bluuebunny/crossref_metadata_2025 huggingface dataset:
Physical activity, skeletal muscle β‐adrenoceptor changes and oxidative metabolism in experimental chronic heart failure†
Authors: Michel C , Chati Z , Mertes P‐M , Escanye J‐M , Zannad F
Published: August 2009

Summary— In chronic heart failure (CHF), changes in sympathetic nervous activity and skeletal muscle metabolism contribute to a limitation in the capacity for exercise. The aim of this study was to investigate the potential relationships between physical deconditioning, skeletal muscle β‐adrenoceptor (β‐AR) characteristics and muscle metabolic changes in rats with coronary ligation‐induced experimental CHF. Muscle β‐AR and norepinephrine levels were assessed in rats with CHF that had been treated with propranolol at 28 mg/kg/day and compared with rats with CHF that had not been treated and those that had undergone sham operations. The soleus muscle was investigated because of its predominantly oxidative fibre‐type composition. Measurements of spontaneous locomotion activity were carried out using telemetry. After 85 days, muscle energetic phosphate levels were assessed using 31P‐magnetic resonance spectroscopy. The phosphocreatine resynthesis rate was decreased in the untreated CHF rats (15 ± 3 vs 33 ± 5 mmol L−1 min−1 in the sham‐operated rats, p < 0.05), but this had been partially reversed in the rats given propranolol (22 ± 3 mmol L−1 min−1, non‐significant (NS) when compared with the sham‐operated rats). Spontaneous activity did not differ among the three groups of animals. Soleus β‐adrenoceptor density was decreased in rats with CHF (8.8 ± 3.0 fM/mg of protein vs 22.0 ± 7.0 fM/mg of protein in the sham‐operated rats, p < 0.05) and normalized in the propranolol‐treated rats (31.9 ± 7.0 fM/mg of protein, NS vs the sham‐operated rats; p < 0.05 vs the untreated rats with CHF). Unchanged spontaneous activity in the rats with CHF suggests that physical deconditioning could not account for the muscle metabolic changes. Changes in skeletal muscle energy metabolism were accompanied by changes in β‐AR density, occurring in typically oxidative β‐AR‐rich muscles, reversible after β‐blocker therapy and therefore suggestive of β‐AR downregulation.
Effect of a single oral dose of two erythromycin ethylsuccinate formulations on gastric emptying in healthy volunteers: A scintigraphic study
Authors: Delatour F , Le Guludec D , Caron F , Faurisson F , Torlotin JC , Rouveix B
Published: August 2009

Summary—Macrolides are potential gastrokinetic agents. The purpose of this study was to assess the effect of a single oral dose of two erythromycin formulations on gastric emptying of the solid and liquid phases in twelve healthy volunteers and to seek a correlation between pharmacokinetic parameters and changes in gastric emptying. The gastric emptying times of liquids and solids were measured simultaneously by means of a scintigraphic technique after a single oral administration of amorphous erythromycin ethylsuccinate (500 mg), crystalline erythromycin ethylsuccinate (1000 mg) or a placebo, in a double‐blind crossover study in three separate weeks. Blood samples were obtained for erythromycin assay. The two oral formulations induced a similar acceleration of gastric emptying. When compared to the placebo, both erythromycin preparations significantly shortened the gastric transit time of solids and liquids (respectively 30% and 20% on average,p< 0.01). The incidence of gastrointestinal side‐effects was similar with the two erythromycin forms and the placebo. No correlation was found between the peak serum erythromycin concentrations and the solid or liquid gastric half‐lives. With the amorphous formulation, the area under the plasma time‐concentration curves was small and solid and liquid gastric emptying were strongly accelerated, pointing to a direct effect on the gastrointestinal smooth muscle.
Fluoxetine in orthostatic hypotension of Parkinson's disease: A clinical and experimental pilot study
Authors: Montastruc JL , Pelat M , Verwaerde P , Brefel‐Courbon C , Tran MA , Blin O , Rascol O , Senard JM
Published: August 2009

Summary— Recent clinical studies have reported a beneficial effect of fluoxetine, a serotonin reuptake inhibitor, in patients with severe refractory orthostatic hypotension. The present study was undertaken to investigate the effect of fluoxetine in orthostatic hypotension occurring during Parkinson's disease on both blood pressure values and number of clinical symptoms during orthostatic procedure evaluated using a validated clinical rating scale. In a pilot study performed in fourteen patients with idiopathic Parkinson's disease plus orthostatic hypotension, fluoxetine hydrochloride (20 mg orally daily during one month) significantly reduced the fall in systolic blood pressure [‐33 ± 21 (SD) mmHg before fluoxetine vs ‐22 ± 19 mmHg after fluoxetine, P = 0.03] elicited by standing without modifying heart rate. The drug also significantly reduced the number of postural symptoms occurring during the orthostatic procedure [2.9 ± 1.5 (SD) before fluoxetine vs 1.2 ± 1.3 after fluoxetine, P = 0.006]. A similar pattern of response was obtained in an experimental model of neurogenic orthostatic hypotension obtained in chronically sino‐aortic denervated dogs submitted to an 80° head‐up tilt test procedure under chloralose anaesthesia. Fluoxetine did not change plasma noradrenaline levels. This pilot study suggests a slight but clinically significant effect of fluoxetine on both hemodynamic parameters and clinical symptoms in parkinsonian patients suffering from orthostatic hypotension.
Myocardial β‐adrenergic reactivity in volume overload‐induced cardiac hypertrophy in the rat
Authors: Communal C , Ribuot C , Durand A , Demenge P
Published: August 2009

