bluuebunny/crossref_metadata_2025 huggingface dataset:
EFFECT OF MODAFINIL ON PANCREATIC EXOCRINE SECRETION IN RATS. A COMPARISON WITH ADRAFINIL AND RELATED DRUGS
Authors: CHARIOT J. , APPIA F. , VAILLE C. , ROZÉ C.
Published: August 2009

Summary— The effects of modafinil and adrafinil, 2 drugs that induce locomotor hyperactivity, and those of the parent compounds CRL 40467 and CRL 40385, were studied on the external pancreatic secretion of anaesthetized and conscious rats. In anaesthetized rats modafinil, adrafinil, and CRL 40385 antagonized the central vagal stimulation of protein output induced by 2‐deoxy‐D‐glucose in the pancreatic juice. In conscious rats, modafinil and adrafinil inhibited the output of protein in the basal interdigestive pancreatic secretion. Modafinil was more active than adrafinil as an inhibitor of pancreatic secretion. The effects of modafinil and adrafinil were different from those of sympathetic amines and dopamine: they did not stimulate the output of bicarbonate in anaesthetized rats, and pancreatic inhibition observed in conscious rats was not inhibited by either yohimbine or prazosin.
PROLONGED BETA BLOCKADE DUE TO TERTATOLOL: A COMPARATIVE STUDY WITH PROPRANOLOL AND ATENOLOL
Authors: DESCHE P. , COURNOT A. , GUERY O. , PROST J.F. , DUCHIER J.
Published: August 2009

Summary— Submaximal exercise heart rate was measured after oral administration of placebo, tertatolol 5 mg, propranolol 80 mg, and atenolol 100 mg to 12 subjects in a double‐blind cross‐over study. The peaks of beta‐blocking activity, observed at 2 hr, were of similar extent for the 3 drugs. The duration of activity of tertatolol, a beta blocker with a short elimination half‐life, extended up to 24 hr as did that of atenolol, but was longer than that of propranolol which reached only 18 hr. These results support once‐daily administration of tertatolol in therapy.
L‐ARGININE METHYLESTER REDUCES Ca2+/Cl− ‐DEPENDENT L‐[3H]GLUTAMATE BINDING AND Ca2+‐ACTIVATED NEUTRAL PROTEASE ACTIVITY IN RAT HIPPOCAMPAL MEMBRANES
Authors: BENNARDINI F. , FAILLI P. , MATUCCI R. , BARTOLINI A. , MALCANGIO M. , MASSARI M. , FRANCONI F. , GIOTTI A.
Published: August 2009

Summary— Specific binding of L‐[3H]glutamate was measured in Tris‐HCl buffer in rat hippocampal membranes. In these experimental conditions 1 mM CaCl2 induced an increase in binding due to an increase in Bmax.

L‐Arginine methylester did not modify the Cl−‐dependent binding of L‐[3H]glutamate, but it decreased Ca2+ /Cl− ‐stimulated binding in a dose‐dependent manner, decreasing Bmax without changing KD. L‐Arginine methylester reduced calcium‐activated neutral protease activity in a dose‐dependent manner. Serine protease inhibitors (aprotinin and di‐isopropylfluorophosphate) did not affect L‐[3H]glutamate binding, whereas leupeptin reduced it in a dose‐dependent manner. L‐Arginine did not mimic the effect of L‐arginine methylester in either model.
STIMULATION OF MYOCARDIUM DURING REPERFUSION INJURY BY A NEW INOTROPE‐VASODILATOR AGENT, MCI‐154
Authors: WYNSEN J.C. , SHIMSHAK T.M. , PREUSS K.C. , GROSS G.J. , BROOKS H.L. , WARLTIER D.C.
Published: August 2009

Summary—The systemic and coronary hemodynamic actions of a newly synthesized inotropic agent structurally related to milrinone and amrinone, MCI‐154 (0.5‐4.0 μg/kg/min IV), were studied in 2 groups of conscious, chronically instrumented dogs with normal or depressed postischemic, reperfused myocardium after a 15‐min coronary artery occlusion. In an additional group of control experiments, the time course of recovery of postischemic, reperfused myocardium was studied to verify the constancy of regional segment shortening in the previously ischemic zone during the time corresponding to drug infusion. Similar inotropic actions of MCI‐154 were observed in both normal and postischemic, reperfused hearts, indicating significant contractile reserve to be present in ‘stunned’ myocardium. Global contractility as measured by peak positivedP/dt was significantly increased in both groups. In postischemic, reperfused myocardium 90 min after initiation of reflow, regional segment function remained depressed at 44% of control but improved to 93% of control after administration of MCI‐154. In addition, MCI‐154 produced significant dose‐related decreases in mean arterial pressure, left ventricular end‐diastolic pressure, end‐diastolic segment length, and diastolic coronary vascular resistance. The data demonstrate that in addition to producing beneficial hemodynamic changes, MCI‐154, a new non‐sympathomimetic inotropic agent, markedly enhances regional contractility of postischemic, reperfused myocardium.
EFFECTS OF VARIOUS PHARMACOLOGICAL AGENTS ON ISOLATED HUMAN BRONCHIAL AND PULMONARY ARTERIAL AND VENOUS MUSCLE PREPARATIONS CONTRACTED BY LEUKOTRIENE D4
Authors: BOURDILLAT B. , HAYE‐LEGRAND I. , LABAT C. , RAFFESTIN B. , NOREL X. , BENVENISTE J. , BRINK C.
Published: August 2009

Summary—The response of isolated human bronchial muscle preparations to leukotriene D4(LTD4, 0.1 μM; 0.22 ± 0.03 g/mm2) was similar to that of histamine (50 μM; 0.21 ± 0.02 g/mm2). Isolated pulmonary venous preparations also contracted to these same concentrations of both agonists (LTD4, 0.32±0.19 g/mm2; and histamine, 0.36±0.07 g/mm2). However, pulmonary arterial preparations responded to histamine (50 μM, 0.59±0.10 g/mm2) but exhibited a reduced response to LTD4(0.3 μM, 0.06 ± 0.01 g/mm2). Bronchial and pulmonary venous muscle preparations from the human lung had the same sensitivities to LTD4(pD2values: bronchus, 7.95±0.08 and vein, 7.76±0.07). When bronchial or pulmonary venous muscle preparations were incubated for 30 min with either diltiazem (10μM), indome‐thacin (1.7 μM) or L‐cysteine (3 μM), the LTD4cumulative concentration‐effect curves following these drug treatments were similar to controls. However, FPL‐55712 (10 μM) significantly shifted the LTD4concentration‐effect curves produced in bronchial preparations to the right. In isolated pulmonary arterial preparations none of these drug treatments enhanced the LTD4response.

