bluuebunny/crossref_metadata_2025 huggingface dataset:
The NMDA receptor complex
Authors: Scatton B.
Published: August 2009

Summary—The synaptic responses elicited by glutamate and aspartate in the CNS are mediated by distinct groups of receptors which include the ionotropic NMDA receptor. The NMDA receptor is activated by high‐strength synaptic input and produces relatively sustained depolarization which can lead to repetitive burst firing. These characteristics allow it to be involved in the maintainance of rhythmic neuronal activity and in the modulation of synaptic efficacy and plasticity. Overstimulation of the NMDA receptor appears to play a pivotal role in the physiopathology of ischemic brain injury. The NMDA receptor contains an integral cationic channel which is highly permeable to Ca2+as well as to Na+ and K+. This receptor has several domains in addition to the NMDA recognition site: i) a divalent cation binding site within the channel pore, at which Mg2+ions bind, ii) a binding site recognized by dissociative anesthetics and MK‐801 within the channel; and iii) modulatory sites sensitive to glycine, Zn2+and polyamines. The NMDA receptor is strictly controlled by Mg2+ions in a voltage‐dependent manner. Moreover, it is modulated by protons, by changes in the redox state and by endogenous physiological substances,egNO and arachidonic acid. Selective antagonists now exist for the NMDA recognition site and glycine and polyamine modulatory sites. Molecular cloning of the NMDA receptor has identified a subunit termed NMDA‐R1 and four additional subunits (NMDA‐R2A through NMDA‐R2D). Functionally distinct NMDA receptor subtypes are formed by heteromeric assembly of NMDA‐R1 with NMDA‐R2 subunits. NMDA receptor subunits contain consensus phosphorylation sites for protein kinases at the cytoplasmic domain. The high Ca2+permeability and sensitivity to channel block by Mg2+are imparted by asparagine residues in a putative channel‐forming segment of the protein transmembrane 2. The knowledge of the molecular structure of the NMDA receptor will help to understand the molecular mechanisms responsible for its regulatory features and the molecular bases of neurotoxicity.
Influence of renal function on the pharmacokinetics of diacerein after a single oral dose
Authors: Debord P. , Louchahi K. , Tod M. , Molinier P. , Berdah L. , Perret G. , Petitjean O.
Published: August 2009

Summary— The pharmacokinetics of diacerein (a new anti‐inflammatory analgesic antipyretic drug) following a single oral dose of 50 mg was studied in 12 healthy volunteers and two groups of eight patients with mild or severe renal insufficiency. Statistical analysis using a Kruskal‐Wallis rank sum test showed a significant difference between the three groups for the following parameters. In severely uraemic patients, median AUC0‐∞ was multiplied by a factor of ca 2: 40.5 mg h/l versus 21.3 in healthy subjects, P = 0.04; and t1/2 was prolonged by the same factor: 9.6 h versus 4.3 in the control group, P = 0.003. Apparent drug availability and renal clearance assessed through urinary data decreased with renal failure, respectively: 14.5% and 0.045 l/h versus 35.4% (P = 0.01) and 0.13 l/h (P = 0.008) in healthy subjects. Amounts of glucuro and sulfo conjugates in urine were lower in severely uraemic patients. Intermediate values were observed for mildly uraemic patients. Other parameters: lag‐time, Cmax, tmax, Vss/F, urinary glucuro‐ to sulphoconjugate ratios did not change significantly. Apparent total clearance of rhein was poorly correlated with creatinine clearance and this was related to a decrease of non‐renal clearance of rhein in renal insufficiency. It was concluded that, from a pharmacokinetic point of view, a reduction (50%) in the maintenance dosage of diacerein should be considered in severe renal failure.
Dopaminergic modulation of visual sensitivity in man
Authors: Masson G. , Mestre D. , Blin O.
Published: August 2009

Summary— A large body of experimental evidence supports the hypothesis that dopamine is a functional neuromodulator at many levels of the visual system. Intrinsic dopaminergic neurons were characterized in most mammalian retina, including man. These neurons give rise to a dendritic plexus covering the retina. Thus, dopamine seems to be involved in the organization of the ganglion cell and the bipolar cell receptive fields and modulates physiological activity of photoreceptors, both processes which underlie sensitivity and spatial selectivity of visual processing in the early stage of the visual system. Moreover, few data are now available concerning the functional significance of dopaminergic modulation of visual sensitivity in man. Parkinson's disease is a specific disorder of central dopaminergic systems. Abnormalities in the pattern‐evoked potentials and electroretinogram have been found in parkinsonian patients. Contrast sensitivity, a useful tool for measuring visual spatio‐temporal sensitivity in man, has also been shown to be modified due to this affection. Dynamic contrast sensitivity is primarily decreased in these patients, distinguishing them from the normal aging process. Because these modifications in shape of the contrast sensitivity function are reversed by L‐Dopa, and that neuroleptic administration could reproduce them in schizophrenian patients, it was suggested that dopamine might tune the contrast sensitivity function in man. We have recently shown that subcutaneous apomorphine induces changes in contrast sensitivity in healthy volunteers, which preferentially affect motion sensitivity. These dopaminergic sensitive modifications in the shape of the contrast sensitivity function might reflect a change in the range of sensitivity of the visual system, both in dynamic and spatial properties. This could be explained by a modification in the spatial and dynamic properties of the ganglion cell responses in the retina. Moreover, we suggest both from our results and from the review of the literature that human psychophysical data confirm the hypothesis that dopamine may be involved in light retinal adaptation, as light‐induced and dopamine‐induced modifications in the shape in the contrast sensitivity function are quite similar.
Antimalarial 4‐aminoquinolines: mode of action and pharmacokinetics
Authors: Pussard E. , Verdier F.
Published: August 2009

