Henri Doods - Academia.edu (original) (raw)

Papers by Henri Doods

Shock (Augusta, Ga.), 2005

Na(+)/H(+) exchange (NHE) is involved in the myocardial injury that occurs during ischemia and re... more Na(+)/H(+) exchange (NHE) is involved in the myocardial injury that occurs during ischemia and reperfusion. The goal of the present study was to investigate the role of NHE in hypovolemic circulatory shock by using a potent NHE-1 selective inhibitor BIIB513. Acute rapid hemorrhage was induced in 14 pigs by bleeding (30 mL/kg over 30 min). Seven pigs were used as saline control. Seven other pigs received 3 mg/kg BIIB513 at 30 min after hemorrhage. Each experiment consisted of 2 h of hypovolemia followed by 2 h of fluid resuscitation. One control animal died before the experiment was completed. Six other control animals survived the entire experiment. In contrast, all the BIIB513 treated animals survived the entire protocol. Acute rapid blood loss resulted in impaired myocardial performance as well as severe hemodynamic and metabolic alterations. NHE blockade attenuated the hypovolemic hypotension and improved myocardial performance. NHE blockade also attenuated the metabolic acidosis...

Objective: This study was undertaken to examine the effects of BI113823, a potent small molecule ... more Objective: This study was undertaken to examine the effects of BI113823, a potent small molecule orally active non-peptide B1 receptor antagonist in an experimental model of endotoxin-induced direct lung injury in mice, and indirect lung injury and survival in cecal ligation and puncture (CLP) induced polymicrobial sepsis in rats.

The Journal of Neuroscience : The Official Journal of the Society for Neuroscience

Aged memory-impaired (AI) and unimpaired (AU) 24-25-month-old Long-Evans rats were used to invest... more Aged memory-impaired (AI) and unimpaired (AU) 24-25-month-old Long-Evans rats were used to investigate the integrity of various cholinergic markers during normal aging and to establish if alterations can possibly relate to cognitive disabilities. AI and AU rats were classified on the basis of their performance in the Morris swim maze task. Choline acetyltransferase activity (ChAT) was not differentially altered in various cortical and hippocampal areas between these two groups. Similarly, quantitative receptor autoradiography did not reveal significant differences in 3H-pirenzepine/muscarinic M1 and 3H-hemicholinium-3/high-affinity choline uptake binding sites in AI versus AU rats. In contrast, 3H-AF-DX 384/putative muscarinic M2 binding was significantly increased in certain cortical and hippocampal areas of the age-impaired animals. These increments were correlated with decreased in vivo acetylcholine (ACh) release capacity in the AI rats. Most interestingly, the muscarinic M2 ant...

The invention relates to 3-aza-bicyclo[3.1.0]hexane-6-carboxylic acid amide derivatives of genera... more The invention relates to 3-aza-bicyclo[3.1.0]hexane-6-carboxylic acid amide derivatives of general formula (I), which are agonists of somatostatin receptor subtype 4 (SSTR4), useful for preventing or treating medical disorders related to SSTR4. In addition, the invention relates to processes for preparing pharmaceutical compositions as well as processes for manufacture of the compounds according to the invention.

The Journal of infectious diseases, Jan 26, 2015

This study examined the therapeutic effects of an orally active non-peptide kinin B1 receptor an... more This study examined the therapeutic effects of an orally active non-peptide kinin B1 receptor antagonist, BI113823, in a clinically relevant experimental model of polymicrobial sepsis in rats. Sepsis was induced by cecal ligation and puncture (CLP). Animals received treatment with either vehicle or BI113823. The experiment was terminated 15 hours after CLP in SET 1 animals. Seven-day survival following CLP was determined in SET 2 animals. Compared to vehicle treatment, administration of BI113823 reduced neutrophil and macrophage infiltration, reduced cytokine production, attenuated intestinal mucosal hyperpermeability, prevented hemodynamic derangement, and improved cardiac output. Furthermore, administration of BI113823 reduced lung iNOS expression and lung injury score and attenuated NF-ĸB activation and apoptosis in the liver. Treatment with BI113823 also reduced plasma levels of cardiac troponin, aspartate aminotransferase, alanine aminotransferase, urea, and lactate, as well...

