Crotaline

Anticancer Agents Med Chem. 2014;14(9):1237-48.

Antineoplastic activity of monocrotaline against hepatocellular carcinoma.[Pubmed: 25028149]

Plants are fantastic sources for present day life saving drugs. MonoCrotaline a natural ligand exhibits dose-dependent cytotoxicity with potent antineoplastic activity. This study was intended to disclose the therapeutic potential of monoCrotaline against hepatocellular carcinoma.
METHODS AND RESULTS:
The in silico predictions have highlighted the antineoplastic potential, druglikeness and biodegradability of monoCrotaline. The in silico docking study has provided an insight and evidence for the antineoplastic activity of monoCrotaline against p53, HGF and TREM1 proteins which play a threatening role in causing hepatocellular carcinoma. The mode of action of monoCrotaline was determined experimentally by in vitro techniques such as XTT assay, NRU assay and whole cell brine shrimp assay have further supported our in silico studies.
CONCLUSIONS:
The in vitro cytotoxicity of monoCrotaline was proved at IC50 24.966 μg/mL and genotoxicity at 2 X IC50 against HepG2 cells. Further, the credible druglike properties with non-mutagenicity, non-toxic on mammalian fibroblast and the potential antineoplastic activity through in vitro experimental validations established monoCrotaline as a novel scaffold for liver cancer with superior efficacy and lesser side effects.

Eur J Pharm Sci. 2014 Oct 1;62:161-70.

Naringenin adds to the protective effect of L-arginine in monocrotaline-induced pulmonary hypertension in rats: favorable modulation of oxidative stress, inflammation and nitric oxide.[Pubmed: 24878387]

The present study was directed to investigate the possible modulatory effect of naringenin when co-administered with L-arginine in monoCrotaline-induced pulmonary hypertension in rats.
METHODS AND RESULTS:
Pulmonary hypertension was induced by a single subcutaneous injection of monoCrotaline (60 mg/kg). L-arginine (500 mg/kg) and naringenin (50 mg/kg) were orally administered daily, alone and in combination, for 3 weeks. Mean arterial blood pressure, electrocardiography and echocardiography were then recorded and rats were sacrificed and serum was separated for determination of total nitrate/nitrite level. Right ventricles and lungs were isolated for estimation of oxidative stress markers, tumor necrosis factor-alpha, total nitrate/nitrite and transforming growth factor-beta. Myeloperoxidase and caspase-3 activities in addition to endothelial and inducible nitric oxide synthase protein expression were also determined. Moreover, histological analysis of pulmonary arteries and cardiomyocyte cross-sectional area was performed. Combined therapy provided a significant improvement in L-arginine protective effect toward preserving hemodynamic changes and alleviating oxidative stress, inflammatory and apoptotic markers induced by monoCrotaline treatment. Furthermore, combined therapy prevented monoCrotaline-induced changes in endothelial and inducible nitric oxide synthase protein expression as well as histological analysis compared with either treatment alone.
CONCLUSIONS:
In conclusion, naringenin significantly adds to the protective effect of L-arginine in pulmonary hypertension induced by monoCrotaline in rats.

Ann Emerg Med. 2001 Feb;37(2):175-80.

Role of surgical intervention in the management of crotaline snake envenomation.[Pubmed: 11174236 ]

Crotaline venoms produce various toxic effects. Although these are most commonly treated with specific antivenoms, surgical management of snakebite has also been practiced for many years.
METHODS AND RESULTS:
Surgical approaches to pit viper envenomation include incision or excision of the bite site, fasciotomy, and digit dermotomy. The evidence regarding each of these procedures is sparse; however, incision or excision of the bite site are difficult to advocate.
CONCLUSIONS:
Fasciotomy and digit dermotomy may be appropriate in carefully selected patients.

Int Heart J. 2015 May 13;56(3):354-9.

