bluuebunny/crossref_metadata_2025 huggingface dataset:
Is it possible to predict the activity of a new antidepressant in animals with simple psychopharmacological tests?
Authors: Bourin M
Published: August 2009

Summary—Behavioural tests for predicting antidepressant activity in the animal provide a closer approximation than other tests of states of depression in man but are often long and costly to perform (except the behavioural despair test). The tests proposed here presuppose a pharmacological interaction (except the Porsolt test) but are simple enough to allow screening: included are antagonism of reserpine hypothermia, ptosis and akinesia; antagonism of effects induced by oxotremorine; antagonism of high‐dose apomor‐phine; and potentiation of yohimbine toxicity. In combination with the study of motor activity in the mouse, these tests allow assessment of the specificity of antidepressant activity by establishing a ratio between the ‘antidepressant’ dose and the ‘stimulant’ or “sedative” dose. It can be predicted that a substance will be antidepressant and sedative or stimulant at the same dose if the ratio is close to 1; if the ratio is less than 1, at antidepressant doses the substance will be very sedative or stimulant according to the case. The specificity of the tests discussed can be debatable. Antagonism of reserpine‐induced hypothermia indicates substances with direct or indirect beta‐mimetic activity, ptosis antagonism, substances with alpha‐adrenergic (not antidepressants) or serotoninergic (possibly antidepressants) activity; and akinesia antagonism, a direct or indirect dopaminergic activity (sometimes found in antidepressants) with psychostimulant activity. The oxotremorine test is related to the anticholinergic activity of subtances, exept in the case of hypothermia antagonism. The high‐dose apomorphine test seems to be specific for substances inhibiting norepinephrine reuptake. The yohimbine test is simple to carry out, relatively inexpensive and does not fail to screen any molecule known to be effective to‐date. The behavioural despair test is a good complement for screening except for drugs having a beta‐agonist activity, it appears that this test is dependent on functional relationships between alpha 2 and serotononergic systems.
The effect of pertussis toxin on α1‐adrenoceptor‐mediated vasoconstriction by the full agonist, cirazoline, and the partial agonist, (‐)‐dobutamine, in pithed rats
Authors: Ruffolo RR , Motley ED , Nichols AJ
Published: August 2009

Summary—The role of pertussis toxin‐sensitive guanine nucleotide regulatory proteins (G‐proteins) in the signal transduction process(es) involved in postjunctional vascular α1‐adrenoceptor‐mediated vasoconstriction produced by the full agonist, cirazoline, and the partial agonist, (‐)‐dobutamine, have been investigated in the cardiovascular system of the pithed rat. Pertussis toxin pretreatment (50 μg/kg, iv, 3 days prior to experimentation) only slightly inhibited the pressor response of cirazoline, and the degree of inhibition produced by pertussis toxin was roughly equivalent to the inhibition produced by the calcium channel antagonist, nifedipine (1 mg/kg, ia). In contrast, pertussis toxin pretreatment produced marked inhibition of the α1‐adrenoceptor‐mediated pressor response to the partial agonist, (‐)‐dobutamine, and this large degree of inhibition was qualitatively and quantitatively similar to the degree of inhibition produced by nifedipine. The differential pattern of inhibition of full and partial α1‐adrenoceptor agonists by pertussis toxin suggests that the vasoconstrictor response of an α1‐adrenoceptor partial agonist, which is more dependent upon the translocation of extracellular calcium than a full agonist, as evidenced by its sensitivity to inhibition by nifedipine, involves a pertussis toxin‐sensitive G‐protein that couples the α1‐adrenoceptor to the calcium channel. Furthermore, for α1‐adrenoceptor‐mediated vasoconstriction by full agonists with high intrinsic efficacy, which involves both intracellular and extracellular pools of calcium, and particularly the former, pertussis toxin only inhibits that component of the α1‐adrenoceptor response which is dependent upon the translocation of extracellular calcium, accounting for the limited degree of inhibition of the response to cirazoline by pertussis toxin and by nifedipine. By inference, the other component of the α1‐adrenoceptor‐mediated pressor response to a full agonist, which is dependent upon the mobilization of intracellular stores of calcium through a process believed to involve the activation of phospholipase C, likely utilizes a pertussis toxin insensitive G‐protein that is distinct from that which we propose couples the α1‐adrenoceptor to the calcium channel. We conclude, therefore, that the α1‐adrenoceptor in the vasculature of the pithed rat may be coupled to 2 distinct G‐proteins, only one of which is sensitive to inhibition by pertussis toxin and links the α1‐adrenoceptor to the membrane calcium channel, and which may be utilized by both full agonists and partial agonists.
Effect of ponsinomycin on the pharmacokinetics of dihydroergotamine administered orally
Authors: Couet W. , Mathieu HP , Fourtillan JB
Published: August 2009

Summary— Ponsinomycin is a new macrolide antibiotic. Its effect on DHE pharmacokinetics was investigated in this study. Twelve young healthy volunteers received a single 9 mg oral dose of DHE before and on the 8th day of treatment (800 mg twice daily) with ponsinomycin. DHE was assayed in plasma by RIA. Because of low plasma levels, only peak concentrations could be accurately compared for a ponsinomycin effect. We observed a 3–40‐fold increase in maximum DHE plasma levels in the majority of cases and a much more important effect on one occasion, when DHE was administered in the presence of ponsinomycin. These data are consistent with an increase of DHE bioavailability in the presence of ponsinomycin, probably related to a reduction of its first‐pass elimination. This pharmacokinetic interaction is likely to have clinical consequences and administration of ponsinomycin should be avoided in patients treated orally with DHE.
A double‐blind comparison of perindopril and hydrochlorothiazide‐amiloride in mild to moderate essential hypertension
Authors: Andrejak M. , Santoni JP , Carré A. , Deruyttere M. , Magometschnigg D. , Gotzen R. , Stumpe KO
Published: August 2009

