bluuebunny/crossref_metadata_2025 huggingface dataset:
Oncogenic proteins new targets for chemotherapeutic agents against cancer
Authors: Rey I. , Soubigou P. , Cartwright T. , Tocqué B.
Published: August 2009

Summary— Over the past 10 years, more than 40 potentially oncogenic genes, termed protooncogenes, have been identified in the human genome. Little is known of the physiological role of the proteins encoded by these genes, but they seem to be involved in the reception and transmission of hormonal and other environmental information from the cell membrane to the nucleus. These proteins may acquire transforming properties when over‐expressed or if structurally altered following partial deletions or point mutations. Cytogenetic analysis shows loss of genetic material from specific chromosomal loci in many human tumors, suggesting that the absence of a functional gene at these loci may permit tumor development. The genes involved have been termed “anti‐oncogenes”. Understanding the control mechanisms of cell proliferation is essential in order to understand how cancer cells escape from this control. To this end, numerous oncogenes have been cloned, permitting the production of modified forms of oncogenic proteins and identification of the regions essential for their biological activity. Availability of large amounts of protein also allows the production of specific antibody which can be used to verify whether blockage of a given protein results in reversion of the transformed phenotype. If it can be shown that the expression of an oncogenic protein is essential for transformation, it should be possible to search for molecules that inhibit its action or which mimic the effects of an anti‐oncogene. This type of research is already well advanced for the oncogenic ras proteins, and models have been established that permit both screening for potential inhibitors and design of specific antagonists.
Inhibition of human and rabbit platelet activation by Ketotifen
Authors: Devillier P , Arnoux B , Keraly C Lalau , Landes A , Marsac J , Benveniste J
Published: August 2009

Summary— The effects of Ketotifen and disodium cromoglycate were investigated on human and rabbit platelet activation. Ketotifen inhibited dose‐dependently human and rabbit platelet aggregation. The paf‐acether pathway was the most markedly influenced by Ketotifen in human and rabbit platelets (IC50 = 38.8 ± 7.7 μM and 7.2 ± 4.5 μM respectively) as compared to adenosine diphosphate (IC50 > 100 μM and 79 ± 19 μM) and to arachidonic acid (IC50 > 100 μM and 98 ± 28 μM). Similar concentrations of Ketotifen inhibited the ATP release from human platelets induced by paf‐acether. Disodium cromoglycate up to 5 × 10−4 M did not inhibit platelet aggregation induced by paf‐acether, adenosine diphosphate and arachidonic acid.
Pharmacodynamics of CY 216 in healthy volunteers: inter‐individual variations
Authors: Rostin M , Montastruc JL , Houin G , D'Azemar P , Bayrou B , Boneu B
Published: August 2009

Summary— The pharmacodynamic parameters of a low molecular weight heparin (LMWH, CY 216) and their inter‐individual variations were investigated. In a cross over study 100 anti‐factor Xa IC U/kg were injected, one week apart, to 12 healthy‐volunteers by intravenous (IV) or subcutaneous (SC) route. The pharmacological effects were followed by performing activated partial thromboplastin time (APTT), thrombin clotting time (TCT) and a chromogenic anti‐factor Xa assay. The main pharmacodynamic parameters were calculated from the anti‐factor Xa activity disappearance curves. Five to ten min after IV injection, the APTT ranged between 56 and 98 sec (baseline 40 sec), the TCT between 28 and 99 sec (baseline 19 sec) and the anti‐factor Xa activity between 1.58 and 2.28 IC U/ml. The anti‐factor Xa activity half‐life ranged between 1.5 and 2.9 h. After SC injection, there were no detectable APTT and TCT prolongations; the maximum anti‐factor Xa activity ranged between 0.36 and 0.88 IC U/ml and the half life between 1.5 and 6.4 h. These results indicate that, as for standard heparin, there are large inter‐individual variations in the anticoagulant responses to a given dose of CY 216 an observation which may have clinical implications.
Electrotherapy in mice: dopaminergic and noradrenergic effects in the Tail Suspension Test
Authors: Teste JF , Martin I , Rinjard P
Published: August 2009

Summary— The Tail Suspension Test (TST) is a psychotropic screening test which is used principally to detect antidepressant activity. Electrotherapy (ECT) is used to treat depressions which are resistant to the usual antidepressant drugs and has proved to have a profile in the TST approaching that of antidepressants after treating mice at the rate of 2 shocks per day for 5 days. The results of a single treatment were not statistically different from those of the control group, whereas single daily treatment for 5 days showed a reduction in immobility which did not differ significantly from the control group. The reduction in immobility, induced by 5 days of ECT treatment twice daily, was antagonized by sulpiride and prazosine but not by yohimbine, methysergide, metergoline and DL propranolol. The results suggest that electrotherapy leads to an increase in noradrenergenic and dopaminergic activities expressed by a reduction in immobility in the TST.
Effects of low concentrations of arachidonic acid derived mediators on the membrane potential and respiratory burst responses of human neutrophils as assessed by flow cytometry
Authors: Fletcher MP , Halpern GM
Published: August 2009

