhomme Edith , Fabiani Jean‐Noël , Verbeuren Tony
Published: August 2009

Abstract—Cutaneous blood vessels are very sensitive to changes in environmental temperature. The influence of variations in local temperature on the mechanisms involved in the basal tone, present in isolated human saphenous veins has not yet been studied. In the present study, segments with and without endothelium of human saphenous veins obtained from coronary bypass surgery patients were mounted for isometric tension recording in oxygenated physiological salt solution (PSS). After stabilisation of the basal tone, the local temperature was rapidly either decreased from 37 °C to 24 °C (cooling) or increased from 37 °C to 42°C (warming). When antagonists or inhibitors were used the preparations were incubated for 30 min with the drugs. During basal conditions, cooling caused relaxations of the saphenous vein segments with endothelium and warming caused contractions; the absence of the endothelium did not modify these responses. In veins without endothelium, the warming‐induced contractions were significantly inhibited by verapamil (10 μM) and by the antagonist of TP‐receptors (receptors for thromboxane A2) Bay u 3405 (1 μM). The warming induced contractions were not affected by cyclooxygenase or lipoxygenase inhibition. At 37°C, the isoprostanes (8‐iso‐PGE2and 8‐iso‐PGF2α) induced potent contractions that were significantly inhibited by Bay u 3405 (1 μM). The data show that a basal tone is present in isolated resting human saphenous vein segments at 37°C. This basal tone is decreased by local cooling and enhanced by local wanning and is not dependent on the presence of the endothelium. The warming‐induced contraction of the veins is mediated by a non‐cyclooxygenase, non‐lipoxygenase metabolite (iso‐prostanc?) that interacts with TP‐receptors and via an extracellular calcium‐dependent pathway.
Small platform stress increases [3H]Ro 15–4513 binding in the cerebellum of mice
Authors: Pokk Paavo , Vassiljev Vitali , Väli Marika
Published: August 2009

Abstract— Small platform stress was induced in male BALB/c mice by placing them on small platforms (d = 3.5 cm) surrounded by water for 24 or 72 h. This experimental model contains several factors of stress, like rapid eye movement (REM) sleep deprivation, isolation, immobilization and falling into the water. After 24 h small platform stress exposure latency to sleep was measured after the administration of the benzodiazepine receptor agonist diazepam (1.0 and 2.5 mg/kg, i.p.) and the benzodiazepine receptor inverse agonist Ro 15–4513 (1.0 mg/kg, i.p.). As could be expected, diazepam significantly shortened the latency to sleep. Surprisingly the administration of Ro 15–4513 also shortened the latency to sleep. In addition [3H]Ro 15–4513 binding was measured in the cerebellum of control and small platform stressed mice. Small platform stress for 24 h did not alter the maximal number of [3H]Ro 15–4513 binding sites (Bmax) and decreased their affinity (KD). Small platform stress for 72 h significantly increased the number of [3H]Ro 15–4513 binding sites and decreased their affinity. These effects were due to changes in diazepam‐sensitive binding. In conclusion, it could be supposed that exposure of mice to small platform stress causes changes in the function of the [3H]Ro 15–4513 binding sites, probably a shift of binding sites toward agonist conformation, that leads to changes in the effects of Ro 15–4513.
Involvement of protein phosphatases in differential regulation of renal proximal tubular PAH and sodium‐dependent dicarboxylate transport*
Authors: Gabriëls G. , Mauß S. , Werners A. , Greven J.
Published: August 2009

