IPS Therapeutique Inc.
IPS Therapeutique Inc.
Shopp G.M.,Shopp Nonclinical Consulting LLC |
Helson L.,Signpath Pharma |
Bouchard A.,IPS Therapeutique Inc. |
Salvail D.,IPS Therapeutique Inc. |
Majeed M.,Sabinsa Corporation
Anticancer Research | Year: 2014
Crizotinib (Xalkori®) and nilotinib (Tasigna®) are tyrosine kinase inhibitors approved for the treatment of nonsmall cell lung cancer and chronic myeloid leukemia, respectively. Both have been shown to result in electrocardiogram rate-corrected Q-wave T-wave interval (QTc) prolongation in humans and animals. Liposomes have been shown to ameliorate drug-induced effects on the cardiac-delayed rectifier K+ current (IKr, KV11.1), coded by the human ether-a-go-go-related gene (hERG). This study was undertaken to determine if liposomes would also decrease the effect of crizotinib and nilotinib on the IKr channel. Crizotinib and nilotinib were tested in an in vitro IKr assay using human embryonic kidney (HEK) 293 cells stably transfected with the hERG. Dose-responses were determined and the 50% inhibitory concentrations (IC50s) were calculated. When the HEK 293 cells were treated with crizotinib or nilotinib that were mixed with liposomes, there was a significant decrease in the IKr channel inhibitory effects of these two drugs. When isolated, rabbit hearts were exposed to crizotinib or nilotinib, there were significant increases in QTc prolongation. Mixing either of the drugs with liposomes ameliorated the effects of the drugs. Rabbits dosed intravenously (IV) with crizotinib or nilotinib showed QTc prolongation. When liposomes were injected prior to crizotinib or nilotinib, the liposomes decreased the effects on the QTc interval. The use of liposomal encapsulated QT-prolongation agents, or giving liposomes in combination with drugs, may decrease their cardiac liability. © 2014, International Institute of Anticancer Research. All rights reserved.
Helson L.,Signpath Pharma |
Bouchard A.,IPS Therapeutique Inc. |
Majeed M.,Sabinsa Inc
Journal of Receptor, Ligand and Channel Research | Year: 2011
Background: The duration of the QT interval on the standard electrocardiogram (ECG) is measured from the beginning of the QRS complex (depolarization of the cardiac myocyte) to the end of the T-wave (completion of the repolarization phase of the cardiac myocyte). Repolarization is a result of currents generated by the outward flow of K+ through the K+ channels. Obstruction of ion flow in the channel leads to delayed repolarization, evidenced by a prolonged QT interval. Clinically, this is known as the long QT syndrome (LQTS), which, when expressed, can lead to severe cardiac arrhythmias and sudden death. Obstruction of K+ ion flow can result from gene mutations (eg, the human ether-a-go-go-related gene [hERG]) resulting in phenotypic abnormalities in K+ channels and/or common structurally diverse drugs. These gene abnormalities or drug-induced changes result in decreased cardiac delayed-rectifier K+ current (I Kr, or KV11.1) in congenital or acquired LQTS, respectively. Increased risk of LQTS is a major drug development hurdle, and many drugs have been withdrawn during preclinical development, assigned black box warnings following approval, or withdrawn from the market. Autosomal recessive or dominant LQTS based upon 500 possible mutations in ten different genes coding for K+ channels has an incidence of 1:3000 or about 100,000 persons in the USA. Prolonged QT intervals or risk of LQTS occurs in 2.5% of the asymptomatic US population. The probability of cardiac death in patients with asymptomatic congenital LQTS who are concomitantly medicated with LQTS-inducing drugs appears to have increased. Methods: E-4031 (methanesulfanalide), terfenadine (Seldane®), curcumin, liposomal curcumin, empty liposomes, empty liposomes vortexed with E-4031, or terfenadine and empty liposomes vortexed with curcumin were assayed for their effects on the K+-selective I Kr tail current inhibition using human embryonic kidney (HEK 293) cells stably transfected with the hERG gene via the whole-cell manual patch clamp technique. Results: E-4031, terfenadine, and curcumin inhibit I Kr channel following nM-to-μM exposures. Empty liposomes had no effect on I Kr. Both the liposomal curcumin formulation and vortexed mixtures of empty liposomes and curcumin prevented the I Kr inhibitory effect of curcumin in a dose-dependent manner. Empty liposomes vortexed with E-4031 prevented the effect of E-4031 to a lesser extent, while empty liposomes vortexed with terfenadine did not alter its I Kr inhibitory activity. Conclusion: Curcumin causes an inhibition of the hERG tail current density. The liposomal curcumin formulation, as well as a mixture of empty liposomes with curcumin or with E-4031, blocked drug-induced I Kr inhibition. However, empty liposomes mixed with terfenadine did not alter terfenadine's I Kr inhibitory effects. The liposomes protected against the inhibitory effect of some compounds on the K+-selective I Kr current, independent of their potency.