Summary—The purpose of this study was to evaluate the changes in myocardial β‐adrenergic reactivity in animals undergoing a 4 week cardiac volume overload. Aortocaval shunt (ACS) or sham operation (sham) were performed in male Wistar rats, and 4 weeks later, isoproterenol dose‐effects (chronotropic, inotropic and lusitropic properties) were studied after pithing. Noradrenaline (NA) and adrenaline (A) concentrations and NA turn‐over index were evaluated in plasma and heart ventricles, while β‐adrenoceptor characteristics in ventricle homogenates and slices with [125I]iodocyanopindolol, and the β(1)/β(2)‐adrenoceptor ratio were estimated. Four weeks of cardiac volume overload resulted in a 55% increase in ventricle weight/body weight ratio (from 2.5 ± 0.1 to 3.9 ± 0.1 mg/g in sham and ACS rats, respectively) and a 20% increase in protein contents (from 11.3 ± 0.7 to 13.8 ± 1.1 mg/100 mg ventricles in sham and ACS rats, respectively). Furthermore, NA and A concentrations and NA turn‐over index were increased in ACS rats (14, 40 and 80% versus sham, respectively). A shift to the right of the responses in heart rate, left ventricular systolic pressure, +dP/dtmaxand ‐d/P/dtmaxresponses following increasing doses of isoproterenol was observed, without change in the dose inducing maximum effect. Total β‐adrenoceptor characteristics and β(1)/β(2) ratio were unchanged. However, β(1)‐adrenoceptor density increased in epicardium while decreasing in endocardium of left ventricle from ACS rats. Rightward shift at lower doses of isoproterenol‐induced cardiac responses in volume‐overloaded rats are not likely due to overall β‐adrenoceptor density changes.
Nociceptin‐induced apparent hyperalgesia in mice as a result of the prevention of opioid autoanalgesic mechanisms triggered by the stress of an intracerebroventricular injection
Authors: Suaudeau C , Florin S , Meunier J‐C , Costentin J
Published: August 2009

Summary—The effects on nociperception of nociceptin/Orphanin FQ (noc/OFQ), the endogenous ligand of the ORL1 (opioid receptor like 1) receptor, have been evaluated in mice upon intracerebroventricular injection of 10 to 10 000 ng doses of the peptide. In the hot plate test (55 °C) the licking, rearing and jump latencies were significantly reduced by noc/OFQ (100–250 ng). Noc/OFQ (100–1000 ng) also reduced the latency to tail withdrawal in the tail flick test. In the formalin test (injection in a hind paw of a formalin solution), noc/OFQ (100 ng) increased significantly the duration of paw licking and/or biting at the earliest period of observation. In the writhing test, the number of writhes evoked by intraperitoneal administration of dilute acetic acid was not modified by noc/OFQ at doses in the range of 10–1000 ng, but was decreased by 10 000 ng. The reduction in jump latency in the hot plate test was observed even when mice were pretreated with morphine (2 mg/kg, sc). The analgesic effect of acetorphan (5 mg/kg, iv) was also reduced by nociceptin (100 ng); on the other hand the hyperalgesic effect of naloxone (4.5 mg/kg, sc) was not additive with that of nociceptin (100 ng). Comparing in various tests the nociceptive thresholds of uninjected mice to that of saline icv injected mice, it appeared that the latter injection induced an increase in these thresholds which was prevented by nociceptin. It is suggested that nociceptin displays hyperalgesic effects by preventing autoanalgesic (opioidergic) mechanisms triggered by the stress elicited by intracerebroventricular injection.
Secreted and intracellular phospholipases A2 inhibition by 1‐decyl 2‐octyl‐glycerophosphocholine in rat peritoneal macrophages
Authors: Boucrot P , Bobin‐Dubigeon C , Elkihel L , Letourneux Y , Jugé M , Gandemer G , Petit JY
Published: August 2009

Summary— Compounds able to inhibit phospholipases A2 can be considered as potential anti‐inflammatory drugs. In this respect, the inhibitory effect of the phospholipid analogue 1‐decyl 2‐octyl‐rac‐glycero‐3‐phosphocholine (decyloctyl‐GPC) added to the culture medium of rat peritoneal macrophages stimulated with ionophore A23187 was determined, (a) The substrate of phospholipase A2 1‐octadecanoyl 2‐[14C]eicosatetraenoyl‐sn‐glycero‐3‐phosphocholine ([14C]20:4‐GPC) was added to the culture medium. In macrophages + extracellular fluids, its hydrolysis at the 2‐position, produced [14C]non‐phosphorous lipids which reached 12% of the dose at 0.14 μM, 73% at 0.9 and > 90% at 1.6 μM; in experiments where macrophages and extracellular fluids were analyzed separately, decyloctyl‐GPC initially added at 4 μM, significantly inhibited the release of [14C]fatty acids and the eicosanoid synthesis, demonstrating its ability to inhibit secreted and/or intracellular phospholipases A2. (b) Extracellular fluids were separated from the macrophages and incubated with [14C]20:4‐GPC: 48% of the dose was hydrolyzed by extracellular fluid‐associated secreted phospholipase A2 and decyloctyl‐GPC at 3 μM, reduced this hydrolysis by 50%. (c) [3H]arachidonic acid ([3H]20:4) was added to the culture medium and was esterified in the macrophage membrane phospholipids. Activation of intracellular phospholipase A2 induced the release of [3H] fatty acids and eicosanoid synthesis. These releases were inhibited by 50% with decyloctyl‐GPC added at 4 μM. (d) [3H]20:4 and [14C]20:4‐GPC were added to the culture medium of the macrophages. [3H] and [14C] fatty acids and eicosanoids were released in macrophages or extracellular fluids. They were significantly reduced by the phospholipid analogue added at 4 μM. It is concluded that secreted and intracellular phospholipases A2 were both inhibited by decyloctyl‐GPC which extensively reduced the 20:4 release from exogenous and membrane phospholipids and therefore eicosanoid synthesis.
Enhancement of aspirin‐induced gastric damage by cholestasis in rats
Authors: Dehpour AR , Mani AR , Alikhani Z , Zeinoddini M , Savadkoohi S Toor , Ghaffari K , Sharif A , Sabbagh B , Nowroozi A , Sadr S
Published: August 2009

