- Noida, Uttar Pradesh, India
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Crit Care Med 2016 • Volume 44 • Number 12 (Suppl.) that multiple CPR events during a single hospitalization are associated with significantly higher risk of in-hospital mortality. Methods: We performed a retrospective analysis of the... more
Crit Care Med 2016 • Volume 44 • Number 12 (Suppl.) that multiple CPR events during a single hospitalization are associated with significantly higher risk of in-hospital mortality. Methods: We performed a retrospective analysis of the Nationwide Inpatient Sample, the largest all-payer inpatient care database in the USA, for the years 2012 and 2013. All patients aged<18 years who had a CPR performed following hospitalization were included. The outcome was in-hospital mortality (IHM) and primary independent variable is number of CPRs performed during the same hospitalization. Multivariable logistic regression analysis was used to examine the impact of number of CPRs on IHM. Patient and hospital level characteristics were adjusted in regression model. Results: During the study period, a total of 11,270 children had a CPR. Of these, 10,955 had one CPR and 315 had more than one CPR. Mean age was 1.5 years. 55% were males. Medicaid(55%) was the predominant payer. 45.9% where Whites, re...
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Introduction: Insulin dependent type I diabetes mellitus (TIDM) can be well-controlled with the use of exogenous insulin, however during illness, poor management of TIDM, failure of the insulin pump to deliver insulin, or prior to a... more
Introduction: Insulin dependent type I diabetes mellitus (TIDM) can be well-controlled with the use of exogenous insulin, however during illness, poor management of TIDM, failure of the insulin pump to deliver insulin, or prior to a diagnosis of TIDM, glucose levels can rise drastically resulting in a condition called diabetic ketoacidosis (DKA). DKA accounts for a majority of hospitalizations due to diabetes, especially in children, and accounts for a significant number of deaths. ET-1 has been found to regulate insulin response and has been implicated in insulin resistance. The present study was conducted to determine the involvement of ET-1 and ET receptors in DKA and to find out whether ETA receptor antagonists can be used to improve the treatment of DKA. Methods: Male Sprague-Dawley rats weighing 300 to 350 g (Harlan, Indianapolis, IN) were injected IP with 150 mg/kg of streptozotocin (STZ) in 0.05 mol/L citrate buffer, pH 4.3 to induced diabetes, while non-diabetic control rat...
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Endothelin B (ETB) receptors present in abundance the central nervous system (CNS) have been shown to have significant implications in its development and neurogenesis. We have targeted ETB receptors stimulation using a highly specific... more
Endothelin B (ETB) receptors present in abundance the central nervous system (CNS) have been shown to have significant implications in its development and neurogenesis. We have targeted ETB receptors stimulation using a highly specific agonist, IRL-1620, to treat CNS disorders. In a rat model of cerebral ischemia intravenous administration IRL-1620 significantly reduced infarct volume and improved neurological and motor functions compared to control. This improvement, in part, is due to an increase in neuroregeneration. We also investigated the role of IRL-1620 in animal models of Alzheimer’s disease (AD). IRL-1620 improved learning and memory, reduced oxidative stress and increased VEGF and NGF in Aβ treated rats. IRL-1620 also improved learning and memory in an aged APP/PS1 transgenic mouse model of AD. These promising findings prompted us to initiate human studies. Successful chemistry, manufacturing and control along with mice, rat and dog toxicological studies led to completion...
