bluuebunny/crossref_metadata_2025 huggingface dataset:
Effects induced by chronic treatment with selective D1or D2antagonists on open‐field behavior and colonic temperature
Authors: Maldonado R. , Baamonde A. , Daugé V. , Féger J.
Published: August 2009

Summary—We have studied the behavioral responses in open‐field and the changes in body temperature induced after chronic treatment with a selective D1antagonist, SCH 23390, a selective D2+ antagonist, sulpiride, or a non specific but preferential D2antagonist, haloperidol. After chronic treatment with SCH 23390 or sulpiride, rats were challenged with SKF 38393, selective D1agonist, or LY 171555, selective D2agonist, in order to study the responses of D1and D2stimulation. After chronic SCH 23390, an increase of the locomotion and of the number of rears were observed whereas, no changes were induced by chronic sulpiride or haloperidol. Acute treatment with sulpiride blocked the hyperlocomotion induced by chronic SCH 23390. In naive rats acute administration of SKF 38393 or LY 171555 did not produce any change in locomotion or rearing. In rats treated chronically with SCH 23390 this acute administration of LY 171555 induced an increase of the number of squares and of the number of rears. In these animals, acute administration of SKF 38393 also augmented the number of squares crossed. In contrast, chronic sulpiride did not modify behavioral responses obtained after acute SKF 38393 or LY 171555. Colonic temperature was not changed after acute SKF 38393 while acute LY 171555 induced a hypothermia. Chronic sulpiride did not modify the responses of SKF 38393 or LY 171555, but an increase in body temperature was observed after acute SKF 38393 in animals chronically treated with SCH 23390. The present results support a different behavioral expression of D1and D2supersensitivity in rats. Furthermore, chronic treatment with a D, antagonist induced facilitatory effects on D2behavioral responses; however, these D1‐D2interactions were not observed in body temperature responses.
Effect of hypophysectomy on caffeine elimination in rats
Authors: Bienvenu T. , Pons G. , Rey E. , Richard MO , D'Athis P. , Olive G.
Published: August 2009

Summary—Two groups of 8‐week‐old Sprague‐Dawley male rats were used: 8 hypophysectomized (H[‐]), operated on day 0, treated by daily sc tetracosactid (ACTHs: 10 μg), and thyroxine (T4:5 μg/100g); 7 sham‐operated, treated by sc saline solution. ACTHs, T4, saline solution were administered on days 7–16. The animals receivedpocaffeine (CAF) 4 mg/kg as citrate salt on day 15. Ten blood samples were drawn from the tail. Plasma CAF concentrations were determined by HPLC. CAF apparent clearance and apparent volume of distribution were lower in H(‐) rats than in controls: 0.281 ± 0.072vs0.455 ± 0.165 1/kg/h (‐38%;P<0.05) and 0.520 ± 0.239vs1.28 ± 0.266 1/kg (‐59%;P<0.01) respectively. CAF half‐life was lower in H(‐) rats than in controls: 1.33 ± 0.621vs2.12 ± 0.676 h (‐37%;P<0.01). CAF is a drug with a low hepatic extraction ratio and low plasma protein binding. CAF clearance is therefore primarily dependent on intrinsic clearance, which depends on the activity of the enzymes involved in CAF metabolism. These data suggest that hepatic CAF metabolism is reduced in H(‐) rats treated by SC ACTHs and T4. The decrease in CAF apparent volume of distribution is probably related to dehydration, as suggested by increase in urine flow and hematocrit. The CAF half‐life was probably low because the volume of distribution was proportionally more decreased than the clearance. Our results suggest that the pituitary gland plays a role in the regulation of hepatic CAF metabolizing enzymes.
The pharmacokinetics of the antidepressant tianeptine and its main metabolite in healthy humans – influence of alcohol co‐administration
Authors: Salvadori C , Ward C , Defrance R , Hopkins R
Published: August 2009

Summary— A balanced 3 way cross‐over study involving 12 young healthy volunteers (6 men and 6 women) was used to determine the pharmacokinetic parameters of the antidepressant tianeptine following a single dose administered by oral and intravenous route. The influence of alcohol on the pharmacokinetics of tianeptine when given per os was also investigated. Kinetic parameters of metabolite MC5, the C5 side chain beta–oxidation product of tianeptine, were simultaneously determined. Following intravenous administration total clearance and volume of distribution of tianeptine were 230±59 ml·min−1 and 0.47±0.14 1.kg−1 respectively. When given orally, tianeptine was absorbed rapidly (tmax = 0.94 ± 0.47 h). The mean systemic availability was estimated to be 99 ±29%. Tianeptine was eliminated from plasma with a half‐life of 2.5± 1.1 h, mainly via extrarenal route since its renal clearance averaged 0.38±0.47 ml·min−1. Plasma levels of metabolite MC5 were lower than those of the parent drug but decreased with a longer half‐life (7.2 ±5.7 h). Alcohol co‐administration decreased tianeptine absorption rate and lowered tianeptine plasma levels by about 30% but did not affect those of the MC5 metabolite.
Positron emission tomography studies of brain receptors
Authors: Mazière B. , Mazière M.
Published: August 2009

Summary—Probing the regional distribution and affinity of receptors in the brain,in vivo, in human and non human primates has become possible with the use of selective ligands labelled with positron emitting radionuclides and positron emission tomography (PET). After describing the techniques used in positron emission tomography to characterize a ligand receptor binding and discussing the choice of the label and the limitations and complexities of thein vivoapproach, the results obtained in the PET studies of various neurotransmission systems: dopaminergic, opiate, benzodiazepine, serotonin and cholinergic systems are reviewed.
Alpha‐adrenoceptor subtypes and regional myocardial blood flow distribution during coronary occlusion in dogs
Authors: Berdeaux A. , Arthaud A. , Lambert C. , Giudicelli JF
Published: August 2009

