Fundamental and Clinical Pharmacology (FUND CLIN PHARMACOL)

Publications in this journal

• Article: AT1 blockade abolishes left ventricular hypertrophy in heterozygous cMyBP-C null mice: role of FHL1.

  Vignier N, Le Corvoisier P, Blard C, SambinL, Azibani F, Schlossarek S, Delcayre C, Carrier L, Hittinger L, Su JB
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  ABSTRACT: This research investigated the impact of angiotensin AT1 receptor (Agtr1) blockade on left ventricular (LV) hypertrophy in a mouse model of human hypertrophic cardiomyopathy (HCM), which carries one functional allele of Mybpc3 gene coding cardiac myosin-binding protein C (cMyBP-C). Five-month-old heterozygous cMyBP-C knockout (Het-KO) and wild-type mice were treated with irbesartan (50 mg/kg/day) or vehicle for 8 weeks. Arterial blood pressure was measured by tail cuff plethysmography. LV dimension and function were accessed by echocardiography. Myocardial gene expression was evaluated using RT-qPCR. Compared with wild-type littermates, Het-KO mice had greater LV/body weight ratio (4.0 ± 0.1 vs. 3.3 ± 0.1 mg/g, P < 0.001), thicker interventricular septal wall (0.70 ± 0.02 vs. 0.65 ± 0.01 mm, P < 0.02), lower Mybpc3 mRNA level (−43%, P < 0.02), higher four-and-a-half LIM domains 1 (Fhl1, +110%, P < 0.01), and angiotensin-converting enzyme 1 (Ace1, +67%, P < 0.05), but unchanged Agtr1 mRNA levels in the septum. Treatment with irbesartan had no effect in wild-type mice but abolished septum-predominant LV hypertrophy and Fhl1 upregulation without changes in Ace1 but with an increased Agtr1 (+42%) in Het-KO mice. Thus, septum-predominant LV hypertrophy in Het-KO mice is combined with higher Fhl1 expression, which can be abolished by AT1 receptor blockade, indicating a role of the renin-angiotensin system and Fhl1 in cMyBP-C-related HCM.
  Fundamental and Clinical Pharmacology 04/2013;
• Article: Anti-diarrhoeal and ulcer-protective effects of violacein isolated from Chromobacterium violaceum in wistar rats.

  Antonisamy P, Kannan P, Ignacimuthu S
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  ABSTRACT: Violacein was isolated from Chromobacterium violaceum, a soil Gram-negative bacterium collected from the forest water body soil sample from Kolli Hills of Tamil Nadu, India. In the present study the anti-diarrhoeal and ulcer-protective properties of violacein were investigated in Wistar rats using castor oil, magnesium sulphate and ethanol. The intestinal transit in rats was significantly (P < 0.001) reduced and gastric emptying was delayed; 40 mg/kg of violacein elicited a greater anti-motility activity than 0.1 mg/kg of atropine. Violacein exhibited ulcer-protective properties against ethanol-induced ulceration in rats with maximal anti-ulcer activity at 40 mg/kg. Violacein also exerted significant anti-enteropooling effects, causing a dose-related inhibitory effect on castor oil-induced enteropooling in rats. A profound anti-diarrhoeal activity was observed when violacein was tested in diarrhoeic rats. The frequencies of defaecation as well as the wetness of the faecal droppings were significantly reduced. Furthermore, violacein (40 mg/kg) produced 87.84% inhibition of castor oil-induced diarrhoea in rats. The results suggested that violacein can be used for the treatment of diarrhoeal and ulcer-related diseases.
  Fundamental and Clinical Pharmacology 08/2009; 23(4):483-490.
• Article: Medicinal poisoning in Morocco: retrospective study from 1980 to 2004

  Soulaymani A, Abouali F, Rhalem N, Mokhtari A, Soulaymani R
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  ABSTRACT: Abstracts of the 12th Annual Meeting of the French Society of Pharmacology and Therapeutics, the 75th Annual Meeting of the Society of Physiology, the 29th Pharmacovigilance Meeting, the 9th APNET Seminar and the 6th CHU CIC Meeting: 9-11 April 2008: Clermont-Ferrand, France.
  Fundamental and Clinical Pharmacology 06/2008; 22(sup1):474-474.
• Article: The ASPOC project on perioperative chemoprophylaxis in general surgery: preliminary results from eight European countries

  P. Papaioannidou, A. Sabo, V. Vlahovic-Palcevski et al
  Fundamental and Clinical Pharmacology 01/2008; 22:35.
• Article: Systemic administration of adenosine ameliorates pentylenetetrazol-induced chemical kindling and secondary behavioural and biochemical changes in mice.

