bluuebunny/crossref_metadata_2025_split huggingface dataset:
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.
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).
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 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.
IS MONITORING PLASMA LEVELS OF NETILMICIN NECESSARY IN NEONATES?
Authors: AUTRET E. , LAUGIER J. , BRETEAU M. , LIONNET C. , FURET Y. 
Published: August 2009

Summary— Thirty‐two neonates were treated with netilmicin 3 mg/kg every 12 h by IV infusion for 30 min for suspected infections, colonization, or proven infections. Pharmacokinetic studies were performed in order to define the situations in which monitoring of plasma levels would be appropriate.Mean plasma levels were within the therapeutic range and did not differ in fullterms and preterms. In the 4 children who had 2 successive pharmacokinetic studies, plasma levels were increased between H1 and H5 at the second evaluation due to netilmicin accumulation.Plasma half‐life was longer in proven infections and seemed to decrease in preterms with increased gestational age.These results suggest that the dosage schedule should be left inchanged, but that administration time should be reduced from 30 to 20 min and that peak and trough plasma levels should be measured only in proven infections, in very premature babies (gestational age < 33 wk), and during netilmicin treatment longer than 5 d.
PHARMACOKINETICS OF LIDOCAINE AND BUPIVACAINE IN RETROBULBAR AND FACIAL BLOCK
Authors: LE NORMAND Y. , DE DIEULEVEULT C. , ATHOUEL A. , QUEINNEC M.C. , DE VILLEPOIX C. , LAROUSSE C. 
Published: August 2009

Summary— Analgesia can be obtained during ophthalmic surgery by regional anesthesia using local anesthetic agents. As in other indications, neurological complications may occur, especially because the site of injection is close to the central nervous system. In order to evaluate the risk of retrobulbar and facial block obtained after 40 mg lidocaine and 20 mg bupivacaine injection, pharmacokinetics of both drugs was evaluated in plasma obtained from 11 patients. In addition, 3 cerebrospinal fluid samples were analyzed.Maximal plasma concentration was 0.73 ± 0.33 μg.ml‐1 for lidocaine and 0.19 ± 0.06/ng‐ml‐1 for bupivacaine, obtained 24.7 ± 23.0 min and 12.0 ± 3.7 min after the end of injection, respectively. CSF/plasma ratio was in the range 0.05–0.26 for lidocaine and 0.56– 1.33 for bupivacaine.In all patients, regional anesthesia was sufficient to perform surgery without any other analgesic drug. No sign of cardiovascular or respiratory toxicity was observed during the study.
A NEW EX VIVO METHOD FOR THE STUDY OF NASAL DROPS ON CILIARY FUNCTION
Authors: LEVRIER J. , MOLON‐NOBLOT S. , DUVAL D. , LLOYD K.G. 
Published: August 2009

Summary— Any pharmaceutical nasal preparation should respect the physiological function of the mucociliary transport system and should undergo testing to this effect. An experimental protocol has been developed using the guinea pig in order to assess the effects of commercial nasal drop preparations on mucociliary function. The method presented here consists of applying in vivo the test solution on the nasal respiratory epithelium. After a specified contact time and following rapid sacrifice of the animal, the mucosa is removed; the beating frequency of the cilia is then recorded ex vivo by micro‐photo‐oscillography.The method is sensitive to compounds known to diminish mucociliary function as sodium mercurothiolate inhibits ciliary movement of the nasal epithelium ex vivo. This inhibition of ciliary movement is long‐lasting, although reversible.This method can be used to test the action of intranasally administered pharmaceutical preparations on mucociliary function. Commercially available solutions of the nasal vasoconstrictors tymazoline, fenoxazoline or oxymetazoline do not alter ciliary movement ex vivo at dose levels equal to or greater than those clinically utilized. ATP significantly enhances nasal ciliary frequency in instances where a low basal rate occurred.Thus, this method can be used for the testing of the maintenance of nasal ciliary function in the presence of compounds and preparations which will be applied into the nostrils. The advantages over previous techniques include a closer approach to the therapeutic utilization and the maintained physiological conditions of the mucosa during drug administration.
α‐ADRENOCEPTOR PROPERTIES IN RAT STRAINS SENSITIVE OR RESISTANT TO SALT‐INDUCED HYPERTENSION
Authors: ATTARI A. EL , QING W. , BEN‐ISHAY D. , PARINI A. , DAUSSE J.‐P. 
Published: August 2009

