bluuebunny/crossref_metadata_2025 huggingface dataset:
Comparative effects of different uptake inhibitor antidepressants in two pain tests in mice
Authors: Ardid D. , Marty H. , Fialip J. , Privat AM , Eschalier A. , Lavarenne J.
Published: August 2009

Summary—The purpose of this study was to compare the analgesic effect of acute injections (1.25 and 20 mg/kg, ip) of several anti‐depressants with different effects on monoamine reuptake, on two pain tests in mice (hot‐plate and phenylbenzoquinone‐induced abdominal writhes). Serotonergic inhibitors (citalopram, fluvoxamine and clomipramine) were more effective in the hot‐plate test whereas noradrenaline reuptake inhibitors (desipramine and maprotilline) were more effective in the writhing test. The mixed antidepressants (amitriptyline and to a lesser degree trimipramine) were more effective in the two tests than the other antidepressant drugs. Changes in motor activity of clomipramine and amitriptyline could not account for the modifications of pain threshold. Amineptine (a dopamine reuptake inhibitor) failed to induce any antinociceptive effect in the hot‐plate test and was hyperalgesic in the writhing test, which could be explained by an increased motor activity. These findings indicate that the antinociceptive potency of reuptake inhibitors varies according to their monoamine specificity and the nature of stimuli. They would suggest that the preferential choice of serotonergic antidepressants in the management of chronic pain is arguable.
In vitro stability of the inhibition of serum converting enzyme by fosinopril
Authors: Grima M. , Barthelmebs M. , Stephan D. , Welsch M. , Imbs JL
Published: August 2009

Summary— With captopril, it has been shown that an erroneous measurement of serum angiotensin converting enzyme (ACE) can be induced by the dissociation of the inhibitor‐ACE complex during long‐term storage. We have studied the possible dissociation of the fosinopril‐ACE complex during the storage of serum samples from healthy male volunteers given a single dose of fosinopril. Serum samples were collected from 5 volunteers, 5 min before, then 4 and 24 h after a unique oral dose of 10 mg fosinopril. ACE activity was measured by a colorimetric and a fluorimetric assay during the hour following the sampling (day 0) and after 21 or 61 days of storage at −20 or −196°C. The degree of ACE inhibition measured in vitro in fresh serum samples differed according to the technique used. Fosinopril has a long‐lasting effect with 80% inhibition 24 hours after drug administration. Storage at −20 and −196°C induced a significant decrease in the degree of inhibition measured with the colorimetric method. With the fluorimetric method, a decrease in ACE inhibition was only observed after storage at −20°C but not at −196°C.
Further evidence that propentofylline (HWA 285) influences both adenosine receptors and adenosine transport
Authors: Fredholm BB , Fastbom J. , Kvanta A. , Gerwins P. , Parkinson F.
Published: August 2009

Summary—We have examined the actions of a novel xanthine derivative, propentofylline (HWA 285), that has been shown to protect against ischemic brain damage in rats and gerbils, on adenosine receptors (A1and A2), and on adenosine transporters using several techniques, cells and tissues. Propentofylline and its hydroxylated metabolite A 72 0287 were about 20 times less potent than theophylline in displacing A1‐agonist binding to membranes from rat cortex, and A1‐antagonist binding to whole DDT, MF‐2 smooth muscle cells. A1‐agonist binding to adenosine A1‐receptors in several brain structures was inhibited in a concentration‐dependent manner by A 72 0287 and propentofylline as judged by quantitative autoradiography (IC50‐values 300–600 μM inegstriatum and in cortex layer IV). In two functional assays. A1‐receptor mediated effects were blocked by propentofylline. A1‐receptor‐mediated inhibition of cyclic AMP accumulation was virtually abolished by 100 μM propentofylline. The A1‐receptor‐mediated inhibition of evoked acctylcholine release was also reduced by propentofylline, but in this case the effect is not due exclusively to adenosine receptor antagonism but also to another action since the presynaptic inhibitory effect of carbachol was also inhibited. Adenosine A2‐receptors were also antagonized by propentofylline as judged by a concentration‐dependent antagonism of A2‐agonist‐induced cAMP accumulation in human T‐leukemia cells (possessing putative A2b‐receptors; pA2‐value 180 μM compared to 0.26 μM for 8‐cpt), and in PC‐12 cells (possessing putative A2a‐receptors, K1‐value 365 μM). Finally, adenosine transporters were affected by propentofylline and A 72 0287. Thus, [3H]‐nitrobenzylthioinosine‐binding to guinea‐pig cardiac membranes was blocked by propentofylline or A 72 0287 (Ki270 μM). The present results show that propentofylline and its hydroxylated metabolite can influence adenosine mechanisms in a multitude of ways. How these different actions may contribute to the ability of propentofylline to reduce the magnitude of ischemic damage is discussed.
Regulation of human basophil activation. IV. Dissociation between cationic dye binding and histamine release: role of Ca2+ions*
Authors: Beauvais F. , Hiéblot C. , Burtin C. , Benveniste J.
Published: August 2009