Summary— In the last ten years, the widespread increase in Plasmodium falciparum resistance to chloroquine has prompted research into antimalarial 4‐aminoquinolines, empirically used up to now. The mechanism of action of 4‐aminoquinolines is characterized by the concentration of the drug in the digestive vacuole of the intraerythrocytic parasite. Various hypotheses have been advanced to explain the specificity of action on the parasite; the most recent one is the inhibition of the haem polymerase of the parasite, leading to the accumulation of soluble haem toxic for the parasite. Chloroquine‐resistant parasites accumulate the drug to a lesser extent than do sensitive parasites. Recent findings have shown that chloroquine resistance can be reversed by various tricyclic drugs, which are able to restore the effective concentrations of chloroquine in the infected erythrocyte, but intrinsic mechanisms of action of these reversing agents are unknown. Four‐aminoquinolines are extensively distributed in tissues and characterized by a long elimination half‐life. Despite similarities in their chemical structures, these drugs show differences in their biotransformation and routes of elimination: chloroquine is partly metabolized into a monodesethylderivative and eliminated mainly by the kidney. In contrast, amodiaquine is a prodrug and amopyroquine is poorly metabolized; both drugs are excreted mainly in the bile. The understanding of the pharmacokinetics of 4‐aminoquinolines has led to an improvement in empirically defined therapeutic regimens. Finally, the emergence of severe adverse‐effects after prolonged prophylaxis with amodiaquine and the lack of cross resistance of Plasmodium falciparum between chloroquine and amopyroquine, have led to a proposal for the use of intramuscular amopyroquine as an alternative for the treatment of chloroquine‐resistant malaria.
Representation of affinity in the case of co‐operativity in protein‐ligand binding
Authors: Monot C. , Lapicque F. , Benamghar L. , Muller N. , Payan E. , Netter P.
Published: August 2009

Summary— We have already proposed a “Global Association Function” to represent the global affinity of proteins to a drug; it was first applied in the case of independent binding sites. In this paper, we show that this same function can also be used to assess interactions between sites by varying the number of interacting sites and their co‐operativity level. The resulting curves in two application cases are given together with the corresponding Scatchard plot: i) in a system with one single class of identical and interacting sites, ii) in a system with two classes of sites in which either primary or secondary are interacting; unexpectedly, in this latter case we also observed that sometimes positive co‐operativity occasionally resulted in a concave‐up Scatchard plot which is unusually admitted. In addition, as described in one example, our function is assumption free; this might be an advantage over usual methods, such as discrete parameter methods, because they require additional and empirical hypotheses on their related binding model.
Evidence for pH as an important parameter to control when studying the contractility of isolated rabbit cerebral arteries
Authors: Deckert V. , Pruneau D. , Elghozi JL
Published: August 2009

Summary— Isolated rabbit basilar (BA), middle (MCA) and posterior (PCA) cerebral arteries mounted in an isometric Mulvany myograph and stretched to a given level of resting tension, developed a spontaneous slow‐rising contraction. This tone presented the main features of a classical myogenic tone since it was not suppressed by repetitive washings, was not dependent on the presence of endothelium and was markedly influenced by the concentration of extracellular calcium. In addition, we observed that the occurrence of myogenic tone was dependent on the pH of the medium buffer. Decreasing pH of the Krebs solution from 7.54 to 6.81 by lowering NaHCO, concentration from 25 to 5 mM. reduced the amplitude of the myogenic tone developed by the arteries. We investigated the influence of such changes of pH on the contractile response to potassium chloride (KCl) and to 5‐hydroxytryptamine (5‐HT). We demonstrated that the contractile response to KCl (124 mM) was not affected by the pH of the organ bath whereas the maximum contraction to 5‐HT (10 μM) was significantly affected in BA but not in MCA and PCA. Furthermore, we found that three consecutive concentration‐response curves to 5‐HT were reproducible when obtained at pH 7.15 and 7.30 for BA and MCA. In PCA, 5‐HT‐induced responses were reproducible at pH 7.30 whereas the sensitivity of the repeated response curves to 5‐HT was reduced at pH 7.15. We also noted a larger variability of the response to 5‐HT for the three arteries at this pH. Thus, it appeared that bathing rabbit cerebral arteries in a buffer medium at pH 7.30 is suitable for studying their reactivity to 5‐HT. These results highlight the importance of controlling the pH of medium buffer when studying in vitro the reactivity of rabbit cerebral arteries. In addition, they define appropriate conditions to minimize the myogenic tone and to allow vigorous and reproducible contractile responses to 5‐hydroxytryptamine.
Medullary hypotensive effect of endothelin1in anaesthetized animals
Authors: Feldman J. , Tibiriça E. , Stutzmann J. , Bousquet P.
Published: August 2009

Summary—In anaesthetized animals, systemic injection of ET1at doses from 3 to 100 ng·kg−1provoked only a transient hypotensive effect. At 300 ng·kg−1we observed the classical biphasic effect, consisting of a transient lowering of the arterial pressure followed by a long‐lasting hypertensive effect. Direct injection of the peptide into the vertebral artery of anaesthetized animals only affected arterial pressure (AP) when the blood‐brain barrier was permeabilised. Under these conditions, a dose‐dependent decrease in AP was observed, which was not associated with a significant effect on the heart rate. Micro‐injections of the peptide in the medullary nucleus reticularis lateralis area (NRL), a medullary vasopressive centre, at doses of 30 to 60 ng·kg−1led to a significant reduction in mean arterial pressure (MAP) (17 ± 4% and 36.5 ± 6%) respectively without a significant change in heart rate. These effects lasted less than 2 hours. These results suggest a possible role of ET1as a neuromodulator involved in the central regulation of vasomotor tone, in the NRL region.
Effects of SR 48968 on the neuropeptide gamma‐induced contraction of the human isolated bronchus
Authors: Qian Y. , Advenier C. , Naline E. , Bellamy JF , Emonds‐Alt X.
Published: August 2009