Summary— Hypaque‐Ficoll purified (95%) neutrophils (PMN) from normal healthy subjects were assessed for FMLP‐elicited membrane potential (Δφ) responses and dichlorofluorescein (DCF) fluoresence (a measure of intracellular hydrogen peroxide production) using flow cytometry and appropriate fluorescent probes. Superoxide (O2) production was measured spectrophotometrically as the superoxide dismustase‐inhibitable reduction of cytochrome C. The modulatory effects of dilute solutions of the arachidonic acid‐derived inflammatory mediators LTB4, LTC4, LTD4, PGE1, PGE2 and PGF2α (10−9 – 10−5 M) were assessed in these systems. While LTB4 enhanced the proportion of cells depolarizing to the chemoattractant N‐formyl‐methionyl‐leucyl‐phenylalanine (FMLP) 2–3 × with a maximum effect in the 10−9 – 10−8 M range, LTC4 and LTD4 showed no such enhancement except at high concentrations (10−6 M). Unlike LTB4, LTC4 and LTD4 were unable to enhance FMLP mediated PMN O2 or DCF responses at any concentration tested, implying a divergence between the effects of the leukotrienes on membrane potential and oxidant responses. Pre‐incubation of PMN with prostaglandins E1 or E2 led to a dose dependent inhibition of the proportion of depolarizing PMN in response to FMLP; PGF2α did not show such an effect. The present data indicate that LTB4, in addition to being a powerful direct neutrophil activator, may act in a priming capacity by increasing the proportion of subsequently FMLP responsive cells, while PGE's inhibit. These modulatory effects appear relatively specific for LTB4 and the E‐series prostaglandins.
Influence of acetaminophen on antipyrine kinetics in rats
Authors: Vial T , Sauveur C , Descotes J
Published: August 2009

Summary— Studies have suggested that acetaminophen may inhibit the liver metabolism of several drugs. Due to the expected clinical relevance of these findings, the present study was undertaken to examine acetaminophen effects on in vivo drug metabolism in the rat, using the model substrate antipyrine. Oral doses of 15 mg/kg acetaminophen were administered twice daily for 7 days. Antipyrine kinetics were determined before and immediately after acetaminophen treatment in rats (used as their own control). Acetaminophen treatment significantly increased antipyrine half‐life by 29% and reduced its clearance by 24%, without affecting its volume of distribution. Further studies are warranted to determine the relevance and mechanism of these findings.
Oxygen‐derived free radicals and postischemic myocardial reperfusion: therapeutic implications
Authors: Richard VJ , Murry CE , Jennings RB , Reimer KA
Published: August 2009

Summary—Oxygen‐derived free radicals have been implicated in the pathogenesis of various disease states, including myocardial ischemia and reperfusion. In this article, we review 1) the evidence linking free radical production and myocardial injury during myocardial ischemia and reperfusion and 2) results of studies of the effects of the pharmacological therapies available potentially to prevent free radical‐mediated injury. Free radicals can be produced during ischemia and reperfusion by several different biochemical pathways. Of these, the xanthine oxidase reaction and the output of free radicals by neutrophils that have accumulated in damaged tissue have been studied extensively. When produced, free radicals can potentially damage myocytes or endothelial cells through peroxidation of membrane lipids or damage to proteins or nucleic acids. Using electron spin resonance spectroscopy, several studies have shown a ‘burst’ of oxygen free radicals immediately after reperfusion. Moreover, exogenous generation of intravascular free radicals has been shown to produce marked vascular and myocyte damage, as well as contractile dysfunction. ‘Anti‐free radical’ interventions, such as xanthine oxidase inhibitors and free radical scavengers have been reported to prevent contractile dysfunction and reperfusion‐induced arrhythmias after an episode of reversible ischemic injury. However, after more severe episodes of ischemia, such interventions have had conflicting effects on myocardial infarct size. ‘Anti‐free radical’ interventions could be of potential use in situations where reversible ischemic injury occurs. In situations where reperfusion is achieved after irreversible ischemic injury has occured, the potential beneficial effect of these treatments on infarct size is more doubtful.
How chronically administered valproate increases chlordiazepoxide transfer through the blood‐brain barrier
Authors: Riant P , Bree F , Urien S , Hamberger C , Albengres E , Tillement JP
Published: August 2009

Summary— Sodium valproate (VPA) is a drug widely used in the treatment of epileptics often in association with benzodiazepines. Recent animal studies have shown that the addition of valproate increases diazepam levels in the cortex and the cerebellum (Hariton et al, 1985). The aim of our study was to determine the effect of VPA on the transfer of benzodiazepines through the blood‐brain barrier. They were investigated using the intracarotid injection technique in rats as described by Oldendorf (1971). Our results show that the 14C‐chlordiazepoxide brain extraction is significantly higher in rats on prolonged valproate treatment than in controls. With regard to plasma protein binding effects on chlordiazepoxide transport, our data indicate that a fraction of the protein‐bound chlordiazepoxide could transfer from the intracapillary space to the brain tissue space because of enhanced drug dissociation from albumin in the brain microcirculation (Kd in vitro = 74.1 μM; Kd in vivo = 793.7 μM). Two distinct mechanisms can be deduced from this study: 1) chlordiazepoxide is displaced from HSA by valproate, 2) in addition, this fatty acid could increase drug permeation through the blood brain barrier (PS/F (chlordiazepoxide) = 0.60 in controls, PS/F (chlordiazepoxide) = 0.97 in treated rats). On the contrary, the washout of the benzodiazepine from the rat brain does not seem to be modified by the addition of valproate.
Influence of diazepam, alpidem, zolpidem and zopiclone, on the response to adenosine of the guinea pig isolated trachea
Authors: Candenas ML , Devillier P. , Naline E. , Advenier C.
Published: August 2009