Summary—In previous studies we observed thatin vitrohistamine release from human basophils could be dissociated from the loss of affinity of basophil granules for a cationic dye, toluidine blue. In the present study we further explored the intracellular signals leading to the decrease in toluidine blue positive basophil (TB+) numbers, with or without histamine release. Since Ca2+mobilization is a crucial event in secretion and particularly in histamine release, we studied the role of Ca2+in histamine release as compared to TB+ decrease. In the presence of external Ca2+(2 mM): i) Ca2+channel antagonists verapamil and nifedipine up to 10 μM were without effect on IgE‐mediated histamine release and TB+ decrease; ii) loading of the leucocytes with Quin2 or preincubation with TMP‐8, an internal Ca2+antagonist, significantly inhibited the release of histamine and the decrease of TB+ basophils. In the absence of added external Ca2+: i) histamine release was abolished whereas the decrease of TB+ was not modified, even in the presence of EGTA; ii) the decrease of TB+ could be inhibited by prolonged EGTA preincubation, by Quin2 loading and incubation with TMB‐8. We conclude that histamine release requires both external Ca2+influx and mobilization of internal Ca2+. In contrast, no influx of external Ca2+is required for TB+ decrease in which, however, internal Ca2+mobilization appears to play an important role.
Effects of riluzole (2‐amino‐6‐trifluoromethoxy benzothiazole) on striatal neurochemical markers in the rat, with special reference to the dopamine, choline, GABA and glutamate synaptosomal high affinity uptake systems
Authors: Samuel D. , Blin O. , Dusticier N. , Nieoullon A.
Published: August 2009

Summary— Riluzole, a new compound with anticonvulsant properties, was found to induce a dose‐dependent decrease in the uptake of 3H‐dopamine, 3H‐GABA and 3H‐glutamate into striatal synaptosmes when added to the incubation medium or after in vivo administration, whereas an inlubition of 3H‐choline uptake was detected only in the in vitro experiments. Interestingly, riluzole affected 3H‐dopamine and 3H‐glutamate uptake differentially since 3H‐dopamine uptake was found to be more sensitive to the compound. Moreover, riluzole inhibited 3H‐dopamine uptake competitively and 3H‐glutamate uptake non‐competitively, which further suggests that the action of the compound is selective. After in vivo injection, riluzole did not affect the striatal dopamine, DOPAC, serotonin, 5HIAA, glutamate, aspartate or GABA contents. Since this compound was previously reported to induce a decrease in the spontaneous release of glutamate, serotonin, dopamine and possibly acetylcholine, the hypothesis is put forward that riluzole may, at least at high concentrations, have general effects on the striatal nerve terminals affecting both the uptake and release processes. This action may be correlated with the recently identified blocking properties of the compound on the sodium channels, as previously shown for local anaesthetics.
Differential effects of cromakalim on pancreatic vascular resistance and insulin secretionin vitro
Authors: Petit P. , Hillaire‐Buys D. , Mir AK , Loubatières‐Mariani MM
Published: August 2009

Summary—The effects of the potassium channel opener cromakalim on vascular resistance and insulin output were investigatedin vitrowithin the same experimental preparation, the isolated rat pancreas perfused at a constant pressure with a physiological solution containing 8.3 mM glucose. Cromakalim induced a clear and concentration‐dependent dilatory response of pancreatic vessels; the concentration‐response curve obtained in the range of 10−8‐10−5M had a sigmoidal shape with a linear part between 10−7and 10−6M. Cromakalim did not inhibit insulin release at these concentrations. These results differ from those obtained with diazoxide, which has been previously shown both to inhibit insulin secretion and induce vasodilatation of the pancreatic vascular bed in a similar range of concentrations (10−6– 10−5M). The data presented provide evidence for a selective effect of cromakalim on pancreatic vascular resistance. Our present and previous results support the view that cromakalim is effective on K+ channels of vascular smooth muscle that differ from the ATP‐sensitive K+ channel opened by diazoxide in insulin‐secreting B‐cells.
Pharmacokinetics of glafenine and glafenic acid in patients with cirrhosis, compared to healthy volunteers
Authors: Vermerie N. , Kusielewicz D. , Tod M. , Nicolas P. , Perret G. , Fauvelle F. , Petitjean O.
Published: August 2009

Summary— Pharmacokinetic parameters were evaluated in 12 patients with alcoholic cirrhosis and 12 healthy volunteers after a single 400 mg oral dose of glafenine. Glafenine (G) and its major active metabolite glafenic acid (GA) were measured at regular intervals using a specific high performance liquid chromatographic method. Glafenine absorption was significantly delayed in cirrhotic patients (CP) (Tmax = 2.8 ± 1.3 hvs 1.5 ± 0.4 h, p < 0.01) and was dramatically reduced in 3 patients. The large hepatic ‘first pass’ effect observed in healthy volunteers was markedly reduced in CP (ratio Cmax GA/Cmax G = 3.6 ± 2.9 vs 18.9 ± 9.8, p < 0.001; ratio areas under the curves AUC GA/AUC G = 2.3 ± 2.3 vs 18.2 ± 11.2, p < 0.001). The elimination half‐life of G was prolonged in the CP (13.0 ± 13.1 h vs 1.5 ± 0.5 h, p < 0.01). In CP, GA elimination half‐life was increased (12.0 ± 13.4 h vs 4.3 ± 1.3 h, NS) but the difference did not reach statistical significance because of large variability. The significant rise of G plasma concentrations (Cmax = 2.2 ± 2.1 mg/L vs 0.7 ± 0.2 mg/L, p < 0.05) and its longer half‐life would lead to an accumulation if the usual dosage regimen was prescribed for CP and could result in nephrotoxicity. On the other hand, lower dosage would be ineffective because only GA is active and nephrotoxic. Hence, G should be given with great caution to CP.
Tolerance and pharmacokinetics of propacetamol, a paracetamol formulation for intravenous use
Authors: Depré M. , van Hecken A. , Verbesselt R. , Tjandra‐Maga TB , Gerin M. , de Schepper PJ
Published: August 2009

