Effect of subclinical, clinical and supraclinical doses of calcium channel blockers on models of drug-induced hepatotoxicity in rats

Drug-related hepatotoxicity is the leading cause of acute liver failure, and hepatic problems are responsible for a significant number of liver transplantations and deaths worldwide. Calcium has been associated with various metabolic processes that lead to cell death and apoptosis, and increased cytosolic Ca2+ has been implicated in hepatotoxicity. This study was designed to investigate the effects of calcium channel blockers (CCBs) on isoniazid-rifampicin, zidovudine and erythromycin-induced hepatotoxicity in rats. Treatment groups comprised control, hepatotoxicant, hepatotoxicant along with each of silymarin, nifedipine, verapamil and diltiazem at subclinical, clinical and supraclinical doses. A day to the end of treatment for each model, rats were subjected to the hexobarbitone-induced hypnosis test. On the last days of treatment, blood samples were collected and serum was analyzed for relevant biochemical parameters. Animals were sacrificed after blood collection and livers were harvested, and samples obtained for in vivo antioxidant indices assay and histopathology. The hepatotoxicants significantly increased serum levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT) and alkaline phosphatase (ALP), as well as duration of sleep in the hypnosis test. These drugs significantly reduced the hepatic levels of reduced glutathione (GSH), superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) and increased the level of malondialdehyde (MDA). The CCBs at the various doses significantly reversed the effects of isoniazid-rifampicin, zidovudine and erythromycin. The results obtained in this study suggest that the CCBs possess hepatoprotective activity in drug-induced hepatotoxicity and may be beneficial at the subclinical and clinical doses

Gastroprotective Effects of the Aqueous Seed Extract of Entada gigas (Linn.) Fawc. and Rendle (Fabaceae) in Ulcer Models in Rats

Background: The extract of Entada gigas Linn. (Fabaceae) is used for the treatment of ulcer in Nigerian local medicine. Objectives: This study investigated the gastroprotective effects of the aqueous seed extract of E. gigas on gastric ulcers in rats. Methodology: The ethanol- (EIU), pylorus ligation- (PLIU) and cold restraint stress (CRSIU)-induced ulcer models were used. The aqueous seed extract was administered at doses of 50-400 mg/kg p.o. Estimations of gastric content volume, pH and titratable acidity in PLIU test and ulcer score/index in all models were done. Results: In the EIU test, E. gigas produced significant reduction (p < 0.05) in ulcer scores, with peak effect elicited at 100 mg/kg (2.30 ± 0.99; 87.22% inhibition), compared with control (10.80 ± 0.80). This effect was comparable to that of misoprostol (3.00 ± 1.31; 83.33% inhibition). In the PLIU test, the extract caused significant reduction (p < 0.05) in the ulcer score compared with control (6.30 ± 0.70). Peak effect was elicited at the dose of 200 mg/kg (ulcer score 2.90 ± 0.83; 63.17%). This effect was comparable to that of cimetidine (2.60 ± 0.93; 66.98%). Also, the extract at 50 and 200 mg/kg, and cimetidine 100 mg/kg (0.24 ± 0.07, 1.06 ± 0.22 and 1.02 ± 0.16 mL/4 h, respectively) significantly reduced (p < 0.05) the volume of gastric content relative to control (2.32 ± 0.33 mL/4 h). In the CRSIU test, E. gigas caused significant reduction (p < 0.05) in the ulcer score, with the greatest effect produced at the dose of 50 mg/kg (0.80 ± 0.49; 92.38% inhibition), relative to control (4.20 ± 0.64). This effect was comparable to that of misoprostol (1.40 ± 0.60; 80% inhibition). Conclusion: The aqueous seed extract of E. gigas possess significant antiulcer activity mediated via cytoprotective and anti-secretory mechanisms. Keywords: Entada gigas, Fabaceae, ulcer, gastroprotective effect, cytoprotective, anti-secretory

Global incidence, prevalence, years lived with disability (YLDs), disability-adjusted life-years (DALYs), and healthy life expectancy (HALE) for 371 diseases and injuries in 204 countries and territories and 811 subnational locations, 1990–2021: a systematic analysis for the Global Burden of Disease Study 2021