Summary— The aim of this 3‐month double‐blind multicenter trial was to compare the antihypertensive efficacy and tolerability of the ACE inhibitor perindopril with those of a diuretic combination. After 1 month of receiving placebo, 165 patients with essential hypertension were randomised to perindopril 4 mg (n = 82) or to 50 mg hydrochlorothiazide + 5 mg amiloride (n = 83). The patients were treated for 3 months with monthly assessments, “uncontrolled” patients (DBP > 90 mm Hg) had their dosage doubled and then, if necessary, atenolol 50 mg was added. At the end of the 3‐month study, mean decreases in supine and standing systolic and diastolic blood pressures were similar in both groups. In the perindopril group, BP control was obtained in 56% of the patients with the 4 mg dosage and required an increase to 8 mg alone in 16% and with atenolol in 5%. The corresponding percentages in the diuretic group were 48, 23 and 13%. The overall percentage of “controlled” patients was similar in the 2 groups, respectively 78 and 84%. The nature and incidence of complaints were comparable in the 2 groups. Adverse laboratory changes were more frequent in the diuretic group: decrease in blood sodium (140.5 vs 139.1 mmol/1; P < 0.01), potassium (4.2 vs 3.9 mmol/1; P < 0.01) with 10 patients having significant hypokalemia, increase in blood urea, triglycerides and uric acid. By contrast, a transient increase in blood potassium with a decrease in triglycerides was observed in the perindopril group.
Effects of taurine on rat aortain vitro
Authors: Ristori MT , Verdetti J.
Published: August 2009

Summary—The effects of taurine on vascular tone of isolated thoracic aortic rings were investigated. We have observed that: 1) taurine is able to induce reduction of the basal contractile tone; 2) taurine exerts a relaxing action in artery segments preconstricted with high potassium medium noradrenaline; 3) the effect of taurine is either dependent on endothelium, nor mediated by adrenoceptors or muscarinic cholinoceptors; 4) in vessels with basal tone or in those preconstricted with noradrenaline, the presence of endothelium reduces the taurine‐induced relaxation; 5) the actions of taurine are independent of extracellular calcium; 6) taurine increases the vasodilatation induced by a perfusion with a calcium‐free medium. The physiological role of taurine in the maintenance of vascular tone in normal and pathological situations is discussed.
Salicylic acid disposition in children with rheumatoid arthritis
Authors: Barzaghi N. , Lamedica G. , Gatti G. , Cottafava F. , Massocco D. , Marchese N.
Published: August 2009

Summary— The plasma level profile of SA and SUA after a single oral dose of ASA was studied in 8 children with juvenile rheumatoid arthritis, aged 3.5–15.0 years. Pharmacokinetic parameters were on average similar to those reported in the literature for adult subjects, although a somewhat larger intersubject variability was found.
Clonidine but not propranolol decreases plasma neuropeptide Y (NPY) levels
Authors: Poncet MF , Damase‐Michel C. , Valet P. , Tran MA , Montastruc JL , Montastruc P.
Published: August 2009

Summary—The effects of acute administration of two antihypertensive drugs, clonidine and propranolol, on plasma NPY and catecholamine levels were compared in sinoaortic denervated (a model associated with a marked increase in sympathetic tone and a rise in blood pressure) and normal conscious dogs. Clonidine decreased plasma noradrenaline and NPY concentrations in both groups of animals. Propranolol failed to change plasma noradrenaline and NPY levels in sinoaortic denervated dogs but elicited a decrease in plasma noradrenaline with no change in NPY levels in normotensive animals. The present experiments show that changes in plasma noradrenaline and NPY concentrations are not always simultaneous. The decrease in plasma NPY concentrations could contribute to the sympatholytic effect of clonidine.
Metabolism of digoxin, digoxigenin digitoxosides and digoxigenin in human hepatocytes and liver microsomes
Authors: Lacarelle B. , Rahmani R. , de Sousa G. , Durand A. , Placidi M. , Cano JP
Published: August 2009

Summary—In vitrometabolism of digoxin and its cleavage‐related compounds was investigated using hepatocytes in primary culture and microsomal fractions both isolated from human livers. On these models, digoxin (DG3) and digoxigenin bisdigitoxoside (DG2) were not shown to be significantly metabolizedin vitroin man. Therefore, it appeared that the stepwise cleavage of DG3and DG2sugars was not cytochrome P450dependent. This enzymatic system probably plays a minor role in humans for this particular reaction. However, digoxigenin monodigitoxoside (DG1) and digoxigenin (DG0) which are known to be formed after intra‐gastric hydrolysis of DG3, were extensively converted to polar compounds (mainly glucuronides). In addition, using human liver microsomes, a wide variability in UDP‐glucuronyl transferase (UDPGT) activities responsible for DG1glucuronidation was demonstrated. These results suggest that two main factors may contribute to the overall interindividual variability of digoxin biotransformation: i), the individual intra‐gastric pH which influences the sugar cleavage leading to DG1and DG0; ii), a variability in the level of the hepatic UDPGT specific for digitalis compounds conjugation.
A comparative pharmacokinetic and pharmacodynamic study of conventional and sustained‐release preparations of acebutolol in healthy volunteers
Authors: Fleurot O. , Lecocq B. , Lecocq V. , Le Liboux A. , Montay G. , Frydman A. , Jaillon P.
Published: August 2009