Critical Care Medicine, 2015

Hypertension, 2015

This study examined whether the kinin B1 receptor is involved in the pathogenesis of pulmonary hy... more This study examined whether the kinin B1 receptor is involved in the pathogenesis of pulmonary hypertension, and whether its inhibition could reduce inflammation, pulmonary hypertension, vascular remodeling, and right heart dysfunction. Male Wistar rats underwent left pneumonectomy. Seven days later, the rats were injected subcutaneously with monocrotaline (60 mg/kg). The rats were then randomly assigned to receive treatment with vehicle or with BI113823 (a selective B1 receptor antagonist, 30 mg/kg, twice per day) via oral gavage from the day of monocrotaline injection to day 28. By day 28, BI113823-treated rats had significantly lower mean pulmonary artery pressure, less right ventricular hypertrophy, and pulmonary arterial neointimal formation than that of the vehicle-treated rats. Real-time polymerase chain reaction revealed that there was a significant increase in mRNA expression of B1 receptors in the lungs of monocrotaline-challenged pneumonectomized rats. Treatment with BI113823 significantly reduced macrophage recruitment, as measured via bronchoalveolar lavage. It also markedly reduced CD-68 positive macrophages and proliferating cell nuclear antigen positive cells in the perivascular areas, reduced expression of inducible nitric oxide synthase, matrix metalloproteinase 2 and 9, and B1 receptors compared with measurements in vehicle-treated rats. These findings demonstrate that kinin B1 receptors represent a novel therapeutic target for pulmonary arterial hypertension.

Journal of cardiovascular pharmacology and therapeutics, 2007

Monocyte chemoattractant protein-1 (MCP-1) is a stimulator of collateral artery growth and has be... more Monocyte chemoattractant protein-1 (MCP-1) is a stimulator of collateral artery growth and has been shown to increase collateral artery conductance in rabbits and pigs. The minimal infusion duration and the minimally effective dose of MCP-1 are currently unknown, as is the sustainability of the therapeutic effect over a longer observation period than tested before. MCP-1 was infused intra-arterially in pigs after unilateral femoral artery occlusion in different doses and infusion durations between 2 hours and 2 weeks. Two weeks after ligation, arterial conductance under maximal vasodilatation was measured. The long-term efficacy was investigated in 2 additional groups of animals after 6 weeks. Infusion with 2 microg/min of MCP-1 for 6 hours was sufficient to double arterial conductance, and arterial conductance after 6 weeks was still significantly increased.

Neuropharmacology, 2002

Calcitonin gene-related peptide (CGRP) is a potent vasodilator in brain vessels and it has been i... more Calcitonin gene-related peptide (CGRP) is a potent vasodilator in brain vessels and it has been implicated in the pathogenesis of migraine headache. Blocking post-junctional CGRP receptors, mediators of trigeminal-induced vasodilation, has been suggested as a potential antimigraine strategy. In this study, we tested the ability of a new non-peptide CGRP receptor antagonist, BIBN4096BS, to inhibit the CGRP-induced dilation in human and/or bovine brain vessels and compared it to that of the antagonist alpha-CGRP(8-37). BIBN4096BS and alpha-CGRP(8-37) both blocked the alpha-CGRP-induced dilation in bovine middle artery segments with respective potency (pK(B) values) of 6.3 and 7.8. In human pial vessels, BIBN4096BS was particularly potent. When tested at 10(-14)-10(-9) M concentrations, it induced a rightward shift in the alpha-CGRP concentration-response curve and yielded a biphasic Schild plot suggesting interaction with more than one receptor population, as was also indicated by the...

Pharmacological reviews, 1998

Based on structural and evolutionary criteria, neuropeptide Y (NPY) b , peptide YY (PYY) and panc... more Based on structural and evolutionary criteria, neuropeptide Y (NPY) b , peptide YY (PYY) and pancreatic polypetide (PP) are closely related polypeptides (Larhammar, 1996a). They are composed of 36 amino acids each and share considerable amino acid homology, amidated ...