Background: Detailed, comprehensive, and timely reporting on population health by underlying causes of disability and premature death is crucial to understanding and responding to complex patterns of disease and injury burden over time and across age groups, sexes, and locations. The availability of disease burden estimates can promote evidence-based interventions that enable public health researchers, policy makers, and other professionals to implement strategies that can mitigate diseases. It can also facilitate more rigorous monitoring of progress towards national and international health targets, such as the Sustainable Development Goals. For three decades, the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) has filled that need. A global network of collaborators contributed to the production of GBD 2021 by providing, reviewing, and analysing all available data. GBD estimates are updated routinely with additional data and refined analytical methods. GBD 2021 presents, for the first time, estimates of health loss due to the COVID-19 pandemic. Methods: The GBD 2021 disease and injury burden analysis estimated years lived with disability (YLDs), years of life lost (YLLs), disability-adjusted life-years (DALYs), and healthy life expectancy (HALE) for 371 diseases and injuries using 100 983 data sources. Data were extracted from vital registration systems, verbal autopsies, censuses, household surveys, disease-specific registries, health service contact data, and other sources. YLDs were calculated by multiplying cause-age-sex-location-year-specific prevalence of sequelae by their respective disability weights, for each disease and injury. YLLs were calculated by multiplying cause-age-sex-location-year-specific deaths by the standard life expectancy at the age that death occurred. DALYs were calculated by summing YLDs and YLLs. HALE estimates were produced using YLDs per capita and age-specific mortality rates by location, age, sex, year, and cause. 95% uncertainty intervals (UIs) were generated for all final estimates as the 2·5th and 97·5th percentiles values of 500 draws. Uncertainty was propagated at each step of the estimation process. Counts and age-standardised rates were calculated globally, for seven super-regions, 21 regions, 204 countries and territories (including 21 countries with subnational locations), and 811 subnational locations, from 1990 to 2021. Here we report data for 2010 to 2021 to highlight trends in disease burden over the past decade and through the first 2 years of the COVID-19 pandemic. Findings: Global DALYs increased from 2·63 billion (95% UI 2·44–2·85) in 2010 to 2·88 billion (2·64–3·15) in 2021 for all causes combined. Much of this increase in the number of DALYs was due to population growth and ageing, as indicated by a decrease in global age-standardised all-cause DALY rates of 14·2% (95% UI 10·7–17·3) between 2010 and 2019. Notably, however, this decrease in rates reversed during the first 2 years of the COVID-19 pandemic, with increases in global age-standardised all-cause DALY rates since 2019 of 4·1% (1·8–6·3) in 2020 and 7·2% (4·7–10·0) in 2021. In 2021, COVID-19 was the leading cause of DALYs globally (212·0 million [198·0–234·5] DALYs), followed by ischaemic heart disease (188·3 million [176·7–198·3]), neonatal disorders (186·3 million [162·3–214·9]), and stroke (160·4 million [148·0–171·7]). However, notable health gains were seen among other leading communicable, maternal, neonatal, and nutritional (CMNN) diseases. Globally between 2010 and 2021, the age-standardised DALY rates for HIV/AIDS decreased by 47·8% (43·3–51·7) and for diarrhoeal diseases decreased by 47·0% (39·9–52·9). Non-communicable diseases contributed 1·73 billion (95% UI 1·54–1·94) DALYs in 2021, with a decrease in age-standardised DALY rates since 2010 of 6·4% (95% UI 3·5–9·5). Between 2010 and 2021, among the 25 leading Level 3 causes, age-standardised DALY rates increased most substantially for anxiety disorders (16·7% [14·0–19·8]), depressive disorders (16·4% [11·9–21·3]), and diabetes (14·0% [10·0–17·4]). Age-standardised DALY rates due to injuries decreased globally by 24·0% (20·7–27·2) between 2010 and 2021, although improvements were not uniform across locations, ages, and sexes. Globally, HALE at birth improved slightly, from 61·3 years (58·6–63·6) in 2010 to 62·2 years (59·4–64·7) in 2021. However, despite this overall increase, HALE decreased by 2·2% (1·6–2·9) between 2019 and 2021. Interpretation: Putting the COVID-19 pandemic in the context of a mutually exclusive and collectively exhaustive list of causes of health loss is crucial to understanding its impact and ensuring that health funding and policy address needs at both local and global levels through cost-effective and evidence-based interventions. A global epidemiological transition remains underway. Our findings suggest that prioritising non-communicable disease prevention and treatment policies, as well as strengthening health systems, continues to be crucially important. The progress on reducing the burden of CMNN diseases must not stall; although global trends are improving, the burden of CMNN diseases remains unacceptably high. Evidence-based interventions will help save the lives of young children and mothers and improve the overall health and economic conditions of societies across the world. Governments and multilateral organisations should prioritise pandemic preparedness planning alongside efforts to reduce the burden of diseases and injuries that will strain resources in the coming decades. Funding: Bill & Melinda Gates Foundation

Global burden of 288 causes of death and life expectancy decomposition in 204 countries and territories and 811 subnational locations, 1990–2021: a systematic analysis for the Global Burden of Disease Study 2021