Summary— Neuropeptide gamma (NPγ) induced a contractile response of the human isolated bronchus which was potentiated by the neutral endopeptidase inhibitor, phosphoramidon, but was not modified by atropine and indomethacin. NPγ was 3.31‐fold more potent than NKA. Contractile response curves to NPγ were shifted to the right and maximal responses reduced by the non‐peptide NK2‐receptor antagonist, SR 48968. The pKB of SR 48968 (8.94 ± 0.18, n = 15), calculated according to Kenakin (1987) was very close to that reported for [Nle10]‐NKA (4–10), a specific agonist of neurokinin NK2‐receptors (8.86 ± 0.13, n = 13), suggesting that the contractile effects of NPγ on the human isolated bronchus were mediated through NK2A‐receptors.
Is debrisoquine hydroxylation modified during acute viral hepatitis?
Authors: Joanne C. , Paintaud G. , Bresson‐Hadni S. , Magnette J. , Becker MC , Miguet JP , Bechtel PR
Published: August 2009

Summary— Drug metabolism in the liver may be decreased during liver diseases. However, the extent of impairment of specific isozymes of cytochrome P450 is largely unknown. We have studied the debrisoquine hydroxylation capacity of 17 patients with acute viral hepatitis and 106 unrelated healthy subjects. Debrisoquine metabolic ratio was increased in extensive metabolizers (EM) with acute viral hepatitis as compared with healthy EMs (median metabolic ratio: 1.20 vs 0.84, P < 0.05). However, there was no difference in phenotype prevalence between patients and controls. Our results suggest that acute viral hepatitis only has a marginal effect on the activity of CYP2D6 and that substrates of this enzyme may be given in normal therapeutic doses to this category of patients.
Systemic, regional and cerebral hemodynamic effects of a new angiotensin converting enzyme inhibitor, imidapril, in healthy volunteers
Authors: Démolis P. , Annane D. , Duhazé P. , Giudicelli JF
Published: August 2009

Summary— The effects of two single oral doses (5 mg and 20 mg) of a new angiotensin I‐converting enzyme inhibitor, imidapril, on a) systemic hemodynamics (arterial pressure, heart rate, cardiac output), b) brachial and common carotid arteries' hemodynamics (diameter and blood flow, pulsed Doppler technique), c) cerebral hemodynamics (middle cerebral artery mean blood flow velocity, transcranial Doppler technique), and d) biological parameters (plasma converting enzyme activity, active plasma renin, plasma aldosterone, catecholamines, and atrial natriuretic factor) were investigated and compared with those of a placebo during the 24 h period following administration in a randomized, double‐blind, cross‐over study performed in six healthy volunteers. Imidapril induced a strong, dose‐dependent and sustained inhibition of plasma converting enzyme activity and at the 20 mg dose an increase in active plasma renin. Other investigated biological parameters were not drug‐affected. Imidapril, whatever the dose, did not significantly affect systemic hemodynamic parameters. Imidapril, 20 mg, significantly increased common carotid artery blood flow and diameter and brachial artery diameter. Brachial blood flow also tended to increase but this was not significant. The middle cerebral artery mean blood flow velocity investigated in only five volunteers, underwent spontaneous variations after placebo, and these variations were not affected by imidapril, suggesting that imidapril, whatever the dose, does not influence cerebral blood flow. Thus, imidapril's vasodilating properties apparently affect only the muscular (brachial artery) and cutaneous (external carotid artery) territories, but do not influence the cerebral vascular bed.
Methodological approaches to pharmaco‐economics
Authors: Souêtre EJ , Qing W. , Hardens M.
Published: August 2009

Summary— Due to the increased need for cost‐containment policies, most decision makers are facing the issue of the efficiency of health care strategies. In this context, economic evaluation becomes a major instrument. However, the credibility of economic data depends on a number of methodological steps: selection of strategy of economic evaluation (cost/effectiveness, cost/benefit, generation of economic hypotheses, study design (cross‐sectional, prospective, naturalistic), data collection (data‐base, physicians), data analysis (costing, statistics). In this respect, the conduct of proper economic evaluation relies on a combination of expertise in clinical epidemiology as well as in health economics.
Structure activity relationship of phosphoramidon derivatives for in vivo endothelin‐converting‐enzyme inhibition
Authors: Bigaud M. , Hauss B. , Schalk C. , Jauch MF , D'Orchymont H.
Published: August 2009

Summary— The structure activity relationship of phosphoramidon analogues was studied for their ability to reduce the hypertensive effect of exogenous proET‐1, probably via inhibition of an endothelin converting enzyme activity (ECE). Results concerning in vivo ECE and in vitro thermolysin inhibitions were compared. In contrast to the phosphoryl group of phosphoramidon, which was found to be an absolute requirement, the rhamnose moiety was of very little importance for the inhibition of either enzyme. Furthermore, the tryptophan residue of phosphoramidon appeared to be particularly important for the ECE inhibition, whereas thermolysin inhibition seemed to depend greatly on the leucine residue. It is concluded that in vivo ECE and thermolysin differ in the way they recognise phosphoramidon. The existence of an hydrophobic pocket, specific for the recognition of the tryptophan residue of phosphoramidon, could be proposed for ECE.
Comparative study of erythromycin, troleandomycin and tylosin on the rabbit intestine
Authors: Kounenis G. , Koutsoviti‐Papadopoulou M. , Elezoglou V.
Published: August 2009

