Coronary Artery Bypass Grafting Following COVID-19 Infection: Difficulties and Challenges.

The COVID-19 pandemic has raised challenges and dilemmas to perform cardiac surgery in the patients following COVID-19 infection due to lasting adverse impacts of the disease on the lungs. A 74-years-old patient, recently infected by COVID-19, with previous myocardial infarction and multiple percutaneous coronary interventions, in-stent thrombosis to the left anterior descending artery, and low resting saturation, presented with chest pain and underwent urgent coronary artery bypass grafting. His postoperative period remained challenging due to high oxygen requirements. He had otherwise an uneventful recovery and was discharged on domiciliary oxygen, which was weaned off over three months and he continues to do well at six months of follow-up. Keywords: Cardiac surgery; COVID-19; coronary artery bypass surgery; pandemic.

Clinical Implications for Exercise at Altitude Among Individuals With Cardiovascular Disease: A Scientific Statement From the American Heart Association.

An increasing number of individuals travel to mountainous environments for work and pleasure. However, oxygen availability declines at altitude, and hypoxic environments place unique stressors on the cardiovascular system. These stressors may be exacerbated by exercise at altitude, because exercise increases oxygen demand in an environment that is already relatively oxygen deplete compared with sea-level conditions. Furthermore, the prevalence of cardiovascular disease, as well as diseases such as hypertension, heart failure, and lung disease, is high among individuals living in the United States. As such, patients who are at risk of or who have established cardiovascular disease may be at an increased risk of adverse events when sojourning to these mountainous locations. However, these risks may be minimized by appropriate pretravel assessments and planning through shared decision-making between patients and their managing clinicians. This American Heart Association scientific statement provides a concise, yet comprehensive overview of the physiologic responses to exercise in hypoxic locations, as well as important considerations for minimizing the risk of adverse cardiovascular events during mountainous excursions.

Novel Papaverine Metal Complexes with Potential Anticancer Activities.

Cancer is one of the leading causes of death worldwide. Although several potential therapeutic agents have been developed to efficiently treat cancer, some side effects can occur simultaneously. Papaverine, a non-narcotic opium alkaloid, is a potential anticancer drug that showed selective antitumor activity in various tumor cells. Recent studies have demonstrated that metal complexes improve the biological activity of the parent bioactive ligands. Based on those facts, herein we describe the synthesis of novel papaverine-vanadium(III), ruthenium(III) and gold(III) metal complexes aiming at enhancing the biological activity of papaverine drug. The structures of the synthesized complexes were characterized by various spectroscopic methods (IR, UV-Vis, NMR, TGA, XRD, SEM). The anticancer activity of synthesized metal complexes was evaluated in vitro against two types of cancer cell lines: human breast cancer MCF-7 cells and hepatocellular carcinoma HepG-2 cells. The results revealed that papaverine-Au(III) complex, among the synthesized complexes, possess potential antimicrobial and anticancer activities. Interestingly, the anticancer activity of papaverine-Au(III) complex against the examined cancer cell lines was higher than that of the papaverine alone, which indicates that Au-metal complexation improved the anticancer activity of the parent drug. Additionally, the Au complex showed anticancer activity against the breast cancer MCF-7 cells better than that of cisplatin. The biocompatibility experiments showed that Au complex is less toxic than the papaverine drug alone with IC50 ≈ 111 µg/mL. These results indicate that papaverine-Au(III) complex is a promising anticancer complex-drug which would make it a suitable candidate for further in vivo investigations.

Preparation of virus-like particle mimetic nanovesicles displaying the S protein of Middle East respiratory syndrome coronavirus using insect cells.

