Varespladib in the Treatment of Snakebite Envenoming: Development History and Preclinical Evidence Supporting Advancement to Clinical Trials in Patients Bitten by Venomous Snakes.

The availability of effective, reliably accessible, and affordable treatments for snakebite envenoming is a critical and long unmet medical need. Recently, small, synthetic toxin-specific inhibitors with oral bioavailability used in conjunction with antivenom have been identified as having the potential to greatly improve outcomes after snakebite. Varespladib, a small, synthetic molecule that broadly and potently inhibits secreted phospholipase A2 (sPLA2s) venom toxins has renewed interest in this class of inhibitors due to its potential utility in the treatment of snakebite envenoming. The development of varespladib and its oral dosage form, varespladib-methyl, has been accelerated by previous clinical development campaigns to treat non-envenoming conditions related to ulcerative colitis, rheumatoid arthritis, asthma, sepsis, and acute coronary syndrome. To date, twenty-nine clinical studies evaluating the safety, pharmacokinetics (PK), and efficacy of varespladib for non-snakebite envenoming conditions have been completed in more than 4600 human subjects, and the drugs were generally well-tolerated and considered safe for use in humans. Since 2016, more than 30 publications describing the structure, function, and efficacy of varespladib have directly addressed its potential for the treatment of snakebite. This review summarizes preclinical findings and outlines the scientific support, the potential limitations, and the next steps in the development of varespladib's use as a snakebite treatment, which is now in Phase 2 human clinical trials in the United States and India.

Phytotoxicity and oxidative stress perspective of two selected nanoparticles in Brassica juncea.

This study elaborates the consequences of oxidative stress caused by copper oxide (CuO) and titanium dioxide (TiO2) nanoparticles (NPs) in Brassica juncea. Effect of these two NPs on plant physiology, reactive oxygen scavenging enzyme system (ascorbate peroxidase, catalase, superoxide dismutase), proline content and lipid peroxidation has been estimated in leaves as well as root tissues. Bioaccumulation of NPs has also been evaluated in the current study and the interrelated cascade of the enzymatic system with H2O2 production was identified. The uptake of NPs in plant leaves was confirmed by scanning electron microscopy, X-ray diffraction, and Fourier Transform Infrared Spectroscopy. Plant growth was found to be diminished with elevated levels of CuO NPs whereas TiO2 NPs had shown an opposite effect. The plant species accumulated lower concentration of NPs and displayed considerable tolerance against stress, probably due to well-organized and coordinated defense system at the root and shoot level by the intonation of antioxidative enzymes.

Epigallocatechin-3-gallate, a natural polyphenol, inhibits cell proliferation and induces apoptosis in human ovarian cancer cells.

BACKGROUND: Epigallocatechin-3-gallate (EGCG) is a polyphenol constituent present in green tea previously shown to inhibit cancer growth. However, studies on human ovarian cancer are limited. This study evaluated, the effects of EGCG as a potential anti-proliferative and pro-apoptotic agent in the human ovarian cancer line, SKOV-3. MATERIALS AND METHODS: The MTS assay which measures metabolic activity of cells, bromodeoxyuridine (BrdU) incorporation assay, and flow cytometry were used for the cell proliferation studies and cell morphology, DNA fragmentation analysis and the TUNEL assay for apoptotic effects. RESULTS: The EGCG treated SKOV-3 cells showed inhibition of cell viability and proliferation in a dose-dependent manner. Furthermore, EGCG-mediated SKOV-3 cell growth inhibition was associated with apoptotic changes as evident by cell cycle arrest and accumulation of cells in the apoptotic phase, cell morphological changes, DNA fragmentation and TUNEL-positive apoptotic cells. CONCLUSION: In SKOV-3 cells, EGCG inhibits cell proliferation via DNA synthesis reduction and induces apoptotic cell death via DNA damage, thus elucidating a novel, plausible mechanism of EGCG anti-tumorigenic property.

Prevalence of transfusion-transmitted virus infection in patients on maintenance hemodialysis from New Delhi, India.