Summary— The macrolide antimicrobial agents, erythromycin, troleandomycin and tylosin were tested for their effect on isolated whole segments of the rabbit duodenum, jejunum, ileum and ascending colon, as well as on strips of the circular and longitudinal smooth muscle of the ascending colon. The 14‐membered macrolides erythromycin and troleandomycin were found to possess a concentration‐dependent contractile effect on the intestinal smooth muscle. The order of potency was: erythromycin > troleandomycin. The 16‐membered macrolide tylosin was found to have a much weaker potency than erythromycin and troleandomycin. In addition, the circular smooth muscle of the ascending colon was found to be more sensitive to the compounds tested than the longitudinal smooth muscle.
The role of an initial single‐blind placebo period in phase I clinical trials*
Authors: Nony P. , Boissel JP , Girard P. , Lion L. , Haugh MC , Fareh S. , De Breyne B.
Published: August 2009

Summary— The effect of an initial single‐blind placebo period in a phase 1 clinical trial was assessed in 12 volunteers who underwent five weekly treatment periods, consisting of treatment on the first day and a six‐day wash‐out period. An initial single‐blind placebo period was followed by three different single doses of a platelet‐aggregation factor inhibitor and another placebo period, under a double‐blind Latin square design. Reports of abnormal symptoms were collected using a questionnaire designed by our group. A total of 13 abnormal symptoms were reported during the first period and only nine for the following four periods, indicating a clear placebo period effect. These preliminary results suggest that an initial single‐blind period may be usefully included in phase 1 clinical trials.
Pharmacokinetic and pharmacodynamic study of suriclone imipramine interaction in man
Authors: Perault MC , Chapelle G. , Bouquet S. , Chevalier P. , Montay G. , Gaillot J. , Chakroun H. , Guillet P. , Vandel B.
Published: August 2009

Summary— Suriclone is a novel cyclopyrrolone exhibiting anxiolytic activity. Twelve healthy Causasian male volunteers participated in the study. A single dose of suriclone 0.4 mg, imipramine 75 mg, suriclone 0.4 mg + imipramine 75 mg, or placebo was given according to a 4 × 4 Latin‐square design in order to assess the effect of drug association on pharmacokinetics and psychomotor performances. Visual analogue scale ratings, critical flicker frequency, choice visual reaction time, and Pauli, picture memory and Sternberg tests were performed before and 1.5, 6 and 9 h after drug administration. Suriclone, with the exception of the Pauli test, had no effect on psychomotor performances. The imipramine‐suriclone association appeared to disturb some performances (no statistical significance), probably due to the effect of imipramine. Blood samples were collected for determination of imipramine and suriclone plasma levels respectively by high‐performance liquid chromatography and radioimmunoassays. Suriclone AUC, Cmax and Tmax were not affected by imipramine, and reciprocally.
Drug‐induced parkinsonism: a review
Authors: Montastruc JL , Llau ME , Rascol O. , Senard JM
Published: August 2009

Summary—The main clinical features, pathophysiology and underlying mechanisms of drug‐induced parkinsonism are reviewed. The clinical manifestations of drug‐induced parkinsonism are often indistinguishable from idiopathic Parkinson's disease. However, some subtle differences may exist: for example drug‐induced parkinsonism is often associated with tardive dyskinesias, bilateral symptoms and the absence of resting tremor, etc. Besides toxins (egmanganese, carbon monoxide or MPTP), many drugs are known to produce parkinsonism: dopamine blocking drugs (true neuroleptics used as antipsychotics: phenothiazines, butyrophenones, thioxanthenes but also sulpiride, “hidden” neuroleptics prescribed as anti‐nausea or anti‐vomiting drugs (such as metoclopramide and other benzamide derivatives), dopamine depleting drugs (reserpine, tetrabenazine), alpha‐methyldopa, calcium channel blockers (flunarizine, cinnari‐zine, etc). The putative role of other drugs (egfluoxetine, lithium, amiodarone) as well as the therapeutic management of this side effect are reviewed.
Opioidergic control of the spinal release of neuropeptides. Possible significance for the analgesic effects of opioids
Authors: Bourgoin S. , Benoliel JJ , Collin E. , Mauborgne A. , Pohl M. , Hamon M. , Cesselin F.
Published: August 2009

Summary—Several neuropeptides play a key role in the transfer (substance P, calcitonin gene‐related peptide, etc) and control (enkephalins, cholecystokinin, etc) of nociceptive messages from primary afferent fibres to spino‐thalamic neurones in the dorsal horn of the spinal cord. This first relay in nociceptive pathways has been shown to be a major target for opioids such as analgesic drugs, and the effects of exogenous (mainly morphine) and endogenous opioids on the release of neuropeptides within the dorsal horn are reviewed here for a better understanding of the cellular mechanisms responsible for their antinociceptive action. Complex modulations of thein vitro(from tissue slices) andin vivo(in halothane‐anaesthetized rats whose intrathecal space was perfused with an artificial cerebrospinal fluid) release of substance P and calcitonin gene‐related peptide by opioids have been reported, depending on the opioid receptor (mu, delta, kappa, and their subtypes) stimulated by these compounds. In particular, the inhibition by delta agonists of substance P release from primary afferent fibres, and that by the concomitant stimulation of mu and kappa receptors of the release of calcitonin gene‐related peptide are very probably involved in the analgesic action of specific opioids and morphine at the level of the spinal cord. Furthermore, the negative modulation (through presynaptic opioid autoreceptors) by delta and mu agonists of the spinal release of met‐enkephalin, and the complex inhibitory/excitatory influence of delta, mu and kappa receptor ligands on the release of cholecystokinin within the dorsal horn very likely also contribute to the antinociceptive action of these drugs and morphine. The reviewed data strongly support the existence of functional interactions between mu and kappa receptors within the spinal cord, and their key role in the analgesic action of non specific opiates (acting on mu, delta and kappa receptors) such as morphine.
Drugs designed to maintain the transparence of the ocular lens
Authors: Chanalet L. , Lapalus P.
Published: August 2009