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Centhaquin is a compound that produces hypotension and bradycardia in higher doses and resuscitation in lower doses. It is water insoluble, and is unsuitable for intravenous use. We prepared the citrate salt of centhaquin and evaluated... more
Centhaquin is a compound that produces hypotension and bradycardia in higher doses and resuscitation in lower doses. It is water insoluble, and is unsuitable for intravenous use. We prepared the citrate salt of centhaquin and evaluated its cardiovascular efficacy vs. centhaquin. Centhaquin citrate was prepared and characterized; its purity was determined by HPLC. Mean arterial pressure (MAP), heart rate (HR), pulse pressure (PP), cardiac output (CO), stroke volume (SV) and stroke work (SW) following intravenous administration of centhaquin and the citrate (0.05, 0.15 and 0.45 mg.kg(-1)) were determined in anaesthetized male Sprague-Dawley rats. Centhaquin citrate was 99.8% pure and water soluble. Centhaquin (0.05, 0.15 and 0.45 mg.kg(-1)) produced a maximal decrease in MAP of 15.6, 25.2 and 28.1%, respectively; while centhaquin citrate produced a greater (p&amp;amp;lt;0.001) decrease of 35.7, 47.1 and 54.3%, respectively. The decrease in PP and HR produced by the citrate was greater than centhaquin (p&amp;amp;lt;0.001). At 0.45 mg.kg(-1) centhaquin produced a maximal decrease of 20.9% (p&amp;amp;lt;0.01) in CO, while centhaquin citrate produced a decrease of 42.1% (p&amp;amp;lt;0.001). Reduction in SV (p&amp;amp;lt;0.01) and SW (p&amp;amp;lt;0.001) produced by centhaquin citrate were greater than centhaquin. Centhaquin citrate has greater cardiovascular activity compared to centhaquin.
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Centhaquin (PMZ-2010) is a cardiovascular active agent (0.01 to 0.05 mg/kg) which has been shown to have resuscitative effect in a (1) rat model of fixed pressure blood loss, (2) rabbit model of uncontrolled bleeding with trauma, and (3)... more
Centhaquin (PMZ-2010) is a cardiovascular active agent (0.01 to 0.05 mg/kg) which has been shown to have resuscitative effect in a (1) rat model of fixed pressure blood loss, (2) rabbit model of uncontrolled bleeding with trauma, and (3) pig model of massive blood loss. PMZ-2010 produced a decrease in heart rate and vascular resistance; however, it increased mean arterial pressure by increasing cardiac output. We embarked on studies to develop PMZ-2010 as a resuscitative agent for hypovolemic shock. Toxicological studies were carried out and intravenous injection of PMZ-2010 in mice, rats and rabbits showed LD50 >100 mg/kg, 79.43 mg/kg and 9.55 mg/kg, respectively. The No Observed Adverse Effect Level (N.O.A.E.L.) of PMZ-2010 determined after repeated (28 days) intravenous injections of different doses in mice, rats and rabbits was found to be 1.0 mg/kg. A 14 day repeated dose toxicity study of PMZ-2010 (0.01, 0.10 and 1.0 mg/kg, iv) in canine model (beagle dog) was conducted and...
Research Interests: Medicine and Circulation
Sovateltide (IRL-1620, PMZ-1620), an endothelin-B receptor agonist, administered intravenously following acute cerebral ischemic stroke increased cerebral blood flow, had anti-apoptotic activity and produced neurovascular remodeling. Its... more
Sovateltide (IRL-1620, PMZ-1620), an endothelin-B receptor agonist, administered intravenously following acute cerebral ischemic stroke increased cerebral blood flow, had anti-apoptotic activity and produced neurovascular remodeling. Its safety and tolerability were confirmed in healthy human volunteers (CTRI/2016/11/007509). A prospective, multi-centric, randomized, double-blind, parallel, controlled clinical study to compare efficacy of sovateltide with standard treatment in patients with acute cerebral ischemic stroke (CTRI/2017/11/010654; NCT04046484) was conducted in 40 patients, of which 36 completed 90-day follow-up. Patients received saline (n=18; 11 male and 7 female) or sovateltide (n=18; 15 male and 3 female) within 24 hours of onset of stroke. Standard treatment in both cohorts was similar. Mean age in saline and sovateltide cohorts was 58.34±1.73 and 49.83±2.79 years, respectively. Number of patients receiving investigational drug within 20 hours of onset of stroke were...
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Over the past decade, herbal medicine has become an item of global importance, with both medicinal and economic implications. Widespread use of herbs throughout the globe has raised serious concerns over their quality, safety and... more
Over the past decade, herbal medicine has become an item of global importance, with both medicinal and economic implications. Widespread use of herbs throughout the globe has raised serious concerns over their quality, safety and efficacy. Thus, accurate scientific assessment has become a prerequisite for acceptance of herbal health claims. Ailanthus excelsa Roxb is a tree, indigenous to central and southern India, belongs to family Simaroubaceae is widely used in Ayurveda and evidence based phytotherapy. The tribal population uses the plant for antifertility, anthelmintic and rejuvenating purpose. Alkaloids, flavonoids, triterpenoids and bitter principles like quassinoids are reported in this plant. Several quassinoids from Simaroubaceae are designated as potent antimalarial especially against the chloroquine-resistant Plasmodium falciparum. The roots of this plant also serve as substitute for Oroxylum indicum, one of the constituents of an ayurvedic formulation Dasmularista . In t...