Summary—The involvement of postsynaptic α‐adrenoceptors in the distribution of regional myocardial blood flows (RMBFs, microsphere technique) within the left ventricle has been investigated during intermittent coronary artery occlusion in open‐chest anesthetized dogs. Two types of RMBFs distribution were assessed: (1) between endocardial (endo) and epicardial (epi) layers (endo/epi ratio) and (2) between nonischemic (NIZ) and ischemic zones (IZ) (IZ/NIZ ratio). Equipressor doses of selective α1‐(cirazoline after rauwolscine) and α2‐(UK‐14,304 after prazosin) adrenoceptor agonists were infused in dogs previously submitted to ganglionic and muscarinic blockade. In a control group, aortic pressure was mechanically raised by aortic stenosis to levels similar to those reached with both α‐adrenoceptor agonists. Cirazo‐line and aortic stenosis increased RMBFs in IZ and NIZ but did not alter the calculated coronary resistance in NIZ and did not affect endo/epi and IZ/NIZ ratios. In contrast, UK‐14,304 preferentially augmented coronary resistance in NIZ, increased IZ/NIZ ratio (bothP< 0.05) but did not affect endo/epi ratio in IZ and NIZ. Thus, we conclude that if transmural distribution of RMBFs (endo/epi ratio) is not preferentially controlled by any α‐adrenoceptor subtype, postsynaptic α2‐adrenoceptors are of importance during coronary occlusion in promoting a favorable redistribution of RMBFs from NIZ towards IZ by inducing a selective NIZ coronary vasoconstriction (iea “reverse coronary steal”).
Pharmacokinetics of norfloxacin in the elderly
Authors: Lepage JY , Caillon J. , Malinowsky JM , Lequerré S. , Cozian A. , Le Normand Y. , Potel G. , Drugeon H. , Baron D.
Published: August 2009

Summary— 9 elderly and 9 younger adult patients, with proven post‐operative lower urinary tract infection were treated with 400 mg of norfloxacin twice daily for 5 days. Pharmacokinetics of norfloxacin were measured on days 1 and 5. Compared to the younger adult patients, the elderly showed a decreased creatinine clearance and, following the last dose on day 5, an increased maximum plasma concentration of norfloxacin, an increased area under the concentration‐time curve and a decreased total body clearance of norfloxacin. These results confirm that in elderly, as in younger adult patients, the pharmacokinetics of norfloxacin can be described by a linear model and accumulation of the drug during repetitive multiple doses is predictable. The differences between the two groups cannot be considered as clinically significant so that no dose change would be required in elderly patients within the range of creatinine clearance studied.
Clinical consequences of polymorphic drug oxidation
Authors: Alván G.
Published: August 2009

Summary—Many characters are genetically regulated as polymorphisms. This means that discrete groups are seen within the distribution of a certain character. Drug metabolism is no exception and the polymorphism of acetylation is recognised since the 50's. Polymorphic drug oxidation was discovered in the 70's and has been extensively studied. There are two fully established polymorphisms in drug oxidation named as the debrisoquine/sparteine and the s‐mephenytoin hydroxylation polymorphisms. The metabolism of a number of important drugs cosegregates with that of debrisoquine. Among these drugs are β‐blockers, antiarrhytmics, tricyclic antidepressants and neuroleptics. Apart from accumulation of parent drug and active metabolite, also reduced formation of active metabolite occur for some drugs in slow metabolisers. There are, however, few cases where the presence of polymorphic drug metabolism is of significant disadvantage. The polymorphisms will add to variability in drug clearance but the potential clinical importance should be evaluated for each drug. The cytochrome P‐450 isozyme responsible for debrisoquine hydroxylation is of high affinity‐low capacity character, which means that it can be saturated under certain circumstances. This will decrease the difference in drug metabolic rate between rapid and low metabolisers as will inhibitors of the debrisoquine isozyme like cimetidine, quinidine and propafenone. The debrisoquine isozyme is not readily inducible. In cases where a major metabolic route or the formation of an active metabolite are polymorphically controlled, knowledge about a patient's oxidator status might be of practical value for dose adjustments especially if there is a narrow therapeutic ratio or an established concentration‐effect relationship. For some drugs it is difficult to differentiate between insufficient therapeutic effect and symptoms of overdosage. Tricyclic antidepressants and neuroleptics meet some of these criteria and patients who get recurrent treatment may benefit if the physician has knowledge about debrisoquine metabolic phenotype. Otherwise, the clinical consequences of polymorphisms in drug oxidation seem so far to be limited, considering that a number of disease conditions have not shown any clear association with oxidation status. The polymorphisms in drug metabolism should be considered as a part of natural variability which could in fact be larger with other drugs that do not show polymorphic elimination.
Effects of (±) dobutamine and its (+) and (‐) enantiomers in the isolated rat portal vein
Authors: Vidal‐Beretervide K.
Published: August 2009

Summary—Employing the isolated rat portal vein for testing (±) dobutamine, and its (+) and (‐) enantiomers, we have confirmed the results obtained by Ruffoloet al(1981, 1983) using different methods. In the rat portal vein, (‐) dobutamine acts as an alpha agonist, less potent than noradrenaline. The race‐mate acts as an alpha‐agonist with about half the potency of (‐) dobutamine. The (+) isomer shows no effects. In the presence of the alpha blocker BE 2254, all compounds, (±), (+) and (‐) dobutamine, showed dose‐dependent beta effects. These were surely the result of the action on β2adrenoreceptors since they could be antagonized by the potent and specific β2antagonist ICI 118–551. We have found that (+) dobutamine is, as a β2agonist, 355 to 1 480 times less potent than isoprenaline and 12–16 times more potent than (‐) dobutamine. The pA2of ICI 118–551 against (+) dobutamine is 9,36 (±0,04). This high value is further proof that the beta receptor population of the rat portal vein is β2.
Determination of free concentration of piroxicam and naproxen in plasma. The influence of experimental conditions in equilibrium dialysis
Authors: Hundal ø , Rugstad HE
Published: August 2009