These results show that isolated human pulmonary arterial preparations are less responsive to LTD4than bronchial or venous preparations. In addition, the data obtained subsequent to the various drug treatments indirectly suggest that the LTD4contraction is not modified by a calcium channel blocker or by inhibition of the endogenous products of the cyclooxygenase pathway.
COMPARISON OF THE PROTECTIVE EFFECT OF VARIOUS FLAVONOIDS AGAINST LIPID PEROXIDATION OF ERYTHROCYTE MEMBRANES (INDUCED BY CUMENE HYDROPEROXIDE)
Authors: AFFANY A. , SALVAYRE R. , DOUSTE‐BLAZY L.
Published: August 2009

Summary— An experimental model system was designed to test the antioxidant effects of various phar‐macologic compounds. Cumene hydroperoxide induces in vitro the peroxidation of erythrocyte membrane and the subsequent formation of malonaldehyde and fluorescent lipid‐soluble products. The protective effect of various flavonoids was compared to that of butylated hydroxytoluene (BHT). Protective effect was evaluated by the inhibition of peroxidation product formation. In this experimental system, querce‐tin and catechin showed a protective effect against lipid peroxidation as high as that of BHT. Morin, rutin, trihydroxyethylrutin, and naringin were active but to a lesser degree, whereas flavone was devoid of antioxidant activity.
PHARMACOKINETICS OF ORALLY ADMINISTERED TIZANIDINE IN HEALTHY VOLUNTEERS
Authors: TSE F.L.S. , JAFFE J.M. , BHUTA S.
Published: August 2009

Summary— The pharmacokinetics of tizanidine, a new centrally acting muscle relaxant, have been studied in 18 normal male volunteers who received orally a single 5 mg dose, a single 20 mg dose, or repeated administration of 4 mg every 8 hr for 13 doses of [14C]tizanidine. Serial blood and breath samples and complete urine and feces were collected and analyzed for total radioactivity as well as intact tizanidine. Tizanidine was rapidly and almost completely absorbed from the gastrointestinal tract, although the estimated bioavailability was only 21% due to extensive first‐pass metabolism. The pharmacokinetics of tizanidine appeared to be linear in the 0–20 mg dose range, as indicated by the dose‐proportional blood levels of total radioactivity as well as of parent drug. Absorbed tizanidine was almost completely metabolized before excretion, the major excretory route being via the kidneys. The terminal half‐lives of tizanidine and radioactivity were ca 3 hr and 61 hr, respectively, and 76%‐77% of the administered radioactivity was recovered within 120 hr. Repeated administration of [14C]tizanidine resulted in no apparent change in pharmacokinetic characteristics. During the 4 mg q 8 hr regimen, blood levels of tizanidine reached steady state after only 2 or 3 doses, whereas those of total radioactivity approached steady state after approximately 4 days. The degree of accumulation of radioactivity, unlike that of parent drug, was inconsistent with the terminal half‐life, but instead implied a shorter effective half‐life of ca. 16 hr. It appears that the terminal phase of the blood radioactivity profile represents a metabolite that is reversibly bound to and slowly released from a specific tissue depot, and that this binding involves a finite amount of drug regardless of the dose. The oral administration of [14C]tizanidine prescribed in the present study was safe and well tolerated.
STUDY OF DRUG CONSUMPTION IN A WORKING ENVIRONMENT IN FRANCE
Authors: BANCAREL Y. , BLANC M.P. , CHARRIN G. , CHASTAN E. , COLDEFY J.F. , COTTES L. , DUCAP A. , EVRARD P. , GALIAY C. , GUIRAUD J.C. , HOTELIER G. , GARCIA G. , JANSOU P. , FERREIRA D. , LOUIS A. , MARTIN F. , MONTASTRUC N. , SARDA R. , SAINT‐PIERRE Y. , MONTASTRUC J.L.
Published: August 2009

Summary— 1. The present study was conducted to investigate drug consumption in a working environment by means of an anonymous questionnaire given to 2221 subjects and answered in the presence of the work physician.

2. Among the 2221 subjects, 922 had taken at least 1 drug during the week just preceding the medical visit to the company.

3. Women used significantly more hypnotics, sedatives, analgesics, and endocrinologic drugs and homeopathic agents than men, who tended to take more respiratory drugs.

4. Consumption of drugs significantly increased with age.

5. The mean value of estimated difficulty of work was higher in subjects taking drugs in general, as well as hypnotics, sedatives, analgesics, anti‐inflammatory agents and gastrointestinal drugs. There was a significant relationship between difficulty of work and total number of medicines taken.

6. Manual workers in general, took no more drugs than nonmanual workers, except for analgesics, anti‐inflammatory drugs, and antibiotics. Nonmanual workers used homeopathy more than manual workers.

7. The presence of extraprofessional problems was associated with an increase in drug consumption.
BINDING OF LOOP DIURETICS TO THEIR RENAL RECEPTORS: USE AS A SCREENING MODEL FOR POTENTIAL DIURETIC ACTIVITY
Authors: GIESEN‐CROUSE E. , FANDELEUR P. , WELSCH C. , ENGLERT H. , LANG H.J. , SCHMIDT M. , IMBS J.L.
Published: August 2009

Summary—Loop diuretics of the benzoic acid and aryloxyacetic acid families inhibit Na+K+Cl−cotransport. The ranking order of potencies measured in the thick ascending limb of Henle's loop and the ranking order of affinities for [3H]piretanide receptors on renal plasma membranes are the same. Potencies and affinities correlate well (correlation coefficientr= 0.959 for the medulla andr= 0.951 for the cortex). Therefore, measurement of [1H]piretanide binding is proposed to facilitate screening for loop diuretic action.
LIMITATIONS OF THE BENZODIAZEPINE RECEPTOR NOMENCLATURE: A PROPOSAL FOR A PHARMACOLOGICAL CLASSIFICATION AS OMEGA RECEPTOR SUBTYPES
Authors: LANGER S.Z. , ARBILLA S.
Published: August 2009

Summary—At present, the nomenclature of benzodiazepine (BZ) receptors is based on historical association with the BZ structure. However, it is mainly through the new compounds chemically unrelated to BZ that the central and peripheral subtypes of BZ receptors have been characterized. We therefore propose the nomenclature of a Greek letter omega, as ω1, ω2, and ω3to designate the central BZ1, BZ2, and peripheral BZ receptors, respectively. Among the several classes of non‐BZD drugs with affinity for different receptors, the imidazopyridines provide a valuable tool for the characterization of omega receptor subtypes.