Summary— Pharmacokinetics and the degree of β‐blockade of sustained release (SR) acebutolol (500 mg/day) and conventional acebutolol (200 mg tid) were examined after the first oral dose and after 10 days of treatment in ten healthy volunteers. After the first dose, acebutolol Cmax did not significantly differ between the two formulations; however, on day 10 acebutolol Cmax was significantly higher after SR formulation. Cmax of diacetolol, the major metabolite, did not differ between SR and conventional acebutolol neither on day 1 nor on day 10. The dose‐corrected relative bio‐availability of acebutolol was not different from 100% on day 1 and day 10; however the dose‐corrected diacetolol AUC, SR/conventional ratio, was significantly lower than 100% on days 1 and 10. Both acebutolol preparations exerted a significant reduction in exercise tachycardia over 24 h on day 1 and day 10; however, conventional acebutolol exhibited a greater reduction 24 h after the first dose. Exercise‐induced increase in systolic blood pressure was similarly inhibited by both treatments except for 24 h after the first dose when systolic blood pressure was significantly higher with SR than with conventional acebutolol. The percent reduction in heart rate during exercise was linearly correlated with log acebutolol plasma concentrations for each treatment regimen. These results suggest that β‐blockade exerted by SR acebutolol in healthy volunteers is equivalent to that of conventional acebutolol.
Flerobuterol: a potential antidepressant drug related to β‐adrenergic agonists. Experimental profile in mice
Authors: Duteil J. , Rambert FA , Pointeau AM , Mangiameli P. , Assous E.
Published: August 2009

Summary—The potential antidepressant effect of flerobuterol (dl‐(fluoro‐2 phenyl)‐1 t‐butylamino‐2 ethanol), a new drug related to β‐adrenoceptor agonists, was evaluated and compared with imipramine and salbutamol using classical psychopharmacological tests in mice. Like imipramine and salbutamol, flerobuterol (0.5–32 mg kg−1, ip) fully prevented apomorphine (16 mg kg−1, sc)‐ and partly reversed reserpine‐ and oxotremorine‐induced hypothermia. At higher doses (16–32 mg kg−1), flerobuterol enhanced the toxic effects of yohimbine. Unlike imipramine, flerobuterol and salbutamol did not reduce immobility duration in the behavioural despair test. Salbutamol and flerobuterol decreased locomotor activity. Flerobuterol did not induce mydriasis, did not prevent oxotremorine‐induced tremors or salivary and lacrimal gland secretion and did not reduce reserpine‐induced palpebral ptosis. Propranolol (8 mg kg−1, ip) but not α‐methyl‐paratyrosine (75 mg kg−1, ip) prevented the flerobuterol‐induced antagonism of apomorphine‐induced hypothermia. Our results suggest that flerobuterol demonstrates potential antidepressant activity, which could be related to β‐adrenoceptor activation in mice.
Effects of cicletanine on vasoactive systems in conscious sinoaortic‐denervated dogs
Authors: Damase‐Michel C. , Girolami JP , Bascands JL , Tran MA , Moatti JP , Pecher C. , Berthet P. , Tarrade T. , Montastruc JL
Published: August 2009

Summary—The present study investigates the antihypertensive action of cicletanine, a new antihypertensive compound with diuretic properties (or placebo), on vasopressor (catecholamines, renin‐aldosterone) as well as vasodepressor (prostaglandins, kallikrein‐kinin) systems in conscious chronic sinoaortic denervated (SAD) dogs. Cicletanine (10 mg/kg twice a day, per os, for one month) lowered blood pressure and heart rate. The antihypertensive action does not involve an effect on sympathetic tone (since plasma catecholamine levels were unmodified) or on plasma aldosterone levels. By contrast, urinary 6 keto PGF1or PGE2levels and kallikrein activity were enhanced. This result indicates that the antihypertensive effect of cicletanine is associated with a stimulation of potential vasodepressor systems (such as prostaglandins or kinins).
Influence of sex and oestrogen replacement on the disposition of dexamethasone in rats
Authors: Lamiable D. , Vistelle R. , Fay R. , Bensussan B. , Millart H. , Wiczewski M. , Choisy H.
Published: August 2009

Summary—The disposition of dexamethasone (DXM, 2 mg/kg, iv) was studied in ovariectomized female rats treated with oestrogen (0.1 mg and 1 mg of oestradiol benzoate) and in male rats. Oestradiol replacement had no effect on body or liver weights or on the DXM pharmacokinetic parameters (CL, Vdss, AUC, MRT and t1/2) of the female groups. If the Vdss seemed slightly greater in male than in female rats, this difference disappeared after normalization based on body weight. In contrast, CL was greater in the male rats even after normalization. For all the animals, significant correlations were observed between body weight and Vdss (r= 0.731,P< 0.001) or CL (r= 0.639,P< 0.001). Terminal half life and MRT were negatively correlated with CL (r= − 0.481,P< 0.01 andr= − 0.575,P< 0.01, respectively) but not with Vdss. Although oestrogen replacement did not seem to affect the pharmacokinetics of DXM, the increase in the CL in male rats should be the main determinant observed between the sexes. These results are consistent with a slower metabolism found for various drugs metabolized by the cytochrome P‐450 in female rats.
Tolerance pattern to GABAmimetic analgesics and their influence on morphine tolerance and dependence
Authors: Srinivasan D. , Ramaswamy S. , Bapna JS , Srinivasan B.
Published: August 2009