  Kiran Kumar Akula, Ashish Dhir, S K Kulkarni
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  ABSTRACT: Adenosine is one of the inhibitory neuromodulators in the brain and is considered to be responsible for seizure arrest and postictal refractoriness. Adenosine, adenosine receptor agonists, and adenosine uptake blockers are known to reduce the severity and duration of amygdala-kindled seizures. The present study was carried out to elucidate the anticonvulsant and neuromodulatory effect of systemic adenosine on the pentylenetetrazol (PTZ)-induced chemical kindling in mice. Kindling was induced by chronic administration of a subconvulsive dose of PTZ (40 mg/kg, i.p.) on every other day for a total period of 9 days. Adenosine was administered daily, 30 min before PTZ or vehicle. The kindling score was recorded immediately following PTZ administration according to a prevalidated scoring scale. Various behavioral and biochemical estimations were performed on day 10 (i.e. 24 h after the last dose of PTZ). Chronic PTZ treatment progressively increased the seizure score with the maximum score reached on day 9. Behavioral analysis found hyperlocomotor activity, anxiogenic response, hyperalgesia and amnesia in kindled mice. Biochemical analysis revealed that chronic treatment with PTZ significantly increased lipid peroxidation (malondialdehyde levels), nitrite (NO(2-) levels), adenosine deaminase (ADA) and total RNA levels and decreased catalase, reduced glutathione (GSH) levels in brain homogenates, and a depletion of adrenal ascorbic acid. Daily treatment with adenosine (25 and 50 mg/kg, i.p.) for 9 days led to a significant decrease in PTZ-induced kindling score and also reversed various behavioral and biochemical alterations produced by PTZ. The results of the present study suggested that systemic adenosine administration reversed the behavioral and biochemical alterations induced by chronic PTZ.
  Fundamental and Clinical Pharmacology 01/2008; 21(6):583-94.
• Article: Association between antipsychotic drugs, antidepressant drugs and venous thromboembolism: results from the EDITH case-control study.

  K Lacut, G Le Gal, F Couturaud, G Cornily, C Leroyer, D Mottier, E Oger
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  ABSTRACT: Cohort studies suggest that exposure to antipsychotic agents may be associated with an increased risk of venous thromboembolism (VTE). Few data concerning antidepressant drugs are available. Using a different methodological approach, the aim of this study was to estimate the association between neuroleptic and antidepressant drug use and the risk of VTE. We report the results of a case-control study designed to evaluate interactions between acquired and inherited risk factors of VTE. We included 677 cases hospitalized with deep vein thrombosis and or pulmonary embolism with no major acquired risk factor for VTE, and 677 controls matched for gender and age. Drug exposure was defined as current use of drugs at admission. Neuroleptic exposure was associated with an increased risk of VTE (OR = 2.1, 95% CI 1.4-3.2). Among neuroleptics, antipsychotic agent use was associated with a 3.5-fold increased risk of VTE (OR = 3.5, 95% CI 2.0-6.2). No association was found between antidepressant drug exposure and the risk of VTE (OR = 1.1, 95% CI 0.9-1.5). In this hospital-based case-control study, exposure to antipsychotic drugs was associated with an increased risk of VTE. These results, added to previous results, suggest that clinicians should consider antipsychotic drug exposure as a potential risk factor of VTE. More studies are needed in order to further elucidate this adverse effect, and to determine the possible predisposing factors and the biological mechanisms involved.
  Fundamental and Clinical Pharmacology 01/2008; 21(6):643-50.
• Article: Orofacial dyskinesia associated with tiemonium.