Most BZ are nonselective ligands for the central ω1and ω2receptors, while selectivity for ω1receptor subtypes is present in several non BZ chemical series: imidazopyridines (zolpidem), triazolopyridazines (CL 218872), betacarbolines (β‐CCE), and pyrazoloquinolines (CGS 8216). Selective ligands for the ω2subtype are not available so far.

The so‐called peripheral BZ receptor is also present in the central nervous system; therefore, the proposed nomenclature of ω3receptors resolves this paradox because it does not designate location and is defined in terms of pharmacological specificity. Selective ligands for ω3receptors include the BZ Ro 5–4864, and the isoquinolinecarboxamide PK 11195, while the imidazopyridine alpidem is the ligand with the highest affinity for this receptor subtype.
EFFECTS OF NORADRENALINE ON THE ISOLATED HUMAN BRONCHUS. COMPARISON WITH THE ISOLATED GUINEA PIG TRACHEA
Authors: NALINE E. , ADVENIER C. , MATRAN R. , BAKDACH H. , TOTY L.
Published: August 2009

Summary—The pharmacodynamic activity of noradrenaline was evaluated comparativelyin vitroon isolated human bronchi and on guinea pig tracheal spirals. Noradrenaline exerted a contractile effect on both preparations under resting tone and in the presence of propranolol 10−6M; maximal noradrenaline‐induced contraction was 15–20% of maximal acetylcholine (ACh)‐induced contraction. Without propranolol, the contractile effect of noradrenaline was negligible when the preparations were under resting tone and absent when they were precontracted with ACh. In contrast, noradrenaline exerted a strongly relaxant effect on both human bronchi (‐log ED505.24±0.17;N=5) and guinea pig tracheae (‐log ED506.15±0.29;N=8). With maximal contraction induced by ACh 3.10−3M the ‐log ED50of both preparations were shifted to the right by functional antagonism and became 4.72±0.17 and 5.31±0.11, respectively. The pKDvalues of noradrenaline, calculated according to Furchgott and Bursztyn (1967), were 4.79±0.04 in human bronchi (N=5) and 4.77±0.16 in guinea‐pig tracheae (N=8). In the presence of cocaine plus phenoxybenzamine these values were not significantly modified in human bronchi and only slightly modified in guinea pig tracheae. It is concluded that noradrenaline induces a strong beta‐adrenergic response and a negligible alpha‐adrenergic response from both human bronchi and guinea pig tracheaein vitro.
INDUCTIVE EFFECTS OF FENOFIBRATE AND METABOLISM OF PHENOBARBITAL
Authors: MOUNIÉ J. , CHAMPION L. , GOUDONNET H. , ESCOUSSE A. , TRUCHOT R.C.
Published: August 2009

Summary—The inductive effects of fenofibrate (FF) and phenobarbital (PB) were investigated in male Wistar rats. FF treatment produced an inductive effect on liver weight, cytochrome P450 content, and aniline hydroxylase (AH) and bilirubin UDP‐glucuronosyltransferase (UDP‐GT) actvities in liver microsome fraction. PB and FF inductive effects were additive on liver weight but were not additive on P450 microsomal concentrations. On the contrary, FF administration decreased the inductive effect of PB on bilirubin UDP‐GT activity. When FF and PB treatment were coupled, plasma and liver PB concentrations were not affected, whereas OHPB concentrations, especially in liver homogenate, were greatly decreased. Thus it can be concluded that the production of OHPB from PB was probably not accelerated, but the elimination of OHPB, the main metabolite of PB, was considerably enhanced. These results are to be compared with recent reports of structure‐dependent induction of bilirubin glucuronidation by arylcarboxylic acids chemically related to clofibrate.
ARE THERE CIRCADIAN AND CIRCANNUAL VARIATIONS IN ACUTE TOXICITY OF PHENOBARBITAL IN MICE?
Authors: BRUGUEROLLE B. , PRAT M. , DOUYLLIEZ C. , DORFMAN P.
Published: August 2009

Summary— The present work aims to document the possible influence of the time of the year on the circadian pattern of phenobarbital acute toxicity in mice by determination of phenobarbital acute toxicity at four different months of the year (i.e. October, January, April, and July).

Our data indicate an important variation of phenobarbital acute toxicity throughout the year, with the maximum mortality occuring in January (i.e. minimum LD50) the minimum in July (i.e. maximum LD50). Thus, the season, not often taken into account, is an important determinant in toxicological studies.
APPLICATION OF THEOPHYLLINE METABOLITE ASSAYS TO THE EXPLORATION OF LIVER MICROSOME OXIDATIVE FUNCTION IN MAN
Authors: NALINE E. , SANCEAUME M. , PAYS M. , ADVENIER C.
Published: August 2009

Summary—The effects on theophylline oxidative metabolism of 3 inhibitors of liver microsome activity — cimetidine, troleandomycin and ketoconazole — were investigated in 6 healthy volunteers. The 3 compounds increased plasma theophylline half‐life by 73.6±15.6% (P<0.01), 107.8±9.7% (P<0.001) and 21.7±6.8% (P<0.02), respectively, and reduced plasma theophylline clearance by 38.3±4.8% (P<0.001), 51.4±2.4% (P<0.001), and 8.9±7.8% (NS), respectively. Troleandomycin inhibited to the same extent the 2 theophylline metabolism pathways:N‐demethylation resulting in the formation of 1‐methyluric acid (1‐MU) and 3‐methylxanthine (3‐MX), and 8‐hydroxylation resulting in the formation of 1,3‐dimethyluric acid (1,3‐DMU). The production clearances of these metabolites were almost equally depressed by 60.2±3.9%, 60.2±2.1%, and 51.7±4.5%, respectively. Cimetidine predominantly inhibited theN‐demethylation pathway; the production clearances of 1‐MU and 3‐MX were depressed by 58.5±4.0% and 57.5±4.1% (P<0.001), respectively, whereas the production clearance of 1,3‐DMU was depressed by 38.3±6.1% (P<0.001). Ketoconazole had no significant effect on the production clearances of theophylline metabolites. Measurement of theophylline metabolite formation clearances might be a useful test to explore liver microsome oxidative function.
ENHANCEMENT OF ANTIBODY RESPONSE AND DELAYED‐TYPE HYPERSENSITIVITY BY THALIDOMIDE IN MICE
Authors: DESCOTES J. , TEDONE R. , EVREUX J.‐C.
Published: August 2009

Summary— Renewed interest in thalidomide stemmed from the suggestion by several authors that it might prove useful against immune‐related diseases. Despite interesting preliminary findings, little is actually known regarding its immunoenhancing properties in vivo.