Summary—The possible development of acute and chronic tolerance to 4, 5, 6, 7‐tetrahydroisoxazole‐(5, 4‐C) pyridin‐3‐ol (THIP) and muscimol‐induced analgesia was tested using the acetic acid induced writhing assay. Acute tolerance developed to their analgesic actions on repeated exposure at a 4‐h interval which was sensitive to naloxone. Chronic tolerance gradually developed to these agents from the 4th day and was appreciable after 10 days of treatment. Injection of THIP or muscimol prior to morphine attenuated the acute tolerance developed to morphine analgesia. These findings reveal that acute and chronic tolerance developed to THIP and muscimol induced analgesia and are suggestive of a role for opioidergic system in the development of acute tolerance to their analgesic effect. However, these agentsper sedid not produce any dependence phenomena and failed to affect morphine dependence indicating that different mechanisms might be operating in the development of tolerance and dependence.
Dopaminergic transmission and (+)amphetamine‐induced lethality in aggregated mice
Authors: Duterte‐Boucher D. , Duhamel F. , Costentin J.
Published: August 2009

Summary—In aggregated mice the lethal dose 50% (LD50) of (+)amphetamine was found to be clearly lower than in isolated animals (dose ratio: 6:1), whereas with the pure dopamine uptake inhibitor GBR 12783, the ratio was only 2. Pretreatment of mice with GBR 12783 (20 or 40 mg/kg ip) did not reduce the lethality of (+)amphetamine (10 mg/kg) in aggregated mice. Taking into account their relative affinity for D1 and D2 dopamine receptors, various DA antagonists were opposed to (+)amphetamine (20 mg/kg) in aggregated mice. The specific D1 antagonist SCH 23390 was especially effective (ID5010μg/kg). The specific D2 antagonists (±) sulpiride and metoclopramide were effective for high doses (ID50= 43 and 19 mg/kg respectively). The dopamine antagonists haloperidol and α‐flupenthixol, less specific as regards D1 vs D2 receptors, had an ID50of 66 and 186 μg/kg respectively. Association of the D1 antagonist SCH 23390 with the D2 antagonist (±) sulpiride resulted in an apparent additive effect for reducing the (+)amphetamine‐induced lethality. A semi‐chronic treatment with either the D1 agonist SKF 38393 (7 times 20 mg/kg) or (+)amphetamine (6 times 10 mg/kg) performed in isolated mice did not reduce the lethality induced by (+)amphetamine (20 mg/kg) in aggregated mice. The antagonism of the (+)amphetamine‐induced lethality in aggregated mice, frequently used to screen meuroleptics, reveals their antagonistic activity towards D1 or D2 dopamine receptor types.
Effects of S‐carboxymethyl‐l‐cysteine on pulmonary sialyl transferase activity in vitro, in healthy and in sulphur‐dioxide‐induced bronchitic rats
Authors: Berry CN , Lloyd KG , Louisot P.
Published: August 2009

Summary— S‐carboxymethyl‐l‐cysteine (carbocysteine) improves the visco‐elastic properties of bronchial mucus in vivo, possibly as a result of an increase in the relative proportions of sialomucins in bronchial mucus. Carbocysteine was therefore studied in vitro and ex vivo in both normal and bronchitic rats on pulmonary sialyl transferase, responsible for the addition of sialic acid to mucus glycoproteins. Bronchitis was induced in male Sprague‐Dawley rats by repeated exposure to sulphur dioxide for two weeks. During this time they received either 500 mg kg−1 day−1 carbocysteine or its vehicle by the oral route. Rats not being exposed to SO2 received the same treatment. The animals were then killed, and subcellular fractions prepared by differential centrifugation of lung homogenates. Sialyl transferase was assayed using CMP−14C sialic acid as substrate and desialysed fetuin as exogenous acceptor. Enzyme activity was located in both the (Golgi‐containing) 10 000 g and 100 000 g pellets with minor activity in the cytosolic supernatants. When tested in vitro between 1016 and 10−3 M, carbocysteine had no effect on sialyl transferase activity in microsomes taken from healthy or bronchitic rats. Repeated administration of carbocysteine was without effect on the sialyl transferase activity in 10 000 g pellets taken from healthy rats. However, in bronchitic rats there was a small but statistically significant (P < 0.05) increase in enzymic activity in the treated group compared to the animals receiving the vehicle. There was no difference in the activity of the microsomal enzyme compared to vehicle‐treated controls in either healthy or bronchitic rats. We conclude that it is possible that an increase in sialyl transferase activity in a Golgi‐containing fraction of bronchitic lungs could explain the relative increase in sialomucins in bronchitic subjects.
Compared plasma and brain pharmacokinetics of clomipramine and its metabolite demethylclomipramine in two strains of mice (NMRI and CD1)
Authors: Marty H. , Varoquaux O. , Fialip J. , Cordonnier P. , Duroux E. , Bulach C. , Eschalier A. , Advenier C. , Pays M. , Bastide P.
Published: August 2009

Summary—The fate of clomipramine (CMI) and its main demethylated metabolite demethylclomipramine (DCMI) was studied in two strains of Swiss mice (NMRI and CDI) after intraperitoneal injection. A study of its distribution among various tissues showed that fixation was most marked in lungs, perirenal fat and kidneys, and only moderate in the brain. The pharmacokinetic parameters of both molecules were determined in brain tissue and plasma. Absorption was rapid (tmaxCMI = 14 min), metabolism prompt (tmaxDCMI = 17 or 18 min according to the breed) and elimination rapid from both plasma and brain tissue. The first two stages were similar in the two strains, but elimination of CMI from both plasma and brain was faster in the NMRI mice (plasmat1/2= 53 min against 165 min in the CDI mice). Both values were well below that reported for man (mean plasmat1/2= 24 h). The data presented can serve as a basis for designing true chronic administration protocol in animals.
Sodium lactate reversal of electrophysiological effects of imipramine in guinea‐pig ventricular myocardium
Authors: Adamantidis MM , Adnet‐Bonte C. , Adnet P. , Durocher A. , Dupuis BA
Published: August 2009