Summary— Research into the biological basis of lens transparency has demonstrated the implication of lens sugar stress in the diabetic cataract whereas senile cataract is the result of natural degeneration which is enhanced by various external factors such as cosmic and ionizing rays, or oxidative processes. Drugs have been developed which are aimed at being effective on lens pathological physiology and metabolism, concurrently. Such molecules: aldose reductase inhibitors (ARIs: sorbinil, AD‐5467, CT‐112 and imirestat), acetyl salicylic acid (ASA), salicylate (SA) and sodium monomethyl trisilanol orthohydroxybenzoate (SMB, a prodrug for salicylate) have undergone pharmacodynamic, pharmacokinetic and/or clinical studies which are presented here. ARIs have shown efficacy in slowing down and preventing the progression of experimental sugar cataracts; sorbinil can partially reverse the very early morphological signs of sugar cataract. Sorbinil and imirestat have also demonstrated anti‐oxidant properties. ARIs administration (per os or by topical instillation) generally results in lens levels compatible with concentrations that are efficient on biochemical mechanisms of cataract formation. However, at the present time, clinical evaluations are in progress and as yet, there is no confirmation of their efficacy in man. ASA and SA can prevent various mechanisms of lens protein denaturation; they inhibit AR and prevent, in vitro, the formation of some pigments found in the aged cataractous lens. Extrapolation of the ASA ocular pharmacokinetics results in animal to man, suggest that ASA administration per os could result in efficacious levels in the lens. This is also sustained by the observation of a reduced frequency of cataracts in ASA treated diabetic rhumatoid arthritis patients. SMB pharmacokinetic studies have shown small but persistent levels of the active principle in the lens. They suggest that the capsule slows down SA diffusion into the lens and that, on the contrary, lens epithelium facilitates its penetration. Preliminary results of pharmacodynamic studies are given.
Changes in brain MAO activity and glycogen levels upon chronic alcoholization of three successive generations of rats
Authors: Nevo I. , Parvez S.
Published: August 2009

Summary— Changes in neurobiological parameters were examined from early life (10 days post‐natal) until late adulthood (8 months post‐natal) in three successive generations of alcoholized rats. The mean daily consumption of alcohol by the 2nd and 3rd generation rats (7.40 ± 0.22 and 7.70 ± 0.20 g ethanol/kg body weight, respectively) was significantly greater than that of the 1st generation alcoholized group (4.26 ± 0.33 g/kg). Brain/body weight ratios of alcoholized rats, 10 days post‐natal, were significantly greater than controls, with 1st generation alcoholized rats presenting significantly greater brain/body weight ratios than those of the 2nd or 3rd generation, which tended toward control weights and ratios. This difference between alcoholized rats and controls persisted, although to a lesser extent, at 8 months post‐natal. Glycogen content in the brains of rats of all alcoholized generations was significantly lower than in controls at 10 days post‐natal, with a reversal of this situation in later life for 2nd and 3rd generation rats, which presented significantly greater cerebral glycogen levels than control or 1st generation alcoholized rats (which had an equivalent cerebral glycogen content). In 10‐day‐old rat pups, monoamine oxidase (MAO) activity in brain tissues had a tendency (mostly non‐significant) to be greater in alcoholized rats than in controls, with a reversal of this situation, ie a statistically significant decrease in MAO activity in the 2nd and 3rd alcoholized generations with respect to controls, in 8‐month‐old rats. MAO activity in adrenal glands of alcoholized rats was greater than in controls at 10 days post‐natal, and this difference persisted at 8 months.
Effects of triiodothyronine and dexamethasone on plasma and tissue angiotensin converting enzyme in the rat
Authors: Michel B. , Grima M. , Coquard C. , Welsch C. , Barthelmebs M. , Imbs JL
Published: August 2009

Summary— In order to identify tissue specific regulation of angiotensin converting enzyme (ACE), the effects of dexamethasone (0.04 mg sc per day for 7 days) and triiodothyronine (T3) (0.5 mg/kg sc per day for 10 days) on ACE activity were investigated in different tissues in male Wistar rats. ACE activity was measured by fluorimetry in the plasma, heart, lung and kidney. In the kidney, ACE activity was measured in the medulla, cortex and brush border of proximal tubular cells and 3H‐ramiprilat binding was used to characterise the changes in brush border ACE activity. Dexamethasone elicited a significant increase in lung ACE activity and a significant decrease in plasma ACE activity, but did not alter enzyme activity in the other tissues studied. T3 produced a significant decrease in lung ACE activity and an increase in ACE activity in the plasma and heart. In the kidney, ACE activity was not modified in the medulla whereas in the cortex and brush border ACE activity was doubled. This increase in ACE activity corresponded to a similar increase in the maximum number of binding sites of 3H‐ramiprilat, suggesting that the increase in activity corresponded to an increase in the ACE level. The increased heart and kidney ACE activity in response to T3 may contribute to the cardiovascular effects of thyroid hormones through increased local angiotensin II generation. These results show that under dexamethasone or T3, ACE activity can vary from one tissue to another, suggesting that the ACE regulatory mechanism acts differently in each tissue.
The effect of different calcium antagonists and a calcium agonist on the metabolism of propranolol by isolated rat hepatocytes
Authors: Vercruysse I. , Vermeulen AM , Belpaire FM , Massart DL , Dupont AG
Published: August 2009