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Introduction: Endothelin-1 (ET-1) is a potent vasoactive peptide that acts on ETA and ETB receptors and has been implicated in hemorrhagic shock (HS). Centhaquin, a cardiovascular active agent, is ...
Introduction: PMZ-2010 (centhaquin), was found to be a highly effective resuscitative agent in animal models of hemorrhagic shock and is currently in clinical development (CTRI/2017/03/008184). Met...
Introduction: Centhaquin citrate (PMZ-2010) is a novel agent that has been shown to reduce blood lactate, increase cardiac output and mean arterial pressure, and decrease vascular resistance in hem...
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Triple negative breast cancer (TNBC) features among the most aggressive manifestations of cancer due to its enhanced metastatic potential and immunity to therapeutics which target hormone receptors. Under such scenarios, anti-cancer... more
Triple negative breast cancer (TNBC) features among the most aggressive manifestations of cancer due to its enhanced metastatic potential and immunity to therapeutics which target hormone receptors. Under such scenarios, anti-cancer compounds with an ability to influence multiple targets, or an entire process, will have an advantage over specific signal transduction inhibitors. To counter the metastatic threat it is essential to target cellular components central to the processes of cancer cell migration and adaptation. Our previous work on a novel triterpenoid, AECHL-1, explored its anti-cancer potential, and linked it to elevated ER stress in cancer cells, while its anti-angiogenic potential was credited for its ability to manipulate the cytoskeleton. Here, we broaden its range of action by showing that it curbs the metastatic ability of TNBC cells, both in vitro in MDA-MB-231 cell line and in vivo, in mouse models of metastasis. AECHL-1 does so by disrupting the cytoskeletal network, and also suppressing NF-κB and β-Catenin mediated key molecular pathways. These activities also contributed to AECHL-1 mediated suppression of TGF-β/TNF-α induced Epithelial to Mesenchymal Transition (EMT) and cancer stem cell characteristic. Thus, we present AECHL-1 as a promising therapeutic inhibitor of metastatic disease.
Research Interests: Cancer stem cells, Cancer Biology, Medicine, Epithelial-Mesenchymal Transition, Cytoskeleton, and 13 moreSignal Transduction, Humans, Mice, Female, Animals, NF-kappa B, Beta-Catenin, Cancer Metastasis, Cytoskeletal dynamics, Cell Proliferation, Triterpenes, Neoplasm metastasis, and Neoplastic Stem Cells
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Centhaquin citrate is a novel agent that is being developed for use in the resuscitation of patients with haemorrhagic shock. While pharmacokinetics have been described in small animal models, the pharmacokinetic parameters of centhaquin... more
Centhaquin citrate is a novel agent that is being developed for use in the resuscitation of patients with haemorrhagic shock. While pharmacokinetics have been described in small animal models, the pharmacokinetic parameters of centhaquin citrate in large mammals have yet to be described. Four healthy Beagle dogs (two males and two females) were given an intravenous bolus of 1.0 mg/kg centhaquin citrate. Plasma concentrations were measured at baseline and at ten time points within 24 h after administration. Multiple compartmental models were built and compared. The nonparametric adaptive grid function within the Pmetrics package for R was used for parameter estimation. Predicted concentrations were calculated using population mean and individual Bayesian posterior parameters. Centhaquin citrate pharmacokinetic parameters were best described using a two-compartment model. Median (IQR) values for Ke , Vc , Vp , Kcp and Kpc were 4.9 (4.4-5.2) h(-1) , 328.4 (304.0-331.9) l, 1000.6 (912.3-1042.4) l, 10.6 (10.3-11.1) h(-1) and 3.2 (2.9-3.7) h(-1) , respectively. Pharmacokinetic parameters of centhaquin citrate in a large mammal have been described. A large volume of distribution and rapid elimination were observed, consistent with previous work in rats.