Summary—Overdose cardiac effects of imipramine are due to fast Na channel blockade and are clinically reversed by administration of sodium lactate which induces alkalosis (about pH 7.50) and hypernatremia (about 8 mM). The mechanisms of this beneficial effect of Na lactate were exploredin vitroon guinea‐pig ventricular myocardium using the microelectrode technique. The time‐course effects of the clinically relevant concentration of 10 μM imipramine on action potential characteristics were examined at pH 7.20 and pH 7.50. To test whether alkalinisationper seis important or whether an increase in Na concentration plays a major role in the reversal effect, preparations were exposed to increasing concentrations (1, 3, 10, 30, 100 mM) of either Na lactate, bicarbonate or chloride in the absence or in the presence of 10 μM imipramine at pH 7.50. The influence of elevating osmolality was evaluated with equivalent concentrations of sucrose. Imipramine alone significantly depressed Vmaxand shortened action potential duration at all phases of repolarisation. All three high sodium solutions reversed imipramine effects. However the reversal effect was already obvious with 10 mM Na lactate and 10 mM NaHCO3but not 10 mM NaCl. Osmolality did not reverse the imipramine‐induced Vmaxdepression. The results suggest that at the clinically relevant 10 mM concentration, sodium lactate and bicarbonate may displace imipramine from its receptor site on the Na channel by causing alkalosis at the membrane level without profoundly affecting the driving force of the Na current, whereas at the upper concentrations, the increase in Na ion concentrations is predominantly involved in the reversal of imipramine effects.
Contractile effect ofα,β‐methylene ATP on the guinea‐pig isolated trachea
Authors: Candenas ML , Devillier P. , Naline E. , Advenier C.
Published: August 2009

Summary—The effects ofα,β‐methylene adenosine 5′‐triphosphate (α,β‐methylene ATP), 2‐chloroadenosine and R‐PIA (N6‐(L‐2‐phenylisopropyl)‐adenosine) and their interaction with dipyridamole, indomethacin, 8‐phenyl‐theophylline, diazepam and other agonists of central or peripheral benzodiazepine receptors were studied on the guinea‐pig isolated trachea.α,β‐methylene ATP exerted contractile effects on the guinea‐pig isolated trachea; ‐ log EC50andEmaxvalues were 8.86 ± 0.19 and 31.3 ± 2.3 (n= 31) (%vsacetylcholine 10−3M) respectively. In comparison with other purinergic receptor agonists, the rank order of potency was:α,β‐methylene ATP > 2‐chloroadenosine > R‐PIA.α,β‐methylene ATP and 2‐chloroadenosine had significantly (P< 0.05) greater efficacy (Emax) than R‐PIA. Indomethacin (3 times 10−6M) and 8‐phenyltheophylline (10−7to 10−5M) significantly reduced the contractile effect of 2‐chloroadenosine and R‐PIA but did not affectα,β‐methylene ATP‐induced contraction. Conversely, dipyridamole significantly reduced (10−7M) or suppressed (10−6M) the contractile effects ofα,β‐methylene ATP whereas it only partially reduced (10−6M) the contractile effects of high concentrations of 2‐chloroadenosine or R‐PIA. Diazepam potentiated the efficacy ofα,β‐methylene ATP. TheEmax(%vsacetylcholine 10−3M) values were 26.1 ± 2.0 (n= 10) in control conditions and 45.9 ± 4.6 (n= 5;P< 0.05) in the presence of diazepam 10−5M. Diazepam did not modify the contractile effects of 2‐chloroadenosine or R‐PIA. Ro5–4864 (10−7to 10−5M), an agonist of peripheral benzodiazepine receptors, potentiated the contractile effects ofα,β‐methylene ATP to the same extent as diazepam. Clonazepam, an agonist of central benzodiazepine receptors, did not modify these effects. Antagonists of central (flumazenil) or peripheral (RP 52028) benzodiazepine receptors had no influence on the interaction between diazepam or Ro5–4864 andα,β‐methylene ATP. In conclusion,α,β‐methylene ATP exerts on guinea‐pig isolated trachea a contractile effect which is not modified by indomethacin and 8‐phenyltheophylline, but is reduced by dipyridamole. It is suggested that this effect might involve P2xreceptor stimulation.
The role of monoamine oxidase in the metabolism of exogenous noradrenaline by the human saphenous vein*
Authors: Branco D. , Caramona M. , Araújo D. , Osswald W.
Published: August 2009

Summary—Human saphenous vein segments were obtained from patients subjected to coronary bypass surgery. As determined by HPLC‐ED, the veins had a relatively low content of noradrenaline and high content of the deaminated metabolites, dihydroxyphenylglycol (DOPEG) and dihydroxymandelic acid (DOMA). In vein segments which had been incubated with3H‐noradrenaline (0.1 μmol/l), the oxidative deamination pathway predominated over the 0‐methylating one. Deamination occurred both at the neuronal and extraneuronal level; DOPEG appearing to be a good index of intraneuronal deamination, whereas DOMA and O‐methylated and deaminated metabolites were mainly formed extraneuronally. Both MAO type A and MAO type B selective inhibitors reduced the deamination of noradrenaline; deamination was also found to be partially sensitive to semicarbazide. Inhibition of neuronal uptake or of deamination increased O‐methylation. The human saphenous vein thus metabolizes exogenous noradrenaline following a pattern which substantially differs from that shown to occur in various blood vessels from other animal species.
Pharmacological analysis of the cardiac effects of 5‐HT and some 5‐HT receptor agonists in the pithed rat
Authors: Dabiré H. , Chaouche‐Teyara K. , Cherqui C. , Fournier B. , Schmitt H.
Published: August 2009