Summary— In this study the seventy of aspirin‐induced gastric mucosal damage was investigated in rats with obstructive cholestasis. Cholestasis was induced by ligation and resection of the bile duct under general anesthesia. Two weeks after operation, the rats were fasted for 24 hours. Aspirin was administered orally in doses of 0, 128, 192, 266 and 335 mg/kg, and the animals were killed four hours after dosing. The dose of 266 mg/kg was chosen for a study of the time‐dependency; other groups of animals were killed at time intervals of one, three, five, seven and nine hours after aspirin administration. The results showed that aspirin induces more severe gastric damage in bile duct resected rats compared with sham‐operated and control animals. Salicylate levels of serums were also measured but there was no significant difference in serum salicylate levels between bile duct resected, sham‐operated and control rats. It can be concluded that cholestasis can potentiate aspirin‐induced gastric damage in rats.
Alzheimer's disease: relationship between muscarinic cholinergic receptors, β‐amyloid and tau proteins
Authors: Pavía J , de Ceballos ML , de la Cuesta F Sanchez
Published: August 2009

Summary—Senile dementia is one of the most important health problems in developed countries. The main disease causing dementia is Alzheimer's disease that is characterized by the progressive deterioration of the cholinergic system, β‐amyloid production and deposition, and neurofibrillary tangle formation. Most of the reviewed data, along with data from experiments performed in our laboratory, suggest that there are no changes in the number of muscarinic receptors between Alzheimer and control brains, although the receptors expressed in Alzheimer's disease brains can be anomalous in their function. The muscarinic receptor‐G‐protein interaction also seems to be impaired in Alzheimer's disease compared with control brains, as well as the G‐protein system, with an important decrease in the function of the Gq/11, the most important G‐protein stimulating phosphoinositide hydrolysis in human brain; in addition, the second messenger system is also impaired, with a decrease in the synthesis of phosphoinositides and in the number of IP3receptors. Muscarinic cholinergic receptors are also linked to β‐amyloid production, stimulation of the M1subtype with agonists results in the processing of the β‐amyloid precursor protein to non‐amyloidogenic products and administration of a fraction of the β‐amyloid (β‐amyloid 25–35) to rats, results in a decrease in the number of muscarinic receptors in brain. M1agonists also decrease the phosphorylation of tau proteins, playing again a modulatory role in the pathogenesis of Alzheimer's disease. The existence of a link between β‐amyloid and tau proteins also has been reported; treatment of hippocampal neurones with β‐amyloid, or the 25–35 residue fragment, resulted in an increase in tau protein phosphorylation. The particular contribution of muscarinic receptors, β‐amyloid and tau proteins in the pathogenesis of Alzheimer's disease remains still unclear. Probably Alzheimer's disease could be due to a progressive degeneration in the relationship between the three components covered in this review.
Effects of norepinephrine on NMDA‐induced neurotoxicity in cerebellar granular cell culture of rat pups
Authors: Gepdiremen A , Sönmez S , Kiziltunç A , Ikbal M , Erman F , Düzenli S.
Published: August 2009

Summary—In this study, norepinephrine was tested in 0.1, 1, 10, 25 and 50 μM doses in 100 μM NMDA toxicity on cerebellar granular cell culture of rats. NMDA in 100 μM concentration induced cell death significantly with respect to controls. Death cell population was 1.08 ± 0.44% in control and 22.15 ± 2.46% in 100 μM NMDA (P< 0.0001). None of the norepinephrine concentrations administrated 15 min prior to NMDA was able to reduce death cell scores to control levels. Results were 8.75 ± 0.83% in 0.1 4mUM, 7.0 ± 1.01% in 1 μM, 17.25 ± 1.31% in 10 μM, 35.5 ± 1.38% in 25 μM and 17.9 ± 1.72% in 50 μM norepinephrine plus 100 μM NMDA administrated groups (P< 0.0001 for all with respect to control). Labetalol, as an alpha and beta blocker in 0.5 μM concentration which was given 15 min prior to norepinephrine was able to block the effects of it. In comparison with 100 μM NMDA administered group, only low doses of norepinephrine reduced the death cell scores significantly (for 0.1 and 1 μM norepinephrine plus NMDA groups;P< 0.0001). For 10 and 50 μM norepinephrine plus NMDA groups, death cell scores were found statistically insignificant from the NMDA‐administered group (P> 0.05 for both) while for the 25 μM norepinephrine plus NMDA group, the death cell score was found to be statistically increased (P< 0.0001).
A study comparing biopharmaceutic characteristics of four once daily controlled release diltiazem preparations
Authors: Hendriks MGC , Dogterom P , Ebels JT , Oosterhuis B , Geertsema LR , Hulot T , Bianchetti G , Jonkman JHG
Published: August 2009