Middle East respiratory syndrome coronavirus (MERS-CoV) first emerged in 2012, and over 2000 infections and 800 deaths have been confirmed in 27 countries. However, to date, no commercial vaccine is available. In this study, structural proteins of MERS-CoV were expressed in silkworm larvae and Bm5 cells for the development of vaccine candidates against MERS-CoV and diagnostic methods. The spike (S) protein of MERS-CoV lacking its transmembrane and cytoplasmic domains (SΔTM) was secreted into the hemolymph of silkworm larvae using a bombyxin signal peptide and purified using affinity chromatography. The purified SΔTM forms small nanoparticles as well as the full-length S protein and has the ability to bind human dipeptidyl peptidase 4 (DPP4), which is a receptor of MERS-CoV. These results indicate that bioactive SΔTM was expressed in silkworm larvae. To produce MERS-CoV-like particles (MERS-CoV-LPs), the coexpression of spike proteins was performed in Bm5 cells and envelope (E) and membrane (M) proteins secreted E and M proteins extracellularly, suggesting that MERS-CoV-LPs may be formed. However, this S protein was not displayed on virus-like particles (VLPs) even though E and M proteins were secreted into the culture supernatant. By surfactant treatment and mechanical extrusion using S protein- or three structural protein-expressing Bm5 cells, S protein-displaying nanovesicles with diameters of approximately 100-200 nm were prepared and confirmed by immuno-TEM. The mechanical extrusion method is favorable for obtaining uniform recombinant protein-displaying nanovesicles from cultured cells. The purified SΔTM from silkworm larvae and S protein-displaying nanovesicles from Bm5 cells may lead to the development of nanoparticle-based vaccines against MERS-CoV and the diagnostic detection of MERS-CoV.

Blood pressure and hypertension in people living at high altitude in Nepal.

This study aimed to describe blood pressure (BP) and hypertension (HT) in samples of high altitude populations of Nepal and to explore associations of systolic and diastolic BP with altitude. This was a cross-sectional survey of cardiovascular disease and associated risk factors among 521 people living at four different altitude levels, all above 2800 m, in the Mustang and Humla districts of Nepal. Data on BP was available for all 521 participants. Systolic and diastolic BP levels were highest at the altitude of 3620 m (the highest area surveyed) but did not consistently increase with altitude. Using the cut-point of ≥ 140/90 mmHg (systolic/diastolic), the prevalence of HT (or on anti-hypertensive medication) was 46.1%, 40.9% and 54.5%, respectively, at 2800, 3270 and 3620 m of Mustang district, and 29.1% at 2890 m of Humla district. In a multivariate model adjusting for potential confounders, there was strong evidence of a relationship between systolic BP and altitude; mean systolic BP increased by 15.6 mmHg (95% CI: 4.0-27.2), P = 0.009 for every 1000 m elevation. Although diastolic BP and the probability for HT or on anti-hypertensive medication also tended to increase with increasing altitude levels, there was no evidence of a relationship. In the present study three out of four communities living at higher altitude levels showed a greater prevalence of HT among those aged 30 years or older compared with the overall national data. These findings indicate a probable high risk of raised BP in high altitude populations in Nepal.

Biochemical, Oxidative, and Physiological Changes Caused by Acute Exposure of Fentanyl and Its 3 Analogs in Rodents.

Synthesis and bioefficacy of fentanyl and its 8 new 1-substituted analogs (1-8) were earlier reported by us. Of these 8 compounds, N-(1-(2-phenoxyethyl)-4-piperidinyl)propionanilide (2), N-isopropyl-3-(4-( N-phenylpropionamido)piperidin-1-yl)propanamide (5), and N- t-butyl-3-(4-( N-phenylpropionamido)piperidin-1-yl) propanamide (6) were found to be more effective and less toxic compared to fentanyl. The present study reports the acute effect of fentanyl (0.50 Median Lethal Dose (LD50); intraperitoneal) and its 3 analogs (2, 5, and 6) on various biochemical and oxidative parameters in mice and various physiological parameters in rats. Blood alkaline phosphatase (1 hour and 7 days) and urea levels (1 hour) were significantly elevated by fentanyl, while alanine aminotransferase levels (1 hour) were increased by both fentanyl and analog 2 compared to the corresponding control. Increase in partial pressure of carbon dioxide and decrease in partial pressure of oxygen were also caused by fentanyl and analog 2 (1 hour). Analog 6 alone elevated malondialdehyde levels in the brain, liver, and kidney tissues (7 days). The LD50 of fentanyl and analogs 2, 5, and 6 were found to be 0.879, 87.88, 69.80, and 55.44 mg/kg, respectively, in rats. Significant decrease in heart rate, mean arterial pressure, respiratory rate (RR), and neuromuscular transmission was produced by fentanyl and analog 2, while analog 5 decreased the RR alone. The changes, particularly the respiratory depression, were found to be reversed by naloxone, a µ-receptor antagonist. Thereby, indicating involvement of µ-receptor mediated effects of the compounds. To conclude, all the analogs were found to be less toxic compared to fentanyl, suggesting their possible role in pain management.