BACKGROUND Regular, detailed reporting on population health by underlying cause of death is fundamental for public health decision making. Cause-specific estimates of mortality and the subsequent effects on life expectancy worldwide are valuable metrics to gauge progress in reducing mortality rates. These estimates are particularly important following large-scale mortality spikes, such as the COVID-19 pandemic. When systematically analysed, mortality rates and life expectancy allow comparisons of the consequences of causes of death globally and over time, providing a nuanced understanding of the effect of these causes on global populations. METHODS The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2021 cause-of-death analysis estimated mortality and years of life lost (YLLs) from 288 causes of death by age-sex-location-year in 204 countries and territories and 811 subnational locations for each year from 1990 until 2021. The analysis used 56 604 data sources, including data from vital registration and verbal autopsy as well as surveys, censuses, surveillance systems, and cancer registries, among others. As with previous GBD rounds, cause-specific death rates for most causes were estimated using the Cause of Death Ensemble model-a modelling tool developed for GBD to assess the out-of-sample predictive validity of different statistical models and covariate permutations and combine those results to produce cause-specific mortality estimates-with alternative strategies adapted to model causes with insufficient data, substantial changes in reporting over the study period, or unusual epidemiology. YLLs were computed as the product of the number of deaths for each cause-age-sex-location-year and the standard life expectancy at each age. As part of the modelling process, uncertainty intervals (UIs) were generated using the 2·5th and 97·5th percentiles from a 1000-draw distribution for each metric. We decomposed life expectancy by cause of death, location, and year to show cause-specific effects on life expectancy from 1990 to 2021. We also used the coefficient of variation and the fraction of population affected by 90% of deaths to highlight concentrations of mortality. Findings are reported in counts and age-standardised rates. Methodological improvements for cause-of-death estimates in GBD 2021 include the expansion of under-5-years age group to include four new age groups, enhanced methods to account for stochastic variation of sparse data, and the inclusion of COVID-19 and other pandemic-related mortality-which includes excess mortality associated with the pandemic, excluding COVID-19, lower respiratory infections, measles, malaria, and pertussis. For this analysis, 199 new country-years of vital registration cause-of-death data, 5 country-years of surveillance data, 21 country-years of verbal autopsy data, and 94 country-years of other data types were added to those used in previous GBD rounds. FINDINGS The leading causes of age-standardised deaths globally were the same in 2019 as they were in 1990; in descending order, these were, ischaemic heart disease, stroke, chronic obstructive pulmonary disease, and lower respiratory infections. In 2021, however, COVID-19 replaced stroke as the second-leading age-standardised cause of death, with 94·0 deaths (95% UI 89·2-100·0) per 100 000 population. The COVID-19 pandemic shifted the rankings of the leading five causes, lowering stroke to the third-leading and chronic obstructive pulmonary disease to the fourth-leading position. In 2021, the highest age-standardised death rates from COVID-19 occurred in sub-Saharan Africa (271·0 deaths [250·1-290·7] per 100 000 population) and Latin America and the Caribbean (195·4 deaths [182·1-211·4] per 100 000 population). The lowest age-standardised death rates from COVID-19 were in the high-income super-region (48·1 deaths [47·4-48·8] per 100 000 population) and southeast Asia, east Asia, and Oceania (23·2 deaths [16·3-37·2] per 100 000 population). Globally, life expectancy steadily improved between 1990 and 2019 for 18 of the 22 investigated causes. Decomposition of global and regional life expectancy showed the positive effect that reductions in deaths from enteric infections, lower respiratory infections, stroke, and neonatal deaths, among others have contributed to improved survival over the study period. However, a net reduction of 1·6 years occurred in global life expectancy between 2019 and 2021, primarily due to increased death rates from COVID-19 and other pandemic-related mortality. Life expectancy was highly variable between super-regions over the study period, with southeast Asia, east Asia, and Oceania gaining 8·3 years (6·7-9·9) overall, while having the smallest reduction in life expectancy due to COVID-19 (0·4 years). The largest reduction in life expectancy due to COVID-19 occurred in Latin America and the Caribbean (3·6 years). Additionally, 53 of the 288 causes of death were highly concentrated in locations with less than 50% of the global population as of 2021, and these causes of death became progressively more concentrated since 1990, when only 44 causes showed this pattern. The concentration phenomenon is discussed heuristically with respect to enteric and lower respiratory infections, malaria, HIV/AIDS, neonatal disorders, tuberculosis, and measles. INTERPRETATION Long-standing gains in life expectancy and reductions in many of the leading causes of death have been disrupted by the COVID-19 pandemic, the adverse effects of which were spread unevenly among populations. Despite the pandemic, there has been continued progress in combatting several notable causes of death, leading to improved global life expectancy over the study period. Each of the seven GBD super-regions showed an overall improvement from 1990 and 2021, obscuring the negative effect in the years of the pandemic. Additionally, our findings regarding regional variation in causes of death driving increases in life expectancy hold clear policy utility. Analyses of shifting mortality trends reveal that several causes, once widespread globally, are now increasingly concentrated geographically. These changes in mortality concentration, alongside further investigation of changing risks, interventions, and relevant policy, present an important opportunity to deepen our understanding of mortality-reduction strategies. Examining patterns in mortality concentration might reveal areas where successful public health interventions have been implemented. Translating these successes to locations where certain causes of death remain entrenched can inform policies that work to improve life expectancy for people everywhere. FUNDING Bill & Melinda Gates Foundation