Summary— An equilibrium dialysis method was established in order to investigate possible relationships between free drug concentrations of piroxicam and naproxen and clinical events. Therefore the influence of variations in pH, phosphate concentration and sodium azide concentration of the dialysis buffer on the free concentrations of piroxicam and naproxen was investigated. Piroxicam was found to have a pH‐dependent protein binding. Therefore a good control of pH during the dialysis process is necessary. This has been achieved by increasing the buffer capacity of the dialysis buffer, by adding an antibacterial agent to the dialysis buffer and by cleansing the dialysis cells with 70% ethanol before use to prevent bacterial growth. Addition of 0.03% sodium azide as an antibacterial agent and the use of a 0.09 mol/l phosphate buffer gave good pH control. A method to correct for deviations of pH in measurements of free concentrations of piroxicam by a simple mathematical correction has been found. As naproxen was found to have a protein binding independent of pH, a pH‐correction is not necessary for this drug. Standardized conditions in determination of protein binding of drugs by equilibrium dialysis are important, as composition of the dialysis buffer and pH of plasma compartment at equilibrium may influence the free concentration measurements. Comparisons of data from experiments using different methods are therefore difficult; the importance of pH‐control is stressed. With the methods used in the present investigation, equilibrium dialysis in connection with HPLC, the coefficients of variation for piroxicam and naproxen free concentrations are 5.5% and 7.4%, respectively.
Absence of arterial hypertension despite chronic plasma noradrenaline elevation: evidence for down‐regulation of α‐adrenoceptors. A case report
Authors: Senard JM , Durrieu G. , Berlan M. , Estan L. , Valet P. , Tran MA , Garrigues M. , Montastruc JL
Published: August 2009

Summary— A 44 year old‐healthy female presented chronic and stable high levels of plasma noradrenaline (NA) without any major change in adrenaline. The diagnosis of phaeochromocytoma was discarded. These increased levels of NA offered an unique opportunity to investigate under in vivo conditions a putative regulation of alpha‐adrenoceptors by this endogenous catecholamine. Infusion rates of exogenous NA up to 0.74 μg/kg per min were unable to induce any change in blood pressure (or heart rate) in the subject. In contrast, in normotensive controls, an increase in blood pressure (+ 15 mm Hg) was observed with 0.39 μg/kg per min. The magnitude of yohimbine‐induced increase in plasma NA was similar in the subject and in the controls. Platelet α2‐adrenoceptors evaluated by specific [3H]‐yohimbine binding showed a significantly lower level in the subject when compared to controls. The results show that a sustained increase in plasma NA is able to induce down‐regulation of α‐adrenoceptors. This down‐regulation can explain the lack of arterial hypertension despite the increased sympathetic tone.
Lack of evidence of ketoprofen kinetic changes during the oestrous cycle in rats
Authors: Bruguerolle B. , Bouvenot G.
Published: August 2009

Summary—This study was designed to document possible changes in ketoprofen kinetics in female rats related to the stage of the oestrous cycle. At 3 different stages of the oestrous cycle (proestrus, oestrus or dioestrus), 3 different groups of 5 animals each received a single 10 mg/kg intraperitoneal dose of ketoprofen and blood samples were taken at 0.25, 0.5, 0.75, 1, 2, 4, 8 12 and 24 h after administration. Ketoprofen pharmacokinetic parameters (Cmax, T1/2α and β, AUC and MRT) were calculated. Our data did not reveal any significant difference in ketoprofen kinetics related to the oestrous cycle.
Stimulation of D1 and D2 dopamine receptors produces additive anorectic effects
Authors: Ladurelle N. , Duterte‐Boucher D. , Costentin J.
Published: August 2009

Summary—In food‐deprived mice the D1 dopamine agonist SKF 38393 induced dose dependent anorexia (ED50= 2.6 mg/kg). This effect was reversed by the D1 antagonist SCH 23390. In similar conditions, the D2 dopamine agonist RU 24926 also induced dose dependent anorexia (ED50= 0.19 mg/kg). This effect was reversed by the D2 antagonist (±) sulpiride. The mixed D1/D2 agonist apomorphine also induced an anorectic effect (150 μg/kg sc) which was completely reversed by (±) sulpiride (25 mg/kg, ip) but unaffected by SCH 23390 (5–30 μg/kg). The dose response curve obtained by associating SKF 38393 (2.5 mg/kg) with increasing doses of RU 24926 was roughly parallel to that obtained with RU 24926 alone. This indicates that effects of two drugs were additive. Although both D1 and D2 receptors regulate food consumption, the anorectic effect of apomorphine appears to involve only D2 receptors.
Role of nitric oxide in the genesis of excitatory amino acid‐induced seizures from the deep prepiriform cortex
Authors: De Sarro GB , Di Paola E Donato , De Sarro A. , Vidal MJ
Published: August 2009