Salvail D.,IPS Therapeutique Inc. |
Bouchard A.,IPS Therapeutique Inc.
Journal of Pharmacological and Toxicological Methods | Year: 2014
Orthostatic hypotension (OH) is common in humans taking blood pressure-lowering drugs. Drugs which affect heart rate (HR), arterial pressure (BP), or the autonomic system can all contribute to a decrease in baroreflex reserve, rendering patients susceptible to syncope. A model capable of detecting a loss in OH tolerance has been developed. Adult male Wistar rats were anesthetized with urethane and instrumented with pressure transducers in the carotid artery and femoral vein. Sub-dermal ECG leads were attached in a Lead II configuration. Baseline hemodynamic responses to postural changes were measured by tilting the animals to 60° for 1 min. The tilt induced a transient 15-mm Hg hypotension, followed by tachycardia and ensuing maintained hypertension. A double thoracic vagotomy was made which caused an increased HR. Upon tilting, a delayed 30-bpm increase in HR increased BP by 12 mm Hg. Propanolol (500 μg/kg) was injected and HR lowered by 15 bpm while BP lowered by 7 mm Hg. Tilting failed to induce tachycardia and hypertension. Spectral analysis of changes in HR and BP revealed rapid (1 s) and slow (15 s) responses to tilting which were respectively vago-dependent and beta-blocker sensitive. Phenylephrine (5 μg/kg) caused an immediate 20 mm Hg hypertension without change in HR. Spectral analysis of the changes in HR and BP confirmed the enhanced slow sympathetic component, without a rapid parasympathetic component. These experiments confirm the sensitivity of the model and its ability at identifying compounds capable of limiting baroreflex sensitivity.
Catanzaro O.L.,University Argentina nnedy |
Catanzaro O.L.,University of Salvador |
Dziubecki D.,University Argentina nnedy |
Labal E.,University Argentina nnedy |
Sirois P.,IPS Therapeutique Inc.
Peptides | Year: 2010
The effects of lipopolysaccharide (LPS) and desArg9Bradykinin (DBK) on the release of nitric oxide (NO) from macrophages of mice 8, 12 and 18 days after having been treated with low doses of streptozotocin (STZ; 5 × 45 mg/kg) were studied. The results showed that LPS stimulated the release of NO from macrophages of untreated animals by 50% whereas the bradykinin B1 agonist desArg9Bradykinin (DBK) increased the level of NO by 20%. This increased NO production was totally abolished by incubating the cells with R-954, a selective bradykinin B1 antagonist. The release of NO from macrophages of STZ-treated mice incubated in the presence of LPS was more marked and reached approximately 220, 300 and 270% respectively from cells collected 8, 12 and 18 days after the STZ treatment. These significant increases were completely blocked by R-954 and were even below control values. Similarly the results showed that DBK stimulated by 50-75% the release of NO from macrophages of STZ-treated mice. The most marked stimulation was noted when the cells were collected 18 days after the treatment of the animals with STZ. Again in this set of experiments the B1 antagonist completely blocked the release of NO which went even below control values. The results clearly suggest the upregulation of bradykinin B1 receptors in mouse macrophages in the early phase of STZ-induced diabetes, an event that could even precede the onset of the diabetic hyperglycemia. © 2010 Elsevier Inc. All rights reserved.
Kaufman G.N.,Sainte Justine Hospital Research Center |
Zaouter C.,Sainte Justine Hospital Research Center |
Valteau B.,Sainte Justine Hospital Research Center |
Sirois P.,IPS Therapeutique Inc. |
And 2 more authors.