Summary— In the present study we have compared the steady state biopharmaceutic characteristics of four diltiazem once daily controlled release capsules: Mono‐Tildiem LP 300® (300 mg), Adizem® XL (300 mg)1, Cardizem® (300 mg) and Dilacor® (240 mg). Sixteen healthy male volunteers (aged 22.9 ± 3.3 years, range 19–31 years) completed an open label, multiple oral dose, randomized, four‐period crossover study without a washout period in between. The volunteers received each diltiazem formulation once daily for four days. Trough diltiazem and metabolites plasma concentrations were determined on days 3 and 4. The 24‐h plasma concentration‐time profiles were assessed after the dose on day 4 of each period. The following steady state pharmacokinetic parameters for diltiazem were calculated: the minimum plasma concentration (cmin), the maximum plasma concentration (cmax), the time to reach that concentration (tmax), the time interval during which the plasma concentration exceeds 50% of cmax (t50), the area under the plasma concentration‐time curve (AUC72–96) and the peak‐to‐trough fluctuation (PTF). For the metabolites of diltiazem, N‐mono‐desmethyl‐diltiazem (NDM) and desacetyldiltiazem (DAD), AUC72–96 (AUCNDM and AUCDAD) and the ratio metabolite/parent compound were calculated. Steady state was achieved on day 3. Except one, all controlled release formulations have satisfactory controlled release properties allowing once daily administration. However, significant (P < 0.05) differences were found between the pharmacokinetic characteristics which do not allow exchange of the various formulations. Concentrations well below 50 ng·mL‐1 in the morning hours were observed for Dilacor® (240 mg) and Adizem® XL (300 mg), which could be a disadvantage of these formulations as it is well‐known that ischaemic events occur at a higher rate during that part of the day. The plasma concentration profiles of NDM and DAD, the major circulating metabolites, parallel the plasma concentration profiles for the parent compound. From a clinical point of view, all treatments were well tolerated.
Myocardial β‐adrenergic reactivity in pressure overload‐induced cardiac hypertrophy in the rat
Authors: Communal C , Ribuot C , Durand A , Demenge P
Published: August 2009

Summary—The purpose of this study was to evaluate the changes in myocardial β‐adrenergic reactivity in animals undergoing a 4 week cardiac pressure‐overload. Abdominal aortic constriction (AAC) or sham operation (sham) were performed in male Wistar rats, and 4 weeks later, isoprenaline dose‐effects (chronotropic, inotropic and lusitropic properties) were studied after pithing. Noradrenaline (NA) and adrenaline (A) concentrations and NA turn‐over index (DHPG /NE ratio) were evaluated in heart ventricles, while β‐adrenoceptor characteristics in ventricle homogenates and slices with [125I]iodocyanopindolol and the β(1)/β(2)‐adrenoceptor ratio were estimated. Four weeks of cardiac pressure overload resulted in a 70% increase in ventricle weight/body weight ratio (from 2.5 ± 0.1 to 4.2 ± 0.3 mg/g in sham and AAC rats, respectively) and a 24% increase in protein contents (from 11.3 ± 0.7 to 14.0 ± 1.1 mg/100 mg ventricle in sham and AAC rats respectively). The ventricle NA content was similar in AAC and sham, while the ventricle A content and NA ***turn‐over index were significantly increased in AAC rats (35 and 80% vs sham, respectively). Dose response of isoprenaline was significantly shifted to the right for all studied effects in AAC rats. However, maximal response (in relative values) was similar in AAC and sham rats only for heart rate but not for parameters depending on left ventricle contractile response. The β‐adrenoceptor density was significantly decreased in AAC by 30% without apparent affinity change and due to decreases in β(1)‐sites in septum and to β(1)‐ and β(2)‐adrenoceptors in left ventricle endocardium. Decreases in isoprenaline‐induced cardiac responses in AAC rats are associated with β(1)‐adrenoceptor density reduction and modification of β(1)‐ and β(2)‐adrenoceptor ratio. These modifications are not the only reason for such dose response changes, at least for contractile response.
Hypotensive action of bromocriptine in the DOCA‐salt hypertensive rat: Contribution of spinal dopamine receptors
Authors: Lahlou S , Duarte G Pinto
Published: August 2009

Summary—To assess the role of spinal dopamine receptors in mediation of hypotension induced by systemic administration of the dopamine D2receptor agonist, bromocriptine, conscious deoxycorticosterone acetate (DOCA)‐salt hypertensive rats were pretreated with either intravenous (iv; 500 μg/kg) or intrathecal (it; 40 μg/rat at T9‐T10) domperidone, a selective dopamine D2receptor antagonist that does not cross the blood‐brain barrier. In DOCA‐salt hypertensive rats, iv administration of a sub‐maximal dose of bromocriptine (150 μg/kg) induced a significant decrease in mean aortic pressure (MAP) which was greater and longer lasting than that in uninephrectomized control rats. Intravenous or it pretreatment with domperidone reduced partially, but significantly, the hypotensive effect of bromocriptine (reduction of about 57% and 45% of the maximal effect, respectively). The remaining responses observed during the 60 min postinjection period were still statistically significant as compared with vehicle injection. In contrast, the bromocriptine‐induced hypotension was fully abolished by iv pretreatment with metoclopramide (300 μg/kg), a dopamine D2receptor antagonist that crosses the blood‐brain barrier, or by combined pretreatment with iv and it domperidone. These results suggest that, in DOCA‐salt hypertensive rats, the hypotension induced by iv bromocriptine is mediated partly through a peripheral D2dopaminergic mechanism and partly through stimulation of spinal dopamine D2receptors, as has been demonstrated in conscious normotensive rats.
Differential time course of the vasodilator action of various calcium antagonists
Authors: van der Lee R , Kam KL , Pfaffendorf M , van Zwieten PA
Published: August 2009