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The modus operandi for an anti-cancer drug must allow for an efficient discrimination system between tumorigenic and non-tumorigenic cells. Targeting ER stress and mitochondrial function in cancer cells appears to be a suitable option, as... more
The modus operandi for an anti-cancer drug must allow for an efficient discrimination system between tumorigenic and non-tumorigenic cells. Targeting ER stress and mitochondrial function in cancer cells appears to be a suitable option, as these processes are dysregulated in tumor cells. AECHL-1, a novel triterpenoid, exhibits potent anticancer activity against an array of cancer cell lines however, its mechanism of action remains elusive. Molecular targets of AECHL-1 were investigated using breast adenocarcinoma cells MCF-7, MDA-MB-231 and mammary epithelial cell line MCF 10A in vitro and xenograft tumors in SCID mice in vivo. Western blotting, flow cytometry, and immunohistochemical studies were employed to delineate the molecular pathways. AECHL-1 caused a transient elevation of ER stress proteins along with a prolonged phosphorylation of eIF2α in breast cancer cells. This was accompanied by a simultaneous release of calcium from ER stores and subsequent mitochondrial accumulation...
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Centhaquin citrate is a novel agent being developed for use in the treatment of haemorrhagic shock. It has decreased mortality in rat, rabbit and pig models of hypovolaemic shock compared to hypertonic saline and lactated... more
Centhaquin citrate is a novel agent being developed for use in the treatment of haemorrhagic shock. It has decreased mortality in rat, rabbit and pig models of hypovolaemic shock compared to hypertonic saline and lactated Ringer&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s resuscitation. The pharmacokinetics of centhaquin citrate have not been described to date. Sixteen male Sprague Dawley rats were given an intravenous bolus of 0.45 mg/kg centhaquin citrate. Rats were divided into two groups; plasma concentrations were measured at five time points for each group within 24 h after administration. Competing compartmental pharmacokinetic models were assessed. The nonparametric adaptive grid function within the Pmetrics package for R was used for parameter estimation. Predicted concentrations were calculated using population median and individual Bayesian posterior parameters. A two-compartment model of centhaquin citrate best fit the data. Median (IQR) values for elimination coefficient (Ke ), volume of distribution (V) and intercompartmental transfer rates (Kcp, Kpc ) were 8.8 (5.2-12.8) h(-1) , 6.4 (2.8-10.4) l, 11.9 (4.6-15.0) h(-1) and 3.7 (2.3-9.1) h(-1) , respectively. This is the first report of the pharmacokinetic parameters of centhaquin citrate in a rat model. Centhaquin citrate was found to have a short half-life with a large volume of distribution.
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A novel chemical moiety triterpenoid AECHL-1 isolated from root bark of Ailanthus excelsa having anti-cancer properties exhibiting remarkable activity in treatment of various forms of tumors with specificity wherein it blocks the growth... more
A novel chemical moiety triterpenoid AECHL-1 isolated from root bark of Ailanthus excelsa having anti-cancer properties exhibiting remarkable activity in treatment of various forms of tumors with specificity wherein it blocks the growth of four tumor cell lines with distinct origins and of different p53 status (B16F10 mouse melanoma, PC3 human prostate cancer, MCF-7 and MDA-MB-231 human breast cancer), having following characteristic IR, NMR and mass spectra IR (KBr): 3425, 3419 (hydroxyl group), 2972, 2966, 2923, 2873 (alkyl C—H stretch), 1733 (δ lactone), 1718 (Bi acetyl), 1680 (C═O conjugation with alkene), 1652 (—C═C stretching), 1600 (aromatic), 1492, 1454, 1394 (methyl stretching), 1222 (δ lactone), 1184, 1110, 1051, 1031 (acetals), 1018 nm (alkanes). 1H-NMR (DMSO, 400 Hz) δ: 0.95 (3H, t, 4′-CH3), δ:1.15 (3H, d, H-24), δ:1.235 (3H, d, 5′-CH3), δ: 1.5 (2H, ddd, 5′-CH2), δ: 1.73 (3H, ddd, H-21), δ: 1.83 (1H, s, H-9), δ: 1.87 (1H, s, H-14), δ: 1.9 (2H, s, H-18), δ: 2.16 (3H, s, H...