Male and female Swiss mice, aged 6–8 wk, were given 0.5 or 25 mg/kg/day of thalidomide orally for 4 wk. Various immunological parameters were then assessed. When compared to controls, mice exposed to the higher dose presented with a significantly increased thymus weight index, whereas spleen weight index remained unchanged. Anti‐sheep erythrocyte plaque‐forming cells and hemagglutinin titers were increased by 44% and 29%, respectively. Contact hypersensitivity to picryl chloride was enhanced by 62%. Finally, colloidal carbon clearance was not altered. Interestingly, the lower dose (5 mg/kg/day) exerted no effect whatsoever.
LACK OF EVIDENCE FOR AXONAL TRANSPORT OF D1 AND D2 RECEPTORS IN THE NIGRO‐STRIATAL PATHWAY OF THE RAT
Authors: SAVASTA M. , DUBOIS A. , SCATTON B.
Published: August 2009

Summary— The possibility that D1 and D2 dopamine receptors are axonally transported in the nigro‐striatal pathway has been investigated in the rat by placing a coronal knife cut (sparing the striato‐nigral pathway) through the medial forebrain bundle (MFB) and autoradiographically examining the density of D2 (as labeled by [3H]spiperone in the presence of ketanserin) and D1 (as labeled by [3H]SCH 23390) receptors. The efficacy of MFB transection has been assessed by measuring in parallel the binding of [3]ketanserin, a ligand that has been reported to be axonally transported in this bundle. At 12 h post‐transection, there was a minor accumulation of [3H]spiperone binding on both sides of the transection. However, (+)butaclamol (1 μM) failed to displace the ligand build‐up at the knife cut, thus demonstrating the nonspecific nature of [3H]spiperone accumulation. Similar results were observed at 24, 48, and 72 h after severing the MFB. MFB transection also failed to cause changes in specific [3H]SCH 23390 binding at the knife cut at 12–72 h post‐surgery. In contrast, a dramatic accumulation of [3H]ketanserin binding sites was observed rostral and caudal to the cut at 12 h post‐transection, attesting to the efficacy of the lesion. These results confirm the existence of both anterograde and retrograde transport of [3H]ketanserin binding sites and suggest that D1 and D2 receptors are not axonally transported in fibers of the nigro‐striatal pathway.
IMMUNOTOXICOLOGY: PROBLEMS AND CHALLENGES
Authors: SPREAFICO F.
Published: August 2009

Summary—After the definition of immunotoxicology and of the main current domains of this recently recognized, multifaceted discipline, this article examines the health significance of xenobiotically induced immune abnormalities and considers the possible mechanisms through which damage to the immune system can occur. In the second part of this review, the current status of knowledge and the problems still open with regard to preclinical testing for nonallergic immunotoxicities are examined, and current views on the general strategy for such testing discussed.
CHARACTERIZATION OF β‐ADRENOCEPTORS IN MYOMETRIUM OF PREPARTURIENT RATS
Authors: MALTIER J.P. , LEGRAND C.
Published: August 2009

Summary—The purpose of this study was to characterize the β‐adrenoceptor subtypes in pregnant rat myometrial membrane fractions and to determine the concentration of β2‐adrenoceptors in uterus during late pregnancy. Two methods are compared. A non‐subtype‐selective antagonist radioligand β‐[3H]dihydroalprenolol ([3H]DHA) was used to label all of the β‐adrenoceptors. [3H]DHA bound to both β1‐ and β2‐adrenoceptors with indistinguishable affinity (KD= 1.31 nM, Bmax= 174 fmol/mg protein). Computer modelling of competition curves of unlabeled selective antagonists or agonists was then required in order to determine reliably β1‐ and β2‐adrenoceptor affinities and proportions: the β2‐adrenoceptors represent 35.5% and the β2‐adrenoceptors 64.5% of the entire β‐adrenoceptor population in rat gravid myometrium at term.

The second approach utilized the radioligand [3H]hydroxybenzylisoproterenol ([3H]HBI) which is a very high‐affinity β‐adrenoceptor agonist. The characteristics of the (3H)HBI binding sites are essentially those expected of β2‐adrenoceptors, but the [3H]HBI binding sites represent only 34% of [3H]DHA binding sites and may represent the fraction of β2‐adrenoceptors that mediate adenylate cyclase stimulation and uterine relaxation.

Between 21 d 09 h and 22 d 09 h of gestation, the number of β2‐adrenoceptors was constant (mean = 225.6±20.2 fmol/mg protein). At term, the number of [3H]HBI binding sites dropped (‐75%) during the last 7 h of pregnancy, suggesting a reduced ability to elicit relaxation through β‐adrenoceptor activation in parturient myometrium of rat.
PLASMA KININ‐PRECURSOR LEVELS IN CLINICAL INTESTINAL INFLAMMATION
Authors: SHARMA J.N. , ZEITLIN I.J. , MACKENZIE J.F. , RUSSELL R.I.
Published: August 2009