Summary— It is rather the rate of the vasodilator effect than its magnitude which determines the triggering of reflex tachycardia associated with dihydropyridine calcium antagonists (DHP‐CA). We therefore compared the rate of the vasodilator effects of a series of CA (both DHP and non‐DHP) in rat isolated mesenteric artery preparations (size 256 ± 3 μm, length 2 mm) from male Wistar rats (weighing 300–350 g) in an isolated wire myograph according to Mulvany and Halpern [12]. The mean force of the KCl‐induced contraction amounted to 2.3 ± 0.1 mN/mm. Potency (given as IC50‐values), differential time course of action and recovery of the contractile response of the vessels after wash‐out were established. These three parameters adhere to the following sequences; (1. potency) S,S‐barnidipine > (S)‐lercanidipine > barnidipine HCl > amlodipine > nifedipine, lacidipine > (R)‐lercanidipine > verapamil, mibefradil; (2. differential time course) lacidipine, amlodipine > (S)‐ and (R)‐lercanidipine. S,S‐barnidipine, barnidipine HCl > mibefradil, verapamil, nifedipine; (3. recovery) nifedipine > verapamil, S,S‐barnidipine, amlodipine > barnidipine, lacidipine > mibefradil, (R)‐lercanidipine > (S)‐lercanidipine. In conclusion, S,S‐barnidipine proved to be the most potent vasodilator agent; interestingly, barnidipine was 20 times less potent when applied as a racemic mixture. A slow onset of action in DHP is a very important mechanism in preventing reflex tachycardia. For non‐DHP (verapamil, mibefradil) reflex tachycardia probably is prevented by a direct effect on the conductive tissue in the myocardium.
Intracolonic glycerol induces abdominal contractions in rats: Role of 5‐HT3 receptors
Authors: Botella A , Fioramonti J , Eeckhout C , Bueno L
Published: August 2009

Summary— Serotonin and 5‐HT3 receptors may be involved in the activation of nociceptive afferent pathways by rectal distension. In rats, intracolonic infusion of glycerol is able to trigger nociceptive inputs as evidenced by the occurrence of abdominal constrictions. This work was designed to evaluate the influence of 5‐HT3 receptor antagonists on this reflex and to approach the site of action by comparing their relative efficacies according to the route of administration. Male Wistar rats (250–350 g) were surgically prepared for abdominal electromyography and a catheter was placed in the colonic lumen. Five days after surgery, electrical activity of abdominal muscles was recorded before and during (20 min) intracolonic infusion of glycerol (60% glycerol + 40% saline, rate 0.75 mL/h). Cilansetron was administered intraperitoneally, 15 min before glycerol infusion, at doses of 5 to 500 μg/kg. Granisetron, ondansetron and cilansetron were administred at the dose of 20 μg/kg by intraperitoneal (ip), intravenous (iv) or intracolonic (ic) routes. The number of abdominal spike bursts was used as an index of visceral nociception. Intracolonic infusion of glycerol increased significantly (P < 0.05) the number of abdominal spike bursts during the time of infusion compared with saline (30.6 ± 6.6 vs 4.5 ± 3.4 bursts). When administered ip, cilansetron dose‐dependently reduced the frequency of abdominal spike bursts from the dose of 20 μg/kg ip. Administration ip of granisetron and ondansetron at this dose also significantly reduced the number of abdominal spikes (19.0 ± 6.0 and 18.3 ± 6.9 respectively). Cilansetron, ondansetron and granisetron were also effective by iv and ic routes, cilansetron was more active by the ic route. Serotonin, via 5‐HT3 receptors, is involved in the mediation of abdominal contractions induced by intracolonic infusion of glycerol. 5‐HT3 receptor antagonists are also active by ic route suggesting a local site of action.
The influence of hemorrhagic shock on the pharmacokinetics and the analgesic effect of morphine in the rat
Authors: De Paepe P , Belpaire FM , Rosseel MT , Buylaert WA
Published: August 2009

Summary—The influence of hemorrhagic shock (removal of 30% of the blood volume) on the pharmacokinetics and the analgesic effect of morphine was investigated in conscious rats. Plasma concentrations of morphine after a bolus injection (5 mg/kg) are higher in the shock animals, which is attributed to a small decrease in clearance (‐22%;P> 0.05) and a significant decrease in distribution volume (‐33%;P< 0.05) of the drug. The areas under the plasma concentration‐time curve of the metabolite morphine‐3‐glucuronide (M3G) are significantly higher (+237%;P< 0.01) in the shock rats, which is probably explained by a decreased distribution and renal excretion. The analgesic effect of morphine was evaluated using the tail‐flick test during a continuous infusion (10 mg/kg/h) with measurement of the plasma concentrations of morphine and M3G. Data from these experiments show higher plasma concentrations of morphine (+33%;P< 0.05) and M3G (+66%;P> 0.05) during shock, and a significantly increased analgesic effect (+43%;P< 0.05). Our data suggest that the increased analgesic effect of morphine during hemorrhagic shock can most likely be explained by pharmacokinetic changes resulting in higher morphine concentrations.
Food intake and the presystemic metabolism of single doses of amitriptyline and nortriptyline
Authors: Liedholm H , Lidén A
Published: August 2009

Summary— The influence of food on presystemic metabolism of single doses of amitriptyline (AMI) and nortriptyline (NT) was examined. In randomised order 25 mg tablets of each drug was given to 9 healthy, female volunteers both in the fasting state and together with a standardised breakfast. Concentrations of the drugs and of their dealkylated, hydroxylated and conjugated metabolites were measured by gas chromatography — mass spectrometry (AMI experiment) or high‐pressure liquid chromatography (NT experiment). Standard pharmacokinetic parameters were calculated. Food intake did not consistently or significantly influence the bioavailability of either AMI or NT, nor the demethylation of AMI, nor the hydroxylation or the primary or secondary conjugation of NT. There were large interindividual changes in AUC of AMI after food (+94% to ‐44%). A significant negative correlation between AUC of AMI but not of NT during fasting conditions and per cent change in AUC after food was found (r = ‐0.72, P = 0.029). The implication of this (negative) correlation for an individual patient might be to keep the intake of the drug in standardised relation to food to avoid undue heavy changes in drug concentration, which might just occur with a change in time relation between intake of drug and food. From a mechanistic view the results argue against a direct and selective influence of food on the presystemic oxidation and conjugation of weakly basic drugs but does not exclude that food may reduce the presystemic metabolism of some such drugs indirectly, by enhancing their rate of hepatic delivery. Presentation of data from food interaction studies should not be restricted to general descriptions. It seems equally important to present the variability of individual data to allow inspection of the extent and direction of effects. This should be of interest for patient, prescriber as well as the regulatory agency.
RESPIRATION AND BLOOD PRESSURE VARIABILITY: MECHANICAL AND AUTONOMIC INFLUENCES
Authors: Saul J Philip
Published: August 2009