Summary— The role of nitric oxide (NO) in the genesis of motor and electrocortical seizures elicited by administration of excitatory amino acid agonists into the deep prepiriform cortex (DPC) has been evaluated. Motor and electrocortical seizures occurred in rats receiving unilateral microinjections into the DPC of either N‐methyl‐d‐aspartate (NMDA, 5 and 10 nmol) or kainate (KA, 100 pmol). The selective NMDA receptor antagonist 2‐amino‐7‐phosphonoheptanoate (APH), when microinjected into DPC, prevented the development of seizures induced by both NMDA and KA injected in the same site. In addition, methylene blue (20 nmol, which prevents activation of soluble guanylate cyclase) or NG‐monomethyl‐l‐arginine (NMMA, 40 nmol; a specific inhibitor of nitric oxide synthesis), when microinjected into DPC 15 min prior to either NMDA or KA, significantly protected against seizures elicited by both excitatory amino acid agonists. These data confirm the role of excitatory amino acid transmission in the genesis of seizures elicited from the deep prepiriform cortex. They further suggest that activation of excitatory amino acid receptors within the DPC leads to the release of a substance which shares properties with EDRF/NO and contributes to the genesis of seizure activity in this area.
Effects of troleandomycin and josamycin on thyroid hormone and steroid serum levels, liver function tests and microsomal monooxygenases in healthy volunteers: a double blind placebo‐controlled study
Authors: Uzzan B. , Nicolas P. , Perret G. , Vassy R. , Tod M. , Petitjean O.
Published: August 2009

Summary—Serum TSH levels are moderately but significantly (PANOVA: 0.05) decreased by troleandomycin (T; 1 g bid over a 10‐day period) compared with josamycin (J) (same doses) and placebo (P) in healthy volunteers. T also significantly increases serum estradiol concentration (PANOVA: 0.03). This effect may be related to a T‐induced inhibition of some P450 monooxygenase isoenzymes and more specifically P 450 NF, determined in our study by a decrease in urinary excretion of 6‐β‐hydroxy‐cortisol. Troleandomycin and josamycin both show poor upper GI tolerance. Liver enzymes (SGOT, SGPT, alkaline phosphatase and gGT) are significantly altered by T compared with J and P (PANOVA: 0.007, 0.001, 0.09 and 0.04 respectively). After J, liver function tests are very close to control values (placebo). Liver enzymes are significantly more altered by T than by J (P0.004, 0.001 and 0.06 for SGOT, SGPT and gGT respectively). Using 6 volunteers in a latin‐square designed study, some established effects of oral macrolides were confirmed (poor upper GI tolerance; liver toxicity of T). Some other effects of T were also elicited, which were either unknown (decrease in serum TSH) or expected but which had not previously been assessed in man (increase in serum estradiol; decreased urinary excretion of 6‐β‐hydroxy‐cortisol).
Pharmacokinetics of molsidomine and of its active metabolite, SIN‐1 (or linsidomine), in the elderly
Authors: Spreux‐Varoquaux O. , Ulmer B. , Cordonnier P. , Forestier A. , Pays M. , Ducreuzet C. , Advenier C.
Published: August 2009

Summary— The pharmacokinetics of molsidomine were investigated in six young (25.5 ± 0.6 years) and in six elderly healthy volunteers (81.1 ± 3.1 years). After a 2 mg oral administration, molsidomine elimination half‐life was prolonged in elderly subjects (1.9 ± 0.2 h versus 1.2 ± 0.1 h, P < 0.05) because of a decrease in its plasma clearance (15.1 ± 3.2 l·h−1 versus 41.8 ± 2.5 l·h−1 (P < 0.01) in young volunteers). The elimination half‐life of the active metabolite, SIN‐1 or linsidomine was also prolonged in elderly subjects (1.8 ± 0.2 h versus 1.0 ± 0.08 h, P < 0.05). AUCs of both molsidomine and SIN‐1 were increased in the elderly subjects, but the increase in the former was greater (x 3.4) than the increase in the latter (x 1.6). These results suggest that pharmacokinetics and metabolism of molsidomine are impaired in elderly subjects.
In vivo effects of macrolides on thyroid hormone serum levels and on hepatic type 1 5‘‐deiodinase in rat. A comparative study with amiodarone, phenobarbital and propranolol
Authors: Perret G. , Yin YL , Nicolas P. , Vassy R. , Uzzan B. , Louchahi M.
Published: August 2009

Summary— Very often, an impact on the intracellular metabolism of iodothyronines and more precisely on microsomal deiodinases is evoked to explain thyroid hormone (TH) serum level alterations occurring with numerous drugs. Among them, three at least are also known to interfere with other hepatic microsomal enzymes, amiodarone (AMI), phenobarbital (PHE) and propranolol (PRO). Starting from this statement, we have examined the effects of 5 macrolides on TH serum level and on hepatic 5′ type 1 deiodinase (5′DI) in vivo in rat. Rats were treated orally for eight days either with 200 mg/kg macrolides ‐ erythromycine (ERY), troleandomycine (TRO), josamycine (JOS), midecamycine (MID) and spiramycine (SPI) ‐, or with AMI (45 mg/kg), PHE (50 mg/kg) or PRO (20 mg/kg), these 3 latter drugs for comparative purpose. Total T4, T3 and rT3 were determined by RIA. Hepatic 5′DI was evaluated by measuring released radioactive iodide from a reverse T3 monolabelled with 125I used as substrate. Compared to control group, ERY and TRO decreased T4 (respectively by 28 and 16%) and from these two, only TRO decreased T3 (23%). With JOS, the only major modification was an increment of T3 (26%). AMI gave a typical alteration with a high T4 (130%), a low T3 (26%) and a high rT3 (376%). 5′DI was statistically inhibited by AMI (85%), JOS (49%), TRO (43%) and ERY (35%). The other drugs showed no significant effect. So, three macrolides have both altered TH serum level and 5′DI, findings which have never been reported before. The precise mechanism of this action remains unknown and the resulting effect, being far from the one observed with AMI, tends to demonstrate, for macrolides, an absence of correlation between the extent of 5′DI inhibition and TH serum profile. Besides, comparative analysis of the results observed with macrolides, AMI, PHE and PRO argues against any relationship between 5′DI and cytochrome‐P450 monooxygenases.
Kinetics of allopurinol and its metabolite oxypurinol after oral administration of allopurinol alone or associated with benzbromarone in man. Simultaneous assay of hypoxanthine and xanthine by gas chromatography‐mass spectrometry
Authors: Lartigue‐Mattei C. , Chabard JL , Ristori JM , Bussiere JL , Bargnoux H. , Petit J. , Berger JA
Published: August 2009