Summary— Plasma kinin‐precursor (kininogen) concentrations were measured in the peripheral venous blood of 7 untreated patients with inflammatory bowel diseases, 12 healthy subjects, and 5 uncomplicated fracture cases. The mean plasma kininogen levels were significantly raised (P<0.025) in patients with intestinal inflammation (7.0± 1.0 μg BK Eq/ml), as compared with the value found in healthy subjects (5.7 ± 0.7 fig BK Eq/ml), and in fracture cases (5.0 ± 1.2 μg BK Eq/ml). The packed cell volume did not differ (P>0.05) between patients and control groups. Thus, the raised plasma kininogen levels observed in patients were not the result of nonspecific changes in plasma volume. It is suggested that raised plasma kininogen might be due to increased synthesis to provide substrate for excessive kinin‐formation, to a potent inflammatory agent, or to high synthesis of acute‐phase reactants. The possible significance of this observation is discussed.
BOPINDOLOL IN THE TREATMENT OF MODERATE HYPERTENSION: A DOSE‐RESPONSE STUDY
Authors: MOLEUR P. , PEYRIEUX J.C. , LUCIANI J. , DAVID D. , BOISSEL J.P. ,   the Practitioners of the French Bopindolol Study Group
Published: August 2009

Summary— To determine the optimal antihypertensive dose of bopindolol, we performed a randomized double‐blind study in parallel groups. After 15 days of placebo single‐blind, 115 hypertensive patients received daily for 28 days one of 4 doses: 0 mg (placebo), 0.5 mg, 1.0 mg, 2.0 mg. The reduction of supine diastolic blood pressure (BP) did not exhibit the pattern of a dose‐effect relationship. The effect of 0.5 mg belonged to the plateau of the dose‐effect curve (P=0.1, analysis of variance). The reduction of heart rate (HR) followed a typical dose‐effect curve, with a plateau beginning with 1 mg (P = 0.02). A trend toward an increase in the incidence of side‐effects with dosage was observed (P=0.3). Thus, the optimal antihypertensive dose may be 0.5 mg or less. Previous studies not using parallel randomized groups suggested an antihypertensive dose ranging from 2 to 4 mg. This study confirms that the dose‐effect curves of beta blockers on HR and BP are dissociated. The dose‐effect curve of HR seems unsuitable for assessing the optimal antihypertensive dose of a beta blocker.
EVALUATION OF THE NATRIURETIC AND BETA‐ADRENOCEPTOR‐BLOCKING EFFECTS OF TIENOXOLOL IN NORMAL VOLUNTEERS
Authors: BERDEAUX A. , LOUESLATI E. , GERARD J.L. , PUSSARD E. , GIUDICELLI J.F.
Published: August 2009

Summary— The beta‐adrenoceptor blocking and diuretic properties of tienoxolol (150 mg and 300 mg) were investigated and compared to those of a placebo in a double‐blind, cross‐over trial in six healthy volunteers. Heart rate (HR), systolic and diastolic blood pressures, peak expiratory flow rate (PEFR) at rest and during vigorous exercise, plasma renin activity (PRA) and aldosterone levels at rest, and diuresis and urinary electrolyte excretion values were measured before and at intervals up to 24 h after oral administration of the drugs. In addition, the clearances of electrolytes, uric acid, and creatinine were calculated, as well as the fractional sodium excretion (Fe Na%) before and 4 h and 24 h after drug intake. Finally, tienoxolol plasma levels were measured.

Tienoxolol significantly and dose‐dependently reduced exercise‐induced tachycardia. This effect started 1 h after drug administration, peaked between 4 h and 6 h (‐ 12% and ‐ 17% from control values at 150 mg and 300 mg, respectively), and lasted at least 12 h. Resting HR was decreased at 300 mg (P<0.05), PRA was decreased at both doses (P<0.05), but PEFR was not drug‐affected. 24‐h cumulative sodium excretion was increased (+ 24% at 150 mg [NS], +38% at 300 mg [P<0.01]) as compared to placebo, and Fe Na% did not change, regardless of the dose administered. 24‐h cumulative diuresis was moderately increased by tienoxolol (NS), whereas creatinine clearance rose after the 300‐mg dose, suggesting that tienoxolol might increase glomerular filtration rate. Plasma aldosterone levels remained unchanged. Finally, the elimination half‐life of tienoxolol was 7.5 h.

Thus, in healthy volunteers, tienoxolol behaves as an early acting and relatively long‐lasting selective beta1‐adrenoceptor blocking drug endowed with significant natriuretic properties.
EFFECT OF RENAL FAILURE ON THE PHARMACOKINETICS OF ETHYL LOFLAZEPATE (Victan®) IN MAN
Authors: BA B.B. , ILIADIS A. , DURAND A. , BERGER Y. , NECCIARI J. , CANO J.P.
Published: August 2009

Summary— The kinetics of ethyl loflazepate were studied in patients with various degrees of renal failure. A strong correlation was noted between urinary excretion of metabolite loflazepate and creatinine clearance. In contrast, elimination half‐life and total plasma clearance of the sum of loflazepate+descarboxyloflazepate seemed to be independent of the degree of renal impairment. These results indicate the absence of a risk of accumulation of the 2 main and active metabolites of ethyl loflazepate in patients with renal failure.
SINGLE‐DOSE PHARMACOKINETICS OF AMINEPTINE AND OF ITS MAIN METABOLITE IN HEALTHY YOUNG ADULTS
Authors: LACHATRE G. , PIVA C. , RICHE C. , DUMONT D. , DEFRANCE R. , MOCAER E. , NICOT G.
Published: August 2009

Summary— The pharmacokinetics of the tricyclic antidepressant amineptine (Survector®) and its main metabolite were studied in 12 young healthy adults (6 men, 6 women; mean age 35.8 yr). Plasma samples were taken over 24 h following a single oral dose of 100 mg amineptine chloryhdrate. Plasma levels of both compounds were determined by means of high performance liquid chromatography.

Amineptine was rapidly absorbed. Mean peak plasma concentrations of amineptine and its metabolite occurred 1 h and 1.5 h, respectively, after product administration. The mean apparent volume of distribution was large: 2.4 l.kg−1. Elimination was rapid; the mean half‐lives of the 2 compounds were short: 0.8 h for amineptine and 2.5 h for the metabolite. The mean apparent plasma clearance of amineptine was high (124.8 l.h−1).

When the results were adjusted for body weight and surface area, no significant difference in pharmacokinetic parameters was found between men and women.

Given its pharmacokinetic characteristics there is no risk of amineptine accumulation and thus it is a particularly easy drug to manage.