  Anis Klouz, Ahmed Zaïem, Sameh Trabelsi, Mohamed Hedi Loueslati, Mohamed Lakhal, Chalbi Belkahia
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  ABSTRACT: Tiemonium, an anti-spasmodic drug, can have adverse effects related to its anti-muscarinic effect. Dyskinesia is described with other anti-cholinergic drugs, but there are no reports of dyskinesia associated with tiemonium. We report a reversible orofacial dyskinesia following tiemonium intake (contained in Viscéralgine forte) in a woman with positive rechallenge. She presented these symptoms two times after two separate injections with an interval of 2 months. The case was reported to the Tunisian Centre of Pharmacovigilance.
  Fundamental and Clinical Pharmacology 01/2008; 21(6):657-8.
• Article: Communicative methods of teaching: A structuralistic model of the construction of knowledge in problem based learning

  P. Papaioannidou
  Fundamental and Clinical Pharmacology 01/2008; 22:43.
• Article: Dose-response effect of ellagic acid on circulatory antioxidants and lipids during alcohol-induced toxicity in experimental rats.

  Nagarajan Devipriya, Adluri Ram Sudheer, Venugopal P Menon
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  ABSTRACT: Ellagic acid (EA) is a naturally occurring polyphenolic compound that exhibits antioxidative, anti-inflammatory, anti-hyperlipidaemic and anticarcinogenic activities in a wide range of assays both in vitro and in vivo. It occurs in various foods such as strawberries, grapes, walnuts, etc. The aim of this study was to assess the effect of ellagic acid on alcohol-induced changes in the circulatory antioxidative status, micronutrients and lipid levels in a dose-dependent fashion. Female albino Wistar rats weighing 150-170 g were used to assess the effects of EA against alcohol-induced damage. Three different concentrations of EA (30, 60 and 90 mg/kg body weight) were tested against 20% alcohol via intragastric administration. At the end of the experimental duration of 45 days, we evaluated endogenous antioxidants: both enzymatic (superoxide dismutase, catalase and glutathione peroxidase) and non-enzymatic (vitamin C and E, and reduced glutathione) status, micronutrients, viz. copper and zinc, and lipids: cholesterol, triglycerides, free fatty acids and phospholipids in the circulation. The body weight gain of both alcohol-fed rats and EA-treated rats were also inferred. EA significantly inhibits alcohol-induced toxicity by improving body weight, restoring antioxidant status, modulating micronutrients and attenuating the lipid levels in the circulation. The greatest inhibitory effect was observed with 60 mg/kg body weight of EA in all the biochemical assessments. The results support the hypothesis that EA at the concentration of 60 mg/kg body weight decreases the intensity of alcohol-induced toxicity and could be developed as a potential drug for alcohol abuse in the near future.
  Fundamental and Clinical Pharmacology 01/2008; 21(6):621-30.
• Article: Analysis of drug transporter expression in human intestinal Caco-2 cells by real-time PCR.

  Nathalie Maubon, Marc Le Vee, Lina Fossati, Mathilde Audry, Eric Le Ferrec, Sebastien Bolze, Olivier Fardel
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  ABSTRACT: Expression of drug transporters corresponds to a crucial parameter in intestinal Caco-2 cells widely used for investigating drug absorption. In order to characterize it in an accurate, reproducible and comparative manner, we analyzed mRNA levels of 19 influx and efflux drug transporters through real-time quantitative polymerase chain reaction assays combined with the use of a total RNA reference standard. Profiles of transporter expression were found to be significantly correlated in two independent Caco-2 cell clones and in human small intestine, which may support the use of Caco-2 cells for investigating intestinal drug transport. Several transporters were nevertheless quantitatively expressed at higher (MRP2, MRP3, MRP4, MRP5, MRP6, OATP-A, OATP-B, OCT1 and MCT1) or lower (BCRP) levels in Caco-2 cells comparatively to small intestine. Moreover, MDR1, MRP2, OATP-A and PEPT1 mRNA relative expression were found to differ in the two analyzed Caco-2 cell clones by at least a twofold factor, highlighting that some variations in transporter expression may occur in Caco-2 cells depending on cell origin, and therefore underlining the interest of carefully characterizing transporter levels in any Caco-2 cell clone before its use for drug transport assays.
  Fundamental and Clinical Pharmacology 01/2008; 21(6):659-63.
• Article: Influence of tetrahydrocurcumin on tail tendon collagen contents and its properties in rats with streptozotocin-nicotinamide-induced type 2 diabetes.