Summary—The influence of the dihydropyridine calcium entry blockers nicardipine, amlodipine, nifedipine, isradipine and of the dihydropyridine calcium entry promotor BAY K 8644 on the disappearance rate of propranolol by isolated rat hepatocytes was compared to the effect of diltiazem and verapamil, two non‐dihydropyridine calcium channel blockers and known inhibitors of hepatic cytochrome P450 mixed function oxidases. All compounds dose‐dependently inhibited the disappearance rate of propranolol. Nicardipine and isradipine were more potent in inhibiting the disappearance rate of propranolol than the other dihydropyridines and than diltiazem and verapamil. The inhibitory effect of nicardipine on the disappearance rate of propranolol was not stereoselective and was not influenced by age.
Effects of repeated intravenous administration of diazepam on food intake in rats
Authors: Naruse T.
Published: August 2009

Summary— Effects of repeated intravenous (iv) administration of diazepam on food intake were investigated in freely moving rats implanted with a chronic iv cannula. Diazepam (0.2 and 2 mg/kg) was automatically injected iv at 3‐h intervals for 3 consecutive days. Food intake was measured twice daily, ie for the light phase (7 00–19 00) and dark phase (19 00–7 00). Food intake during the light phase was increased in a dose‐dependent manner following diazepam. Each injection of diazepam provoked hyperphagia, followed by a compensatory hypophagia until the next diazepam injection. Body weight, however, was increased significantly in rats treated with diazepam. When diazepam (2 mg/kg) was automatically injected at 3‐h intervals for 10 consecutive days, tolerance did not develop to the hyperphagia and body weight was increased significantly following diazepam injection. After cessation of diazepam injection, both food intake and body weight decreased. These findings suggest that such excessive iv treatment with diazepam induces hyperphagia showing no tolerance accompanied by an increase in body weight, thus resulting in a trend toward obesity in rats.
Classification and mechanism of action of antiarrhythmic drugs*
Authors: Scholz H.
Published: August 2009

Summary— The present paper reviews classification and mode of action of agents that suppress extrasystoles and tachyarrhythmias. These are classified according to their electrophysiological effects observed in isolated cardiac tissues in vitro (Vaughan Williams, 1989). Fast sodium channel blockers (class I) which reduce the upstroke velocity of the action potential are usually subclassified into three groups, class I A‐C, according to their effect on the action potential duration. Beta‐adrenergic antagonists (class II) exert their effects by antagonizing the electrophysiological effects of beta‐adrenergic catecholamines. Class III antiarrhythmic agents (eg amiodarone) prolong the action potential and slow calcium channel blockers (class IV) suppress the calcium inward current and calcium‐dependent action potentials. The classification of antiarrhythmic drugs is still under debate. This particularly applies to agents of class I and III. The effect of class I agents is frequency‐dependent because the binding affinity of these drugs to the sodium channel is modulated by the state of the channel (modulated receptor hypothesis). Class I agents bind to the channel in the activated and inactivated state and dissociate from the channel in the rested state. This occurs at a drug‐specific rate so that class I agents can be subclassified into only two groups, namely in those of the slow‐ and fast‐recovery type respectively (time constant of reactivation greater or smaller than 1 s). Slow‐recovery class I agents affect regular action potentials at normal heart rates which can more easily lead to a lengthening of the QRS duration in the ECG, to conduction disturbances and hence to pro‐arrhythmic effects. Class I antiarrhythmic agents have also been subclassified according to the saturation behaviour of frequency‐dependent sodium channel blockade (Weirich and Antoni, 1990), but the relevance of this subclassification remains to be elucidated. This applies also to a recent attempt (Hondeghem) to subclassify class III agents according to the frequency dependency of their antiarrhythmic actions.
Effects of salbutamol and BRL 37344 on diastolic arterial blood pressure, plasma glucose and plasma lactate in rabbits
Authors: Reverte M. , Moratinos J.
Published: August 2009

Summary—The aim of this study was to investigate in rabbits the diastolic arterial blood pressure, plasma glucose and plasma lactate responses to salbutamol (a selective beta‐2 adrenoceptor agonist) and BRL 37344 (a selective beta‐3 adrenoceptor agonist) in comparison with CGP 12177 (a potent beta‐1 and beta‐2 adrenoceptor antagonist which also acts as a partial beta‐3 agonist), isoprenaline (a non‐selective beta‐1, beta‐2 and beta‐3 adrenoceptor agonist) and adrenaline (a non‐selective beta and alpha adrenoceptor agonist). All drugs were iv infused at the same dose: 0.3 μg/kg/min (30 min). In sodium pentobarbitone (40 mg/kg)‐anasthetized animals none of these compounds altered diastolic arterial blood pressure. BRL 37344 (0.1, 0.3, 1 μg/kg/min) did not modify this parameter either. In conscious 24‐h fasted rabbits, only adrenaline was able to increase plasma glucose levels. By contrast, under the same experimental conditions, salbutamol, isoprenaline and adrenaline, but not BRL 37344 or CGP 12177, induced a significant increase in plasma lactate levels. Finally, the salbutamol‐mediated plasma lactate response was inhibited in the presence of clonidine (2 μg/kg/min, an alpha‐2 adrenoceptor agonist), a drug considered to have opposite effects (stimulatory and inhibitory) on the adenylate cyclase system. In conclusion, these data suggest that only beta‐2 adrenoceptor stimulation is able to increase plasma lactate levels, a response which is inhibited by alpha‐2 adrenoceptor stimulation.
Inhibition of Na/Ca exchange stimulates insulin release from isolated rat pancreatic islets
Authors: van Eylen F. , Antoine MH , Lebrun P. , Herchuelz A.
Published: August 2009