Summary—It has been reported that dipyridamole and some benzodiazepines potentiate the responses to adenosine in peripheral organs and in particular in the guinea pig isolated atria or trachea by inhibition of adenosine uptake and/or metabolism. In this study, we have examined the sensitization of guinea pig isolated trachea to relaxant responses to adenosine produced by dipyridamole, diazepam and 3 compounds chemically unrelated to benzodiazepines but which display selective agonistic activity towards the central (zolpidem and zopiclone) or peripheral (alpidem) type benzodiazpine receptors. In preparations under spontaneous tone and in the absence of adenosine, dipyridamole (10−5M) and diazepam (10−5–10−4M), alpidem (3 times 10−6M‐10−5M) and zopiclone (10−6–10−4M) induced a relaxation of the airway smooth muscle. In addition, diazepam (10−4M) attenuated the phasic response to histamine (10−5M). Dipyridamole (10−5M) and diazepam (10−4M) respectively produced a 56.2 and 32.4‐fold potentiation of adenosine relaxant effects. Alpidem (10−6–10−5M), zolpidem (10−6–10−4M) and zopiclone (10−6–10−4M) were without any significant effect on the adenosine concentration—response curves. Moreover, alpidem, zolpidem, and zopiclone did not modify the 2‐chloroadenosine dose‐response curves nor the diazepam induced sensitization of adenosine‐induced relaxation. In conclusion, adenosine sensitization of the guinea pig isolated trachea caused by diazepam might involve a peripherla benzodiazpine receptor subtype coupled to a nucleoside transporter system which is different from those recognized by compounds derived fromm the imidazopyridine series.
Studies on the mechanism of arterial vasodilation produced by the novel antihypertensive agent, carvedilol
Authors: Nichols AJ , Gellai M. , Ruffolo RR
Published: August 2009

Summary—The mechanism(s) responsible for arterial vasodilation observed following acute administration of racemic carvedilol, a novel vasodilator/beta adrenoceptor antagonist, has been investigated in rats. In conscious spontaneously hypertensive rats, carvedilol (0.03–3.0 mg/kg, iv) produced a dose‐dependent reduction in blood pressure with no significant effect on heart rate. Because cardiac output was relatively unaffected, the antihypertensive response of carvedilol was associated with a dose‐dependent reduction in total peripheral vascular resistance. Submaximal antihypertensive doses of carvedilol were chosen for mechanism of action studies in pithed rats. Carvedilol (0.3 mg/kg, iv) produced a significant inhibition of the β1adrenoceptor mediated positive chronotropic response to isoproterenol. This same dose of carvedilol also inhibited, but to a lesser degree, the β2adrenoceptor mediated vasodepressor response to salbutamol in pithed rats whose blood pressure was elevated by a constant intravenous infusion of angiotensin II. Thus, carvedilol blocks both β1and β2adrenoceptors at antihypertensive doses, with modest selectivity being observed for the β1adrenoceptor subtype. Carvedilol produced significant inhibition of the α1adrenoceptor mediated pressor response to cirazoline in the pithed rat, but had no effect on the α2adrenoceptor mediated pressor response to B‐HT 933, suggesting that carvedilol is also an α1adrenoceptor antagonist at antihypertensive doses. Carvedilol had no effect on the pressor response elicited by angiotensin II, indicating a lack of nonspecific vasodilator activity. The vasopressor response to the calcium channel activator, BAY‐K‐8644, which is mediated through the opening of voltage dependent calcium channels and the subsequent translocation of extracellular calcium, was significantly inhibited by carvedilol (1 mg/kg, iv), suggesting that carvedilol is also a calcium channel antagonist, consistent with our previousin vitrostudies. In anesthetized spontaneously hypertensive rats, the antihypertensive activity of carvedilol was nearly abolished by combined pretreatment of the rats with high doses of the α1adrenoceptor antagonist, prazosin (1 mg/kg, iv), and the nonselective β adrenoceptor antagonist, propranolol (3 mg/kg, iv), suggesting that the majority of the antihypertensive response produced by carvedilol may be accounted for by blockade of β and α1adrenoceptors. We therefore conclude that carvedilol, at antihypertensive doses, is an antagonist of β1, β2, and α1adrenoceptors, and also of calcium channels in vascular smooth muscle. The β1adrenoceptor blocking properties of carvedilol appear to account for the lack of reflex tachycardia that occurs in response to baroreceptor activation, and the arterial vasodilation appears to result largely from selective α1adrenoceptor blockade, with little or no contribution being derived from calcium channel blockade.
Effects of some chelating agents on bismuth absorption in the rat
Authors: Allain P. , Krari N. , Chaleil D. , Lagier G. , Jouglard J.
Published: August 2009

Summary— Bismuth encephalopathies appeared in the mid‐seventies in France and concerned about 1000 people and led to a fatal outcome in 70 cases. Responsibility of Bi was clearly confirmed by the disappearance of the intoxication after prescription of drugs containing Bi had been more tightly regulated. Since the implication of a substance increasing the intestinal absorption of Bi has been suspected, we studied the concentrations of Bi in the tissues of rats who had been treated with bismuth nitrate basic 400 mg/kg per d for one month with and without an intake of a chelating agent added to the drinking water at a concentration of 10 mmol/1. The chelating agents tested were ethylenediaminetetraacetic acid (EDTA), nitriloacetic acid (NTA) and tripolyphosphate (TPP), cysteine and diethyldithiocarbamate (DEDTC). Cysteine and DEDTC gave the highest increase of Bi in tissues but with a wide dispersion of levels. However, even in the rats with the highest levels of Bi, there were no behavioral problems. EDTA induced an increase of Bi in kidney, brain and bone and NTA in kidney but there was no obvious sign of toxicity. We did not succeed in reproducing in rats the Bi toxicity observed in patients some years ago.
Ceftriaxone diffusion into cardiac fibrin vegetation. Qualitative and quantitative evaluation by autoradiography
Authors: Crémieux AC , Mazière B. , Vallois JM , Ottaviani M. , Bouvet A. , Pocidalo JJ , Carbon C.
Published: August 2009