Summary— In 12 healthy volunteers, paracetamol pharmacokinetics were compared following administration of 1 g propacetamol HCl given intravenously over a 15‐min period and 500 mg paracetamol given orally. Mean ± SD total AUC (μg/ml·h) following the iv formulation was significantly (P < 0.01) greater than following oral paracetamol (25.53 ± 4.27 vs 21.04 ± 4.49) corresponding to a mean oral bioavailability of paracetamol of 82.2 ± 9.4%. Between 1 and 2 h after administration, paracetamol plasma concentrations became very similar following both formulations. In another study, 2 g propacetamol HCl was given both as a 15‐min infusion and as a 2‐min bolus injection to six healthy volunteers. Contrary to mild to moderate local discomfort experienced during the 2‐min bolus injection, the 15‐min infusion was well tolerated without any complaints reported.
The effects of (±)‐idazoxan and its stereoisomers on mouse vas deferens motility in vitro. A comparison with yohimbine
Authors: Carratù MR , Navarra P. , De Serio A. , Serio M. , Preziosi P. , Mitolo‐Chieppa D.
Published: August 2009

Summary— The effects of idazoxan (IDZ) and its stereoisomers were compared to that of a classical α2‐antagonist, yohimbine (YOH), on para‐aminoclonidine (PAC)‐ and norepinephrine (NE)‐mediated inhibition of the twitch response evoked in the mouse vas deferens by low‐frequency (0.1 Hz) field stimulation. (±)‐IDZ and (+)‐IDZ antagonized the inhibitory effects of PAC, (+)‐IDZ being twice as potent as (±)‐IDZ; in contrast, antagonism by (‐)‐IDZ failed to meet Schild criteria for a competitive mechanism. YOH completely reversed the inhibition of twitch response induced by NE, but not that induced by PAC; in the latter case, residual inhibition was almost fully reversed by (+)‐IDZ and to a lesser extent by (±)‐IDZ, while (‐)‐IDZ proved ineffective. These results provide pharmacological evidence of α2‐receptor heterogeneity at the vas deferens level. A possible additional mechanism involving imidazoline binding sites is discussed.
Effects of paraldehyde on the convulsions induced by administration of soman in rats
Authors: Carpentier P. , Lallement G. , Bodjarian N. , Tarricone A. , Blanchet G.
Published: August 2009

Summary— The ability of paraldehyde, a potent central nervous system depressant, to prevent the convulsions induced by the organophosphate soman, an irreversible inhibitor of acetylcholinesterase, was studied in rats. Paraldehyde (0.1–500 mg/kg, im) administered 10 min before soman (100 μg/kg, sc) did not protect against seizures. Co‐administered with atropine sulfate (10 mg/kg, im), paraldehyde produced a clear dose‐dependent anticonvulsant response. Although this pre‐treatment could delay the occurrence of death, it did not produce any change in the soman‐induced 24 h mortality rate. Thus, co‐administration of paraldehyde and atropine sulfate might constitute a valuable tool to be used against the convulsant consequences of soman poisoning. However, supplementary pre‐medication, in addition to paraldehyde and atropine sulfate, remains necessary to improve the antilethal capacity of the pre‐treatment.
A French Version of the Sickness Impact profile (SIP): stages in the cross cultural validation of a generic quality of life scale*
Authors: Chwalow AJ , Lurie A. , Bean K. , du Chatelet I Parent , Venot A. , Dusser D. , Douot Y. , Strauch G.
Published: August 2009

Summary— The Sickness Impact Profile is a quality of life scale developed in the United States which is now widely used in clinical trials in chronic conditions such as chronic obstructive lung disease, angina, rheumatoid arthritis, chronic pain, psoriasis, inflammatory bowel disease and cancer. Validated generic scales permit cross cultural comparisons within disease processes in clinical trials. As a simple, direct translation of a scale is inadequate, we have created a French version of the original US version of the Sickness Impact Profile. The first phase was qualitative. A first French translation of the original US version was back translated into English by three independent translators. A second French version resulted from a consensus reached by a panel of lay subjects and health professionals after comparing the original US version, the first French version and the three back translations. This second version was tested with a group of 40 healthy volunteers. This qualitative phase resulted in a French Test Version with content and face validity. The quantitative phase assessed the equivalence of the rank order of each item, by sub scale, in the US version with that of the French Test Version, ie the rank of the French item was comparable (± 2) to the rank of the corresponding US item. The French Test Version was tested with 47 healthy subjects. Of the 136 items of the Sickness Impact Profile, 13 were retranslated to create a final French version. This was similarly tested on ten healthy subjects. One hundred and thirty‐four of the 136 items had the same (± 1) rank order in the US version and in the Final French version. This French version of the Sickness Impact Profile is available and should be tested in other studies.
Inhibition of [3H] γ‐aminobutyric acid release from guinea‐pig hippocampal synaptosomes by serotonergic agents
Authors: Cloëz‐Tayarani I. , Harel‐Dupas C. , Fillion G.
Published: August 2009