Summary—Cerebral and renal α‐adrenoceptors are implicated in the control of sympathetic activity and of sodium reabsorption respectively. In addition, sodium ions play an important role in the regulation of either α‐adrenoceptor densities and affinities for adrenergic agonists. In the present study, α‐adrenoceptor properties were investigated in genetically predetermined salt‐sensitive and salt‐resistant Dahl and Sabra rats.Cerebral α2‐adrenoceptor densities were higher in salt‐resistant than in salt‐sensitive Dahl and Sabra rats. In contrast, renal α2‐adrenoceptor density was higher in salt‐sensitive than in salt‐resistant rats. No difference in cerebral and renal α1‐adrenoceptor densities was observed between Dahl and Sabra substrains. Noradrenaline content in cerebral and renal cortex were also similar in both these rat substrains.Sodium ions markedly increased cerebral and renal high‐affinity α2‐adrenoceptor densities in salt‐sensitive but not in salt‐resistant rats. Cerebral and renal α1‐adrenoceptor densities were unchanged in salt‐sensitive and salt‐resistant substrains of Dahl and Sabra rats. In addition, sodium ions reduced the affinity of adrenaline for renal α2‐adrenoceptors in salt‐sensitive rats but not in salt‐resistant rats.We can conclude that there exist genetically determined differences in the densities and properties of cerebral and renal α2‐adrenoceptors between salt‐sensitive and salt‐resistant rat strains. Abnormal densities of α2‐adrenoceptors may play a primary role in the role in the development of hypertension in salt‐sensitive animals. These results also suggest an association between absence of sodium regulation of α2‐adrenoceptors and resistance to salt‐induced hypertension. The absence of sodium regulation in salt‐resistant rats may be linked either to a particular receptor conformation or to an abnormal structure of the receptor system. This property may represent a genetically‐mediated change responsible for the resistance to the development of salt‐induced hypertension.
PHARMACOKINETICS OF METAPRAMINE AND ITS DEMETHYLATED METABOLITES IN PLASMA AND BRAIN OF MICE
Authors: BOUGEROLLE A.M. , CHABARD J.L. , ESCHALIER A. , AUMAITRE O. , FIALIP J. , DORDAIN G. , PETIT J. , BERGER J.A. 
Published: August 2009

Summary—Previous studies on pharmacokinetic parameters of tricyclic antidepressants (TCAs) in rodents have shown different results from those obtained for the same drugs in man. The kinetics of metapramine (META) and its major demethylated metabolites (METs) were studied in the SWISS CD 1 mouse after acute administration in order to establish the pharmacokinetic parameters in plasma and brain. The plasma half‐life (T1/2) was very short (87 min) compared with the half‐life (7 h) in man. The metabolism of META was intensive as was the transfer of META and its metabolites into the brain. The kinetic profiles of the substances were quite similar both in plasma and in brain, namely a bicompartment open model. META was rapidly absorbed (Tmax=10 min) into and quickly eliminated (T1/2=40 min) from the brain.These parameters were used to schedule sampling (blood and brain) at the appropriate time after acute administration of increased doses.The administered doses were significantly correlated to firstly the plasma or brain levels of META, secondly the plasma levels of the main monodemethylated metabolite (MET I), and thirdly the plasma or brain levels of META + METs.Finally, the evolution of plasma and brain levels of the substances was studied after repeated injections (i.e. every 40 min) and confirmed the high affinity of META and its metabolites for the brain regions.
MODEL‐INDEPENDENT PHARMACOKINETICS OF COLCHICINE AFTER ORAL ADMINISTRATION TO HEALTHY VOLUNTEERS
Authors: GIRRE C. , THOMAS G. , SCHERRMANN J.M. , CROUZETTE J. , FOURNIER P.E. 
Published: August 2009