The transfer function between broad‐band respiratory activity and the heart rate (HR) response can be used to elucidate the frequency dependent phase and magnitude characteristics of the respiratory sinus arrhythmia (RSA)1. To understand the complex links between respiratory activity and arterial blood pressure (ABP), the transfer functions between instantaneous lung volume (ILV), parameters of arterial pressure, and central venous pressure (CVP) were determined in healthy human volunteers during 6‐minute periods in which the respiratory rate was voluntarily controlled in a predetermined but erratic fashion, or CVP was perturbed with a similar pattern. Pharmacologic autonomic blockade was used to dissect the direct mechanical links between respiration and ABP from the effects of RSA on ABP. The results suggest that with HR fluctuations eliminated, respiration affects ABP in proportion to the rate of change of ILV; however, when neural control of HR remains intact, the RSA plays an important role in the genesis of ABP fluctuations.
Reduction in QT dispersion and ventricular arrhythmias by ischaemic preconditioning in anaesthetized, normotensive and spontaneously hypertensive rats
Authors: Lu Hua‐Rong , Yu Fing , Dai De‐Za , Remeysen Paul , De Clerck Fred
Published: August 2009

Abstract—QT dispersion is a marker for dispersion of ventricular repolarization and electrical instability of the heart. However, QT dispersion remains undocumented in both normotensive rats (NTRs) and spontaneously hypertensive rats (SHRs), in particular in conditions of myocardial ischaemia/reperfusion (isch./rep.) and ischaemic preconditioning (IP). Therefore, we assessed the effects of IP on the dynamic change of QT and QTc dispersion during isch./rep., and on isch.‐ and rep.‐induced ventricular arrhythmias in both NTRs and SHRs. Isch. and rep. were produced by occlusion and release of a snare around the left coronary artery in all rats. The effect of IP (three cycles of 3 min coronary artery occlusion and 5 min rep.) on myocardial repolarization and on development of isch.‐ and rep.‐induced ventricular arrhythmias was studied in 12 NTRs and 12 SHRs. Another 12 NTRs or 12 SHRs were subjected to 10 min of isch. followed by 10 min rep. without IP. SHRs have significantly longer QT‐ and QTc‐intervals as well as QT and QTc dispersion before isch. compared to NTRs. Myocardial isch. and early rep. largely increased QT and QTc dispersion in both NTRs and SHRs and resulted in a high incidence of isch.‐ and rep.‐induced ventricular tachycardia (VT) and fibrillation (VF). IP significantly reduced QT and QTc dispersion in SHRs before isch., and remarkably reduced the elevation of QT and QTc dispersion during a prolonged period of isch. and rep. in all rats. This protective effect on electrophysiology of IP was associated with an antiarrhythmic effect against both isch.‐ and rep.‐induced ventricular arrhythmias in NTRs and SHRs. Our data indicate that: 1) SHRs have a significantly higher baseline dispersion of ventricular repolarization than NTRs; 2) IP provides protection against ventricular arrhythmias in SHRs; 3) the increasing QT dispersion provoked by myocardial isch. and rep. is associated with a high incidence of isch.‐ and rep.‐induced ventricular arrhythmias and; 4) the reduction of QT dispersion by IP may be involved in its protective effect against isch.‐ and rep.‐induced arrhythmias in both NTRs and SHRs.
Post‐stroke treatment with imidapril reduces learning deficits with less formation of brain oedema in a stroke‐prone substrain of spontaneously hypertensive rats
Authors: Yabuuchi Fumie , Takahashi Masaya , Aritake Kosuke , Fujimoto Mineko , Ito Hajime , Tsuzaki Mayumi , Akai Tetsuo , Yamaguchi Motonori , Hayashi Shigehiro , Nishino Yukishige , Bräutigam Matthias
Published: August 2009

Abstract— The present study was undertaken to examine the effects of the ACE (angiotensin converting enzyme) inhibitor imidapril, on the brain, when administered after the onset of stroke in a stroke‐prone substrain of spontaneously hypertensive rats (SHRSP). Learning deficits and induced lesions in the brain as well as in the kidneys and heart were investigated in detail. SHRSP were divided into two groups with or without salt loading at the age of 4 weeks. The salt loading was performed for 7–9 weeks to increase the incidence of stroke. Within 24 h after the first observation of stroke, animals were subsequently treated with 5 mg/kg imidapril orally once a day or the vehicle for up to the age of 27 weeks. Imidapril attenuated progression of neurological abnormalities such as irritability, hyperkinesia and motor dysfunction, and increased survival rate. In three‐panel runway testing, learning deficits did not develop significantly in the imidapril‐treated group, and was comparable to that in the non‐salt‐loaded/non‐stroke group. Imidapril reduced oedema formation in the cortex, hippocampus and striatum, and also suppressed lesion formation in the kidneys and heart. Imidapril thus suppressed progression of neurological deficits with loss of learning ability following onset of stroke, and also suppressed formation of oedema in the brain and decreased the number of lesions in other organs. Imidapril‐induced reduction of cerebrovascular damage, which presumably occurs in the brain after stroke, may account for the inhibitory effects of imidapril on lesion formation and learning impairment.
The roles of P‐glycoprotein and intracellular metabolism in the intestinal absorption of methadone: in vitro studies using the rat everted intestinal sac
Authors: Bouër Ronan , Barthe Laurence , Philibert Claude , Tournaire Cécile , Woodley John , Houin Georges
Published: August 2009