A standard dosage of amineptine was defined for use in healthy young adults.
INTERACTION BETWEEN MOCLOBEMIDE AND ORAL TYRAMINE IN DEPRESSED PATIENTS
Authors: BURGESS C.D. , MELLSOP G.W.
Published: August 2009

Summary— We investigated the pressor response to oral tyramine before and during treatment with moclobemide, a selective monoamine oxidase‐A inhibitor, in 10 depressed patients. Before moclobemide therapy, tyramine was associated with a mean (SD) maximum rise in systolic blood pressure of 4.0 (5.2) mmHg, whereas during moclobemide treatment, tyramine was associated with an increase of 24.9 (14.2) mmHg. Only one subject failed to demonstrate an increased pressor response while taking moclobemide. Moclomebide potentiates the pressor response to oral tyramine, but is safer than older nonselective monoamine oxidase inhibitors.
PREVENTION OF CCL4‐INDUCED LIVER CIRRHOSIS BY SILYMARIN
Authors: MOURELLE M. , MURIEL P. , FAVARI L. , FRANCO T.
Published: August 2009

Summary—The efficacy of silymarin treatment in preventing biochemical and histological alterations in CCl4‐induced liver cirrhosis in rats was studied. Four groups of rats were treated with: (1) CCl4; (2) mineral oil; (3) CCl4+ silymarin; and (4) silymarin. All animals were sacrificed 72 h after the end of treatments. The activities of alkaline phosphatase (alk. phosp.), gamma‐glutamyl transpeptidase (GGTP), glutamic pyruvic transaminase (GPT) and glucose‐6‐phosphatase (G6Pase), and bilirubin content were determined in serum. Na+, K+‐ATPase and Ca++‐ATPase activities were measured in isolated plasma membranes. Lipoperoxidation, triglycerides (TG), and glycogen contents were also measured in liver homogenates.

Liver cirrhosis was evidenced by significant increases in liver collagen, lipoperoxidation, serum activities of alk. phosp., GGTP, GPT, G6Pase, bilirubin content, and liver TG.

Activities of ATPases determined in plasma membranes were significantly reduced, as was liver glycogen content. Silymarin cotreatment (50 mg/kg b.wt) completely prevented all the changes observed in CCl4‐cirrhotic rats, except for liver collagen content which was reduced only 30% as compared to CCl4‐cirrhotic rats. Silymarin protection can be attributed to the agent's antioxidant and membrane‐stabilizing actions.
COMPARATIVEIN VIVOANDIN VITROSTUDY OF THE CARDIAC EFFECTS OF MIDALCIPRAN AND IMIPRAMINE*
Authors: ROUET R.H. , TISNE‐VERSAILLES J. , ADAMANTIDIS M.M. , VINCENT A. , DUPUIS B.A.
Published: August 2009

Summary—Midalcipran is a new antidepressant drug inhibiting both noradrenaline and serotonin uptake without any postsynaptic and anticholinergic activities. Its cardiac effects were compared with those of imipramine, a tricyclic antidepressant drug.

In anaesthetised guinea‐pigs intravenous perfusion of imipramine and midalcipran (1 ml/min from a solution at 0.66 mg/ml) brought about ventricular arrhythmias, respectively at 16.5 and 26.4 mg/kg and cardiac arrest at 58 and 97 mg/kg. The safety index (ratio of i.v. lethal dose and ED50evaluated by the yohimbine test) is 22 times wider for midalcipran than imipramine. Inin vitrostudies on guinea‐pig ventricular myocardium, imipramine exerted a greater class 1 antiarrhythmic effect than midalcipran. The reduction ofVmaxwas significant at 3times10−6M for imipramine and 1times10−5M for midalcipran in normal (4 mM K+) and hyperpolarizing (2.7 mM K+) conditions. At the concentration of 1times10−5M midalcipran significantly lengthened, whereas imipramine non significantly shortened the action potential durations (APD50, APD90).

The results provide confirmation of a lesser depression in sodium conductance with midalcipran as compared to imipramine. Therefore it is proposed that less adverse cardiac effects may be observed at therapeutic doses.
CARDIOVASCULAR EFFECTS FROM STIMULATION OF 5‐HYDROXYTRYPTAMINE RECEPTORS
Authors: SAXENA P. R.
Published: August 2009

Summary—The cardiovascular effects of 5‐hydroxytryptamine (5‐HT), consisting of bradycardia or tachycardia, hypotension or hypertension, and vasodilatation or vasoconstriction, are mediated by three main types of receptors called 5‐HT1‐like, 5‐HT2, and 5‐HT3. In intact animals 5‐HT elicits a short‐lasting bradycardia, accompanied by hypotension,viastimulation of 5‐HT3receptors located on sensory vagal nerve endings in the heart (Bezold‐Jarisch reflex). The nature of 5‐HT receptors mediating tachycardiac responses is species‐dependent. Myocardial 5‐HT1‐like and 5‐HT2receptors subserve tachycardia in the cat and rat, respectively. Tachycardia in the dog and rabbit is due to a release of catecholamines effectedviathe 5‐HT2receptors on the adrenal medulla and the 5‐HT3receptors on postganglionic cardiac sympathetic nerve fibres, respectively. The receptors mediating tachycardia in the pig are unique as they do not resemble any of the three 5‐HT receptors characterized so far. The blood pressure response to 5‐HT is usually triphasic: initial short‐lasting hypotension due to reflex bradycardia (via5‐HT3receptors), a middle pressor phase (via5‐HT2receptors), and a longer‐lasting hypotension (via5‐HT1‐like receptors). Vascular contraction by 5‐HT is generally mediated by 5‐HT2receptors (located primarily on the large conducting vessels), though in some instances (e.g., dog saphenous vein, dog and human basilar artery, and porcine arteriovenous anastomoses) the contractile response is (also) mediatedvia5‐HT2‐like receptors. Venous dilatation and arteriolar dilatation (leading to increased capillary [‘nutrient’] blood flow) occurvia5‐HT1‐like receptors located mainly on the vascular smooth muscles but also on the endothelium; the smooth muscle and endothelial 5‐HT1‐like receptors seem to be heterogeneous. In addition, 5‐HT can elicit vasodilatation and hypotension as a result of decreased sympathetic nervous tone by acting within the central nervous system and by inhibiting noradrenaline release by a presynaptic action. Both these effects also involve 5‐HT1‐like receptors that do not appear to be identical. Last, knowledge of the cardiovascular effects of 5‐HT and the nature of the receptors involved should be helpful in developing 5‐HT‐related compounds that may be useful in the treatment of hypertension, migraine, and peripheral vascular diseases.
CONTROLLED CLINICAL TRIAL OF BEPRIDIL, PROPRANOLOL AND PLACEBO IN THE TREATMENT OF EXERCISE INDUCED ANGINA PECTORIS
Authors: DESTORS J.M. , BOISSEL J.P. , PHILIPPON A.M. , SCHBATH J. ,   B.I.S. RESEARCH GROUP
Published: August 2009

Summary— 191 patients with exercise induced angina pectoris and a mean weekly number of attacks of 11.3 were admitted in a multicentre double‐blind study after an evaluation period on placebo. They were randomly assigned to: bepridil (100–400 mg/d), propranolol (60–240 mg/d), placebo (“strengh” 100–400) and treated for 6 months. During the first 8 weeks the treatment was individually titrated.