Summary— The pharmacokinetics of colchicine were studied after oral administration of three doses (0.5, 1.0 and 1.5 mg) to nine healthy male volunteers according to randomized cross‐over design. Plasma and urine samples were collected during 48 h after ingestion, and assayed for colchicine levels by a specific and highly sensitive radio‐immunoassay. Pharmacokinetic parameters t1/2β, AUC, MRT, CIT/F, CIR, Vd area/F) were calculated by model‐independent methods and compared across doses by multiway analysis of variance. Terminal half‐life (15.5–19.2 h), mean residence time (15.7–20.3 h), oral systemic (32.2–40.3 l/h) and renal (3.9–4.7 l/h) clearances, and oral volume of distribution (11.4–14.9 l/kg) did not differ significantly between doses, whereas the area under the concentration‐time curve was proportional to dose. Our results show that:

within the dose range studied (0.5–1.5 mg), the pharmacokinetics of colchicine are linear;
monitoring colchicine levels up to 48 hours yields much larger estimates of terminal half‐life and volume of distribution than previously reported from considerably shorter studies.
L 4 ‐ IMPORTANCE OF IMIDAZOLINE RECEPTORS IN THE CARDIOVASCULAR RESPONSES TO CLONIDINE AND RILMENIDINE IN CONSCIOUS RABBITS
Authors: Head G.A. , Sannajust F. 
Published: August 2009

SummaryThe present paper summarizes our studies concerning the involvement of imidazoline and α2‐adrenoceptors in the cardiovascular actions of centrally acting drugs rilmenidine, clonidine and methyldopa. We have found that they produce very similar cardiovascular autonomic effects which relate directly to the function of central monoamine neurotransmitters. They mimic certain elements of the noradrenergic neuron system in the central nervous system, in particular the brainstem actions which involve hypotension, bradycardia and resetting of the baroreceptor heart rate reflex. By contrast they turn off serotonergic pathways that are pressor, produce tachycardia and inhibit the baroreceptor heart rate reflex. Recent studies using specific receptors antagonist drugs idazoxan and 2‐methoxy‐idazoxan indicate that in conscious rabbits the imidazoline receptor actions of rilmenidine is of primary importance at doses which would be considered clinically relevant. We further conclude that the α2‐adrenoceptors and the imidazoline receptors are likely to be located in series i.e. along the same cardiovascular autonomic pathways in the brainstem but presumably at different sites.
Dynamics of the cationic and secretory responses to A‐4166 in perifused pancreatic islets
Authors: Jijakli H , Ulusoy S , Malaisse WJ 
Published: August 2009

Summary— The dynamics of the cationic and secretory response to A‐4166, a hypoglycemic meglitinide analogue, was investigated in rat islets prelabelled with either 86Rb or 45Ca and placed in a perifusion system. In the absence of D‐glucose, A‐4166 (10 μM) provoked an immediate, sustained and rapidly reversible inhibition of 86Rb outflow, this contrasting with a short‐lived stimulation of insulin release. In the presence of 6 mM D‐glucose, A‐4166 provoked a rapid, sustained and rapidly reversible stimulation of both insulin release and 45Ca efflux. The latter cationic response was suppressed in the absence of extracellular Ca2+, in which case A‐4166 even caused a modest decrease in effluent radioactivity.These findings support the view that A‐4166 acts mainly in the islet B‐cell by closing ATP‐responsive K+ channels, leading to subsequent depolarization of the plasma membrane and gating of voltage‐sensitive Ca2+ channels. Independently of the latter effect, A‐4166 may also affect the intracellular distribution of Ca2+ ions. The present data further indicate that A‐4166 belongs to those hypoglycemic agents that cause rapidly reversible changes in cationic and secretory events, at variance with highly potent sulfonylureas such as glibenclamide or glimepiride.
In vitro and in vivo vasodilating effects of KRN4884, Ki1769 and Ki3005, pyridinecarboxamidine derivatives
Authors: Izumi H , Kawahara J , Takeuchi A , Izawa T , Ogawa N 
Published: August 2009