Arthritis Research and Therapy | Year: 2011
Introduction: Endothelin-1, a vasoconstrictor peptide, influences cartilage metabolism mainly via endothelin receptor type A (ETA). Along with the inflammatory nonapeptide vasodilator bradykinin (BK), which acts via bradykinin receptor B1 (BKB1) in chronic inflammatory conditions, these vasoactive factors potentiate joint pain and inflammation. We describe a preclinical study of the efficacy of treatment of surgically induced osteoarthritis with ETA and/or BKB1 specific peptide antagonists. We hypothesize that antagonism of both receptors will diminish osteoarthritis progress and articular nociception in a synergistic manner.Methods: Osteoarthritis was surgically induced in male rats by transection of the right anterior cruciate ligament. Animals were subsequently treated with weekly intra-articular injections of specific peptide antagonists of ETA and/or BKB1. Hind limb nociception was measured by static weight bearing biweekly for two months post-operatively. Post-mortem, right knee joints were analyzed radiologically by X-ray and magnetic resonance, and histologically by the OARSI histopathology assessment system.Results: Single local BKB1 antagonist treatment diminished overall hind limb nociception, and accelerated post-operative recovery after disease induction. Both ETA and/or BKB1 antagonist treatments protected joint radiomorphology and histomorphology. Dual ETA/BKB1 antagonism was slightly more protective, as measured by radiology and histology.Conclusions: BKB1 antagonism improves nociceptive tolerance, and both ETA and/or BKB1 antagonism prevents joint cartilage degradation in a surgical model of osteoarthritis. Therefore, they represent a novel therapeutic strategy: specific receptor antagonism may prove beneficial in disease management. © 2011 Kaufman et al.; licensee BioMed Central Ltd.
PubMed | University of Helsinki and IPS Therapeutique Inc.
Type: | Journal: Clinical and experimental nephrology | Year: 2016
Renal ischemia-reperfusion predisposes to acute kidney injury (AKI) and mortality. APAC, mast cell heparin proteoglycan mimetic is a potent dual antiplatelet and anticoagulant inhibiting thrombosis in several vascular models.Clinically relevant (0.06 and 0.13mg/kg) and high (0.32 and 7.3mg/kg) heparin doses of APAC and unfractionated heparin (UFH) were administered i.v. in pharmacological studies. Antithrombotic action of APAC and UFH was assessed with platelet aggregation to collagen, activated partial thromboplastin (APTT) and prothrombin (PT) times. Pharmacodynamics of [APAC in contrast to UFH inhibited platelet aggregation. During 0.06 and 0.13mg/kg dose regimens APTT and PT remained at baseline, but at the high APTT prolonged fourfold to sixfold. Overall bio-distribution and clearance of APAC and UFH were similar. After bilateral 30-min renal artery clamping, creatinine, urea nitrogen and neutrophil gelatinase-associated lipocalin concentrations and histopathology indicated faster renal recovery by APAC (0.13mg/kg). APAC, unlike UFH, prevented expression of innate immune ligand hyaluronan and tubulointerstitial injury marker Kim-1. Moreover, in severe bilateral 1-h renal artery clamping, APAC (0.13mg/kg) prevented AKI, as demonstrated both by biomarkers and survival. Compatible with kidney protection APAC reduced the circulating levels of vascular destabilizing and pro-inflammatory angiopoietin-2 and syndecan-1. No tissue bleeding ensued.APAC and UFH were similarly eliminated via kidneys and liver. In contrast to UFH, APAC (0.13mg/kg) was reno-protective in moderate and even severe IRI by attenuating vascular injury and innate immune activation.
Li G.F.,Soochow University of China |
Pan Y.Z.,Soochow University of China |
Sirois P.,IPS Therapeutique Inc. |
Li K.,Soochow University of China |
Xu Y.J.,Soochow University of China
Osteoporosis International | Year: 2012
Osteoporosis has until now been considered to be a disease associated with abnormal calcium metabolism. However, an increasing number of clinical observations strongly suggest the association of iron overload with bone diseases, particularly in osteoporosis in menopausal women. The recent identification of hepcidin sheds new light into the crucial role of iron homeostasis in bone metabolism. Decreasing iron overload in cell studies as well as in animal experiments has been shown to improve bone cell metabolism and growth in vitro and in vivo. In view of the significant iron overload found in the aging population, especially in females, the therapeutic potential of lowering iron overload for the treatment of osteoporosis is suggested. © International Osteoporosis Foundation and National Osteoporosis Foundation 2012.
PubMed | Singapore Institute of Medical Biology, Université de Sherbrooke and IPS Therapeutique Inc.