  Leelavinothan Pari, Pidaran Murugan
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  ABSTRACT: Changes in the structural and functional properties of collagen caused by advanced glycation might be of importance for the etiology of late-stage complications in diabetics. Curcumin is the most active component of turmeric. It is believed that curcumin is a potent antioxidant and anti-inflammatory agent. Tetrahydrocurcumin (THC) is one of the major metabolites of curcumin, exhibiting many of the same physiological and pharmacological activities of curcumin and in some systems may exert greater antioxidant activity than curcumin. In diabetic rats, hydroxyproline and collagen content as well as its degree of cross-linking were increased, as shown by increased extent of glycation, collagen-linked fluorescence, neutral salt collagen, and decreased acid and pepsin solubility. Administration of THC for 45 days to diabetic rats significantly reduced the accumulation and cross-linking of collagen. The effects of THC were comparable with those of curcumin. In conclusion, administration of THC had a positive influence on the content of collagen and its properties in streptozotocin- and nicotinamide-induced diabetic rats. THC was found to be more effective than curcumin.
  Fundamental and Clinical Pharmacology 01/2008; 21(6):665-71.
• Article: The mechanisms of vasorelaxant effect of leptin on isolated rabbit aorta.

  Ayşe Saide Sahin, Hulagu Bariskaner
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  ABSTRACT: In the present study, we analysed the effects of leptin on rabbit aorta and the mechanisms underlying these effects. Leptin (10(-12)-10(-9) m) induced concentration-dependent relaxation in intact rabbit aorta rings precontracted with phenylephrine (10(-6) m). Removal of endothelium abolished the effects of leptin. Pretreatment of rings with N(omega)-nitro-l-arginine methyl ester (10(-4) m 20 min) or catalase (1200 U/mL 20 min) significantly reduced the relaxant response to leptin when compared with the control group. The incubation of brefeldin A (3.5 x 10(-5) m 90 min), indomethacin (10(-5) m 20 min), tetraethylammonium (10(-4) m 20 min), and glibenclamide (10(-5) m, 20 min) did not affect the leptin-induced vasodilation. These results suggest that leptin relaxes the rabbit aorta. The relaxation is mediated by endothelium-derived nitric oxide and hydrogen peroxide.
  Fundamental and Clinical Pharmacology 01/2008; 21(6):595-600.
• Article: Effects of L-arginine and phosphodiesterase-5 inhibitor, sildenafil, on inflammation and airway responsiveness of sensitized BP2 mice.

  B Al Qadi-Nassar, F Bichon-Laurent, K Portet, P Tramini, B Arnoux, A Michel
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  ABSTRACT: Nitric oxide (NO) levels are elevated in the exhaled breath of asthmatic patients and NO is considered as a biomarker of airway inflammation. However, the functions of NO in the airways are not completely understood. L-arginine, as the substrate of NO synthases, is the precursor of NO which stimulates guanylate cyclase and leads to the formation of cyclic GMP (cGMP). Sildenafil, a phosphodiestérase-5 (PDE-5) inhibitor, prevents the degradation of cGMP. In this study the effects of L-arginine and sildenafil treatment, alone or in combination, were evaluated in ovalbumin-sensitized BP2 mice. These effects concerning the airway responsiveness to inhaled methacholine (MCh) were evaluated by whole-body plethysmography (WBP), the inflammatory response evaluated by bronchoalveolar lavage fluid (BALF) analyses and lung tissue biopsies (eosinophilic inflammation associated with lung remodelling), and NO metabolite measurements (by Griess reaction) in BALF. Ovalbumin sensitization induced: (a) an inflammatory reaction with eosinophil and neutrophil influx in BALF and lung; and (b) an increased bronchial responsiveness to MCh. L-arginine treatment [50 mg/kg intraperitoneally (i.p.), for 7 days] increased the relative amount of eosinophils and neutrophils in BALF, had a tendency to increase the airway responsiveness to inhaled MCh and increased the NO metabolite level in BAL. Sildenafil treatment (20 mg/kg i.p. for 7 days) did not affect the airway responsiveness to MCh and had a lower effect compared with L-arginine on inflammatory reactions. The combination of the two treatments resulted in a dramatic enhancement of the airway responsiveness to inhaled MCh. The relative amount of eosinophils was increased and lung histology showed obvious worsened tissular lesions such as epithelial shedding and hypertrophy, hyperplasia of smooth muscle cells, and fibrosis. These findings are consistent with the notion that NO production plays a role in the development of airway inflammation and hyperresponsiveness of sensitized mice and highlighted the potential risk of the L-arginine dietary complement or PDE5 treatment in asthmatic patients.
  Fundamental and Clinical Pharmacology 01/2008; 21(6):611-20.
• Article: Evaluation of two evidence-based knowledge transfer interventions for physicians. A cluster randomized controlled factorial design trial: the CardioDAS Study.