Summary—The vasodilating potencies and mechanism of action of a novel pyridinecarboxamidine derivative, KRN4884 (5‐amino‐N‐(2‐(2‐chlorophenyl)ethyl]‐N'‐cyano‐3‐pyridinecarboxamidine] were compared with those of Ki 1769 [N‐cyano‐N'‐(2‐phenylethyl)‐3‐pyridinecarboxamidine] and Ki3005 [N‐[2‐(2‐chlorophenyl)ethyl]‐N'‐cyano‐3‐pyridinecarboxamidine] in rat isolated aortas and in anesthetized normotensive rats. In vitro, KRN4884 (10‐10‐10‐6M), Ki3005 (10‐10‐10‐6M) and Ki30O5 (10‐10‐10‐6M) produced concentration‐dependent relaxations. KRN4884 was about 100‐ and 10‐fold more potent than KU769 and Ki3005, respectively. The relaxant effects of these compounds were antagonized by glibenclamide. In vivo, KRN4884 (1–10 μg/kg, intravenously [iv]), KM769 (10–100 μg/kg, iv) and Ki3005 (3–30 μg/kg, iv) produced dose‐dependent decreases in mean blood pressure with slight increases in heart rate. At 10 μg/kg, iv, the hypotensive effect of KRN4884 was about the same as that of Ki3005 and about 5‐fold more pronounced than that of Ki 1769.The hypotensive action remained for a longer period after KRN4884 administration. In rats pre‐treated with glibenclamide (20 mg/kg, iv), the hypotensive effect of KRN4884 was abolished. These results suggest that the effect of KRN4884 in vitro and in vivo is based on its K channel opening action and that the in vitro vasorelaxant effect of these compounds in aortic rings does not predict their relative hypotensive effect in vivo.
Introduction
Authors: Bousquet P 
Published: August 2009

Ce numéro supplémentaire de Fundamental and Clinical Pharmacology contient les résumés des communications présentées au symposium « Mécanismes nerveux de l'hypertension » (Strasbourg, 21 juin 1996)Ce symposium correspondait à une réunion satellite du 16e Congrès Scientifique de la Société Internationale d'Hypertension qui s'est tenu à Glasgow (Royaume‐Uni) quelques jours plus tard.Cette manifestation concernait les principaux aspects fondamentaux et cliniques de la régulation nerveuse du tonus vasomoteur et de ses dysfonctionnements. Le programme s'est déroulé sur une journée.Les deux premières sessions ont été consacrées à des présentations générales et à des exposés de travaux récents portant sur les structures cérébrales, les neurotransmetteurs et les voies impliquées dans le contrôle de la pression artérielle. Une troisième session a été consacrée aux neurohormones, avec un point particulier sur les modèles transgéniques. La quatrième session a porté sur le baroréflexe et la variabilité tensionnelle. La dernière session a abordé les aspects cliniques de l'implication du système nerveux sympathique dans l'hypertension.Cette journée a été émaillée de discussions très intéressantes.Je remercie tous les participants et les présidents de séance qui ont rendu ce symposium très agréable et intéressant. Je suis reconnaissant à Biopharma (du Groupe de Recherche Servier, France) pour son aide généreuse qui a permis que ce symposium se tienne dans des conditions fécondes et contribue ainsi à son succès. Je remercie également l'Institut National de la Santé et de la Recherche Médicale (France) pour son soutien.
Provision of NHS‐funded spectacles in South London
Authors: Jessa Zahra , Evans Bruce J.W. , Thomson David W. , Rowlands Gill 
Published: August 2009

AbstractBackground:  In the UK the National Health Service (NHS) funds primary eyecare in the form of General Ophthalmic Services (GOS) mostly via ‘sight tests’ with community optometrists. Eligible groups include those aged 60 years or more and many are also entitled to an NHS optical voucher to be used to fund spectacles. Only some optical practices provide spectacles whose cost is fully covered by the voucher value which we describe as voucher value spectacles (VVS). As part of a larger study investigating vision screening in the older population, we sought to investigate the proportion of practices that provide VVS.Methods:  A questionnaire was sent to all optical practices in South London and also a more national sample of optometrists using the UK optometry e‐mail discussion list.Results:  All 75 respondents provide NHS sight tests. VVS were provided by 59% of the total sample (70% of the South London sample). For those who supply VVS, the number of frames that were provided for patients to choose from ranged from 1 to 100, with a median of 16.5. Of those practitioners who did not supply VVS, 13% provided spectacles whose lens cost was fully covered by the NHS Voucher.Discussion:  In South London nearly a third of the practices do not provide VVS and it has been suggested that this is because the voucher values are uneconomic. The limited availability of VVS may act as one of the barriers that result in so many older people in the UK having poor vision simply through lack of appropriate spectacles.