Research Interests: Biology, Apoptosis, Medicine, Angiogenesis, Cytoskeleton, and 15 moreHumans, Anoxia, Endothelial Cells, Mice, Female, Animals, Clinical Sciences, Cell Proliferation, Aorta, Cell Survival, Enzyme Linked Immunosorbent Assay, Chorioallantoic Membrane, Chick embryo, Pharmacology and pharmaceutical sciences, and Human Umbilical Vein Endothelial Cells
In the present study, ethyl acetate, butanol and aqueous fractions derived from total methanol extract of Butea monosperma flowers were evaluated for radical scavenging activities using different in vitro models like reducing power assay,... more
In the present study, ethyl acetate, butanol and aqueous fractions derived from total methanol extract of Butea monosperma flowers were evaluated for radical scavenging activities using different in vitro models like reducing power assay, scavenging of 2,2 diphenyl-1-picrylhydrazyl (DPPH) radical, nitric oxide radical, superoxide anion radical, hydroxyl radical and inhibition of erythrocyte hemolysis using 2, 2' azo-bis (amidinopropane) dihydrochloride (AAPH). Methanol extract along with its ethyl acetate and butanol fractions showed potent free radical scavenging activity, whereas aqueous fraction was found to be devoid of any radical scavenging properties. The observed activity could be due to the higher phenolic content in the extracts (16.1, 25.29, and 17.74% w/w in methanol extract, ethyl acetate and butanol fractions respectively). HPTLC fingerprint profile of the ethyl acetate and butanol fractions were developed which would serve as reference standard for quality control...
Research Interests: Water, Free Radicals, Quality Control, Free Radical, Nitric oxide, and 15 moreButanol, Methanol, Flowers, Indian Journal of Experimental Biology, Ethyl Acetate, Plant extracts, Erythrocytes, Superoxide Anion, Oxidation-Reduction, Standard Reference Materials, Superoxides, Hemolysis, Fractional Derivative, Hydroxyl Radical, and Radical scavenging activity
The roots of Cocculus hirsutus (Linn) Diels was analyzed for preliminary phytochemical studies including physical constant (total ash, acid soluble and insoluble ash and moisture content), extractive values in different solvents... more
The roots of Cocculus hirsutus (Linn) Diels was analyzed for preliminary phytochemical studies including physical constant (total ash, acid soluble and insoluble ash and moisture content), extractive values in different solvents (petroleum ether, benzene, chloroform, methanol and water), and phytochemical tests. The plant is well reputed in traditional system of medicine, present studies will help in further validation and standardization of the plant.
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Research Interests: Cardiovascular, Medicine, Brain, Blood Pressure, Animals, and 15 moreMale, Heart rate, Central Nervous System, Pharmacological, Blood gas analysis, Piperidines, Clonidine, Endothelins, Adrenergic Receptors, Prazosin, Abdominal Aorta, Mean Arterial Pressure, Antihypertensive agents, Aorta Abdominal, and Pharmacology and pharmaceutical sciences
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The effect of repeated administration of centhaquin to pregnant rats on postnatal development, and expression of ETA and ETB receptors was determined. Pregnant rats were treated daily with either saline or centhaquin for 2 weeks. Male rat... more
The effect of repeated administration of centhaquin to pregnant rats on postnatal development, and expression of ETA and ETB receptors was determined. Pregnant rats were treated daily with either saline or centhaquin for 2 weeks. Male rat pups were sacrificed on day 1, 7, 14 and 28 of birth. Brain, kidney and heart were removed to study the expression of ETA and ETB receptor protein levels. Body weight of pregnant rats increased steadily in both vehicle and centhaquin groups. Expression of ETA receptors in the heart and kidney was similar in vehicle and centhaquin treated postpartum rats, but was significantly increased in the brain of centhaquin treated postpartum rats. No change in expression of ETB receptors was observed. In postnatal rats, mean body weight and weights of the brain, kidney and heart increased proportionally with advancing age and were similar in vehicle and centhaquin groups. The expression of ETA receptors in the brain, heart and kidneys was similar in vehicle and centhaquin groups. ETB receptor expression significantly (p&lt;0.001) decreased by 72% and 70% on day 28 compared to rats of age 1, 7 and 14 days in control and centhaquin groups, respectively. Centhaquin treated rats showed similar expression of ETA and ETB receptors compared to vehicle treatment. This study suggests that repeated administration of centhaquin was well tolerated by pregnant rats that gave birth to normal pups. Centhaquin did not affect postnatal development of rats and had similar expression of ETA and ETB receptors compared to control pups.