Abstract— Methadone is used as a treatment for opiate detoxification in methadone maintenance programs. Intra‐ and inter‐patient variations in methadone bioavailability have been observed after oral methadone treatment and this makes it difficult to predict a dosing regimen. Intestinal absorption and metabolism could explain these variations. The in vitro gut sac model was used to study the intestinal absorption of methadone, and it confirmed that methadone is a substrate for P‐glycoprotein. The transport of methadone was increased in presence of P‐gp inhibitors verapamil and quinidine. The appearance of a major metabolite of methadone, 2‐ethylidene‐1, 5‐dimethyl‐3, 3‐diphenyl pyrrolidine (EDDP) in the gut sac contents also demonstrated the existence of intestinal metabolism of methadone.
Heat stress response and myocardial protection
Authors: Joyeux Marie , Godin‐Ribuot Diane , Yellon Derek M. , Demenge Pierre , Ribuot Christophe
Published: August 2009

Abstract—Prior whole‐body hyperthermia is able to protect the myocardium against ischaemia‐reperfusion injury by reducing cellular necrosis, preserving the ventricular function and preventing the occurrence of arrhythmias. These cardioprotective effects are associated with reduction of oxidative stress, preservation of the high‐energy phosphate levels and synthesis of heat stress proteins. A better understanding of this powerful protective adaptation of the myocytes would be of interest for potential clinical application, and rational design of specific agents that activate this mechanism will hopefully follow soon.
Drug transfer across the blood‐brain barrier and improvement of brain delivery
Authors: Jolliet‐Riant Pascale , Tillement Jean‐Paul
Published: August 2009

Abstract—The blood‐brain barrier is formed by the endothelial cells of the brain capillaries. Its primary characteristic is the impermeability of the capillary wall due to the presence of complex tight junctions and a low endocytic activity. Essential nutrients are delivered to the brain by selective transport mechanisms, such as the glucose transporter and a variety of amino acid transporters. Although most drugs enter the brain by passive diffusion through the endothelial cells depending on their lipophilicity, degree of ionization, molecular weight, relative brain tissue and plasma bindings, some others can use specific endogenous transporters. In such cases, binding competition on the transporter with endogenous products or nutrients can occur and limits drug transfer. The blood‐brain barrier can be a major impediment for the treatment of diseases of the central nervous system, since many drugs are unable to reach this organ at therapeutic concentrations. Various attempts have been made to overcome the limiting access of drugs to the brain, e.g. chemical modification, development of more hydrophobic analogs or linking an active compound to a specific carrier. Transient opening of the blood‐brain barrier in humans has been achieved by intracarotid infusion of hypertonic mannitol solutions or of bradykinin analogs. Another way to increase or decrease brain delivery of drugs is to modulate the P‐gly‐coprotein (P‐gp) whose substrates are actively pumped out the cell into the capillary lumen. Many P‐gp inhibitors or inducers are available to enhance the therapeutic effects of centrally acting drugs or to decrease central adverse effects of peripherally active drugs.
Effects of competitive NMDA receptor antagonists on excitatory amino acid‐evoked currents in mouse spinal cord neurones
Authors: D'Hooge Rudi , Raes Adam , Van de Vijver Gerda , Van Bogaert Pierre‐Paul , De Deyn Peter P.
Published: August 2009

Abstract—The effects of CGP 37849 [DL‐(E)‐2‐amino‐4‐methyl‐5‐phosphono‐3‐pentenoatel and its ethylester CGP 39551 on whole‐cell currents evoked by the endogenous excitatory amino acids, L‐glutamate and L‐aspartate, were studied in cultured mouse spinal cord neurones. Although CGP 37849 was the more potent compound, both antagonists inhibited 20 μM L‐aspartate or 2 μM L‐glutamate currents concentration‐dependently and reversibly. We calculated IC50values of 370 ± 180 nM for CGP 37849 and 2200 ± 140 nM for CGP 39551 (inhibition of L‐aspartate current), and 210 ± 25 nM for CGP 37849 and 6000 ± 4700 nM for CGP 39551 (inhibition of L‐glutamate current). Both CGP 37849 and CGP 39551 selectively blockedN‐methyl‐D‐aspartate (NMDA)‐evoked inward current. Current evoked by 5 μM kainate or 5 μM α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionate (AMPA) was unaffected by 10 μMM CGP 39551. Current evoked by NMDA was concentration‐dependently blocked by CGP 39551 with an IC50of 2100 ± 220 nM. After application of 10 μM CGP 37849, 17 ± 6% of the current evoked by 5 μM L‐glutamate remained. This residual current was due to non‐NMDA receptor activation since application of 25 μM 2‐amino‐5‐phosphonovalerate (APV) together with CGP 37849 did not significantly alter the residual current, whereas application of 6‐cyano‐7‐nitroquinoxaline‐2,3‐dione (CNQX) with CGP 37849 did significantly inhibit this current. Clamping cells at potentials ranging from −80 to +60 mV showed a linear potential‐current relationship for the 20 μM L‐aspartate‐evoked current with reversal potential around 0 mV. The proportion of the L‐aspartate current antagonized by CGP 37849 or CGP 39551 appeared to be independent of clamping potential. The concentration‐current relationship of L‐aspartate in the absence of the antagonists showed an EC50of 49 ± 14 μM. Upon application of 1 μM CGP 37849 and 10 μM CGP 39551, the L‐aspartate concentration‐current curve shifted to higher concentrations, and resulted in a 5‐ and 13‐fold increase in the EC50of L‐aspartate, respectively, whereasImaxwas not changed by application of the antagonists. Thus, the potent NMDA antagonists CGP 37849 and CGP 39551 were shown to inhibit excitatory amino acid responses specifically by competitive binding to the neurotransmitter recognition site of the NMDA receptor. Selective, competitive antagonism of L‐glutamate‐ and L‐aspartate‐evoked NMDA receptor responses probably underlies the effects of CGP 37849 and CGP 39551 such as their anticonvulsant, neuroprotcctant and antidepressant actions.
Effects of histamine H2receptor agonists and antagonists on the isolated guinea pig gallbladder
Authors: Coruzzi Gabriella , Pozzoli Cristina , Poli Enzo , Coppelli Gabriella , Bertaccini Giulio
Published: August 2009