Summary— Allopurinol, oxypurinol, hypoxanthine and xanthine were assayed simultaneously using a highly specific method combining gas chromatography and mass spectrometry. Two hypo‐uricaemic prescriptions were compared: i) 300 mg of allopurinol (AL); and ii) 100 mg of allopurinol plus 20 mg of benzbromarone (AL + BZB). When administered acutely, their effects on blood uric acid levels were similar. Analysis of the pharmacokinetic parameters of allopurinol and its metabolite after each treatment showed dose‐linearity for the metabolite but not for the drug itself. The area under the concentration time curve for allopurinol was 40.3 ± 9.3 μmol 1−1 h after AL, against 8.4 ± 3.9 μmol−1 h after AL + BZB, while for oxypurinol it was 948.0 ± 125.4 μmol 1−1 h after AL and 285.2 ± 77.9 μmol 1−1 h after AL + BZB. The difference in dosage form may partly account for this difference, but the benzbromarone also seems to be involved. Its role on the blood uric acid lowering action of the drug association is complex. Although benzbromarone appreciably favors the elimination of oxypurinol, which should result in a weakening of its hypo‐uricaemic action, this is offset by enhanced elimination of hypoxanthine and xanthine. Renal clearance of xanthine was significantly increased under AL + BZB (173.1 ± 65.6 ml/min against 112.2 ± 32.9 ml/min after AL). Similarly, blood xanthine levels were proportionately higher in the presence of benzbromarone. The action of the two agents may thus be synergistic and not antagonistic, a pharmacological justification for the therapeutic use of this drug association.
Regional hemodynamic effects of rilmenidine and clonidine in the conscious spontaneously hypertensive rat
Authors: Smits JFM , Struyker‐Boudier HAJ
Published: August 2009

Summary—Rilmenidine is an oxazoline analogue that has antihypertensive properties that resemble those of clonidine. Since rilmenidine has recently been described to have a relatively greater affinity for imidazoline receptors than clonidine, it was of interest to study whether this has functional consequences with regard to the regional hemodynamic responses. We investigated regional hemodynamics in conscious spontaneously hypertensive rats, equipped with miniature Doppler flow probes on the renal and mesenteric arteries and on the abdominal aorta. Clonidine (3–30 μg/kg) and rilmenidine (0.2–3 mg/kg) induced similar, dose‐dependent reductions in heart rate. Both also induced an early hypertensive response, which was greater with rilmenidine, and similar later blood pressure reductions, which were maintained over 3 h. The early hypertensive response was associated with generalized vasoconstriction. Rilmenidine caused slightly greater mesenteric and hindquarter constriction than clonidine, whereas renal effects did not differ significantly. During the hypotensive phase, rilmenidine was a less potent mesenteric and hindquarter vasodilator than clonidine. During this phase, renal blood flow was at control levels, probably indicating autoregulation of renal flow. The minor differences in regional hemodynamic effects suggest that clonidine and rilmenidine can both be used as potent antihypertensives. The fact that rilmenidine has been suggested to possess less sedative side‐effects suggests that, on this basis, it may be superior for antihypertensive drug therapy.
Changes in plasma glucose and lactate evoked by α and β2‐adrenoceptor stimulation in conscious fasted rabbits
Authors: Reverte M. , Garcia‐Barrado MJ , Moratinos J.
Published: August 2009

Summary—In conscious fasted rabbits, the iv infusion of salbutamol (3 μg/kg per min) and clonidine (2 μg/kg per min) induced a blood glucose increase amenable to blockade, respectively by ICI 118551 (1 μg/kg per min) and idazoxan (20 μg/kg per min). Amidephrine (10 μg/kg per min) and salbutamol mediated an increase in plasma lactate which was attenuated by prazosin (50 μg/kg, sc) and ICI 118551 respectively. Clonidine did not alter basal plasma lactate. The iv infusion of adrenaline (0.3 μg/kg per min) evoked an increase in plasma lactate more sensitive to blockade by ICI 118551 than by prazosin. ICI 118551 also shortened the hyperglycaemic response to adrenaline, 3‐Mercaptopicolinic acid (25 mg/kg) reduced salbutamol‐ and adrenaline‐mediated hyperglycaemia and increased at the same time the lactate/glucose ratio. Our data show that plasma lactate levels may be regulated by α1‐ and β2‐excitatory adrenoceptor stimulation. However, only the increase in blood lactate derived from β2‐adrenergic stimulation seems to contribute to the overall catecholamine‐mediated hyperglycaemia.
Possible involvement of dopamine D‐1 and D‐2 receptors in diazepam‐induced hyperphagia in rats
Authors: Naruse T. , Amano H. , Koizumi Y.
Published: August 2009