Transfusion-transmitted virus (TTV) has been reported from a number of hemodialysis (HD) units from various countries throughout the world. TTV has been associated with liver diseases, viral hepatitis B, and C. Clinical details and information regarding TTV prevalence from India are insufficient. The prevalence and clinical significance of TTV infection were studied in New Delhi, India in HD patients. Serum samples were derived from 75 patients on maintenance HD, and 75 age- and sex-matched voluntary blood donors were examined for TTV viremia by nested polymerase chain reaction (PCR) using primers derived from UTR (A) region of the TTV genome. The prevalence of TTV DNA in patients on HD (83%) was significantly (p<0.05) higher than in blood donors (43%). Clinical background including the mean age, sex, mean duration of HD, and mean alanine aminotransferase (ALT) levels did not differ significantly between TTV DNA-positive and -negative HD patients. Fifty-four (72%) TTV-positive HD patients and 7 (56%) TTV-negative HD patients had blood transfusion histories (p>0.05). Among TTV-positive patients, Hepatitis B virus (HBV) co-infection was present in 14.2% cases while hepatitis C virus (HCV) co-infection was absent. Persistent elevation of ALT levels was observed in 7(9.3%) HD patients; 3 (43%) of them were TTV positive and 4 (57%) were TTV negative (p>0.05). All 3 TTV-positive patients with elevated ALT levels were co-infected with HBV. Patients with TTV infection alone showed normal ALT levels. Prevalence of TTV infection is high in North Indian patients on maintenance HD. Also, none of the exclusively TTV DNA-positive patients had clinical or biochemical signs of liver disease. TTV seems to spread through parenteral routes. More often, TTV seems to be associated with parenterally transmitted virus HBV, indicating a parenteral mode of TTV transmission. The pathogenicity of TTV remains unclear from the present study.

Prognostic value of 99mTc-Sestamibi stress Myocardial Perfusion Single Photon Emission Computed Tomography (SPECT) in ischemic heart disease.

AIM: To study prognostic value of 99mTc-Sestamibi stress Myocardial Perfusion Single Photon Emission Computed Tomography (SPECT) in suspected or diagnosed ischemic heart disease, in an urban Indian population. METHODS: Eight hundred and eighty one patients with clinically suspected or diagnosed ischemic heart disease who underwent 99mTc-MIBI stress-rest Myocardial Perfusion SPECT (MPS) between 1st February 2001 to October 2002 were followed up for 14 +/- 2 months after the scan by questionnaire and telephonic interview with queries about cardiac death, myocardial infarct (hard events) and admission for unstable angina, CABG and PTCA (soft events). Patients were classified into pre-test: low, intermediate or high risk subsets based on clinical risk factors and ECG criteria. They were then reclassified based on MPS scan into post-test: high, intermediate and low risk subsets. Subsequent cardiac event rate was compared in the three subsets. A 12-lead ECG was an integral component of the stress MPS evaluation. RESULTS: MPS changed (1) the pre-test low risk category in 114 out of 613 patients to intermediate and 102 to high risk; (2) pre-test intermediate risk in 110 patients out of 163 to low risk and 19 patients to high risk (3) pre-test high risk category in 56 patients out of 105 to low risk and 28 to intermediate risk (total change 429 out of 881 patients). The hard cardiac event rate at one year was less than 0.5% in low risk, 2.3% in intermediate risk and 4.2% in high risk group. CONCLUSIONS: 99mTc-Sestamibi stress SPECT MPS thus provided incremental information for prognostic evaluation of patients with suspected or diagnosed coronary artery disease by assessing the effect of ischemic burden on LV function. This incremental information is crucial since coronary arteriography alone is not enough for prognosis and management decisions. Patients with a normal or low risk MPS have generally a benign prognosis with a low annual hard cardiac event rate of 0.5%. Future challenge is to identify high risk subsets within this group, with CT coronary calcium score > or = 100 and inflammation markers such as high hsCRP so that more aggressive secondary preventive measures can be instituted to prevent future hard cardiac events.