  Emmanuel Amsallem, Christelle Kasparian, Michel Cucherat, Sylvie Chabaud, Margaret Haugh, Jean-Pierre Boissel, Patrice Nony
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  ABSTRACT: To investigate the potential benefits of two modes of evidence-based knowledge transfer ('active' and 'passive' modes) in terms of improvement of intention of prescription, knowledge, and real prescription in practice, we performed an open randomized controlled trial (CardioDAS) using a factorial design (two tested interventions: 'active' and 'passive' knowledge transfer) and a hierarchical structure (cluster of physicians for each department level). The participants were cardiologists working in French public hospitals. In the 'passive' transfer group, cardiologists received evidence-based knowledge material (available on Internet) every week for a duration of 1 year. In the 'active' transfer group, two knowledge brokers (EA, PN) visited the participating departments (every 2 months for 1 year, 2 h per visit). The primary outcome consisted in the adjusted absolute mean variation of score (difference between post- and pre-study session) of answers to simulated cases assessing the intention to prescribe. Secondary outcomes were the variation of answers to a multiple-choice questionnaire (MCQ) assessing knowledge and of the conformity of real prescriptions to evidence-based reference assessing the behavioral change. Twenty-two French units (departments) of cardiology were randomized (72 participating cardiologists). In the 'active' transfer group, the primary outcome was more improved than that in the control (P = 0.031 at the department level, absolute mean improvement of 5 points/100). The change in knowledge transfer (MCQ) was also significant (P = 0.039 at the department level, absolute mean improvement of 6 points/100). However, no benefit was shown in terms of prescription conformity to evidence. For the 'passive' mode of knowledge transfer and for the three outcomes considered, no improvement was identified. CardioDAS findings confirm that 'active' knowledge transfer has some impact on participants' intent to prescribe and knowledge, but no effect on behavioral outcome. 'Passive' transfer seems far less efficient. In addition, the size of the benefit remains small and its consequences limited in practice.
  Fundamental and Clinical Pharmacology 01/2008; 21(6):631-41.
• Article: Glitazones in the treatment of cardiovascular risk factors.

  Mohamed Amine Bouhlel, Giulia Chinetti-Gbaguidi, Bart Staels
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  ABSTRACT: This review focuses on the recent advances on the role of the nuclear receptor peroxisome proliferator-activated receptor gamma in the modulation of vascular lipid homeostasis and the inflammatory response and the potential role of these activities in the modulation of metabolic and cardiovascular disease.
  Fundamental and Clinical Pharmacology 12/2007; 21 Suppl 2:7-13.
• Article: The pharmacologic elegance of inhibiting cholesterol absorption and synthesis while providing a homeostatic balance.

  Alberico L Catapano
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  ABSTRACT: The recent discoveries on the concerted role of several mechanisms involved in regulating the balance of body cholesterol highlight the role of intestinal absorption. Selective modulators of intestinal cholesterol absorption are available that offer a new pharmacologic approach to the modulation of total body cholesterol homeostasis and to a more effective reduction of low-density-lipoprotein cholesterol.
  Fundamental and Clinical Pharmacology 12/2007; 21 Suppl 2:21-6.
• Article: Biomarkers, C-reactive proteins and statins in acute coronary syndromes.

  Kausik K Ray
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  ABSTRACT: Atherosclerosis is now widely accepted as an active process involving a pathological vascular triad of vascular cellular activation, inflammation, and thrombosis. Several biomarkers show promise for risk prediction in high risk patients in large scale studies. Some are modified by statin therapy and may be targets for future therapeutic drug development whereas others identify high risk groups that benefit from specific treatments such as intensive statin therapy. Further understanding the role of different biomarkers will help better understand the pathophysiology of ACS as well as provide personalized medical care.
  Fundamental and Clinical Pharmacology 12/2007; 21 Suppl 2:31-3.