European Journal of Pain, 2014

BioMed Research International, 2013

The aim of the present study was to investigate the effects of sabiporide, a potent and selective... more The aim of the present study was to investigate the effects of sabiporide, a potent and selective NHE1 inhibitor, on myocardial ischemia-induced arrhythmias and myocardial infarction and the possible pathways related to the cardioprotection afforded by sabiporide treatment. Anesthetized rats were subjected to myocardial ischemia via left main coronary artery occlusion for 30 minutes, followed by 2 hours of reperfusion. Administration of sabiporide (0.01-3.0 mg/kg) prior to coronary artery occlusion dose-dependently reduced ischemia-induced arrhythmias and infarct size with an ED50 value of 0.14 mg/kg. Administration of sabiporide (1.0 mg/kg) prior to reperfusion also reduced infarct size by 38.6%. The reduction in infarct size was accompanied by a decrease in circulating levels of creatine phosphokinase and troponin I. In addition, sabiporide (1.0 mg/kg) given prior to coronary artery occlusion or immediately before reperfusion significantly reduced phosphorylation of the extracellular signal-regulated kinase (ERK1/2) and the expression of the inducible nitric oxide synthase (iNOS) following myocardial ischemia-reperfusion. This study demonstrates that sabiporide is a potent and effective cardioprotective agent during myocardial ischemia and reperfusion, by reducing serious ventricular arrhythmias and myocardial infarct size. The cardioprotection afforded by sabiporide is attributed in part to inhibition of ERK1/2 phosphorylation and suppression of iNOS expression.

Drug Discovery Today: Disease Mechanisms, 2006

ABSTRACT Migraine is a common debilitating neurovascular disorder. Because of their dual role in ... more ABSTRACT Migraine is a common debilitating neurovascular disorder. Because of their dual role in modulating neuronal and vascular events, neuropeptides have been implied to be of importance in migraine pathophysiology. Most clinical trials investigating neuropeptide receptor ligands for the treatment of migraine, however, did not show the desired results. The only exception so far is Olcegepant (BIBN4096BS), a potent and selective antagonist of the calcitonin gene related peptide (CGRP) receptor. In a clinical study, this compound proved to be effective in treating migraine headache, highlighting the essential role of CGRP for pathophysiology of migraine.

Pain, 2009

The current study assessed whether the chronic constriction injury (CCI) model of neuropathic pai... more The current study assessed whether the chronic constriction injury (CCI) model of neuropathic pain causes depression-like behaviour in animals, and if this depression-like behaviour can be reversed by anti-nociceptive and/or antidepressant drugs. CCI of the sciatic nerve in rats was selected as a neuropathic pain model, mechanical hypersensitivity was assessed by punctuate mechanical stimuli, and depression-like behaviour was evaluated in the forced swimming test (FST) measuring the time of immobility, climbing and swimming. The CCI rats displayed a significant mechanical hypersensitivity (sham 27 ± 2 g, CCI 12 ± 2 g; P < 0.001) and a significant increase in time of immobility (sham 133 ± 14 s, CCI 201 ± 9 s; P < 0.001). As time of swimming was unchanged, immobility was increased at the expense of climbing behaviour (sham 105 ± 17 s, CCI 63 ± 9 s; P < 0.05). There was no difference in ambulation between sham and CCI animals. In sham and CCI animals, desipramine (20 mg/kg) significantly reduced immobility (sham + vehicle 134 ± 19 s, sham + desipramine 79 ± 13 s; P < 0.01, CCI + vehicle 195 ± 8 s, CCI + desipramine 140 ± 11 s; P < 0.05) and increased climbing behaviour (sham + vehicle 118 ± 21 s, sham + desipramine 182 ± 16 s; P < 0.05, CCI + vehicle 59 ± 8 s, CCI + desipramine 112 ± 14 s; P < 0.05) with little effect on mechanical hypersensitivity. In contrast in CCI animals the cannabinoid CB2-selective agonist GW405833 (2,3-dichloro-phenyl)-[5-methoxy-2-methyl-3-(2-morpholin-4-yl-ethyl)-indol-1yl]-methanone) (30 mg/kg) significantly attenuated immobility (CCI + vehicle 191 ± 7 s, GW405833 145 ± 14 s; P < 0.01) and mechanical hypersensitivity (CCI + vehicle 15 ± 1 g, CCI + GW405833 24 ± 1 g; P < 0.001). Moreover, differently from desipramine, GW405833 did not change the climbing behaviour. These data suggest that rats subjected to the CCI model of neuropathic pain develop depression-like behaviour, which can be reversed by appropriate anti-nociceptive treatment.