Summary—We studied the effects of (m‐trifluoromethyl‐phenyl)piperazine (TFMPP) and quipazine on the K+‐evoked [3H]GABA release from guinea‐pig hippocampal synaptosomes loaded with [3H]GABA. TFMPP and quipazine inhibited the K+‐evoked release of [3H]GABA dose‐dependently (IC50= 153 and 123 μM, respectively). Serotonergic antagonists such as methiothepin (0.1, 0.3 and 1 μM), ketanserin (0.1, 0.3 and 1 μM), dihydroergotamine (0.1 μM), metergoline (0.1 and 0.3 μM), methysergide (0.3 μM), propranolol (1 μM) and yohimbine (1 μM) did not significantly alter the inhibitory effect of TFMPP on [3H]GABA release suggesting that neither 5‐HT1nor 5‐HT2receptors are involved in this process. By contrast, the effect of TFMPP was diminished by selective 5‐HT3receptor antagonists: MDL 72222 (0.3 μM), tropisetron (0.3 and 1 μM), ondansetron (0.3 μM) and metoclopramide (1 μM). Tropisetron (1 μM) and ondansetron (0.3 μM) also inhibited significantly the quipazine effect whereas methiothepin (1 μM), dihydroergotamine (0.1 μM), yohimbine (1 μM) and ketanserin (1 μM) were ineffective on the quipazine inhibition of [3H]GABA release. Our results show a serotonergic modulatory effect on the K+‐evoked [3H]GABA release from guinea‐pig hippocampal synaptosomes by receptors which are neither 5‐HT1, 5‐HT2or 5‐HT4. They appear to be pharmacologically related to the 5‐HT3type but different from the 5‐HT3ionic channel receptors.
Renal thromboxane A2 synthesis in the Lyon hypertensive rat
Authors: Liu KL , Aissa A Hadj , Benzoni D. , Sassard J.
Published: August 2009

Summary—The aim of the present study was to assess the mechanisms by which norepinephrine (NE) increased the synthesis of prostanoids and revealed a hyperactivity of the Thromboxane (Tx) A2 synthase in the Lyon genetically hypertensive (LH) rat kidney. To this purpose, the effects of NE (1.2 times 10−8to 9.6 times 10−7M) on renal function and prostanoid synthesis were assessed in isolated perfused kidneys following β‐adrenoceptor blockade by sotalol (10−5M) and compared to those of equipressor concentration of an α2‐adrenoceptor agonist, BHT 933 (3.5 times 10−4M) and angiotensin II (AII) (7.7 times 10−9M). Kidneys were isolated from eight week‐old male LH rats and from their normotensive (LN) and low blood pressure (LL) controls and perfused in a single pass system. In baseline conditions, sotalol did not modify renal function or urinary prostanoids in any of the three strains. Following NE stimulation, it potentiated the increase in renal vascular resistance of LL and LN controls but not that of LH rats. The pressure‐natriuresis and the urinary prostanoids remained unchanged. BHT 933 elicited a weak stimulation of prostanoid release while AII markedly increased it and revealed, as did NE, the hyperactivity of the TxA2 synthase. It is concluded that the NE‐induced stimulation of prostanoid synthesis does not involve β‐adrenoceptors and is unrelated to the associated hemodynamic changes. These results also demonstrate that the increased renal synthesis of TxA2observed in LH rat kidney is not a specific response to α‐adrenoceptor stimulation and is likely to involve activation of the phosphoinositide pathway.
L 4 ‐ IMPORTANCE OF IMIDAZOLINE RECEPTORS IN THE CARDIOVASCULAR RESPONSES TO CLONIDINE AND RILMENIDINE IN CONSCIOUS RABBITS
Authors: Head G.A. , Sannajust F.
Published: August 2009

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

Summary—The pharmacodynamics of many antiarrhythmic drugs are altered by heart rate. The ability of sodium channel blockers to decrease conduction velocity (class I action) is more pronounced with rapid heart rates. Drugs with class III action increase action potential duration and refractoriness in the heart. Most drugs with class III actions, currently being developed, produce their action by blocking one or several of the potassium channels responsible for repolarization.In vitroandin vivostudies have shown that their ability to increase repolarization time is less pronounced, or even disappears, at rapid pacing or heart rates. This so called ‘inverse’ rate‐dependence of class III action is a characteristic of all drugs currently used in man except amiodarone, for which prolongation of repolarization time persists to a limited extent with rapid heart rates. It has been suggested that one possible mechanism of the inverse rate‐dependence of class III action is related to the preferential binding of drugs to the potassium channels in the closed, polarized state. An inverse rate‐dependence of class III action has also been found on prolongation of refractoriness. However, preliminary studies suggest that the positive inotropism of class III drugs not only persists but may increase with rapid heart rates. The clinical consequences of this phenomenon remain unclear, especially in view of the fact that the rate‐dependence of class III action on dispersion of repolarization has not been specifically studied and that class III actions tend to decrease in ischemic tissues. However, the increase of action prolongation at slow heart rates may contribute to the bradycardia‐dependent development oftorsades de pointesarrhythmias. Moreover, the rate‐dependence of class III actions needs to be taken into account when studying the relationship between plasma concentrations of new drugs with class III activity and the prolongation of repolarization time they induce.
Evaluation of drug‐induced QT interval modifications in dynamic electrocardiography: the case of bepridil
Authors: Coumel P. , Leclercq J‐F , Naditch L. , Pellerin D.
Published: August 2009