Summary—A pharmacological analysis of the effects of 5‐HT on heart rate has been performed in the pithed rat. 5‐HT induced a dose‐dependent increase in heart rate whereas 5‐HT, receptor agonists — 8‐hydroxy‐2‐(di‐n‐propylamino)tetralin (8‐OH‐DPAT), 5‐methoxy‐N,N‐dimethyl‐tryptamine (5‐MeODMT), 5‐methoxy 3‐(1,2,3,6‐tetrahydro‐4‐piridinyl) 1H indole (RU 24969) and 1‐(m‐trifluoromethylphenyl)‐piperazine (TFMPP) — failed to increase heart rate. The increase in heart rate induced by the selective 5‐HT2receptor agonist 1‐(2,5‐dimethoxy‐4‐iodo‐phenyl)‐2‐aminopropane (DOI) was not significant. The dose‐response curve to 5‐HT for its tachycardic effects was shifted two‐fold to the right by ketanserin and LY 53857 and nine‐fold to the right by methiothepin. The effects of high doses of 5‐HT (higher than 100 μg/kg iv) were antagonized by methiothepin, (‐)propranolol, 2‐{2‐[4(O‐methoxyphenyl)‐piperazine‐1‐yl]‐ethyl}4,4‐dimethyl‐1,3 (2H‐4H) isoquinoline‐dione (AR‐C 239) and by pretreatment with reserpine. The 5‐HT1receptor antagonists, pindolol and spiroxatrine, the 5‐HT3receptor antagonist MDL 72222 and the α2‐adrenoceptor blocking agent idazoxan failed to antagonize the tachycardia induced by 5‐HT. It is concluded that in the pithed rat, the tachycardia induced by 5‐HT remained unexplained (implication of 5‐HT2receptors probably different from the classical vascular 5‐HT2receptor, or implication of 5‐HT1Creceptors?). Moreover, at high doses (higher than 100 μ/kg iv), 5‐HT may increase heart rate by releasing catecholamines.
The effects of acute and repeated doses of suriclone on subjective sleep, psychomotor performance and cognitive function in young and elderly volunteers
Authors: Gilburt SJA , Fairweather DB , Kerr JS , Hindmarch I.
Published: August 2009

Summary—Suriclone is a new anxiolytic drug belonging to the family of cyclopyrrolones. The effects of acute and repeated doses of suriclone on subjective sleep, psychomotor performance and cognitive function were compared to those of placebo in young and elderly volunteers. Young volunteers randomly received suriclone 0.2 mg, 0.3 mg, 0.4 mg or placebo tid, and the elderly received suriclone 0.1 mg, 0.2 mg or placebo tid. After the first single dose and after a three‐day treatment, subjects completed at 1, 2, 4, 12 and 24 h after drug administration the following battery of psychomotor and cognitive tests: critical flicker fusion threshold, choice reaction time, simulated car tracking test, the stroop test and the Sternberg memory scanning task. Visual analogue scales and the Leeds sleep evaluation questionnaire were also administered during the study. No significant effects of suriclone compared to placebo were seen on the psychomotor tests both in young and elderly volunteers. The only significant result was an improvement of the ease of getting to sleep in the young with 0.4 mg suriclone tid. In conclusion, there is little evidence to suggest that suriclone produces any measurable behavioural toxicity, so often seen with many of the benzodiazepines, in either young or elderly subjects.
Quality of life assessment in therapeutic trials: rationale for and presentation of a more appropriate instrument
Authors: Gerin P. , Dazord A. , Boissel J. , Chifflet R.
Published: August 2009

Summary— In therapeutic trials, quality of life studies are usually based on a health model which results in a restrictive view. Therefore, it is important to clearly define the concept of the quality of life, since ambiguous concepts can alter the results. The key to this problem is the clear distinction between the two components of the quality of life, ie subjective and objective. This latter component is the only one considered in the current medical approach. The use of the subjective quality of life introduces a number of methodological problems not found when the objective quality of life is assessed, and thus requires a specific model which can be derived from the model of life goals used by sociologists. This model is presented here and illustrated with some results obtained with a new questionnaire, the Subjective Quality of Life Profile (SQLP) questionnaire. We suggest that both subjective and objective quality of life studies should be considered in order to emphasize the humanistic approach to therapeutic indications.
Potassium channel openers: pharmacological and clinical aspects
Authors: Quast U.
Published: August 2009

Summary—Opening of plasmalemmal K+ channels leads to cellular hyperpolarization which, in excitable tissues possessing voltage‐dependent Ca2+channels, prevents the opening of such channels and thus prevents excitation. In the last few years, an increasing number of compounds have been identified which elicit their effects by opening K+ channels, preferentially in smooth muscle, but also in other excitable tissues. These include the novel benzpyrans, cromakalim and bimakalim, the thioformamide aprikalim, and also well known antihypertensives such as minoxidil sulphate, diazoxide and pinacidil. After a short overview of the various families of K+ channel openers (KCOs), their basic pharmacological properties, including inhibition by the sulfonyl ureas (such as glibenclamide) are presented. The actual discussion concerning the type of K+ channel(s) opened by these compounds and their mechanism(s) of vasorelaxation will be reported. The therapeutic potential of these compounds in the cardiovascular field (as antihypertensives and, in particular, as anti‐ischemic agents in heart and skeletal muscle), and in asthma (where they reverse established airway hyperreactivity) will also be discussed. Improved tissue selectivity may be the essential pre‐requisite for true clinical success of this class of compounds.
KATP channels modulate GABA release in hippocampal slices in the absence of glucose
Authors: Margaill I. , Miquet JM , Doble A. , Blanchard JC , Boireau A.
Published: August 2009