Lipid Profiles, Glycated Hemoglobin, and Diabetes in People Living at High Altitude in Nepal.

This study aimed to describe lipid profiles and the distribution of glycated hemoglobin (HbA1c) in a sample of a high altitude population of Nepal and to explore associations between these metabolic risk variables and altitude. A cross-sectional survey of cardiovascular disease and associated risk factors was conducted among 521 people living at four different altitude levels, all above 2800 m, in the Mustang and Humla districts of Nepal. Urban participants (residents at 2800 m and 3620 m) had higher total cholesterol (TC) and triglyceride (TG) than rural participants. A high ratio of TC to high-density lipoprotein-cholesterol (HDL) (TC/HDL ≥ 5.0) was found in 23.7% (95% CI 19.6, 28.2) and high TG (≥1.7 mmol/L) in 43.3% (95% CI 38.4, 48.3) of participants overall. Mean HbA1c levels were similar at all altitude levels although urban participants had a higher prevalence of diabetes. Overall, 6.9% (95% CI 4.7, 9.8) of participants had diabetes or were on hypoglycaemic treatment. There was no clear association between lipid profiles or HbA1c and altitude in a multivariate analysis adjusted for possible confounding variables. Residential settings and associated lifestyle practices are more strongly associated with lipid profiles and HbA1c than altitude amongst high altitude residents in Nepal.

Electrocardiography in people living at high altitude of Nepal.

OBJECTIVE: The main objective of this study was to estimate the prevalence of coronary heart disease (CHD) of high-altitude populations in Nepal determined by an ECG recordings and a medical history. METHODS: We carried out a cross-sectional survey of cardiovascular disease and risk factors among people living at four different altitude levels, all above 2800 m, in the Mustang and Humla districts of Nepal. 12-lead ECGs were recorded on 485 participants. ECG recordings were categorised as definitely abnormal, borderline or normal. RESULTS: No participant had Q waves to suggest past Q-wave infarction. Overall, 5.6% (95% CI 3.7 to 8.0) of participants gave a self-report of CHD. The prevalence of abnormal (or borderline abnormal) ECG was 19.6% (95% CI 16.1 to 23.4). The main abnormalities were: right axis deviation in 5.4% (95% CI 3.5 to 7.7) and left ventricular hypertrophy by voltage criteria in 3.5% (95% CI 2.0 to 5.5). ECG abnormalities were mainly on the left side of the heart for Mustang participants (Tibetan origin) and on the right side for Humla participants (Indo-Aryans). There was a moderate association between the probability of abnormal (or borderline abnormal) ECG and altitude when adjusted for potential confounding variables in a multivariate logistic model; with an OR for association per 1000 m elevation of altitude of 2.83 (95% CI 1.07 to 7.45), p=0.03. CONCLUSIONS: Electrocardiographic evidence suggests that although high-altitude populations do not have a high prevalence of CHD, abnormal ECG findings increase by altitude and risk pattern varies by ethnicity.

Protective efficacy of various carbonyl compounds and their metabolites, and nutrients against acute toxicity of some cyanogens in rats: biochemical and physiological studies.

Cyanogens are widely used in industries and their toxicity is mainly due to cyanogenesis. The antidotes for cyanide are usually instituted for the management of cyanogen poisoning. The present study reports the protective efficacy of 14 carbonyl compounds and their metabolites, and nutrients (1.0 g/kg; oral; +5 min) against acute oral toxicity of acetonitrile (ATCN), acrylonitrile (ACN), malononitrile (MCN), propionitrile (PCN), sodium nitroprusside (SNP), succinonitrile (SCN), and potassium ferricyanide (PFCN) in rats. Maximum protection index was observed for alpha-ketoglutarate (A-KG) against MCN and PCN (5.60), followed by dihydroxyacetone (DHA) against MCN (2.79). Further, MCN (0.75 LD50) caused significant increase in cyanide concentration in brain, liver and kidney and inhibition of cytochrome c oxidase activity in brain and liver, which favorably responded to A-KG and DHA treatment. Up-regulation of inducible nitric oxide synthase by MCN, PCN and SNP, and uncoupling protein by PCN and SNP observed in the brain was abolished by A-KG administration. However, no DNA damage was detected in the brain. MCN and SNP significantly decreased the mean arterial pressure, heart rate, respiratory rate and neuromuscular transmission, which were resolved by A-KG. The study suggests a beneficial effect of A-KG in the treatment of acute cyanogen poisoning.