Summary— Drug‐induced modifications of QT interval are usually assessed through formulae defining the corrected QT interval “QTc”. They are all based on the assumption that the correction is adequate, and that drug‐induced heart rate variations and rate‐dependent QT changes are proportional. Holler ECG allows to study the repolarization in selected RR cycles while controlling environmental rate‐related and circadian influences. Repolarization duration was evaluated in 15 normal individuals and 13 patients with stable coronary artery disease and no heart failure who did not differ in terms of 24‐hour heart rate, age and sex. The effects of a 3‐month treatment with bepridil were assessed in the latter. Using the conventional evaluation through the corrected QT (Bazett formula), no difference was found between the two groups at baseline, and bepridil induced a non‐significant 5% prolongation of QTc. At Holler recordings, the QTa (Q‐T apex) duration was linearly correlated with the heart rate over 24 hours. To specifically study day‐tonight variations and to exclude the rate‐dependent and short‐term autonomic influences. QTa was studied in populations of averaged QRS‐T selected according to i) the last RR cycle length and ii) an identical mean RR interval during the preceding minute. Both RR values were fixed at 800 ms to obtain the “QTa‐800” measured directly or extrapolated from linearly correlated, other RR values. Using this technique, the two groups differed at baseline in terms of dynamicity of QTa: the QTa/RR regression line slope was steeper in normals, and the strongly significant day‐to‐night difference of QTa‐800 (P < 0.001) observed in them was absent in coronary patients. Bepridil, wliich did not significantly modify the 24‐hour heart rate, lengthened the QTa‐800 by 4–5%: although no more marked than with the QTc, this increase became significant at daytime (P = 0.04) and at night (P = 0.01) because of the inter‐individual consistency of the modifications. These results suggest that the approach of QT evaluation in strictly comparable conditions of environmental rate and time allowed by the Hotter technique is better adapted than the conventional QTc method to assess limited drug‐induced changes.
Comparative evaluation of ulcer prevention efficacy of orally, rectally and sublingually administered omeprazole in three acute gastric ulcer models in rats
Authors: Sastry MSP , Diwan PV , Krishna DR
Published: August 2009

Summary— Ulcer prevention efficacy of orally, rectally and sublingually administered omeprazole was evaluated and compared using ulcer index and percentage inhibition of ulcerogenecity in three different acute gastric ulcer models viz, indomethacin, 0.6N HCl and aspirin (after pylorus ligation) induced ulcers in rats. The ulcer prevention efficacy after oral, rectal and sublingual administration were statistically significant (P < 0.01) in all the models. The differences in ulcer index and percentage inhibition of ulcerogenecity for rectal and sublingual administration were insignificant (P < 0.05) in indomethacin and HCl induced ulcers and were significant (P < 0.05) in aspirin induced ulcers. The ulcer prevention activity was significantly higher (P < 0.05) after rectal and sublingual routes when compared to oral administration in all three models evaluated. Results revealed a faster onset and higher extent of pharmacodynamic activity of omeprazole after rectal and sublingual administration.
Effects of capsaicin on the endothelial permeability in isolated and perfused rabbit lungs
Authors: Delaunois A. , Gustin P. , Ansay M.
Published: August 2009

Summary— Changes in pulmonary endothelial permeability and in microvascular hemodynamics in response to capsaicin (10−4M) were investigated in isolated, perfused rabbit lungs. Blood‐free perfusate was recirculated through ventilated lungs in an isogravimetric state, under zone III conditions with a constant flow. Using the occlusions method, the total pressure gradient between the arterial and the venous levels (δPt) was partitioned into four components: arterial (δPa), pre‐ (δPa') and post‐(δPv') capillary, and venous (δPv). The capillary filtration coefficient (Kf,c) was evaluated by measuring the amount of fluid filtering through the endothelium when arterial and venous pressures were suddenly increased. Capsaicin caused no changes in the vascular pressures at any level of the pulmonary circulation but induced a significant 3‐fold increase in the Kf,c (P < 0.05). This reaction was accompanied by pulmonary oedema. The mechanisms involved in the permeability changes were investigated by testing the capacity of different drugs to block the response to capsaicin. Clonidine (10−7M to 10−5M), morphine (10−6M), aspirin (10−3M), ketanserin (10−8M) and (±) CP 96,345 (10−6M), an antagonist of neurokinin NK1 receptor, completely prevented the effects of capsaicin on the Kf,c. In contrast, terfenadine (10−7) together with cimetidine (10−5M) had no protective effect against capsaicin. It was concluded that capsaicin‐induced pulmonary oedema was due to an increase in the capillary filtration coefficient and not to hemodynamic changes. This alteration in the endothelium permeability is mediated by the release of endogenous peptides from C‐fibers upon the action of capsaicin and subsequent activation of NK1 receptors, probably by substance P. Moreover, 5‐hydroxytryptamine receptors and arachidonic acid derivates are also involved in this reaction.
A microcomputer program to determine the precision of elimination rate constant and half‐life estimates when sampling time is short
Authors: Guédès JP , Couet W.
Published: August 2009

Summary— First‐order elimination of drugs is often assumed in pharmacokinetics and elimination rate constant is then frequently determined by log‐linear regression analysis from plasma concentration measurements. When the time which elapses between the first and the last plasma sample is short compared to the decay half‐life, the elimination rate constant may not be determined with satisfactory precision, in particular because of analytical error. Application of basic principles of linear regression analysis allowed us to quantify the theoretical effect of analytical error on the determination of the drug elimination rate constant in that situation. It was highlighted that the precision of that determination could be efficiently improved by measuring samples in replicate, which should be recommended in practice. A user‐friendly program was developed which can be used prospectively to optimize sampling strategy, and retrospectively to estimate the precision of parameter estimates. The program works on IBM PC and compatible microcomputers and is available on request.
Red cell ion transport abnormalities in experimental hypertension
Authors: Zicha J.
Published: August 2009