Summary— We studied the effects of KATP channel blockers on [3H]GABA release in the absence of glucose in rat hippocampal slices. The omission of glucose induced a marked increase in the efflux of [3H]GABA, which was antagonized by TTX (1 μM), but not by MK 801 (1 μM) or DNQX (100 μM). Glibenclamide (10–100 μM) increased dose‐dependently the release of [3H]GABA evoked in the absence of glucose. An increase in [3H]GABA release was also observed with gliquidone (100–300 μM), another sulfonylurea. The potentiation of [3H]GABA release induced by glibenclamide (100 μM) was antagonized by DNQX but not by MK 801. Thus, in the absence of glucose, KATP channel blockers enhance the release of GABA from rat hippocampal slices; this effect seems to be mediated by an overstimulation of non‐NMDA glutamate receptors. On the basis of results reported in the present paper, we suggest that KATP channels may play a role in the regulation of GABAergic activity during hypoglycemia.
Activation of guinea pig eosinophil respiratory burst by leukotriene B4: role of protein kinase C
Authors: Rabe KF , Giembycz MA , Dent G. , Barnes PJ
Published: August 2009

Summary—Leukotriene B4(LTB4) and the protein kinase C activator, 4‐β‐phorbol dibutyrate (PDBu), both induced a pronounced and concentration‐dependent stimulation of hydrogen peroxide (H2O2) generation by purified guinea pig peritoneal eosinophils in the concentration range 1 nM − 1 μM. The LTB4response was inhibited competitively by the specific LTB4receptor antagonist, U‐75302, with aKBof 25 nM, while the concentration‐response curves for both stimuli were shifted rightwards (3.8‐fold and 2.8‐fold for LTB4and PDBu, respectively) by the competitive protein kinase C inhibitor, 1‐O‐hexadecyl‐2‐O‐methylglycerol at a concentration of 300 μM. LTB4appears, therefore, to induce respiratory burst in eosinophilsviaa receptor‐mediated mechanism involving protein kinase C.
Treatment with growth hormone‐releasing hormone (GHRH) 1–44 in children with idiopathic growth hormone deficiency: a randomized double‐blind dose‐effect study
Authors: Lievre M. , Chatelain P. , Van Vliet G. , Olivier M. , Blanchard J. , Morre M. , Boissel JP ,   GHRH European Multicenter Study (GEMS) Group
Published: August 2009

Summary— One hundred and eleven pre‐pubertal children (70 boys, 41 girls, aged 2.5 to 14.3 years) with growth failure (height 2 SD below the mean for chronological age (CA) and height velocity (HV) below the 10th percentile for bone age) due to idiopathic growth hormone deficiency (peak plasma GH < 20 mUI/1 to two standard provocative tests) were treated with GHRH 1–44 NH2. Patient stratification in two classes was performed according to body weight; in each class, patients were randomly allocated to one of seven GHRH doses, from 30 to 300 μg/day. GHRH was injected subcutaneously, every evening, for six months in a double‐blind fashion. No relationship was found between the absolute or incremental HV during treatment and the dose (range from 1.3 – 23.1 μg/kg/day) of GHRH. However, HV (cm/year) increased from 3.8 ± 0.1 (mean ± SEM) before treatment to 6 ± 0.2 during six months treatment and 47 patients (42%) increased their HV up to at least the mean normal HV for bone age (catch‐up growth). Low titer antibodies to GHRH were found in 19 patients (17.1%) at six months; no adverse effect was observed. Our results suggest that patients showing catch‐up growth were older, had a height closer to the mean for chronological age and a slower pre‐treatment height velocity. Failure to demonstrate a relationship between GHRH dose and changes in growth velocity might be explained by the combination of a placebo effect, insufficient frequency of GHRH administration and heterogeneity of the population.
Pharmacokinetics and pharmacodynamics of zolpidem following repeated doses in hemodialyzed uraemic patients
Authors: Fillastre JP , Geffroy‐Josse S. , Etienne I. , Dhib M. , Rosenzweig P. , Danjou P. , Dubruc C. , Bianchetti G.
Published: August 2009

Summary— Zolpidem, an imidazopyridine derivative, is a chemically novel, non‐benzodiazepine hypnotic agent. Many uraemic patients complain of sleep disorders and ask for hypnotic medication which is well tolerated both clinically and biologically in such patients. We studied the pharmacokinetics and pharmacodynamics of zolpidem in 12 end‐stage renal patients regularly treated by hemodialysis three times a week. Zolpidem (10 mg) was given orally for 14 or 21 days. Pharmacokinetic and pharmacodynamic evaluations were repeated at the end of the study on day 14 or day 21. Cmax, Tmax, t1/2 and the area under the curve were not modified in hemodialyzed patients. After daytime dosing, zolpidem induced the same level of sleepiness after the first and last dose and was well tolerated as a hypnotic agent after the night‐time dosing. From these results, it can be said that zolpidem may be administered safely to patients with severe renal impairment without any modification of the dosage regimen.
Renal dopamine excretion in healthy volunteers after oral ingestion ofl‐Dopa
Authors: Barthelmebs M. , Mbou P. , Stephan D. , Grima M. , Imbs JL
Published: August 2009