Summary— Heterogeneous diffusion of some antibiotics into fibrin rich infectious processes is one explanation of the difficulty to cure infections such as endocarditis. Ceftriaxone is a β lactam antibiotic, potentially useful due to a broad spectrum of activity and its long elimination half‐life. We investigated by means of autoradiography the diffusion of labelled ceftriaxone into large infected cardiac vegetations obtained in a rabbit model of endocarditis. Ten d after infection 250 μCi 14C ceftriaxone was injected over 30 min. Thirty min after the end of infusion (T30) vegetation/blood radioactivity ratio was 0.58 ± 0.4 (n = 3). At T200, radioactivity decreased approximatively 3‐fold, in blood and in vegetations simultaneously. Autoradiography showed that at T30, ceftriaxone was 20–30 times more concentrated at the periphery of vegetation than in the core. Autoradiography obtained at T200 showed a progressive diffusion toward the core. The diffusion gradient may explain the fact that high local concentrations are necessary to sterilize vegetations. The pattern of diffusion of antibiotics in fibrin is an important pharmacokinetic parameter for predicting in vivo activity.
Antagonistic effects of epinephrine, glucagon and methylatropine but not calcium chloride against atrio‐ventricular conduction disturbances produced by high doses of diltiazem, in conscious dogs
Authors: Sabatier J. , Pouyet T. , Shelvey G. , Cavero I.
Published: August 2009

Summary— Conscious dogs (n = 6) with chronically implanted electrocardiogram electrodes and arterial and venous catheters were infused with a large dose of diltiazem (1 mg/dog per min iv over 60 min) to evoke hypotension and atrioventricular disturbances (AVII and AVIII blocks) which lasted for several hours. These effects are also observed in humans after accidentally of intentionally taking overdoses of diltiazem and particularly verapamil. In the intoxicated dog, administration of methylatropine (50,μg/kg/min per min iv over 10 min), epinephrine (0.2 and 0.4 μ/g/kg per min iv over 60 min) and glucagon (2 μg/kg/min iv over 15 min) but not CaCl2 (3 mg/kg/min iv over 15 min) abolished almost entirely the A VII and A VIII blocks produced by diltiazem and re‐established a normal sinus rhythm. However, these treatments failed to normalize AV conduction, and did not modify the moderate hypotensive effects of diltiazem. These findings support available clinical observations that β‐adrenoceptors agonists, glucagon and atropine rather than calcium salts are beneficial for the successful treatment of cardiovascular toxicity associated with the intake of supratherapeutic doses of diltiazem or verapamil.
The binding site for [3H]glibenclamide in the rat cerebral cortex does not recognize K‐channel agonists or antagonists other than sulphonylureas
Authors: Angel I. , Bidet S.
Published: August 2009

Summary— The binding of the potent oral antidiabetic sulphonylurea [3H]glibenclamide was studied in rat cerebral cortex membranes. A single population of high affinity and saturable binding sites with equilibrium constants, Kd = 0.2 ± 0.06 nM and Bmax = 58.6 ± 6.2 fmol/mg protein was found. Specific [3H]glibenclamide binding to rat cerebral cortex membranes was inhibited by glibenclamide and other sulphonylureas, glibenclamide being the most potent drug and the sulphonylurea of the second generation chlorpropamide the least potent. This observation suggests that this site may be related to the hypoglycaemic properties of sulphonylureas and possibly to their interaction with ATP‐sensitive K+‐channel. Nevertheless, other non‐selective K+‐channel antagonists such as TEA, 4‐aminopyridine, quinine, quinidine or apamin failed to interact with this site (IC50 > 100 μM). Similarly, both non‐selective K+‐channel agonists such as cromakalim, pinacidil or minoxidil as well as the pancreatic ATP‐sensitive K+‐channel agonist diazoxide failed to interact with this site. It may thus be concluded that this site, under the present experimental conditions, represents a drug specific recognition site which may be coupled to the hypoglycaemic activity of sulphonylureas, possibly on a particulate ATP‐dependent K+‐channel.
Tachykinins in the rat substantia nigra: effects of selective dopamine receptor antagonists
Authors: Oblin A. , Zivkovic B.
Published: August 2009

Summary—The effects of sustained blockade of dopamine receptors by selective dopamine antagonists on the tachykinin (substance P and neurokinin A) content in the substantia nigra were examined. The treatment of rats for 14 days with D‐1/D‐2 dopamine receptor antagonist haloperidol (2 mg/kg) or selective D‐2 antagonist sulpiride (100 mg/kg) produced a similar and significant decrease in nigral substance P and neurokinin A‐like immunoreactivity content, about 32–36% and 27–28% of control respectively. In contrast, administration of SCH 23390 (1 mg/kg), a selective and potent D‐1 dopamine receptor antagonist, failed to affect the levels of substance P and neurokinin A in the substantia nigra and did not change the sulpiride‐induced reduction of the nigral tachykinin peptides. These results indicate that the D‐1 dopamine receptors are not involved in the modulation of nigral substance P and neurokinin A content and suggest that the blockade of the D‐2 dopamine receptor subtype exerts the same regulation of the tachykinin gene expression, in spite of the existence of three mRNAs encoding substance P and neurokinin A.
Lack of effect by nifedipine on hepatic mixed function oxidase in man
Authors: Horsmans Y. , Desager JP , Pauwels S. , Harvengt C.
Published: August 2009