Abstract—Histamine H2receptor‐mediated responses were examined on cholecystokinin‐octapeptide (CCK‐8)‐precontracted guinea pig gallbladder in vitro, testing histamine and a series of specific histamine H2receptor agonists and antagonists. Among the antagonists tested, zolantidine and compound SKF 92857 were previously shown to antagonize H2receptor‐mediated responses in the heart, but not in the stomach. Histamine, in the presence of the H1receptor antagonist mepyramine (10 μM), and the H2receptor agonists dimaprit, impromidine and amthamine, inhibited CCK‐8 (3 nM)‐induced contractions in a concentration‐dependent fashion, with the following rank orders of potency: impromidine > amthamine > histamine > dimaprit (pD2values were 6.73 ± 0.04, 5.44 ± 0.07, 4.64 ± 0.04 and 3.71 ± 0.05, respectively). The maximal relaxation produced by dimaprit was significantly lower than that produced by histamine, as well as by impromidine and amthamine, which behaved as full agonists. All the H2receptor antagonists examined were able to inhibit amthamine‐induced relaxation. Famotidine (pA2= 7.09 ± 0.26), zolantidine (pA2= 6.54 ± 0.11), compound SKF 92857 (pA2= 6.58 ± 0.13) and aminopotentidine (pA2= 6.86 ± 0.06) competitively antagonised the amthamine‐induced effect, while iodoaminopotentidine produced surmountable antagonism only at low concentrations (1 μM, pA2= 6.83 ± 0.21). Finally, the slowly‐dissociable antagonist loxtidine caused a non‐parallel displacement to the right of the concentration‐response curve to amthamine (pKB= 7.55 ± 0.24), with a significant depression of the maximal response to the agonist, even at the lowest effective concentration (0.3 μM). In conclusion, histamine H2receptors in guinea pig gallbladder resemble those of the heart, as regards their sensitivity to zolantidine and compound SKF 92857, which, by contrast, were unable to antagonize histamine effects at gastric H2receptors in different experimental models.
Destabilase complexes ‐ natural liposome produced by medicinal leeches Hirudo medicinalis
Authors: Nikonov Guennady I. , Titova Elena A.
Published: August 2009

Abstract— Electrophoretic analysis of destabilase preparation demonstrates the presence of protein combinations with MW 12.3, 25 and 50 kD. Fraction (MW 12.3 D) is a monomer of destabilase aggregation having properties of micellar proteins and represents a stable lipid‐ protein complex, where the role of lipid component is played by the stable analogue of prostacyclin (MW 391 D). The synthesis of a low molecular fraction of destabilase is fulfilled with bacteria ‐ symbiont of leeches Aeromonas hydrophila. When the destabilase (MW 12.3 kD) contacts with blood a process of complexe formation is triggered with hirudin and blood plasma kallikrein inhibitor, forming a stable ‘destabilase complex’ (DC; MW 25 kD), possessing also a high aggregation capacity. Polymer forms of the destabilase complex form a liposome changing its spatial orientation depending on the nature of the solvent. Such structural organization provides a high stability of DC components and a rapid penetration through cellular membranes (transmembrane transfer) and it also provides prophylactic antithrombotic action in the case of peroral application to animals, due to the blockade of vascular platelets (inhibition of platelet aggregation by prostacyclin analogue) and plasmic (inhibition of thrombin activity and blood plasma kallikrein) links of the hemostasis process. Destabilase fraction with MW 50 kD is a dimer of the destabilase complex. As a result of DC destruction (liposome), hirudin, prostacycline analogue and blood plasma kallikrein inhibitor are released.
Gastrointestinal absorption of drugs: methods and studies
Authors: Barthe Laurence , Woodley John , Houin Georges
Published: August 2009

Abstract—Physico‐chemical descriptors of drug molecules are often not adequate in predicting their oral bioavailability. In vitro methods can be useful in evaluating some of the different factors contributing to bioavailability. While physical parameters such as drug solubility may effect oral bioavailability, in most cases, the major determining factors are likely to be metabolism, and absorption at the intestinal level. Metabolism may be preabsorptive, as with peptides, or during absorption, particularly as a result of the activity of the intracellular enzyme CYP3A4. Absorption may be transcellular (membrane diffusion, carrier‐mediated, endocytosis) or paracellular, while p‐glycoprotein activity in the apical cell membrane may limit bioavailability by expelling drugs from the mucosal cells. Knowledge of the absorption mechanism is important in determining formulation strategies. The different in vitro techniques used to study absorption have advantages and disadvantages. Ussing chambers can be useful to measure bidirectional transport, but most studies use simple salt media, and full tissue viability is doubtful. Caco‐2 cell monolayers are human cells, but the system is static, and gives very low rates of transport, and exagerated enhancement of the paracellular route compared with small intestine. The rat everted gut sac incubated in tissue culture medium maintains tissue viability and gives reliable data, although it is a closed system. In situ perfusion gives no information on events at the cellular level, and absorption may be reduced by anaesthesia and surgical manipulation. In vivo perfusion in man, with multichannel tubes, gives valuable data, but is not practical for screening. Pharmacokinetic modelling can also give useful data such as the existence of different absorption sites. Permeability values from the literature show that for small hydrophilic molecules, which pass by the paracellular route, the improved everted sac gives values close to those for humans, while values with Caco‐2 cells are orders of magnitude lower.