Withdrawal from the study was considered as “failure”. 19.2% bepridil patients, 21.8% propanolol patients and 17.1% placebo patients stopped their study medication. Severe angina pectoris leading to withdrawal was not observed in bepridil group against 3 cases in placebo (P = 0.03) and 6 in propanolol groups (P = 0.02). In all groups the number of attacks was reduced between 49 and 77%. At wk 8, bepridil patients were improved compared with placebo patients (P = 0.04). Total work performed and duration of exercise on the ergometer were increased in bepridil patients at wk 8 compared with placebo patients. However, all treatment differences had vanished by wk 24.

One patient died in the bepridil group, 2 in the propranolol group and none in the placebo group. The total numbers of fatal or severe non fatal cardiovascular events were not statistically significantly different. There were less severe adverse cardiovascular reactions in the bepridil group than in the propranolol group (P<0.03).
COMBINED EFFECTS OF MIDAZOLAM AND ETHANOL ON SLEEP AND ON PSYCHOMOTOR PERFORMANCE IN NORMAL SUBJECTS
Authors: MONTI J.M. , PIÑEYRO G. , ALVARIÑO F. , LABRAGA P.
Published: August 2009

Summary— A study was carried out on the effects of midazolam 15 mg in conjunction with ethanol 0.5 g/kg on objective and subjective sleep parameters and psychomotor performance in normal subjects. Midazolam significantly decreased total wake time. Total sleep time (TST) increase was related to larger amounts of stage 2 NREM sleep. Ethanol showed similar effects on sleep, although TST increase was associated with nonsignificant increments of NREM sleep and REM sleep. Ethanol slightly potentiated midazolam effects on sleep. Accordingly, total wake time, REM sleep time and number of wakes showed further depression than with midazolam alone. Subjective evaluations showed relatively good correlation with sleep laboratory findings. In addition, the different treatments did not impair subject's psychomotor performance the morning after their administration.
EFFECT OF SELECTIVE ENDOPEROXIDE/THROMBOXANE A2RECEPTOR ANTAGONISM WITH SULOTROBAN ON tPA‐INDUCED THROMBOLYSIS IN A RABBIT MODEL OF FEMORAL ARTERIAL THROMBOSIS
Authors: FUJITA T. , HASAN S. , STORER B.L. , SHEBUSKI R.J.
Published: August 2009

Summary—The thrombolytic efficacy of recombinant tissue‐type plasminogen activator (tPA) in the presence and absence of the selective endoperoxide/thromboxane A2(TXA2) receptor antagonist, sulotroban (BM 13.177, SK&F 95587) was studied in a model of femoral artery thrombosis in the anesthetized rabbit. The thrombus was formed by injection of thrombin, CaCl2and whole blood into an isolated segment of the femoral artery. After 30 min of stable thrombotic occlusion of the femoral artery, tPA was infused IV for 90 min at doses of 5.0, 7.5 and 10.0 μg/kg/min. In other experiments, sulotroban was administered as a bolus dose of 1 mg/kg/IV, followed by a constant infusion of 1 mg/kg/hr concurrent with tPA infusion. Sulotroban had no effect on the incidence of tPA‐induced reperfusion at any dose studied or on residual clot weight.

However, at a tPA dose of 10 μg/kg/min, IV lysis time was reduced in sulotroban treated animals from 65 min to 29 min (P<0.05), and the magnitude of femoral artery blood flow achieved as a result of tPA‐induced reperfusion was greater in sulotroban‐treated animals. These data suggest that adjunctive therapy with a selective endoperoxide/TXA2antagonist improves the response to tPA when tPA is administered at a maximal or near maximally effective pharmacological dose.
EFFECT OF SOTALOL AGAINST REPERFUSION‐INDUCED ARRHYTHMIAS IN SPRAGUE‐DAWLEY AND WISTAR RATS
Authors: LAMONTAGNE D. , ROCHETTE L. , VERMEULEN M. , YAMAGUCHI N. , NADEAU R. , DE CHAMPLAIN J.
Published: August 2009

Summary—The effect of (±)‐sotalol (aβ‐blocker with class III antiarrhythmic activity) against reperfusion‐induced arrhythmias was studied in artificially ventilated, open‐chest, Sprague‐Dawley and Wistar rats. Coronary artery occlusion was produced for 5 min and reperfusion allowed for 10 min. A somewhat different arrhythmic profile was observed between saline‐treated rats of the 2 strains studied, with more Sprague‐Dawley rats experiencing an irreversible ventricular fibrillation (VF) upon reperfusion, compared to Wistar rats, in whom a combination of reversible ventricular tachycardia (VT) and VF was more frequently observed. No difference in action potential characteristics and ventricular effective refractory period determinedin vitro, nor in myocardial noradrenaline content, was found between the 2 strains of rats. (±)‐Sotalol (5 and 10mg/kg, IV) showed marked β‐blocking activity and reduced the mean duration of VT‐VF in both strains studied. It also produced similar increases in action potential duration and refractory periodin vitroin these 2 strains. In a different series of experiments, the antiarrhythmic action of the racemic form was compared to that of (+)‐sotalol using Wistar rats. (+)‐Sotalol had much less β‐blocking activity, and was found to be similarly effective against reperfusion‐induced VT‐VF. It is concluded that the antiarrhythmic effect of sotalol against reperfusion‐induced arrhythmias may not be related to β‐adrenergic blockade but probably to class III type activity. Despite differences in the profile of reperfusion‐induced arrhythmias between Sprague‐Dawley and Wistar rats, both strains were sensitive to the antiarrhythmic action of (±)‐sotalol.
(‐)‐BAY K 8644 LIBERATES A CONTRACTANT FACTOR FROM THE ENDOTHELIUM OF THE RAT AORTA
Authors: LAWSON K. , CAVERO I.
Published: August 2009