Summary— Nifedipine (NF), a calcium channel blocker, is often prescribed in association with other drugs. Therefore, it was interesting to know whether or not, nifedipine, which is metabolized by the cytochrome P‐450NF, was able to induce or to inhibit in vivo the activity of the hepatic mixed function oxidase system. The study was conducted in ten young healthy male volunteers receiving 20 mg NF slow release bid for 15 days. Due to the small number of subjects, comparison of the NF pharmacokinetics at dose 1 and 26 failed to show a bimodality in the frequency distribution of its area under the plasma concentration‐time curve (AUC 274.5 to 317.1 ngml−1 h, NS). Hepatic microsomal autoinduction (t1/2 2.87 to 3.06 h, NS) was not found. No statistically significant effect was seen on the aminopyrine breath test and on the debrisoquine metabolic molar ratio performed before and at the end of the treatment. Unlike what has been suggested by in vitro studies, NF treatment did not modify significantly the urinary excretion of 6 beta‐hydroxycortisol (318 to 265 μg/d, NS). After the last dose, the total oral clearance of NF was highly correlated with the metabolic clearance to 4‐hydroxyantipyrine (r = 0.88; P = 0.005) but the other parameters of antipyrine biotransformation remained unchanged. We conclude that repeated nifedipine oral intake does not modify enzymatic activities of hepatic P‐450 cytochromes involved in the biotransformation of antypirine, aminopyrine, debrisoquine and cortisol.
Behavioral effects of a calcium channel antagonist: nifedipine
Authors: Tazi A. , Farh M. , Hakkou F.
Published: August 2009

Summary—A series of experiments investigated the behavioral effects of a calcium channel antagonist, nifedipine. This antagonist has facilitatory effects on learning and memory as assessed by the active and passive avoidance tests respectively. In the forced swimming test, nifedipine at a dose of 5 mg/kg had an inhibitory effect on immobilization. Finally, nifedipine (2.5 and 5.0 mg/kg) induced an anxiolytic effect in the water consumption test in a novel environment. These findings are discussed with respect to other findings in the same field and to the neurochemical changes known to be induced by calcium channel antagonists.
Central 5HT1A‐receptor binding in normotensive and spontaneously hypertensive rats
Authors: Huguet F. , Brisac AM
Published: August 2009

Summary— Central 5HT1A‐receptors have been found with a high density in brainstem and are involved in cardiovascular control. The high‐affinity binding of [3H]‐8‐OH‐DPAT, a specific 5HT1A‐receptor ligand, was measured in medulla oblongata of normotensive and spontaneously hypertensive rats (SHR). The maximal number of [3H]‐8‐OH‐DPAT binding site (Bmax) was significantly increased in SHR when compared to normotensive rats. Whether central 5HT1A‐receptors are involved in the etiology of hypertension or are influenced by other neurochemical events remains to be investigated.
Do prescribers know the results of key clinical trials?
Authors: Reveilleau S. , Boissel JP , Alamercery Y. ,   GEP (Groupe d‘étude de la Prescription)
Published: August 2009

Summary— A survey was run on a sample of 134 French GPs from the Rhône‐Alpes region, in an attempt to investigate the way they recollect important clinical trials that should have an impact on their practice. It was found that 1) most of them did not remember these trials (however, the awareness score did vary throughout the trials); 2) the correlation between prescription claims and awareness score was very poor.
Effects of calcium channel agonist and antagonists on calcium‐dependent events in CA1 hippocampal neurons
Authors: Rascol O. , Potier B. , Lamour Y. , Dutar P.
Published: August 2009

Summary—The effects of a variety of calcium channel modulators on different calcium‐dependent events in CA1 pyramidal hippocampal neurons were analysed using intracellular recordings in anin vitroslice preparation. The following substances were tested: the dihydropyridine calcium agonist BAY K 8644, the dihydropyridine calcium antagonist nimodipine, the phenylalkylamine verapamil and the snail toxin ω‐conotoxin GVIA (ω‐CgTx). BAY K 8644 increased the repolarization time of the after hyperpolarization (AHP) following a spike burst. This effect was antagonized by nimodipine. BAY K 8644 also prolonged the calcium spike and, in some cases, increased the size of the synaptic events resulting from activation of the Schaffer collateral/commissural system. Nimodipine decreased the size of the AHP in some neurons but had no consistent effect on synaptic events. Verapamil at low concentrations (1–10 μM) had no significant effects on the calcium‐dependent events in the hippocampus. Increasing the concentration (up to 100 μM) led to a progressive suppression of the AHP and of the slow inhibitory postsynaptic potential (IPSP), probablyviaan action on potassium conductances. In addition, the baclofen‐induced hyperpolarization was blocked by verapamil. Interestingly, at this higher concentration, verapamil could suppress the AHP without depressing the calcium spike. ω‐CgTx selectively blocked the synaptic events (especially the IPSPs) but had no effect on non‐synaptic events. This last compound exhibits a high degree of selectivity, acting on N‐type calcium channels which are involved in neurotransmitter release. Our results provide evidence that different classes of agents which act on calcium channels can be used to discriminate between different calcium‐dependent responses in CA1 hippocampal neurons.
The uterotonic action of the aqueous extract of Bridelia atroviridis in the rat
Authors: Corallo A. , Savineau JP , Tricoche R. , Foungbe S.
Published: August 2009