Summary— The original attractive hypothesis on the important role of elevated cell Na+ concentration in the pathogenesis of hypertension stimulated a search for generalized membrane defects and ion transport abnormalities in various easily accessible cells including erythrocytes. An attempt is made here to compare this hypothesis with the data on red cell ion transport alterations that were observed in experimental hypertension over the last 15 years. Several methodological (presence of extracellular Na+ in incubation media, kinetic approach to the evaluation of transport systems) and physiological problems (potassium depletion, age‐dependent changes) are discussed in more detail because they can substantially modify the results obtained. Available data suggest a possible contribution of augmented Na+ leak to the development of both genetic and salt‐dependent experimental hypertension. The role of alterations in the activity of the Na+‐K+ pump or the Na+‐K+ cotransport system still remains unclear.
Dose‐response study of metoclopramide in gastroesophageal reflux in infancy
Authors: Pons G. , Duhamel JF , Guillot M. , Gouyon JB , D'Athis P. , Richard MO , Rey E. , Moran C. , Bouglé D. , Bellissant E. , Ement P. , Dupont C. , Badoual J. , Olive G.
Published: August 2009

Summary— Twenty‐four infants, 1 to 18 months‐old, who were referred to four centers for suspected gastroesophageal reflux and whose esophageal pH after a standard formula meal given at 9 to 10 am (Ho‐day 1) fulfilled the criterion of being < 4 for more than 5% of the time between H1 and H6, entered a double‐blind placebo‐controlled dose‐response trial of metoclopramide (M). Twenty‐four hours later (day 2), patients were randomly assigned to receive either placebo or a single 0.1, 0.2, or 0.4 mg/kg dose of metoclopramide, 30 min before the formula meal (n = 6/group) and the procedure was repeated. Metoclopramide plasma concentration was measured 1 h after dosing (C1h). On day 1, the time during which the esophageal pH was < 4 (time pH < 4), and five other parameters, were not significantly different in the treatment groups. On day 2, time pH < 4 (m(SD)) decreased from 33(13) to 30(33), 39(27), to 36(47), 42(15) to 18(13) and 48(25) to 31(46) min in the placebo, 0.1, 0.2, and 0.4 mg/kg metoclopramide groups, respectively. Possibly due to the large interindividual variability, no significant differences in parameters were observed between the different groups. None of the parameters correlated with the metoclopramide dose. Time pH < 4 expressed as the difference between day 1 and day 2, relative to day 1, decreased significantly as a function of C1h. No side effects were observed. A similar study should be performed after repeated dosing regimen.
Porcine diaphragmatic arteries. Anin vitrocomparative study
Authors: Feletou M. , Grau F. , Teisseire B.
Published: August 2009

Summary—The purpose of the experiment was to determine whether diaphragmatic circulation could be compared to other skeletal muscle circulation or whether it has an originality of its own. Diaphragmatic (phrenic and costophrenic arcade arteries), coronary, femoral and cerebral arteries were taken up from anaesthetized pigs, cut into rings and suspended in organ chambers for isometric tension recording. Vasopressin induced a maximal contraction of the femoral artery, no significant changes in tone in cerebral and coronary arteries, and only minimal contraction (30% of the maximum) in diaphragmatic arteries. These results were obtained in a state of basal level of tension or in vessels contracted with prostaglandin F2α. The endothelium did not influence the response in any of the vessels investigated. Norepinephrine induced a contraction in the femoral artery and a relaxation in the coronary artery which was not influenced by the endothelium. Isoproterenol could relax the coronary but not the femoral or the diaphragmatic arteries. The α2‐adrenoceptor agonist UK 14304 induced endothelium‐dependent relaxation in the diaphragmatic and coronary arteries, but not in the femoral arteries. Phenoxybenzamine unmasked a small α‐adrenoceptor reserve in the diaphragmatic arteries. These results suggest that diaphragmatic circulation has protective mechanisms in order to preserve a correct supply to the vital respiratory muscle it subserves.
Influence of the endothelium on Ca2+dependency of angiotensin II‐induced contractions of rat aortic rings
Authors: van Heiningen PNM , van Zwieten PA
Published: August 2009

Summary—Endothelium‐dependent relaxation has been demonstrated to be involved in the regulation of vascular tone and extracellular Ca2+was found to play a prominent role in this process. Since the dependency on extracellular Ca2+appeared to differ considerably within the arterial tree, possibly as a consequence of vessel‐related endothelium‐dependent mechanisms, we investigated the effects of different compounds affecting Ca2+entry (nifedipine, CoCl2) on angiotensin II‐induced contractions of rat aortic rings with and without endothelium as well as the responses in a Ca2+–“free” solution. For this purpose, rat aortic rings were either undone from their endothelial layer by gentle mechanical rubbing or care was taken to keep the intima intact in case rings where endothelium were required. The presence of an intact endothelium was confirmed by acetylcholine‐induced relaxation. A stronger responsiveness towards angiotensin I, both after a complete concentration‐response curve and after a single maximal concentration of angiotensin II was observed in arterial segments without endothelium. The maximal contraction to a single concentration of angiotensin II (0.1 μM) in the rings without endothelium amounted to 75.8 ± 3.8% of the preceding response to a supramaximal concentration of noradrenaline (= Emax). In rings without the endothelial layer, the contraction was 34.8 ± 3.7% of Emax. This indicates an endothelium‐induced relaxation in aortic rings with endothelium. After incubation with the Ca2+entry blocker nifedipine (1 μM) both rings with and without endothelium were inhibited to the same extent, contractions amounted to 30.7 ± 1.8% and 19.6 ± 1.3% of Emax, respectively. However, incubation in a Ca2+‐“free” medium for 5 min resulted in similar contractions for rings without endothelium (16.4 ± 1.4% of Emax) as for rings with endothelium (15.0 ± 1.6% of Emax). Moreover, CoCl2in a concentration of 300 μM hardly inhibited the contraction of rings with an intact endothelium, a contractile response of 30.5 ± 2.8% of Emaxwas observed. The results of the study suggest that the influx of Ca2+ions is indeed responsible for the endothelium‐mediated relaxation. However, this influx, which cannot be antagonized by nifedipine, but has shown to be affected by CoCl2, suggests that channels intensitive to organic Ca2+entry blockers may be involved.
Pooling plasmas for a rapid answer in pharmacokinetic studies: application to a bioequivalence study of hydrocortisone tablets
Authors: D'Yvoire M Bouvier , Coquerel A. , Chretien P. , Tremblay D.
Published: August 2009