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Research Interests: Cardiovascular, Medicine, Brain, Blood Pressure, Animals, and 15 moreMale, Heart rate, Central Nervous System, Pharmacological, Blood gas analysis, Piperidines, Clonidine, Endothelins, Adrenergic Receptors, Prazosin, Abdominal Aorta, Mean Arterial Pressure, Antihypertensive agents, Aorta Abdominal, and Pharmacology and pharmaceutical sciences
Research Interests:
In the present study, ethyl acetate, butanol and aqueous fractions derived from total methanol extract of Butea monosperma flowers were evaluated for radical scavenging activities using different in vitro models like reducing power assay,... more
In the present study, ethyl acetate, butanol and aqueous fractions derived from total methanol extract of Butea monosperma flowers were evaluated for radical scavenging activities using different in vitro models like reducing power assay, scavenging of 2,2 diphenyl-1-picrylhydrazyl (DPPH) radical, nitric oxide radical, superoxide anion radical, hydroxyl radical and inhibition of erythrocyte hemolysis using 2, 2&amp;amp;#39; azo-bis (amidinopropane) dihydrochloride (AAPH). Methanol extract along with its ethyl acetate and butanol fractions showed potent free radical scavenging activity, whereas aqueous fraction was found to be devoid of any radical scavenging properties. The observed activity could be due to the higher phenolic content in the extracts (16.1, 25.29, and 17.74% w/w in methanol extract, ethyl acetate and butanol fractions respectively). HPTLC fingerprint profile of the ethyl acetate and butanol fractions were developed which would serve as reference standard for quality control of the extracts.
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AECHL-1 treatment for 12 to 48 hr inhibited cell proliferation and induced death in B16F10, MDA-MB-231, MCF-7, and PC3 cells with minimum growth inhibition in normal HEK 293. The antitumor effect of AECHL-1 was comparable with that of the... more
AECHL-1 treatment for 12 to 48 hr inhibited cell proliferation and induced death in B16F10, MDA-MB-231, MCF-7, and PC3 cells with minimum growth inhibition in normal HEK 293. The antitumor effect of AECHL-1 was comparable with that of the conventional antitumor ...
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Centhaquin has been reported to be an effective resuscitative agent. The present study was carried out to determine resuscitative effect of centhaquin when administered using a small volume of 3% hypertonic saline (HS) to hemorrhaged... more
Centhaquin has been reported to be an effective resuscitative agent. The present study was carried out to determine resuscitative effect of centhaquin when administered using a small volume of 3% hypertonic saline (HS) to hemorrhaged rats. Sprague-Dawley rats were anesthetized with urethane, and a pressure catheter SPR-320 was placed in the left femoral artery; another pressure-volume catheter SPR-869 was placed into the left ventricle. Hemorrhage was induced by withdrawing blood and mean arterial pressure (MAP) was maintained at 35 mm Hg for 30 minutes after which resuscitation was performed. Animals were divided in 2 groups: group A received HS and group B received centhaquin (0.05 mg/kg) dissolved in HS. The time by which MAP fell back to 35 mm Hg was observed at that time all animals were administered fresh blood. It was found that centhaquin significantly reduced blood lactate and improved cardiac output and MAP of hemorrhaged rats compared with HS. The time by which MAP fell back to 35 mm Hg in rats treated with HS was 55 ± 6 minutes, whereas it was 161 ± 14 minutes in centhaquin treated rats. Survival time following administration of fresh blood was 79 ± 7 minutes in vehicle-treated group, whereas it was 105 ± 9 minutes in centhaquin-treated rats. The total time of survival of rats treated with HS or centhaquin was 134 ± 12 minutes and 266 ± 16 minutes, respectively. Centhaquin, in small volume, maintained MAP of hemorrhaged rats for a considerable long time and improved the survival time.