Summary—The effects of the aqueous extract of leaves ofBridelia atroviridis(Bridelia), a small African tree, on the mechanical activity of rat uterus were studied. The aqueous extract of leaves ofB atroviridisadministered in a concentration‐dependent manner (5 times 10−6‐1.2 times 10−3g/ml) induced contractions that were antagonized by various calcium entry blockers (nifedipine, diltiazem, manganese chloride). In absence of external calcium ions, repeated applications of a supramaximal concentration of Bridelia (1.2 times 10−3g/ml) evoked sustained and repeated contractions the amplitude of which was = 20% of those obtained in the physiological external calcium concentration. Bridelia‐induced contractions in calcium‐free medium were inhibited by isoprenaline (8 times 10−7M), caffeine (15 times 10−3M) and trifluoperazine (10−5M). Contractile responses induced by Bridelia in both calcium‐containing and calcium‐free media were antagonized by prior incubation of uterus with phorbol 12, 13‐dibutyrate (6 times 10−7M), cholera toxin (6 times 10−8M) or pertussis toxin (5 times 10−7g/ml). These results show that Bridelia has a potent uterotonic action in the rat. The cellular basis of this action appears to be complex, and involves various mechanisms including calcium mobilization from both intra and extracellular compartments and activation of phospholipase C through a G‐protein.
Effects of administration route on valproate pharmacokinetics in the rabbit
Authors: Bourin M. , Guenzet J. , Thomare P. , Kergueris MF , Ortega A. , Larousse C.
Published: August 2009

Summary—The absorption of sodium valproate was studied in 5 rabbits: Each animal received the drug (70 mg/kg)via3 routes: intravenous, gastric and duodenal. For the 2 extravascular routes, the absolute bioavailabilityF, maximal plasma concentrationsCmax, times to peakTmaxand absorption coefficientsKabswere the same. Absolute bioavailability was always close to unity. This indicated that valproic acid was absorbed from the intestine as well as from the whole gastrointestinal tract. The other pharmacokinetic parameters such as terminal plasma half‐life, total clearance and volume of distribution remained unchanged whatever the route of administration.
Nifedipine alters serum theophylline levels in asthmatic patients with hypertension
Authors: Yilmaz E. , Canberk A. , Eroǧlu L.
Published: August 2009

Summary— The effect of nifedipine on serum theophylline levels in 13 female hypertensive patients having asthma on theophylline therapy has been investigated. Administration of a slow release theophylline product in a dose of 200 mg bidaily for 15 days provided a steady‐state trough serum theophylline concentration (11.2 ± 2.7 μg/ml). After this period, 10 mg bidaily nifedipine was added to therapy and trough serum theophylline levels, pulmonary function tests and blood pressure measurements have been performed following 15 and 45 days of simultaneous use of theophylline and nifedipine. No change has been observed in serum theophylline level after 15 days of simultaneous use, however after 45 days, serum theophylline level was significantly lower (7.3 ± 1 μg/ml). There were no changes in clinical responsiveness of either of these drugs.
Amiodarone: influence of the route of administration on thyroid status and cardiac β‐adrenoceptors in the rat
Authors: Yin YL , Nicolas P. , Vassy R. , Uzzan B. , Pussard E. , Berdeaux A. , Perret G.
Published: August 2009

Summary— The influence of 2 different routes of amiodarone (AMIO) administration, oral gavage (OG) and subcutaneous injection (SC), on the density of cardiac β‐adrenoceptors (Bmax), hepatic type I 5′ iodothyronine deiodinase (5′ DI) and thyroid hormone serum concentrations was studied. Compared with respective control values, AMIO treatment (50 mg/kg per day, 7 days) via both OG and SC routes significantly lowered Bmax (OG: 14.6 ± 1.92 vs 18.2 ± 1.03 fmol/mg and SC: 16.6 ± 2.34 vs 19.1 ± 2.05 fmol/mg) and 5′ DI activity (from 409 to 85 and 340 to 47 fmol I−/mg per min, respectively). The SC route induced a fall in thyroid secretion and a generalized hypothyroidism (decreased serum FT4 and FT3, inhibition of body weight gain. The OG route did not modify thyroid secretion. These results demonstrated that the effects on cardiac β‐receptor density in the SC group might be due to the generalized hypothyroidism and that AMIO produced its specific cardiac effects only after oral route medication, suggesting that the oral route is the best choice for studying AMIO cardiac effects on β‐receptor density.
Effect of L‐dopa loading on 5‐HTP decarboxylation in rat brain areas
Authors: Trouvin JH , Maubrey MC , Raynal H. , Jacquot C.
Published: August 2009

Summary—The time course of 5‐hydroxytryptophan (5‐HTP), serotonin (5‐HT), and 5‐hydroxyindoleacetic acid (5‐HIAA) concentrations in four rat brain areas (hypothalamus, hippocampus, striatum and olfactory bulbs) were investigated after treatment withl‐dopa (125 mg/kg, ip) + benserazide (50 mg/kg, ip). 5‐HTP levels increased as early as 0.5 h, showed maximum accumulation at 1.5 h and returned to control levels within 4 h, while 5‐HT was markedly decreased in all four structures, with a maximum effect at 1.5 h (approximately − 70%) in the four areas. The decrease in 5‐HT was not accompanied by changes in 5‐HIAA levels. In agreement with previous studies, these data demonstrate thatl‐dopa loading interferes with serotonin metabolism in the rat brain. However, in addition to the releasing action of newly‐synthesized dopamine, the accumulation of 5‐HTP and the parallel decrease in 5‐HT indicate a reduction in 5‐HT synthesis. This inhibition could be explained by a competitive effect ofl‐dopa for aromatic aminoacid decarboxylase activity.
1H nuclear magnetic resonance and clinical studies of interaction of calcium antagonists and hypoglycemic sulfonylureas
Authors: Monges AM , Pisano P. , Aujoulat P. , Salducci D. , Durand A. , Panagides D. , Bory M. , Crevat A.
Published: August 2009