Injury and Mortality in Young Nepalese Migrant Workers: A Call for Public Health Action.

Approximately 3.5 million Nepalese are working as migrant workers in the Gulf countries, Malaysia, and India. Every year there are more than 1000 deaths and many hundreds cases of injuries among Nepalese workers in these countries excluding India. A postmortem examination of migrant workers is not carried out in most of these countries, and those with work-related injuries are often sent back to home. Uninsured migrant workers also do not have easy access to health care services in host countries due to the high medical and hospital fees. Greater efforts are needed to protect the health and well-being, labor rights, and human rights of migrant workers from Nepal and other South-Asian nations. There is a need to enforce universal labor laws in these countries and to develop accurate records of mortality and morbidity and their causes.

Blood Pressure and Hypertension in Adults Permanently Living at High Altitude: A Systematic Review and Meta-Analysis.

Aryal, Nirmal, Mark Weatherall, Yadav Kumar Deo Bhatta, and Stewart Mann. Blood pressure and hypertension in adults permanently living at high altitude: a systematic review and meta-analysis. High Alt Med Biol. 17:185-193, 2016.-The objective of this study was to estimate the associations between altitude and mean blood pressure (BP) (or prevalence of hypertension [HT]) in adults who live permanently at high altitude. A literature search was conducted in December 2014 using PubMed, Scopus, and OvidSP (MedLine and EMBASE) databases to identify relevant observational studies. Inclusion criteria were reports of studies in populations permanently living at an altitude of ≥2400 m and in those 18 years or older. Meta-regression was used to estimate the association between average BP and HT and altitude. We identified 3375 articles and inclusion criteria were met for 21 reports, which included a total of 40,854 participants. Random-effects meta-regression estimated that for every 1000 m elevation the average systolic BP (SBP) (95% confidence interval [CI]) increased by 17 mmHg (0.2 to 33.8), p = 0.05 and diastolic BP (DBP) by 9.5 mmHg (0.6 to 18.4), p = 0.04 in participants with Tibetan origin. By contrast, in participants with non-Tibetan origin, average SBP decreased by 5.9 mmHg (-19.1 to 7.3), p = 0.38 and DBP by 4 mmHg (-13 to 5), p = 0.38. The odds ratios (95% CI) for the proportion of participants with HT per 1000 m increment in the altitude were 2.01 (0.37 to 11.02), p = 0.446 and 4.05 (0.07 to 244.69), p = 0.489 for Tibetan and non-Tibetan participants, respectively. Sensitivity analysis excluding two studies with older participants (≥60 years) reversed the direction of this effect in non-Tibetans with odds ratio (95% CI) of 0.10 (0.004 to 2.22) per 1000 m, p = 0.143. Overall, this review suggests weak association between BP and altitude in Tibetan origin populations.

Prophylactic efficacy of S-2(2-aminoethylamino)ethyl phenyl sulfide (DRDE-07) against sulfur mustard induced lung toxicity in mice.

OBJECTIVE: The present study was planned to investigate the prophylactic efficacy of S-2(2-aminoethylamino)ethyl phenyl sulfide (DRDE-07), against topically applied SM induced pulmonary toxicity in mouse. MATERIALS AND METHODS: Animals were pretreated with S-2(2-aminoethylamino)ethyl phenyl sulfide (DRDE-07) (249.4 mg/kg by oral gavage) 30 minutes before SM exposure. The SM (6.48 mg/kg) was applied on hair clipped dorsocaudal region (percutaneous) of the animal. The animals were sacrificed on day 1, 3, 5 and 7. The biochemical changes those were observed in the bronchoalveolar lavage (BAL) fluid and lung tissue included protein, LDH, MPO, ß-glucuronidase, MMP-2, MMP-9, activated macrophages, reduced glutathione and lipid peroxidation level. RESULTS AND DISCUSSION: Pretreatment with DRDE-07 (0.2 LD50) attenuated SM-induced changes at all time point tested. BAL fluid biochemical endpoints indicated epithelial and endothelial cell damages as evidenced by increase in BAL protein, LDH level and increased number of activated macrophages. The increased myeloperoxidase activity and ß-glucuronidase level exhibited the degranulation of neutrophils due to SM toxicity in lung. The zymogrphy analysis of BAL fluid showed a significant increase in matrix metalloproteases (MMP) activity due to inflammatory cells accumulation. CONCLUSION: Thirty minutes pretreatment with DRDE-07 decreased vascular permeability reduced the inflammation and oxidative stress, hence may be recommended as a potential prophylactic agent for SM intoxication.