Summary:Possible involvement of dopamine receptors in diazepam‐induced (1 mg/kg, subcutaneous (sc)) hyperphagia was studied in nondeprived rats. Pretreatment with the selective D‐1 antagonist, SCH23390 (0.03 mg/kg, sc) inhibited diazepam‐induced hyperphagia. In addition, pretreatment with the preferential D‐2 antagonists, haloperidol (0.1 to 0.3 mg/kg, sc) and clebopride (0.1 to 0.3 mg/kg, sc) inhibited diazepaminduced hyperphagia in a dose‐dependent manner. Pretreatment with co‐administration of SCH23390 (0.01 mg/kg, sc) and clebopride (0.03 mg/kg, sc) completely inhibited this hyperphagia. The selective D‐2 antagonist, sulpiride (40 mg/kg, sc) and the peripheral D‐2 antagonist, domperidone (10 mg/kg, sc) did not affect diazepam‐induced hyperphagia. However, sulpiride (10 μg, icv) or domperidone (2 μg, icv) administered centrally inhibited this hyperphagia. The highest dose of haloperidol (0.3 mg/kg, sc) or clebopride (0.3mg/kg, sc) and higher doses of SCH23390 (0.01 and 0.03 mg/kg, sc) or SCH23390/clebopride (0.01/0.03 and 0.01/0.1 mg/kg, sc) tended to decrease spontaneous feeding in non‐deprived rats. In addition, the highest dose of haloperidol, clebopride or SCH23390/clebopride inhibited spontaneous feeding in deprived rats. Interestingly, diazepam‐induced hyperphagia was inhibited significantly by doses of haloperidol (0.1 mg/kg, sc), clebopride (0.1 mg/kg, sc) and SCH23390/clebopide (0.003/0.03 and 0.003/0.1 mg/kg, sc) which did not affect spontaneous feeding in non‐deprived or deprived rats. Pretreatment with α‐methyl‐p‐tyrosine (40 mg/kg, IP × 2, 6 and 2 h prior to diazepam administration) failed to inhibit this hyperphagia. Furthermore, pretreatment with a large dose of haloperidol (5 mg/kg, sc, 4 days before diazepam administration) augumented the sub‐hyperphagic effect to diazepam (0.5 mg/kg, sc). Thus, these findings suggest that hyperphagia to diazepam is mediated in part by both dopamine D‐1 and D‐2 receptors in non‐deprived rats.
Compared peripheral vascular responses to intravenous and intra‐arterial administrations of positive inotropic agents in conscious dogs
Authors: Gosgnach M. , Gérard JL , Berdeaux A. , Giudicelli JF
Published: August 2009

Summary—In addition to their direct effects on cardiac contractility, a number of positive inotropic agents also induce, through direct peripheral vasodilation, a reduction in afterload which is of major importance in their beneficial effects in the treatment of congestive heart failure. However, the induced increase in cardiac output can indirectly improve perfusion of peripheral vessels through a flow‐mediated mechanism. Thus, the goal of the present study was to compare the direct peripheral vasomotor effects assessed in the iliac vascular bed of four positive inotropic agents: DPI 201–106, ouabain, milrinone and dobutamine, in the presence and absence of simultaneous changes in cardiac function. These drugs were administered either through intravenous or intra‐arterial (aorto‐iliac catheter) routes in 6 conscious dogs, chronically instrumented for the measurement of heart rate, arterial pressure, left ventricular dP/dt, iliac artery blood flow and iliac artery diameter (sonomicrometry). Intravenous doses were selected as those inducing equipotent positive inotropic responses whereas intra‐arterial doses were below those required to induce any significant change in systemic hemodynamics. Ouabain decreased and milrinone increased both iliac blood flow and diameter after either intravenous or intra‐arterial administrations. In contrast, iliac blood flow did not change after intraarterial administration of DPI 201–106 and dobutamine whereas iliac diameter was not modified by DPI 201–106 and even decreased with dobutamine. After intravenous administration, DPI 201–106 but not dobutamine, increased both iliac blood flow and diameter. Thus, this experimental preparation can differentiate inotropic agents with direct vasodilating (milrinone) or constricting (ouabain) properties and those (DPI 201–106 and dobutamine) with indirect vasodilating effects most likely mediated by the improvement in cardiac function.
Combination of long‐acting furosemide and instant‐acting amiloride: pharmacokinetics and pharmacodynamics in human subjects
Authors: Flouvat B. , Roux A. , Leneveu A. , Prinseau J. , Alexandre JA
Published: August 2009

Summary— The pharmacokinetics and pharmacodynamics of the combination of amiloride (2 times 2.5 mg) and long‐acting furosemide (2 times 10 mg) were compared with amiloride (5 mg) and furosemide (20 mg) in 12 healthy male volunteers aged 26.2 ± 1.6 years and weighing 68.8 ± 6.2 kg, after random order administration. Furosemide and amiloride plasma or urine concentrations were determined by HPLC with fluorimetric detection. The rate of absorption (tmax = 3 h) and the bioavailability of the two diuretics were not significantly modified by their combination. Furosemide plasma half‐life was 2.77 ± 1.04 h after the combination treatment and 2.76 ± 0.98 h alone, amiloride plasma half‐life was respectively 15.7 ± 4.6 h and 14.6 ± 3.7 h. The urinary elimination of furosemide was significantly higher in the 2–4 h interval in the combination treatment, accompanying its delayed maximum effect of diuresis. A synergistic effect was observed after the combination administration of the two diuretics; between the 2nd and the 8th hour, the sodium elimination was significantly increased (P < 0.01) and the potassium excretion was significantly decreased (P = 0.05). After a single dose, no modification of plasma or erythrocyte magnesium levels was observed. This study shows that the combination of the two drugs entails a synergy of their activities which does not involve pharmacokinetic changes.
Neurocytotoxicity: pharmacological implications
Authors: Siesjö BK , Memezawa H. , Smith ML
Published: August 2009