Summary— The hypoglycemic effect of gliclazide is mainly due to its action on ATP stimulated K+ channels, but the calcium ionophoretic effect of this drug may also be involved in its physiological properties. Using 1H NMR we demonstrated the antiionophoretic effect of nifedipine and diltiazem. We attempted to verify whether this in vitro interaction also occurs in vivo. A clinical trial was performed on patients treated concomitantly with gliclazide and nifedipine or diltiazem. Results showed that no in vivo interaction occurred. The discrepancy between in vivo and in vitro results may be explained by a too weak plasma concentration in the case of nifedipine and by a large plasma protein binding in the case of diltiazem.
Cardiac β‐adrenoceptor sensitivity and Parkinson's disease
Authors: Milon D. , Allain H. , Bentue‐Ferrer D. , Martinet JP , Lemaitre MH , Decombe R.
Published: August 2009

Summary— Certain clinical manifestations of Parkinson's disease (PD) (speech or/and balance disturbances) are not linked to brain dopamine deficiency. The purpose of the present study was to search for a possible relationship between those so‐called “non‐dopamine‐dependent” extrapyramidal manifestations and the sensitivity of cardiac β‐adrenoceptors. Fourteen patients aged 51 to 69 were included in the study after having given their informed consent. Any factor or pathology susceptible to modify receptor sensitivity entailed exclusion. In the absence of a reference model for measuring the reactivity of central β‐adrenoceptors, a computation of the isoprenalin dose necessary to increase the resting heart rate by 20 bpm was used as an index for β‐adrenergic system reactivity. In addition to that test, other parameters were recorded: disease duration, motor status scale (Columbia), some cognitive functions (MMS and image differed recall). The cardiac β‐receptor decrease in reactivity to isoproterenol is correlated to PD duration (r = 0.8, P < 0.001). Conversely, the sensitivity of these receptors appeared to be unrelated to the extrapyramidal severity of the disease, hence to the degree of the so‐called “non dopamine‐dependent” disturbances. Furthermore, such results raise the meaning of the impairment of peripheral aminergic receptors in the cognitive disturbances linked to ageing and/or PD.
Monoclonal antibody fluorescent polarisation immunoassay versus 125Iode labelled ligand radioimmunoassay for the measurement of cyclosporine concentrations in whole blood
Authors: Montes C. , Burtin P. , Jacqz‐Aigrain E.
Published: August 2009

Summary— Monoclonal antibody fluorescent polarisation immunoassay for cyclosporine in whole blood was first evaluated. Inter‐ and intra‐assay CVs were < 7%. We also compared concentrations measured by 125I‐RIA and FPIA in specimens obtained from kidney and bone marrow transplanted patients. FPIA correlated well with 125I‐RIA (slope = 1.03, r = 0.989, n = 58) over a wide range of concentrations (44–984 ng/ml). However, an additive bias estimated by the mean difference in cyclosporine concentrations between the 2 readings (44.1 ± 44.3 ng/ml), led to overestimation of cyclosporine concentrations measured by FPIA. The monoclonal FPIA kit is therefore a rapid and reproductive method to monitor cyclosporine concentrations in whole blood. However, FPIA and 125I‐RIA are not interchangeable and the therapeutic range of cyclosporine measured by FPIA should be defined.
Pharmacokinetics of methohexital during cardiovascular surgery with cardiopulmonary bypass
Authors: Foussadier A. , Boulieu R. , Lehot JJ , Ferry S.
Published: August 2009

Summary— The pharmacokinetics of methohexital after intravenous bolus administration was studied during cardiovascular surgery with cardiopulmonary bypass. The effect of body temperature (normother‐mia and hypothermia) during cardiopulmonary bypass on methohexital pharmacokinetics was investigated. The pharmacokinetic data obtained were compared with those from vascular surgery without cardiopulmonary bypass. A marked decrease in plasma methohexital concentrations and therefore in area under curve and a significant increase in clearance and in volume of distribution were observed in the cardiopulmonary bypass groups compared to the vascular surgery group without cardiopulmonary bypass. However, the elimination half‐life and the mean residence time were similar in the 2 groups. Furthermore, the study shows that body temperature during cardiopulmonary bypass does not influence methohexital pharmacokinetics.
Steady‐state population pharmacokinetics of sustained release theophylline in adult asthmatic patients
Authors: Thomas G. , Koen R. , Houze P. , Lagier G. , Gervais P.
Published: August 2009

Summary— The steady‐state population pharmacokinetics of theophylline were studied in 52 asthmatic adult patients who received sustained‐release theophylline as armophylline or euphylline. A total of 92 steady‐state plasma theophylline concentration‐dosage pairs were analyzed using a nonlinear mixed effects model. The pharmacokinetic model used was a one‐compartment open model with single path Michaelis‐Menten elimination. Dosage was adjusted to body weight. The effects of age, gender, alcohol consumption, cigarette smoking, dosage form, concurrent treatment with β‐agonists or steroids, outpatient dosing, and plasma caffeine concentration on maximum elimination rate (Vm) and Michaelis constant for theophylline metabolism (Km) were investigated. Hypothesis testing produced a final model in which Km = 0.42 (mg/l), and Vm (mg/kg per day) was based on cigarette smoking and dosage form, with Vm = 7.54 + 2.01 (smoking) + 1.08 (euphylline). Estimated coefficients of variation for interindividual variability in Km and Vm were 162.6 % and 48.1 %, respectively. Residual variability in dosage rates was estimated as 0.90 mg/kg per day. The identification of factors influencing theophylline disposition should prove useful for the a priori design of theophylline dosage regimens and monitoring of drug levels during therapy.
Pharmacokinetics and ascitic fluid penetration of piperacillin in cirrhosis
Authors: Hary L. , Smail A. , Ducroix JP , Baillet J. , Andrejak M.
Published: August 2009