Summary—l‐Dopa is converted to dopamine by aromatic‐l‐amino acid decarboxylase (AADC). In the kidney, proximal tubular epithelial cells are rich in AADC and urinary free dopamine excretion is a marker for endorenal extraneuronal dopamine synthesis. The urinary free dopamine excretion was analysed in a double‐blind cross‐over study after oral ingestion ofl‐Dopa or a placebo in five healthy volunteers. The drug ingestions were separated by one week's wash‐out. Since in a preliminary study, two volunteers ingesting a singlel‐Dopa dose of 500 mg with breakfast experienced nausea, the five volunteers of the present study were given 300 mgl‐Dopa (50 mg at 9 am with breakfast, 100 mg before lunch and 150 mg before dinner) without any adverse effects.l‐Dopa induced an increase in 24‐h urinary dopamine excretion (HPLC with electrochemical detection). Free urinary dopamine (1900 μg/24 h) accounted for 0.8% of the daily orall‐Dopa dose and represented 10% of total urinary dopamine excretion.l‐Dopa treatment had no significant effect on mean ambulatory arterial blood pressure and heart rate measured from 9 am to 6 pm (Spacelabs) or on 24 h urinary water and sodium excretion.
K+channels and control of ventricular repolarization in the heart
Authors: Carmeliet E.
Published: August 2009

Summary—K+ channels form a large family, in which voltage‐operated and ligand‐operated channels can be distinguished. Under physiological conditions, four K+ currents contribute to the repolarization process and their role is discussed: i) the transient outward current (i1o) is responsible for the rapid initial repolarization process from the crest of the action potential to the plateau level; ii) the delayed K+ current (iK) is involved in the overall repolarization process during the plateau; iii) the inward rectifier (iK1) is responsible for the final rapid repolarization and the maintenance of the resting potential; iv) a ligand‐operated channel activated by acetylcholine and adenosine participates in the repolarization process and the maintenance of the resting potential in nodal, atrial and Purkinje cells. In the context of antiarrhythmic interventions, block of outward K+ current and prolongation of refractoriness is currently considered as an alternative to block of the Na+ current and reduction of conduction velocity. Although some of these drugs show use‐dependent block, the frequency‐dependent changes in current and action potential duration are not ideal.
Experimental models of torsades de pointes
Authors: Weissenburger J. , Davy J‐M , Chézalviel F.
Published: August 2009

Summary— Torsades de pointes is the most typical ventricular tachycardia involving QT‐interval prolongation. It is a rather unusual but potentially lethal ventricular tachycardia with a distinctive morphology favored by bradycardia, antiarrhythmic drugs and hypokalemia and requires specific treatment. Torsades de pointes has been shown to be related to bradycardia‐dependent early afterdepolarizations (EAD) and/or increased dispersion of repolarization. However, although EAD can be obtained relatively easily in vitro with quinidine or sotalol, torsades de pointes are very difficult to reproduce in animal models. The models of torsades de pointes which have been proposed can be categorized as morphological, EAD‐related or pharmacological models. The purpose of the ‘morphological’ models was to reproduce the twisting of QRS axis typical of torsades de pointes, with no consideration of other aspects such as long QT or bradycardia. These models were produced by epicardial electrical or chemical (aconitine) stimulation at two distant ventricular sites or by overdosing of quinidine in dogs with acute myocardial infarction. The second type of model focused on the conditions producing EAD in vitro. Ventricular tachycardias were obtained in anesthetized dogs using toxics such as cesium or anthopleurine, both producing EAD in vitro. These ventricular tachycardias were shown to be sensitive to magnesium, heart rate and autonomic tone, but torsades de pointes remained rare, at least after cesium injections. The pharmacological models that could be used to study the QT‐dependent proarrhythmic effects of drugs are the anesthetized rabbit with alpha‐adrenergic stimulation, and the conscious dog model with chronic AV‐block and diuretic‐induced hypokalemia. Methoxamine‐treated anesthetized rabbits develop ventricular tachycardias during clofilium infusions. These ventricular tachycardias, although appearing at very high heart rates, have typical torsades de pointes aspects and are often associated with giant QT waves. The specificity of the model remains to be tested. In our conscious bradycardic and hypokalemic dogs, quinidine and sotalol but not flecainide, propranolol or lidocaine induced QT‐dependent arrhythmogenic effects and torsades de pointes. Efficacy of high rate stimulations and magnesium were repeatedly observed. This demanding model, especially designed for qualitative drug comparisons, is also well suited to studies on the mechanisms of initiation of torsades de pointes. The pertinence of these models for estimating the risk of QT‐dependent proarrhythmias associated with non‐antiarrhythmic agents remains to be tested.
Early after/depolarizations and triggered activity: mechanisms and autonomic regulation
Authors: Charpentier F. , Drouin E. , Gauthier C. , Marec H Le
Published: August 2009

Summary— An early after/depolarization (EAD) is an abnormality of the repolarization process of an action potential which causes an interruption or a retardation of normal repolarization. Two types were described: phase 3 EADs occur at a takeoff potential of approximately − 60 mV and phase 2 EADs occur at the end of a prolonged plateau at a takeoff potential of between − 10 and − 30 mV. EADs can result from an increase in inward current, a reduction of outward current or both. EADs show cycle‐length dependence: as cycle length increases and repolarization lengthens, EADs occur, and their magnitude increases, at a critical cycle length, can trigger the action potential of these EADs. The autonomic nervous system can also modulate EADs and trigger activity. In cesium‐intoxicated Purkinje fibers, beta‐adrenergic stimulation increases EAD magnitude and the occurrence of triggered activity. Cholinergic stimulation decreases EAD magnitude and suppresses triggered activity occurring after beta‐adrenergic stimulation. Alpha 1‐adrenergic stimulation has no effect on phase 3 EADs but induces phase 2 EADs. In normal Tyrode's solution (0 cesium), phenylephrine prolongs action potential and induces EADs. This effect seems to depend on alpha 1 A stimulation. These electrogenic abnormalities are supposed to be responsible for long QT and torsades de pointes. As our experimental data have shown that both the rate of stimulation and the autonomic nervous system could modulate EADs and trigger activity, we can speculate on the therapeutic implications of such modulations and the role of pacing as well as alpha‐ and beta‐adrenergic antagonists.