Pain, 2013

Calcitonin gene-related peptide (CGRP) is known to play a major role in the pathogenesis of pain ... more Calcitonin gene-related peptide (CGRP) is known to play a major role in the pathogenesis of pain syndromes, in particular migraine pain. Here we focus on its implication in a rat pain model of inflammation, induced by injection of complete Freund adjuvant (CFA). The nonpeptide CGRP receptor antagonist BIBN4096BS reduces migraine pain and trigeminal neuronal activity. Here we demonstrate that the compound reduces inflammatory pain and spinal neuronal activity. Behavioural experiments reveal a reversal of the CFA-induced mechanical hypersensitivity and monoiodoacetate (MIA)-induced weight-bearing deficit in rats after systemic drug administration. To further investigate the mechanism of action of the CGRP antagonist in inflammatory pain, in vivo electrophysiological studies were performed in CFA-injected rats. Recordings from wide dynamic range neurons in deep dorsal horn layers of the lumbar spinal cord confirmed a reduction of neuronal activity after systemic drug application. The same amount of reduction occurred after topical administration onto the paw, with resulting systemic plasma concentrations in the low nanomolar range. However, spinal administration of BIBN4096BS did not modify the neuronal activity in the CFA model. Peripheral blockade of CGRP receptors by BIBN4096BS significantly alleviates inflammatory pain.

Pharmacological research : the official journal of the Italian Pharmacological Society, 2014

This study examined responses of isolated pig coronary arteries after kinin B1 receptor induction... more This study examined responses of isolated pig coronary arteries after kinin B1 receptor induction by endotoxin. Des-Arg9-bradykinin (DBK) induced concentration-dependent, endothelium-independent contractions in lipopolysaccharide (LPS)-treated but not untreated arterial rings. The B1-receptor antagonist SSR240612, but not the B2-receptor antagonist HOE140, prevented the endothelium-independent contractions to DBK. The DBK-induced contractions were blocked by indomethacin (nonselective cyclooxygenase [COX] inhibitor), celecoxib (selective COX-2 inhibitor), and terbogrel (thromboxane-prostanoid [TP] receptor antagonist) but not valeryl salicylate (selective COX-1 inhibitor), AH6809 (an E prostanoid [EP] and PGD2 receptor [DP1] receptor antagonist), AL 8810 (a selective PGF2α [FP] receptor antagonist), or RO1138452 (a selective I prostanoid [IP] receptor antagonist). They were attenuated by N-(p-amylcinnamoyl) anthranilic acid (ACA), and by DETCA plus tiron but not by l-NAME. Quantitat...

European journal of pharmacology, Jan 5, 2015

Somatostatin (SST) is a peptide hormone that regulates the endocrine system and affects neurotran... more Somatostatin (SST) is a peptide hormone that regulates the endocrine system and affects neurotransmission via interaction with G protein-coupled SST receptors and inhibition of the release of different hormones. The aim of this study was to investigate whether the analgesic properties of the selective SSTR4 agonist J-2156 are mediated via peripheral and/or spinal receptors. Effect on mechanical hyperalgesia in the Complete Freund׳s Adjuvant (CFA) model was measured after intraperitoneal application of J-2156. Electrophysiological neuronal recordings were conducted 24h after injection of CFA or vehicle into the paw of Wistar rats. Mechanosensitivity of peripheral afferents of the saphenous nerve as well as of spinal wide dynamic range (WDR) and nociceptive-specific (NS) neurons were measured after systemic or spinal application of J-2156. In CFA animals J-2156 dose dependently reduced hyperalgesia in behavioral studies. The minimal effective dose was 0.1mg/kg. Mechanosensitivity of p...

Trends in Pharmacological Sciences, 2007

Migraine is a complex, debilitating neurovascular disorder. Although knowledge on the main molecu... more Migraine is a complex, debilitating neurovascular disorder. Although knowledge on the main molecular players is still incomplete, recent preclinical and clinical findings indicate that there is a clear correlation between migraine-associated headache and the release of the neuropeptide calcitonin gene-related peptide (CGRP). BIBN4096 was the first CGRP antagonist to be tested in clinical trials for the treatment of migraine. The proven efficacy of this agent, and also the CGRP antagonist MK-0974, to alleviate acute migraine headache provided significant support for the hypothesis that CGRP has an important role in migraine pathophysiology. Moreover, the recently published results from Phase II trials are encouraging and suggest that this new type of drug might offer advantages over existing therapies for patients suffering from migraine and related headaches.