Summary— Two methods of plasma pooling in pharmacokinetic studies are described. The first method allows the estimation of the average plasma profile of all subjects receiving a given dose or formulation, with at most as many assays as there are time points. The second method allows to estimate the individual AUCs of all subjects with only a single assay for each drug administration. These techniques were successfully employed to predict the final results of a bioequivalence study of two formulations of hydrocortisone 10 mg tablets. Plasma pooling methods can provide early partial information on the results of pharmacokinetic studies. They can be most useful in bioequivalence studies, where early estimates of the average curves and individual AUCs can lead to a decision not to proceed with all the assays, if bioequivalence appears unlikely. The pooling methods may also have useful potential applications in Phase I ascending dose‐tolerance studies and in the field of pharmacokinetic studies in small animals. Further studies are necessary to test these methods in order to gain more information on their reliability in the decision‐making process in these fields as well as in bioequivalence studies.
A study of alpha1‐ and alpha2‐adrenoceptor responsiveness in diabetic insipidus dogs
Authors: Tavernier G. , Sénard JM , Montastruc JL , Montastruc P.
Published: August 2009

Summary— The present study was performed to investigate the participation of circulating vasopressin in alpha‐adrenoceptor responsiveness. Thus, we compared the pressor responses induced by selective alpha1‐or alpha2‐adrenoceptor stimulation in two groups of conscious dogs: a) normal animals and b) animals with surgically‐induced diabetes insipidus. In addition, platelet alpha2‐adrenoceptors labelled with (3H)RX821002 were compared in the two groups. The pressor response to alpha1‐adrenoceptor stimulation [ie successive doses of noradrenaline (0.5, 1, 2, 4 μg/kg iv) after propranolol (1 mg/kg iv) plus yohimbine (0.5 mg/kg iv)] was significantly (P < 0.05) less pronounced in diabetic insipidus than in normal dogs. In contrast, the magnitude of the pressor effects of alpha2‐adrenoceptor stimulation [ie noradrenaline after propranolol plus prazosin (1 mg/kg iv)] was the same in the two groups of animals. Bmax and Kd values for (3H)RX821002 binding on platelets were similar in diabetic insipidus and normal dogs. This study shows that alpha1‐ (but not alpha2‐) adrenoceptor responsiveness is decreased in diabetic insipidus suggesting the involvement of vasopressin in the mechanisms of the vascular alpha1 ‐adrenoceptor pressor response.
Lack of effect of phenobarbital on ex vivo leukocyte oxydative metabolism in healthy volunteers
Authors: Pinquier JL , Joseph X. , Delaforge M. , Lejus C. , Boucher JL , de Lauture D. , Kahan A. , Strauch G.
Published: August 2009

Summary— Oxydative metabolism in activated human polymorphonuclears catabolizes leukotriene B4 by a cytochrome P450 ω‐hydroxylase and procainamide by a myeloperoxydase. The percentage of leukotriene B4 metabolized by activated human polymorphonuclears and the apparent enzymatic parameters of procainamide metabolism were studied ex vivo in six healthy volunteers before and after phenobarbital intake (100 mg/day) for 10 days and in six healthy control volunteers. No differences were found between groups for the difference in percentage of leukotriene B4 metabolized between day 11 and day 1. The apparent enzymatic parameters, Km and Vm, of procainamide oxydation did not differ significantly between the groups both on day 1 and day 11. These results do not show any evidence of inducibility of leukotriene B4 and procainamide metabolism in human polymorphonuclears. However, a positive correlation between 6βOH‐cortisol excretion and percentage of leukotriene B4 metabolized was observed on day 11. This study suggests that human polymorphonuclears cytochrome P450 leukotriene B4 ω‐hydroxylase and procainamide metabolism is not a useful method to study cytochrome P450 induction in clinical pharmacology.
Consumption of benzodiazepines in a French university hospital between 1980 and 1991
Authors: Alran C. , Damase‐Michel C. , Celotto N. , Durand MC , Montastruc JL
Published: August 2009