Summary—Recent data suggest that brain damage in ischemia, hypoglycemia, and several other brain diseases is caused by excitotoxic mechanisms which are triggered by presynaptic release of glutamate and related excitatory amino acids, and which involve an abnormal postsynaptic influx of calcium into cells containing a high density of glutamate receptors. This contention is supported by results demonstrating reduction of infarct size in focal ischemia due to middle cerebral artery (MCA) occlusion, and amelioration of neuronal necrosis in hypoglycemic coma, by antagonist which block the NMDA type of glutamate receptor. These results underscore the pathogenetic role of calcium influx into energy‐compromised cells since the NMDA receptor‐linked ion channel has a high conductance to calcium. The issue has been clouded by the inability of NMDA antagonists to ameliorate brain damage due to cardiac arrest, or to forebrain ischemia in rats and gerbils. In these conditions, however, an AMPA receptor blocker (NBQX) has been found efficacious. These results demonstrate that the pathophysiology of ischemic lesions is different in the cardiac arrest type of ischemia and in lesions due to MCA occlusion, and demand an explanation of the differences in therapeutic response. Tentatively, the cardiac arrest type of ischemia is so dense that multiple calcium conductances are activated in the energy‐deprived tissue, explaining why any drug which acts on only one of them (such as an NMDA antagonist) cannot prevent cellular calcium overload. Futher‐more the ultimate brain damage, which is often conspicuously delayed, may be secondary to upregulation of synaptic efficacy, causing increased calcium cycling and calcium‐related damage. In this situation, an AMPA receptor blocker may be efficacious because it blocks “fast” excitation and Na+ influx, an “upstream” event which causes “downstream” calcium influxviamultiple pathways. In the perifocal (“penumbra”) zone of a stroke lesion, the situation is different since depolarisation is initially moderate and/or intermittent. Furthermore, since ATP is still produced (albeit at a reduced rate) the problem is one of a disturbed pump/leak relationship. Then, blockade of a major calcium‐carrying channel by NMDA receptor blockers, or of the trigger to depolarisation by an AMPA receptor antagonist, may improve the pump/leak relationship and carry cells in the penumbra over a critical period.
The l‐arginine — nitric oxide pathway in the canine femoral vascular bed: in vitro and in vivo experiments
Authors: Richard V. , Gosgnach M. , la Rochelle C. Drieu , Giudicelli JF , Berdeaux A.
Published: August 2009

Summary— Vascular endothelial cells synthesize nitric oxide from l‐arginine, and this pathway can be inhibited by various analogues of l‐arginine, including NG‐nitro l‐arginine methyl ester (l‐NAME). To investigate the role of this pathway in the regulation of femoral arterial tone, the effect of l‐NAME was studied in vitro in isolated canine femoral arteries suspended in organ chambers for isometric tension recording, and in vivo in conscious dogs chronically instrumented for the measurement of iliac blood flow and iliac artery diameter. In vitro, l‐NAME induced an endothelium‐dependent contraction, inhibited the endothelium‐dependent relaxations to acetylcholine or bradykinin, and potentiated the relaxation evoked by the nitric oxide donor SIN‐1. In vivo, locally administered l‐NAME induced a decrease in iliac artery diameter and an increase in iliac resistance, potentiated the iliac responses to the organic nitrate nitroglycerin, but did not affect the iliac responses to the endothelium dependent vasodilator acetylcholine. Thus, in the canine femoral vascular bed: a) basal release of nitric oxide contributes in vivo to the maintenance of a permanent vasodilator tone at the level of both large conductance and small resistance vessels; b) the endothelium‐dependent relaxations to acetylcholine and bradykinin in vitro are mostly mediated through the release of nitric oxide from l‐arginine; c) the endothelium‐dependent relaxations to acetylcholine in vivo are probably mediated by a relaxing factor distinct from nitric oxide, or by a nitric oxide‐like molecule released from endothelial pools; and d) removal of the NO‐mediated vasodilator tone by l‐NAME leads to a supersensitivity to nitrovasodilators, both in vitro and in vivo.
Pharmacokinetics of vidarabine in the treatment of polyarteritis nodosa
Authors: Fauvelle F. , Léon A. , Nicolas P. , Tod M. , Guillevin L. , Petitjean O.
Published: August 2009

Summary— The pharmacokinetics of vidarabine were studied in 8 patients with polyarteritis nodosa related to hepatitis B virus infection. The drug was administered by continuous infusion for three weeks at doses of 15 (1 week) and 7.5 (2 weeks) mg/kg per day, during which time 15 plasma exchanges were performed. Plasma was assayed for vidarabine and its principal metabolite, hypoxanthine arabinoside by high pressure liquid chromatography. Vidarabine was not detected in the plasma of any patients. Hypoxanthine arabinoside levels were used to evaluate vidarabine kinetics. The serum levels of hypoxanthine arabinoside ranged from 3.6 to 21.5 mg/l. The mean elimination half‐life (± SD) was 3.0 ± 1.7 h. The plasma clearance (mean ± SD) was 195 ± 270 ml/min when the dose was 7.5 mg/kg per day and 66.3 ± 47 ml/min for a 15 mg/kg per day/dose (NS). Except for the elimination half‐life, these results were not fully consistent with those observed in other studies. The influence of multiple plasma exchanges on vidarabine kinetics is limited and dosage adjustment is not required based on the continuous infusion of vidarabine.
Effects of tilting in the anaesthetized and mechanically ventilated rat: a model of orthostatic hypotension
Authors: Pourrias B. , Marie C.
Published: August 2009

Summary—The main of the present study was to determine the experimental conditions for an animal model of orthostatic hypotension based on tilting in rats. Blood pressure, heart rate and plasma catecholamine levels were measured before and after tilting in conscious and anaesthetized rats either breathing spontaneously or mechanically ventilated. In conscious rats, tilting did not alter arterial blood pressure, but increased heart rate and plasma catecholamine levels. In anaesthetized rats, tilting induced a drop in arterial blood pressure without any modification in plasma catecholamine concentrations. Mechanical ventilation significantly increased the postural hypotension and the percentage of rats showing a decrease in heart rate. Tyramine infusion increased plasma noradrenaline levels, and reduced or counteracted the postural hypotension and bradycardia. The results show that anaesthetized mechanically ventilated rats might constitute an appropriate model of orthostatic hypotension.
Comparative effect of truncal vagotomy and pirenzepine on postprandial secretory response of exocrine pancreas in dogs
Authors: Huertas JR , Madrid JA , Martinez‐Victoria E. , Man̄as M. , Mataix FJ
Published: August 2009