Summary— Na/Ca exchange was recently shown to regulate cytosolic free Ca2+ concentration ([Ca2+]i) in the pancreatic B‐cell. The aim of the present study was to provide direct evidence that inhibition of the activity of the exchange may also increase insulin release. In the presence of extracellular Na+, caffeine stimulated 45Ca outflow but did not increase insulin release from islets perifused in the presence of 2.8 mM glucose. By contrast, in the absence of extracellular Na+, caffeine almost failed to increase 45Ca outflow and reversibly stimulated insulin release despite the fact that the absence of extracellular Na+ per se reduced basal insulin release. Similar findings were observed in islets perifused at a higher glucose concentration (8.3 mM) except that, in the presence of extracellular Na+, caffeine more markedly increased 45Ca outflow and stimulated insulin release. Our data provide direct evidence that inhibition of Na/Ca exchange with resulting blockade of Ca2+ outflow may increase insulin release from the pancreatic B‐cell under suitable experimental conditions.
Pharmacokinetic‐pharmacodynamic modeling between pinacidil or pinacidil‐N‐oxide plasma levels and systemic and regional hemodynamic effects in healthy volunteers
Authors: Bellissant E. , Chau NP , Thuillez C. , Giudicelli JF
Published: August 2009

Summary— Pinacidil (P) lowers blood pressure through peripheral vasodilation, but also induces dose‐dependent side‐effects. In a previous placebo‐controlled, randomized, double‐blind and crossover study, performed in six healthy male volunteers, we investigated the systemic and regional hemodynamic effects of a single oral administration of 25 mg of P (sustained‐release form) and measured the plasma concentrations of P and of its active metabolite, pinacidil‐N‐oxide (PO). In the present study, our goal has been to investigate the relationships between P and/or PO plasma concentrations and P administration effects on systolic, diastolic and mean arterial pressures (SAP, DAP, MAP), heart rate (HR), cardiac output (CO), total peripheral resistance (TPR), brachial and carotid arteries' diameters (BAD, CAD), flows (BAF, CAF) and vascular resistances (BVR, CVR) which were assessed before and at different time intervals after drug intake. Concentration‐effect relationships were investigated using both linear and log‐linear multiple regression models with P, PO or both P and PO as independent variables (six models). Significant linear relationships were observed between P and/or PO and SAP, DAP, MAP, TPR, BAD, BAF, BVR, CAD and CVR. For example, TPR (dynes.s/cm5) = 1308 – 3.031 × P (ng/ml), R = 0.57, P = 0.0037; BVR (mmHg.s/ml) = 58 – 0.261 × P (ng/ml), R = 0.56, P = 0.0042. Almost similar R values were obtained using P, PO, or both P and PO. The use of log‐linear models did not improve the fittings. We conclude that there are significant linear relationships between P plasma concentrations and most of P systemic and regional hemodynamic effects; this finding allows the determination of the best individual P dosage for inducing a given hemodynamic effect, and, using PO instead of P plasma concentrations does not improve the models and is thus useless.
Influence of food and body weight on the pharmacokinetics of penticainide
Authors: Berdaï D. , Demotes‐Mainard F. , Philip F. , Vinçon G. , Montels R. , Necciari J. , Bannwarth B.
Published: August 2009

Summary— The pharmacokinetics of penticainide, a class Ic antiarrhythmic drug, was studied in 16 healthy adults (eight males and eight females) after a single 300‐mg oral dose in fasting conditions and with a standard meal. Penticainide concentrations in plasma and urine were measured by hplc. The pharmacokinetic parameters of penticainide including Cmax, tmax, AUC and t1/2 were not significantly altered in the presence of food. AUC values (mean ± sd) were 50.68 ± 10.8 mg·h·l−1 and 49.52 ± 9.87 mg·h·l−1 in the absence and presence of food, respectively. However, a significant difference was observed between males and females in both fasting and fed conditions with a higher value of the apparent oral clearance in the second group. The values of apparent oral clearance, expressed in weight‐normalized units were 1.33 ± 0.35 ml·mn−1·kg−1 (male) and 1.93 ± 0.34 ml·mn−1·kg−1 (female) in fast conditions (P < 0.01) and 1.38 ± 0.28 ml·mn−1·kg−1 (male) and 1.93 ± 0.49 ml·mn−1·kg−1 (female) in fed conditions (P < 0.02), respectively. The pharmacokinetics of penticainide is not modified by the presence of food, but an influence of body weight may be considered.
Pharmacokinetics of cyclophosphamide in patients with systemic necrotizing angiitis
Authors: Belfayol L. , Guillevin L. , Louchahi K. , Perrin P. , Cherrier P. , Lortholary O. , Bosio AM , Fauvelle F.
Published: August 2009