Time-dependent comparative evaluation of some important biomarkers of acute cyanide poisoning in rats: an aid in diagnosis.

OBJECTIVE: The study focuses on time-dependent comparative evaluation of various biomarkers of acute cyanide poisoning in rats. METHODS: Blood gas (analyzer), lactate, pyruvate, cyanide, thiocyanate (spectrophotometer) and 2-amino-2-thiazoline-4-carboxylic acid (ATCA; gas chromatography-mass spectrometry) in plasma or urine, and various physiological parameters (polygraph) were measured. RESULTS: Cyanide poisoning was characterized by elevated lactate, cyanide, thiocyanate and ATCA concentrations in plasma up to 15 min, 4, 16 and 24 h, respectively, while high urinary thiocyanate and ATCA levels were measured between 4 and 24 h. CONCLUSION: ATCA concentration in plasma and urine was found to be more reliable indicator of cyanide poisoning.

Parasympathomimetic effect of shilajit accounts for relaxation of rat corpus cavernosum.

Previous studies have reported an enhancement of central cholinergic signal cascade by shilajit. For the present study, it was hypothesized that parasympathomimetic effect of shilajit accounting for relaxation of rat corpus cavernosum may be one of the major mechanisms attributing to its traditional role as an aphrodisiac. To test this hypothesis, the acute peripheral effect of standard acetylcholine (ACh), shilajit, and their combination was evaluated on cardiorespiratory parameters such as mean arterial blood pressure (MABP), heart rate (HR), respiratory rate (RR), and neuromuscular transmission (NMT). Furthermore, in vitro effect of standard ACh, shilajit, and their combination was tested on the rat corpus cavernosum. Six groups were used for the in vivo study (N = 5): Group I (control-saline), Group II (ACh), Group III (Sh), Group IV (Sh followed by ACh), Group V (Atropine followed by ACh), and Group VI (Atropine followed by Sh). The in vitro study included four groups: Group I (control-saline), Group II (ACh), Group III (Sh), and Group IV (Sh followed by ACh). The results of the in vivo study confirmed the peripheral parasympathomimetic effect of shilajit (400 µg/mL). The in vitro results revealed that shilajit (400 and 800 µg/mL) relaxed cavernous strips' concentration dependently and enhanced ACh-mediated relaxations. The peripheral parasympathomimetic effects of shilajit were confirmed by blockade of shilajit-induced relaxations (in vitro) and shilajit-induced lowering of MABP and HR (in vivo) by atropine.

Interactive effect of arsenic and fluoride on cardio-respiratory disorders in male rats: possible role of reactive oxygen species.

Epidemiological evidence demonstrates positive correlation between environmental and occupational arsenic or fluoride exposure and risk to various cardio-respiratory disorders. Arsenic-exposure has been associated with atherosclerosis, hypertension, cerebrovascular diseases, ischemic heart disease, and peripheral vascular disorders, whereas Fluoride-exposure manifests cardiac irregularities and low blood pressure (BP). Present study aims to study the combined effects of these toxicants on various cardio-respiratory variables in male rats. Single intravenous (i.v.) dose of arsenic (1, 5, 10 mg/kg) or fluoride (5, 10, 20, 36.5 mg/kg) either alone or in combination were administered. Individual exposure to arsenic or fluoride led to a significant depletion of mean arterial pressure, heart rate (HR), respiration rate and neuromuscular (NM) transmission in a dose-dependent manner. These changes were accompanied by increased levels of blood reactive oxygen species (ROS) and decreased glutathione (GSH) concentrations. An increase in the blood acetyl cholinesterase (AChE) activity was observed in both arsenic or fluoride exposed rats. These changes were significantly more pronounced in arsenic-exposed animals than in fluoride. During combined exposure to arsenic (5 mg/kg) + fluoride (20 mg/kg) or arsenic (10 mg/kg) + fluoride (36.5 mg/kg) the toxic effects were more pronounced compared to individual toxicities of arsenic or fluoride alone. However, combined exposure to arsenic (5 mg/kg) + fluoride (36.5 mg/kg) resulted in antagonistic effects on variables suggestive of altered cardio-respiratory function and oxidative stress. The results from the present study suggest that arsenic or fluoride individually demonstrate cardio-respiratory failure at all doses whereas during combination exposure these toxins show variable toxicities; both synergistic and antagonistic effects depending upon the dose. Moreover, it may be concluded that arsenic and/or fluoride cardio-respiratory toxicity may be mediated via oxidative stress. However, these results are new in the discipline thus requires further exploration.