Summary—The contractile activity of (‐)‐Bay k 8644 was assessed in rat isolated aortic ring preparations bathed in a potassium‐free medium. (‐)‐Bay k 8644 (0.01–3 μM) caused extracellular calcium‐dependent contractile responses, which were significantly greater in tissues with, than deprived of a functional endothelium. In preparations with an endothelium, the contraction was attenuated by quinacrine (1 μM), indomethacin (10 μM) and diclofenac (0.1 μM), but not changed by nordihydroguaiaretic acid (30 μM) or dazoxiben (10 μM). Thus, in the rat aorta bathed in K+‐free medium, (‐)‐Bay k 8644 can cause contractile effects, apparently due to the release of an endothelium‐derived contractant factor (EDCF) which is proposed to be a cyclo‐oxygenase product.
CENTRAL NEUROCHEMICAL EFFECTS OF DIHYDROPYRIDINE CALCIUM ANTAGONISTS
Authors: HUGUET F.
Published: August 2009

Summary—Recent advances in central dihydropyridine (DHP)‐binding sites are reviewed. DHP‐binding sites are pre‐synaptically and post‐synaptically localized in the brain. The functional role of post‐synaptic sites is still unknown, whereas pre‐synaptic sites seem to contribute to the control of calcium uptake and of neurotransmitter release. DHP‐binding sites may be modulated in physiological (age, sex) and pathological events (hypertension, ischaemia, neurological diseases) or after drug treatments (alcohol, morphine, etc.). The reviewed data suggest new therapeutic implications of DHP calcium channel antagonists in the treatment of other diseases and of drug withdrawal syndrome.
CALCIUM ANTAGONISTS AND THE VESTIBULAR SYSTEM: A CRITICAL REVIEW OF FLUNARIZINE AS AN ANTIVERTIGO DRUG
Authors: RASCOL O. , CLANET M. , MONTASTRUC J.L.
Published: August 2009

Summary—Flunarizine, a diphenylalkylamine, is one of the most popular antivertiginous drugs used nowadays in France. However, until now, there are very few preliminary data about the physiological or pathophysiological functions of calcium in the vestibular system. Moreover, experimental and clinical arguments are still insufficient to clearly demonstrate that 1) flunarizine is an effective antivertiginous drug and 2) this putative antivertiginous property is really due to the anticalcic action of the drug and not to a more classical antagonistic effect on Hl receptors. Much more work is needed before accepting the indication of any anticalcic drug as an effective antivertigo treatment.
CLINICAL NEUROPHARMACOLOGY OF CALCIUM ANTAGONISTS
Authors: DELUMEAU J.C. , BENTUE‐FERRER D. , SAIAG B. , ALLAIN H.
Published: August 2009

Summary—Experimental and clinical data clearly demonstrate that calcium antagonists (CA) may have an action on the central nervous system (CNS). The cerebrovascular action of CA justifies their use in cerebral ischaemia, vasospasm and hypoxia. Several clinical trials have demonstrated such beneficial effects. On the other hand a number of reports indicate that CA may have a direct neuronal effect, although most of such trials have not been verified or are mere case reports. In addition, the large number of conditions susceptible to being corrected by CA is impressive: epilepsy, pain, dystonia, dyskinesia, psychiatric conditions, etc. Other papers are disconcerting that report extrapyramidal disorders induced by flunarizine and cinnarizine in the elderly, whereas nicardipine does not produce such side effects and may even alleviate some parkinsonian symptoms. In various experimental models (e.g. stroke, oedema), pharmacological effects have been shown to vary from one compound to the other. Two main questions are yet to be answered: 1) has the direct neuronal effect of CA been clearly established? 2) are the multiple clinical effects on the CNS really linked to calcium antagonism?
EFFECT OF TURPENTINE‐INDUCED INFLAMMATION ON THE DISPOSITION KINETICS OF PROPRANOLOL, METOPROLOL, AND ANTIPYRINE IN THE RAT
Authors: BELPAIRE F.M. , DE SMET F. , CHINDAVIJAK B. , FRAEYMAN N. , BOGAERT M.G.
Published: August 2009

Summary— Plasma concentrations after oral administration of the high extraction drug propranolol are increased in patients and animals with inflammation. This could be due to increased serum propranolol binding, but also to decreased first‐pass metabolism. We studied the pharmacokinetics of 3 drugs in control rats and in rats with turpentine‐induced inflammation: propranolol, which is bound extensively to α1‐acid glycoprotein (α1‐AGP); metoprolol, another high extraction drug, but which is negligibly bound to α1‐AGP; and antipyrine, a low extraction drug, not bound to serum proteins.

After IV administration of propranolol in rats with inflammation, systemic clearance, volume of distribution, and free fraction decreased, and the area under the curve (AUC) increased, whereas the half‐life did not change. As the systemic clearance of a high extraction drug such as propranolol depends on hepatic blood flow only, a fall in hepatic blood flow or transition to a low extraction situation should be postulated. After oral administration of propranolol, the AUC was increased 20‐fold in rats with inflammation; as the decrease in free fraction was only 4‐fold, it can be concluded that a considerable decrease in hepatic intrinsic clearance was present. For metoprolol, in contrast to propranolol, after IV administration, no changes in pharmacokinetic parameters as a result of inflammation were observed. After oral administration, the AUC was increased about 4 times in rats with inflammation; as metoprolol is only negligibly bound to serum proteins, the increase in AUC can be attributed to a decrease in hepatic intrinsic clearance. The differential effect of turpentine on the intravenous kinetics of propranolol and metoprolol can be explained by the fact that propranolol binding is increased by turpentine treatment.

For antipyrine, systemic clearance was decreased, the volume of distribution was unchanged, and the half‐life was increased in the turpentine‐treated rats. As antipyrine is not bound in serum, one can conclude that its hepatic intrinsic clearance was decreased.

Inflammation induced by turpentine treatment decreases the metabolism of high and low extraction drugs.