Summary— Cyclophosphamide pharmacokinetics were investigated following administration to patients with systemic necrotizing angiitis. Ten patients (eight women and two men) received cyclophosphamide as a 1‐h‐rate‐constant intravenous infusion at doses ranging from 600 to 1200 mg. All patients received concomitant oral prednisone (1 mg/kg/d). Blood samples were collected at the end of drug infusion and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24 h later. Serum cyclophosphamide concentrations were assayed by high pressure liquid chromatography. The peak serum cyclophosphamide levels ranged from 15.7 to 29.4 mg/L. The mean cyclophosphamide elimination half‐life was 6.2 ± 1.3 h (mean ± SD). The mean apparent volume of distribution and mean total plasma clearance were, respectively, 0.75 ± 0.22 L/kg (mean ± SD) and 83 ± 22 mL/min (mean ± SD). These results obtained in systemic vasculitic diseases were consistent with those observed in other studies with cancer patients receiving comparable doses of cyclophosphamide.
Influence of hepatic impairment on the pharmacokinetics of nefazodone and two of its metabolites after single and multiple oral doses
Authors: Ferry N. , Bernard N. , Cuisinaud G. , Rougier P. , Trepo C. , Sassard J.
Published: August 2009

Summary— The pharmacokinetics of nefazodone, a new antidepressant, and two of its active metabolites, hydroxynefazodone and m‐chlorophenylpiperazine, were determined after single and repeated oral escalating doses of 50, 100 and 200 mg, in healthy volunteers (n = 13) and patients with mild (n = 13) or severe (n = 6) hepatic impairment. All subjects were classified according to their dextromethorphan oxidation capacity. In healthy volunteers, nefazodone was rapidly absorbed after which the plasma concentrations declined with an apparent elimination half‐life ranging from 2.7 ± 1.7 h to 10.2 ± 4.4 h according to the dosage. Hydroxynefazodone appeared rapidly in plasma and its time‐course (half‐life ranging 1.4 ± 0.9 h to 6.5 ± 1.6 h) paralleled that of nefazodone, while mCPP showed low and variable concentrations. The disproportionately longer half‐life and more markedly increased Cmax and AUC0–48 which was observed with dosage and treatment duration, and moreover AUC0–12 at steady state significantly higher (P < 0.05) than AUC0–∞ after single dose demonstrated the non‐linearity of the pharmacokinetics of nefazodone and hydroxynefazodone. The constant molar AUC0–48 hydroxy‐nefazodone/nefazodone ratio (0.32 ± 0.04) and the close correlation (r2 = 0.95) between kinetic parameters of nefazodone and hydroxynefazodone suggest that nefazodone hydroxylation is not a saturable process. The kinetics of nefazodone and metabolites were significantly affected by severe but not by mild liver insufficiency. As a consequence, on a pharmacokinetic basis nefazodone should be used with caution in severely hepatic impaired patients.
Positron emission tomography and central neurotransmitter systems in movement disorders
Authors: Weeks RA , Brooks DJ
Published: August 2009

Summary— This article discusses the anatomical and neurochemical structure of the basal ganglia and reviews the Positron Emission Tomographic (PET) ligands available for investigating these pathways. We discuss how clinical PET studies have improved our understanding of the neurochemical changes underlying principal movement disorders.
Protective role of glutathione on α1 proteinase inhibitor inactivation by the myeloperoxidase system. Hypothetic study for therapeutic strategy in the management of smokers' emphysema
Authors: Gressier B. , Lebegue S. , Gosset P. , Brunet C. , Luyckx M. , Dine T. , Cazin M. , Cazin JC , Wallaert B.
Published: August 2009

Summary— In smoking subjects with obvious emphysema, the interaction between neutrophil‐derived MPO and H2O2 produced by alveolar inflammatory cells (alveolar macrophages (AM) and polymorphonuclear neutrophils (PMN)) has the ability to spontaneously inactivate, in vitro, the α1 proteinase inhibitor (α1PI). This inactivation can induce a desequilibrium of the protease‐antiprotease balance in the lungs. In this study, we investigated the ability of glutathione to protect α1PI. In a cellular model of α1PI inactivation mimicking the effects of alveolar inflammatory cells present in the lower respiratory tract of smoking patients with emphysema, we demonstrated that glutathione can protect α1PI against the oxidative inactivation by these activated cells. This protection has been computed in a cellular experimentation (AM and MPO‐system) with a 50% inhibitory concentration of 62 μM. Moreover, glutathione has an important inhibitory effect directly on H2O2 released by PMA‐stimulated AM (IC50 = 30 μM) or PMA stimulated PMN (IC50 = 70 μM). The mechanism, which governs glutathione may be a result of a scavenging effect on H2O2 as demonstrated in a free cellular experiment. With this in vitro demonstrated effectiveness, glutathione as a therapeutic antioxidant, via the aerosol, has been proposed, in order to prevent tissue damage, inflicted by an excess of activated phagocytic cells, in some lung diseases such as smoking patients with emphysema.
Angiotensin II induces reduced oxytocin but normal corticotropin release in rats with lesions of the subfornical organ
Authors: Bartanusz V. , Ježová D.
Published: August 2009

Summary— The subfornical organ (SFO) was suggested to be the site of the central nervous system which mediates the stimulatory effect of angiotensin II (AII) on corticotropin (ACTH) release. To verify this hypothesis, ACTH response to peripherally administered All was measured in rats with electrolytic lesion of the SFO. Increase in ACTH levels in response to AII (0.5 μg/kg or 2.0 μg/kg iv within 2 min) in conscious cannulated rats was dose‐related and it was not affected by SFO lesion. The short infusion of AII (2.0 μg/kg) was enough to induce an elevation in plasma oxytocin. Oxytocin response to AII was reduced while that of aldosterone and blood pressure was not modified by SFO lesion. Our data show that an intact SFO is needed for a full response of oxytocin but not of ACTH release to peripherally injected AII.