Delivery of imatinib-incorporated nanoparticles into lungs suppresses the development of monocrotaline-induced pulmonary arterial hypertension.[Pubmed: 25902888]

Platelet-derived growth factor (PDGF) is implicated in the pathogenesis of pulmonary arterial hypertension (PAH). Imatinib, a PDGF-receptor tyrosine kinase inhibitor, improved hemodynamics, but serious side effects and drug discontinuation are common when treating PAH. A drug delivery system using nanoparticles (NPs) enables the reduction of side effects while maintaining the effects of the drug.
METHODS AND RESULTS:
We examined the efficacy of imatinib-incorporated NPs (Ima-NPs) in a rat model and in human PAH-pulmonary arterial smooth muscle cells (PASMCs). Rats received a single intratracheal administration of PBS, FITC-NPs, or Ima-NPs immediately after monoCrotaline injection. Three weeks after monoCrotaline injection, intratracheal administration of Ima-NPs suppressed the development of pulmonary hypertension, small pulmonary artery remodeling, and right ventricular hypertrophy in the rat model of monoCrotaline-induced PAH. We also examined the effects of imatinib and Ima-NPs on PDGF-induced proliferation of human PAH-PASMCs by (3)H-thymidine incorporation. Imatinib and Ima-NPs significantly inhibited proliferation after 24 hours of treatment. Ima-NPs significantly inhibited proliferation compared with imatinib at 24 hours after removal of these drugs.
CONCLUSIONS:
Delivery of Ima-NPs into lungs suppressed the development of MCT-induced PAH by sustained antiproliferative effects on PAS-MCs.

Arterioscler Thromb Vasc Biol. 2014 Jul;34(7):1539-47.

Targeted delivery of pulmonary arterial endothelial cells overexpressing interleukin-8 receptors attenuates monocrotaline-induced pulmonary vascular remodeling.[Pubmed: 24790141]

Interleukin-8 (IL-8) receptors IL8RA and IL8RB (IL8RA/B) on neutrophil membranes bind to IL-8 with high affinity and play a critical role in neutrophil recruitment to sites of injury and inflammation. This study tested the hypothesis that administration of rat pulmonary arterial endothelial cells (ECs) overexpressing IL8RA/B can accelerate the adhesion of ECs to the injured lung and inhibit monoCrotaline-induced pulmonary inflammation, arterial thickening and hypertension, and right ventricular hypertrophy.
METHODS AND RESULTS:
The treatment groups included 10-week-old ovariectomized Sprague-Dawley rats that received subcutaneous injection of PBS (vehicle), a single injection of monoCrotaline (monoCrotaline alone, 60 mg/kg, SC), monoCrotaline followed by intravenous transfusion of ECs transduced with the empty adenoviral vector (null-EC), and monoCrotaline followed by intravenous transfusion of ECs overexpressing IL8RA/B (1.5 × 10(6) cells/rat). Two days or 4 weeks after monoCrotaline treatment, endothelial nitric oxide synthase, inducible nitric oxide synthase, cytokine-induced neutrophil chemoattractant-2β (IL-8 equivalent in rat), and monocyte chemoattractant protein-1 expression, neutrophil and macrophage infiltration into pulmonary arterioles, and arteriolar and alveolar morphology were measured by histological and immunohistochemical techniques. Proinflammatory cytokine/chemokine protein levels were measured by Multiplex rat-specific magnetic bead-based sandwich immunoassay in total lung homogenates. Transfusion of ECs overexpressing IL8RA/B significantly reduced monoCrotaline-induced neutrophil infiltration and proinflammatory mediator (IL-8, monocyte chemoattractant protein-1, inducible nitric oxide synthase, cytokine-induced neutrophil chemoattractant, and macrophage inflammatory protein-2) expression in lungs and pulmonary arterioles and alveoli, pulmonary arterial pressure, and pulmonary arterial and right ventricular hypertrophy and remodeling.
CONCLUSIONS:
These provocative findings suggest that targeted delivery of ECs overexpressing IL8RA/B is effective in repairing the injured pulmonary vasculature.