Summary— The pharmacokinetics of piperacillin were evaluated in seven healthy volunteers, eight cirrhotic patients without ascites and 11 cirrhotic patients with sterile ascites after a single 15‐min intravenous infusion of 4 g of the drug. In ascitic patients, piperacillin rapidly entered the peritoneal fluid. Peritoneal concentrations were higher than 10 mg/l from 0.5 to 8 h after the infusion. Disappearance rate of piperacillin was slower in the ascitic fluid than in plasma. The plasma half life of piperacillin was more prolonged in cirrhotic patients that in control subjects. This difference was more marked in ascitic patients for whom half life was twice as high as in volunteers (1.95 versus 0.91 h; P < 0.01).
Comparative effects on psychomotor performance of the muscle relaxant afloqualone, alone and with ethanol
Authors: Girre C. , Bertaux L. , Dussaucy E. , Palombo S. , Crouzette J. , Fournier PE
Published: August 2009

Summary— The purpose of this study was to investigate the interaction between 40 mg afloqualone, a new centrally acting muscle relaxant and 0.5 g/kg ethanol using a double‐blind three‐way cross‐over trial in which subjects were each given afloqualone with ethanol, ethanol alone and afloqualone alone. We first compared the effects of 40 mg oral afloqualone and 15 mg diazepam (considered as a reference drug) on the psychomotor and cognitive performance and muscular relaxation of 12 healthy male volunteers. Performance was assessed by six objective tests and eight visual analogue self‐rating scales. All the above treatments were separated by a 2‐week interval. Volunteers performed the objective tests 1 h after drug ingestion, and the self‐rating scale evaluations before drug intake and 1, 3.5, 6 and 8 h thereafter. Afloqualone impaired psychomotor performance less than diazepam as shown by the number of correct answers in the digit symbol cancellation test and the time needed to complete this test. However, the measurement of the frontalis muscle action potential showed that the muscle relaxant activity of 40 mg afloqualone was equivalent to that of 15 mg diazepam. Furthermore, afloqualone given at an effective relaxant dose did not enhance the effects of a single dose of ethanol which predominated on either psychomotor performance or subjective feelings.
The in vitro effect of amodiaquine on bone marrow granulocyte‐macrophage progenitor cells from normal subjects
Authors: Aymard JP , Wioland C. , Ferry R. , Netter P. , Streiff F.
Published: August 2009

Summary— Amodiaquine is used for antimalarial prophylaxis and treatment and has been associated with neutropenia and agranulocytosis in man. The effect of the drug on the in vitro growth of bone marrow human myeloid progenitor cells (GM‐CFU) was tested using the soft agar culture technique: 42 haematologically normal subjects were studied and it was found that amodiaquine, at concentrations tested in vitro (0.005, 0.05 and 0.5 μg‐ml−1), had no quantitative effect on the colony and cluster growth. Our results argue against direct toxicity of the drug on GM‐CFU. Therefore, in cases of amodiaquine‐associated neutropenia, alternative mechanisms should be considered: a) abnormaly sensitive GM‐CFU; b) toxic effect of metabolites such as desethyl‐amodiaquine; c) immune‐mediated toxicity.
The comparison of the effects of multi and single doses of buspirone, chlordiazepoxide and hydroxyzine on psychomotor function and EEG
Authors: Blom MW , Bartel PR , Sommers DK , Van Der Meyden CH , Becker PJ
Published: August 2009

Summary— This study compares the effects of buspirone (5 mg), chlordiazepoxide (5 mg), hydroxyzine (10 mg) and placebo on psychomotor function and EEG, when taken thrice daily for a period of two weeks, with those after a single dose administration. Nine healthy volunteers participated in the study. The battery of psychomotor tests included peak velocity of saccadic eye movements (SEM), a Sternberg memory scanning and choice reaction time test (SMS‐CRT) and critical flicker fusion frequency (CFFF). The peak velocity of saccadic eye movements was significantly impaired by the single dose of hydroxyzine (P = 0.03) in comparison to the multidose results. A similar comparison regarding buspirone only approached significance (P = 0.07). The SMS‐CRT and CFFF did not reveal any difference between the multi and single dose regimens. Spectral analysis of the EEG did not distinguish between the multi and single dosage schedules regarding the respective drugs in the low doses administered.
Is yohimbine‐induced increase in salivary secretion a kinin‐dependent mechanism?
Authors: Bagheri H. , Bompart G. , Girolami JP , Montastruc JL , Montastruc P.
Published: August 2009

Summary— We have previously reported that the α2‐adrenoceptor antagonist yohimbine induced a significant increase in both salivary flow rate and kallikrein output. In order to assess the possible role of the kinin‐kallikrein system in the increase in salivary secretion elicited by yohimbine, the effects of aprotinin, an inhibitor of kallikrein activity, were investigated in yohimbine‐treated conscious dogs. Aprotinin (at a dose, 5000 IU/kg iv, which reduced both resting and yohimbine‐induced increase in kininogenase and amidolytic activities of saliva) which remained inactive alone, failed to modify the increase in salivary volume elicited by yohimbine (0.5 mg/kg iv). These results show that the rise in salivary flow rate observed under α2‐adrenoceptor antagonist is not induced by the kinin‐kallikrein system. The release of kallikrein into saliva observed after yohimbine is rather the consequence than the cause of the increase in salivary secretion.
Caffeine kinetic changes during the oestrous cycle in rats
Authors: Bruguerolle B.
Published: August 2009

Summary— This study was designed to document possible changes in caffeine kinetics in female rats both according to the stage of the oestrous cycle and in castrated animals. After a single 12 mg/kg ip dose during proestrus, oestrus, dioestrus, or 15 days after castration, the plasmatic clearance of caffeine varied significantly with higher values during oestrous. The other pharmacokinetic parameters did not vary significantly.