Summary— The comparative effect of truncal vagotomy and associated pyloroplasty and orally administrated pirenzepine (75 mg, 1 h before food intake) on the exocrine pancreatic secretory response to food was studied in conscious dogs. Both pirenzepine administration and truncal vagotomy totally abolished the pancreatic hydromineral and organic secretory response to food intake while postprandial pH of intraduodenal content remained above 6. From the results of our study we conclude that the vago nerve must not be altered in order to assure a pancreatic response to food intake and that pirenzepine is as strong as truncal vagotomy in maintaining pH in postprandial intraduodenal content over 6.
Effects of quinpirole on autonomic nervous control of heart rate in rats
Authors: Roquebert J. , Moran A. , Sauvage MF , Demichel P.
Published: August 2009

Summary—The effects of quinpirole, a specific dopamine DA2 receptor agonist, on autonomic nervous control of heart rate, were studied in normotensive pithed rats, by analysing its action on the tachycardia and bradycardia evoked by electrical stimulation of the cardioaccelerator (10 V; 1 ms; 0.5, 1, 3, 6 Hz) and vagus (10 V; 1 ms; 3, 6, 9 Hz) nerves respectively. Quinpirole (10–50–100 μg kg−1iv) reduced the cardioacceleration elicited by electrical stimulation but not that by noradrenaline (3 μg kg−1iv). The effect on electrical stimulation was blocked by domperidone (0.5 mg kg−1iv) but not by SCH 23390 (0.2 mg kg−1iv) or idazoxan (0.3 mg kg−1iv). At 1, 5, 10, 30μgkg−1iv, quinpirole decreased vagal but not acetylcholine‐induced bradycardia. The effect on electrical stimulation was inhibited by domperidone (0.5 mg kg−1iv) but not by SCH 23390 (0.2 mg kg−1iv), prazosin (0.1 mg kg−1iv) or idazoxan (0.3 mg kg−1iv). The data point to the presence of presynaptic and/or ganglionic dopamine receptors in the sympathetic and parasympathetic innervation of the rat heart, where stimulation inhibits the release of neuromediators.
Rapid changes in 3H‐imipramine platelet binding after chronic treatment with amineptine, a selective dopamine uptake blocker, in major depressed patients
Authors: Gronier B. , Jeanningros R.
Published: August 2009

Summary— The effect of chronic treatment with amineptine (200 mg daily), a tricyclic antidepressant drug selectively blocking dopamine uptake, on 3H‐imipramine binding, was investigated in platelets of major depressed patients in conjunction with changes in clinical state. Before treatment, depressed patients had a significantly lower Bmax (P < 0.01) than age‐ and gender‐matched healthy controls. After only 1 week of amineptine administration, Bmax values increased significantly (P < 0.01) and reached the control value concomitantly with a large and significant clinical improvement (P < 0.01). After 1 month, Bmax was still significantly different from the pre‐treatment value (P < 0.05), and not significantly different from the control value, while the improvement in clinical status persisted. No significant changes in K4 values were observed during treatment. We also verified that amineptine did not displace 3H‐imipramine binding from platelets either in depressed or in control subjects. The results show that the successful treatment with amineptine, an antidepressant drug devoid of affinity for the tritiated imipramine platelet binding site, can rapidly lead to its density normalization.
Potassium channels of the insulin‐secreting B cell
Authors: Petit P. , Loubatières‐Mariani MM
Published: August 2009

Summary—Ionic and electrical events play a central role in the stimulus‐secretion coupling of the pancreatic B cell. Potassium permeability is critically involved in the regulation of B cell membrane potential and insulin secretion. In the absence of glucose, membrane potential remains stable, around − 65 mV. This resting potential is mainly determined by the high potassium conductance of the membrane. The ATP generated by glucose metabolism in B cells blocks the K+(ATP)channels controlling resting membrane potential. Thus, glucose metabolism leads to closure of the ATP‐dependent potassium channels; the resulting decrease in K+ permeability induces depolarization and opening of voltage‐activated Ca‐channels. The subsequent increase in Ca2+influx raises the cytoplasmic concentration of free Ca2+. which in turn triggers exocytosis of secretory granules. Other types of K+ channels have also been identified in the B cell, such as voltage‐ and Ca2+‐dependent K+ channels, which are not a target for the action of glucose, but may play a role in the repolarization of spikes. The modulation of insulin release by some hormones and neurotransmitters involves, among other mechanisms, an interference with the plasma membrane K+ conductance. Thus, galanine, somatostatin and adrenaline, which inhibit insulin release, increase K+ conductance by a G protein‐dependent mechanism; both peptides were reported to open ATP‐sensitive K+ channels in insulin‐secreting cell line RINm5F. It was also observed that extracellular purine nucleotides could interfere with K+ channels. Among the various drugs interfering with insulin secretion, sulfonylureas, such as tolbutamide and glibenclamide, directly inhibit ATP‐dependent K+ channels in the B cell membrane and thereby initiate insulin release. In contrast, potassium channel openers such as diazoxide, antagonize the effects of glucose by increasing K+ permeability of the B cell membrane. Furthermore, other classes of drugs have recently been shown to interact with K+(ATP)channels. Thus, K+ channels of the pancreatic B cell, particularly ATP‐dependent ones, play a crucial role in the electrophysiology of insulin secretion; they are an important target for pharmacological agents designed to modulate this secretion.