Summary— The consumption of benzodiazepines in the Toulouse university hospital from 1980 to 1991 was investigated. During this period, total annual consumption of benzodiazepines as anxiolytics remained stable, whereas their prescription as hypnotics fell (‐70%). Moreover, short half‐life benzodiazepines as hypnotics were preferred to long half‐life ones. In parallel, there was an enhancement in new (zopiclone, zolpidem, buspirone) and old (alimemazine, hydroxyzine) drugs' consumption, the ratio benefits/risks of which have not yet been well defined.
Biochemical and electrophysiological properties of SR 57746A, a new, potent 5‐HT1Areceptor agonist
Authors: Bachy A. , Steinberg R. , Santucci V. , Fournier M. , Landi M. , Hamon M. , Manara L. , Keane PE , Soubrié P. , Fur G Le
Published: August 2009

Summary—SR 57746A (1‐[2‐(naphth‐2‐yl) ethyl]‐4‐(3‐trifluoromethylphenyl)‐1, 2, 5, 6 tetra‐hydropyridine hydrochloride) binds competitively, and with high affinity (Ki= 2.0 ± 0.7 nM) to 5‐HT1Areceptors from rat hippocampusin vitro, but has much less affinity for other 5‐HT receptor subtypes (IC50> 650 nM). SR 57746A produces a concentration‐dependent inhibition of forskolin‐stimulated adenylate cyclase activity in rat hippocampal homogenates, with a maximal effect identical to that of 8‐OH‐DPAT, suggesting that SR 57746A behaves as a full agonist in tthis experimental model. SR 57746A potently displaces [3H]8‐OH‐DPAT binding to rat hippocampal membranesex vivo, with an ID50of 11.1 mg/kg po, 30 min after administration, and 2.8 mg/kg po, 2 h after administration. This effect of SR 57746A is long‐lasting (at least 24 hours at 10 mg/kg po). SR 57746A does not modify the levels of 5‐HT or DA in various brain areas, but decreases the concentrations of 5‐HIAA, and increases those of DOPAC, HVA and 3‐MT. Following iv administration, SR 57746A (0.095 to 0.25 mg/kg) inhibits the spontaneous firing of dorsal raphe neurones, but does not modify the activity of DA neurones in the substantia nigra or ventral tegmental area. Thus, SR 57746A is a potent, selective and full agonist at 5‐HT1Areceptorsin vitroandvivo.
α1and α2‐adrenergic control of large and small coronary arteries during exercise in conscious dogs under β‐blockade
Authors: Vigue B. , Ghaleh B. , Giudicelli JF , Berdeaux A.
Published: August 2009

Summary—The aim of this study was to determine the relative roles of α1‐and α2‐adrenoceptors at the level of large epicardial and small resistance coronary arteries when sympathetic tone is increased by exercise in conscious dogs. The responses of left circumflex coronary artery diameter and blood flow were investigated at rest and during graded treadmill exercise (5, 10 and 12 km/h) in six chronically instrumented dogs during control conditions (saline) and after administration of propranolol (1 mg/kg) either alone or in combination with either prazosin (50 μg/kg), or idazoxan (300 μg/kg), or the association of prazosin + idazoxan (same doses). In control conditions, graded treadmill exercise resulted in a progressive increase in coronary artery diameter (+ 3.8 ± 0.6% from 3479 ± 80 μm) and in a decrease in coronary vascular resistance (‐ 46.0 ± 4.5% from 8.49 ± 1.51 mmHg/cm/s). Propranolol significantly constricted large (‐ 4.4 ± 0.6% from 3486 ± 87 μm) and limited dilation of small coronary arteries during exercise. These coronary effects of propranolol remained unchanged following additional α2‐adrenoceptor blockade by idazoxan but were abolished following α1‐adrenoceptor blockade by prazosin, given either alone or combined with idazoxan. Thus, α1‐ but not α2‐adrenoceptors are responsible for propranolol‐induced constriction of large coronary arteries and limitation of small coronary arteries dilation during exercise in conscious dogs.
Clinical pharmacology of nicardipine in liver transplant patients
Authors: Drici MD , Raucoules M. , Jacomet Y. , Iacono P. , Ichai C. , Grimaud D. , Lapalus P.
Published: August 2009

Summary— Slow calcium channel antagonists are widely used among transplanted patients suffering from hypertension, although some of them tend to reduce hepatic blood flow. The aim of our study was to determine the pharmacological properties of nicardipine in transplanted patients with hypertension. Ten hours after liver transplantation, six patients (three men, three women) received 5 mg of intravenous nicardipine to prevent high blood pressure during intensive care. Prior to the administration and during the study (at the completion of the infusion, 3, 5, 10, 15, 20, 30, 45, and 60 min after infusion), the systemic and splanchnic parameters were measured (Swan Ganz catheter). Blood samples were drawn simultaneously from radial artery and free hepatic veins, in order to obtain the hepatic extraction of nicardipine. The hepatic extraction ratio was around 70% for the first 3 min, then decreased and remained stable thereafter, around 45%, showing a non linear first‐pass metabolism pattern. Plasma hepatic clearance of nicardipine (699–850 ml/min) was close to total plasma clearance throughout the study (978 ± 222 ml/min, from 71 to 87%) and half of the estimated hepatic plasma flow values at the same times (1467–1770 ml/min, from 44 to 51%). No statistically significant changes were observed in cardiac output and hepatic blood flow during the study, although there was a decrease in mean arterial blood pressure from 87 ± 6 mm Hg baseline level to 76 ± 3 mmHg, 60 min after administration. Nicardipine chlorhydrate seems to be appropriate in post operative liver transplant patients when blood pressure must be decreased. Nicardipine safely lowers peripheral resistance, and does not induce changes in hepatic blood flow. Its extraction remains stable, after a hepatic saturation phenomenon.