Abstract—It has been demonstrated that the basolateral organic anion (PAH) transporter and the sodium‐dependent dicarboxylate transporter of rabbit renal proximal tubules are regulated differentially. A variety of protein kinases has been shown to be involved in the regulation of organic anion transport while dicarboxylate uptake, to which the first is coupled functionally, is not inlluenced by these kinases. This study was undertaken to elucidate whether respective transporter activities are modulated differentially by protein phosphatases as well. The experiments were performed on isolated S2segments of proximal tubules microdissected from rabbit kidneys without the use of enzymatic agents.3H‐PAH was used as marker substance of the PAH transporter.14C‐glularate as a marker of the sodium/dicarboxylate cotransporter. 30 s tubular uptake measurements were performed. Vanadate (10−3M). a selective inhibitor of tyrosine phosphatase, did not reduce PAH uptake significantly, while inhibitors of the serine/threonine phosphatases I and 2A. okadaic acid and calyculin A (106M. each) induced a significant decrease of 30 s PAH uptake (by 32.3% ± 7.9% and 25.6% ± 6.4%) but not a change in dicarboxylate transport. These findings indicate that, in addition to a variety of protein kinases, serine/threonine phosphatases have a role in the regulation of renal basolateral PAH transport. There is no effect of these phosphatases on basolateral 30s glularate transport. Thus, additional evidence for differential regulation of short‐time activity of the transporters for PAH and dicarboxylales is provided.
Dopamine D4 receptors and development of newer antipsychotic drugs
Authors: Kulkarni Shrinivas K. , Ninan Ipe
Published: August 2009

Abstract— The last ten years have witnessed the generation of a large amount of information on the neurobiology of dopamine receptors. Molecular biology and pharmacology studies have revealed existence of at least five dopamine receptor subtypes, namely D1, D2, D3, D4 and D5. The discovery of D4 receptors and the putative affinity of clozapine for D4 receptors have kindled development of selective D4 receptor antagonists for the treatment of schizophrenia. Studies on expression of D4 receptor proteins have shown selective localisation of D4 receptors in mesolimbic/mesocortical areas which could probably explain the lack of motor side effects with atypical antipsychotics like clozapine and olanzapine. However, neuropathological and genetic studies on the role of D4 receptors in the pathophysiology of schizophrenia and preliminary clinical studies with selective D4 receptor antagonists have been disappointing. There have been, however, complimentary findings between selective D4 receptor antagonism and genetic approaches such as antisense treatment or gene targeting. The therapeutic potential of D4 receptors as a target for developing antipsychotics will be known only when selective D4 receptor antagonists with varying D2/D4 and D4/5‐HT2A ratios are developed and tested in psychiatric patients.
Ursodeoxycholic acid modulates cyclosporin A oral absorption in liver transplant recipients*
Authors: Caroli‐Bosc François‐Xavier , Iliadis Athanassios , Salmon Laurent , Macheras Panos , Montet Anne‐Marie , Bourgeon André , Garraffo Rodolphe , Delmont Jean‐Pierre , Montet Jean‐Claude
Published: August 2009

Abstract—The aim was to study the ursodeoxycholic acid (UDC) effect on the cyclosporin A (CsA) pharmacokinetics after oral administration of the microemulsion formulation Neoral® (CsA‐ME) in liver transplant recipients, and test the potential protective effect of this bile acid on liver and renal CsA‐ME‐induced toxicity. At entry into the study, 12 patients who underwent orthotopic liver transplantation received CsA‐ME, for at least 6 months. They then received a cotreatment CsA‐ME plus UDC (13.8 mg.kg−1.day−1) for three months. Blood concentrations of CsA were measured using a monoclonal antibody specific for the parent compound. The kinetic data were analysed by a mathematical model incorporating a time dependent rate coefficient for CsA intestinal absorption, before and after UDC treatment. Changes in serum markers of hepatic and renal injury were assessed. Individual serum bile acids were determined by chromatography. Serum levels of UDC increased from 3 to about 45 % of total serum bile acids after UDC treatment. The estimated model parameters indicate that UDC administration modulates CsA intestinal absorption. In the nine non‐cholestatic patients, UDC reduced the absorption rate and the bioavailability of CsA without modifying the elimination rate constant of CsA and the CsA pre‐drug levels. In contrast, in the three cholestatic patients, the bioavailability tended to be higher and the absorption rate faster when CsA was combined with UDC. UDC significantly decreased elevated γ‐glutamyl transferase and creatinine serum levels and induced some clinical improvements such as disappearance of headaches in four patients. In conclusion, a 3‐month UDC treatment modifies CsA intestinal absorption without affecting CsA elimination rate constant. On the other hand, UDC supplementation appears to improve CsA tolerability.