Type: Journal Article | Journal: Journal of medicinal chemistry | Year: 2016
ELABELA (ELA) was recently discovered as a novel endogenous ligand of the apelin receptor (APJ), a G protein-coupled receptor. ELA signaling was demonstrated to be crucial for normal heart and vasculature development during embryogenesis. We delineate here ELAs structure-activity relationships and report the identification of analogue 3 (ELA(19-32)), a fragment of ELA that binds to APJ, activates the Gi1 and -arrestin-2 signaling pathways, and induces receptor internalization similarly to its parent endogenous peptide. An alanine scan performed on 3 revealed that the C-terminal residues are critical for binding to APJ and signaling. Finally, using isolated-perfused hearts and in vivo hemodynamic and echocardiographic measurements, we demonstrate that ELA and 3 both reduce arterial pressure and exert positive inotropic effects on the heart. Altogether, these results present ELA and 3 as potential therapeutic options in managing cardiovascular diseases.
Venkatesh M.,Yeshiva University |
Wang H.,Yeshiva University |
Cayer J.,IPS Therapeutique Inc. |
Leroux M.,IPS Therapeutique Inc. |
And 4 more authors.
Molecular Pharmacology | Year: 2011
The pregnane X receptor (PXR) is a master regulator of xenobiotic clearance and is implicated in deleterious drug interactions (e.g., acetaminophen hepatotoxicity) and cancer drug resistance. However, small-molecule targeting of this receptor has been difficult; to date, directed synthesis of a relatively specific PXR inhibitor has remained elusive. Here we report the development and characterization of a first-in-class novel azole analog [1-(4-(4-(((2R,4S)-2-(2, 4-difluorophenyl)-2-methyl-1,3-dioxolan-4-yl)methoxy)phenyl)piperazin-1-yl) ethanone (FLB-12)] that antagonizes the activated state of PXR with limited effects on other related nuclear receptors (i.e., liver X receptor, farnesoid X receptor, estrogen receptor α, peroxisome proliferator-activated receptor γ, and mouse constitutive androstane receptor). We investigated the toxicity and PXR antagonist effect of FLB-12 in vivo. Compared with ketoconazole, a prototypical PXR antagonist, FLB-12 is significantly less toxic to hepatocytes. FLB-12 significantly inhibits the PXR-activated loss of righting reflex to 2,2,2-tribromoethanol (Avertin) in vivo, abrogates PXR-mediated resistance to 7-ethyl-10-hydroxycamptothecin (SN-38) in colon cancer cells in vitro, and attenuates PXR-mediated acetaminophen hepatotoxicity in vivo. Thus, relatively selective targeting of PXR by antagonists is feasible and warrants further investigation. This class of agents is suitable for development as chemical probes of PXR function as well as potential PXRdirected therapeutics. Copyright © 2011 The American Society for Pharmacology and Experimental Therapeutics.
Chagnon F.,IPS Therapeutique Inc.
Critical Care Medicine | Year: 2016
OBJECTIVE:: Dobutamine is the currently recommended β-adrenergic inotropic drug for supporting sepsis-induced myocardial dysfunction when cardiac output index remains low after preload correction. Better and safer therapies are nonetheless mandatory because responsiveness to dobutamine is limited with numerous side effects. Apelin-13 is a powerful inotropic candidate that could be considered as an alternative noncatecholaminergic support in the setting of inflammatory cardiovascular dysfunction. DESIGN:: Interventional controlled experimental animal study. SETTING:: Tertiary care university-based research institute. SUBJECTS:: One hundred ninety-eight adult male rats. INTERVENTIONS:: Using a rat model of “systemic inflammation–induced cardiac dysfunction” induced by intraperitoneal lipopolysaccharide injection (10 mg/kg), hemodynamic efficacy, cardioprotection, and biomechanics were assessed under IV osmotic pump infusions of apelin-13 (0.25 μg/kg/min) or dobutamine (7.5 μg/kg/min). MEASUREMENTS AND MAIN RESULTS:: In this model and in both in vivo and ex vivo studies, apelin-13 compared with dobutamine provoked distinctive effects on cardiac function: 1) optimized cardiac energy–dependent workload with improved cardiac index and lower vascular resistance, 2) upgraded hearts’ apelinergic responsiveness, and 3) consecutive downstream advantages, including increased urine output, enhanced plasma volume, reduced weight loss, and substantially improved overall outcomes. In vitro studies confirmed that these apelin-13–driven processes encompassed a significant and rapid reduction in systemic cytokine release with dampening of myocardial inflammation, injury, and apoptosis and resolution of associated molecular pathways. CONCLUSIONS:: In this inflammatory cardiovascular dysfunction, apelin-13 infusion delivers distinct and optimized hemodynamic support (including positive fluid balance), along with cardioprotective effects, modulation of circulatory inflammation and extended survival. Copyright © by 2016 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.