Syntheses and characterization of Ru(III) with chelating containing ONNO donor quadridentate Schiff bases.

Complexes of ruthenium(III) with N,N'-disalicylidene-l,2-phenylenediamine (H2dsp), N,N'-disalicylidene-3,4-diaminotoluene (H2dst), 4-nitro-N,N'-disalicylidene-1,2-phenylenediamine (H2ndsp) and N,N'-disalicylidene ethylenediamine (H2salen) have been prepared and characterized by elemental analysis, molar conductivity, spectral methods (mid-infrared, 1H NMR and UV-vis spectra) and simultaneous thermal analysis (TG and DTG) techniques. The molar conductance measurements proved that all these complexes are non-electrolytes. The electronic spectra measurements were used to infer the structures. The IR spectra of the ligands and their complexes are used to identify the type of bonding. The kinetic thermodynamic parameters such as: E*, DeltaH*, DeltaS* and DeltaG* are estimated from the DTG curves. The four ligands and their complexes have been studied for their possible biological antifungal activity.

FTIR, magnetic, 1H NMR spectral and thermal studies of some chelates of caproic acid: inhibitory effect on different kinds of bacteria.

A convenient method for the preparation of complexes of the Cr3+, Mn2+, Fe3+, Co2+, Ni2+, Zn2+, ZrO2+, UO2(2+), Zr4+ and Th4+ ions with caproic acid (Hcap) is reported and this has enabled 10 complexes of caproate anion to be formulated: [Cr(cap)3].5H2O, [Mn(cap)2(H2O)2], [Fe(cap)3].12H2O, [Co(cap)2(H2O)2].4H2O, [Ni(cap)2(H2O)2].3H2O, [Zn(cap)2], [ZrO(cap)2].3H2O, [UO2(cap)(NO3)], [Zr(cap)2(Cl)2] and [Th(cap)4]. These new complexes were synthesized and characterized by elemental analysis, molar conductivity, magnetic measurements, spectral methods (mid infrared, 1H NMR and UV-vis spectra) and simultaneous thermal analysis (TG and DTG) techniques. It has been found from the elemental analysis as well as thermal studies that the caproate ligand behaves as bidentate ligand and forming chelates with 1:1 (metal:ligand) stoichiometry for UO2(2+), 1:2 for (Mn2+, Co2+, Ni2+, Zn2+, ZrO2+ and Zr4+), 1:3 stoichiometry for (Cr3+ and Fe3+) and 1:4 for Th4+ caproate complexes, respectively, as bidentate chelating. The molar conductance measurements proved that the caproate complexes are non-electrolytes. The kinetic thermodynamic parameters such as: E*, DeltaH*, DeltaS* and DeltaG* are estimated from the DTG curves. The antibacterial activity of the caproic acid and their complexes was evaluated against some gram positive/negative bacteria.

Effect of pre-treatment of alpha-ketoglutarate on cyanide-induced toxicity and alterations in various physiological variables in rodents.

OBJECTIVE: To investigate the effects of pre-treatment of alpha-ketoglutarate (alpha-KG) on cyanide-induced lethality and changes in various physiological parameters in rodents. METHODS: The LD50 of potassium cyanide (KCN) given orally (po), intraperitoneally (ip), subcutaneously (sc) or intravenously (iv) was determined in male mice, in the presence or absence alpha-KG given po, ip or iv. alpha-KG was administered 10, 20 or 40 min prior to KCN at 0.50, 1.0 or 2.0 g/kg by po or ip route, and at 0.10, 0.20 or 0.40 g/kg by iv route. Protection index (PI) was calculated as the ratio of LD50 of KCN in the presence of alpha-KG (protected animals) and LD50 of KCN in the absence of alpha-KG (unprotected animals). In a separate experiment, several physiological variables viz. mean arterial pressure (MAP), heart rate (HR), respiratory rate (RR), neuromuscular transmission (NMT) and rectal temperature (RT) were measured in anesthetized female rats pre-treated (-10 min) with po (2.0 g/kg) or iv (0.125 g/kg) alpha-KG and then administered sub-lethal (0.75 LD50) or lethal (2.0, 4.0 or 8.0 LD50) doses of KCN (po). RESULTS: PI of 4.52, 6.40 and 7.60 at -10 min, 3.20, 5.40 and 6.40 at -20 min, and 1.40, 3.20 and 5.40 at -40 min of po administration with a-KG was observed for 0.50, 1.0 and 2.0 g/kg doses, respectively, against KCN given by po route. When KCN was given ip, a PI of 3.38, 4.79 and 5.70 was observed for 0.50, 1.0 and 2.0 g/kg alpha-KG given ip (-10 min), respectively. A lower PI of 3.37, 2.83 and 2.38 was observed when KCN given sc was challenged by 2.0 g/kg alpha-KG given ip at -10, -20 or -40 min, respectively. Similarly, a PI of 3.37, 2.83 and 2.0 was noted when KCN given sc was antagonized by 2.0 g/kg alpha-KG given po at -10, -20 or -40 min, respectively. No appreciable protection was observed when lower doses of alpha-KG (ip or po) challenged KCN given by sc route. Pre-treatment of iv or po administration of alpha-KG did not afford any protection against KCN given po or iv route. Oral treatment of 0.75 LD50 KCN caused significant decrease in MAP and HR after 15 min, RR after 30 min and NMT after 60 min. There was no effect on RT. No reduction in MAP, HR, RR and RT was observed when rats received 2.0 or 4.0 LD50 KCN after pre-treatment of alpha-KG (po; 2.0 g/kg). However, no protection was observed on NMT. Protective efficacy of alpha-KG was not observed on MAP, HR, RR, and NMT decreased by 8.0 LD50 KCN. Decrease in MAP and NMT caused by 2.0 LD50 KCN (po) was resolved by iv administration of alpha-KG. CONCLUSIONS: Cyanide antagonism by alpha-KG is best exhibited when both alpha-KG and KCN are given by po route. The protective effect of a-KG on cyanide-induced changes in several physiological parameters also indicates a promising role of alpha-KG as an alternative cyanide antidote.

Acute toxicity and cardio-respiratory effects of 2-deoxy-D-glucose: a promising radio sensitiser.

OBJECTIVE: To evaluate the acute toxicity of 2-deoxy-D-glucose (2DG) by oral (p.o.) and intravenous (i.v.) routes, and also the cardio-respiratory effects following high doses of 2DG in animal models. METHODS: The LD50 of 2DG (in water) was determined in rats and mice by p.o. route and in mice by i.v. route. The effect of 2-DG (250 mg/kg, 500 mg/kg, and 1000 mg/kg, i.v.) was studied on various cardio-respiratory parameters viz., mean arterial blood pressure, heart rate and respiratory rate in anaesthetised rats. The effect of 2DG (500 mg/kg, 1000 mg/kg, and 2000 mg/kg, p.o.) was also studied on various respiratory parameters viz., respiratory rate and tidal volume in conscious rats and mice using a computer program. RESULTS: The p.o. LD50 of 2DG was found to be >8000 mg/kg in mice and rats, and at this dose no death was observed. The LD50 in mice by i.v. route was found to be 8000 mg/kg. At this dose 2 out of 4 mice died and the death occurred within 6 h. A significant increase in the body weight was observed after p.o. administration of 2DG in rats at 500 mg/kg, 1000 mg/kg, and 2000 mg/kg doses. There was no significant change in the body weight at 4000 mg/kg and 8000 mg/kg by the p.o. route in rats and up to 8000 mg/kg by p.o. as well as i.v. routes in mice. Intravenous administration of 2DG (250 mg/kg, 500 mg/kg, and 1000 mg/kg) in anaesthetised rats showed a time-dependent decrease in the mean arterial blood pressure. There was no change in the heart rate in any of the treatment groups. The tidal volume was not changed significantly by p.o administration in conscious rats, but a significant decrease in the respiratory frequency at 500 mg/kg and 1000 mg/kg doses was observed. In the mice also there was no change in the tidal volume after p.o, administration, but the respiratory frequency decreased significantly at 2000 mg/kg dose. CONCLUSION: 2DG is a safe compound but can cause a fall in the blood pressure and a decrease in respiratory frequency at high doses.