Anxiolytic and sedative properties of hydroethanolic extract of Telfairia occidentalis leaves in mice

Telfairia occidentalis Hook. f., Cucurbitaceae, is a leafy vegetable used in soup and folk medicine in southern Nigeria. This study was conducted to investigate the anxiolytic and sedative activities of the hydroethanolic extract of the leaves of T. occidentalis in mice. The hole-board, elevated plus maze, open-field, light-dark, and social interaction tests were used in this study. T. occidentalis (50-400 mg/kg) and diazepam (1 mg/kg) were administered p.o. to different groups of mice and appropriate observations were made. T. occidentalis increased the number of sectional crossings (p<0.01) and duration of head dips (p<0.05) at doses of 50 and 100 mg/kg respectively; increased number of entries into open arms (p<0.01) at the dose of 100 mg/kg; increased number of central squares crossed (p<0.01) at the dose of 50 mg/kg; and increased number of social interactions (p<0.001) at doses of 50 and 100 mg/kg. At the dose of 400 mg/kg, T. occidentalis reduced number of head dips and sectional crossings (p<0.01); reduced time spent in open arms and increased time spent in closed arms (p<0.01, 0.001) at doses of 200 and 400 mg/kg; reduced number of assisted rearings (p<0.001) at doses of 200 and 400 mg/kg; increased latency of entry into and time spent in dark box (p<0.01, 0.001) at doses of 200 and 400 mg/kg; and reduced number of social interactions (p<0.001) at the dose of 400 mg/kg. The findings in this study suggest that T. occidentalis possess anxiolytic property at doses of 50 and 100 mg/kg, and sedative activity at doses of 200 and 400 mg/kg

Natural Products and/or Isolated Compounds on Wound Healing

The effective treatment of wounds remains a major global health challenge. Failure to heal or elongation of the wound healing process results in increased financial and social stress being placed on health institutions, care-givers, patients, and their families. The occurrence of various forms of wounds such as chronic and acute wounds, pressure ulcers, venous stasis ulcers, and diabetic ulcers has increased over the years in most countries, especially developed countries where life expectancy has been increasing over timeand is accompanied by geriatric diseases. Acute and chronic, non healing wounds impose heavy financial and quality of life burdens on patients. Chronic wounds are normally characterized by intense pain, infection, loss of function, and loss of mobility and may lead to amputations and in some cases even death. With an increase in the prevalence of wounds and the high cost of orthodox medicines, most patients, especially those in developing countries, resort to herbal preparations or remedies which are believed to be readily available and cheap for the treatment thereof. The urgent need for the identification of effective, safe, and cost efficient wound healing promoters which can be introduced into clinical practice is unequivocal. This has driven an increase in the search for potent, cost effective wound healing agents from natural products including medicinal plants.http://www.hindawi.com/journals/ecamam2019Pharmacolog

Sub-Chronic Toxicity of the Hydroethanolic Leaf Extract of Telfairia occidentalis Hook. f. (Cucurbitaceae) in Male Rats

Background: Due to its nutritional and medicinal values, the leaf of Telfairia occidentalis Hook f. (Cucurbitaceae) is consumed in different parts of Nigeria. Acute and sub-chronic toxicity of the hydroethanolic leaf extract of Telfairia occidentalis were investigated in this study. Methods: Sixty-four male rats were randomized into four different groups of 16 animals each and were separately administered 80, 400 and 2000 mg/kg T. occidentalis orally (p.o.) for 60 days. Animals were sacrificed and blood samples were collected for hematological and biochemical analyses. Vital organs were harvested and evaluated for in vivo antioxidants and histopathological changes. Results: A significant (p &lt; 0.05) reduction in weight of the testes, compared to the control group, was observed in the group treated with 2000 mg/kg extract. No significant change was observed in the weight of other vital organs relative to the control group. There were significant (p &lt; 0.01) increases in sperm motility and count in the group administered 80 mg/kg extract and significant (p &lt; 0.001) reductions in both parameters at 2000 mg/kg. There were significant increases in the levels of hemoglobin and packed cell volume at 80 and 2000 mg/kg of the extract. In respect of liver function parameters, significant reductions in aspartate aminotransferase and alanine aminotransferase levels at doses of 400 and 2000 mg/kg relative to control were observed. Compared to control, the extract significantly reduced (p &lt; 0.05) the level of total cholesterol (400 mg/kg) and caused a significant increase in the level of high-density lipoprotein (80, 400 and 2000 mg/kg). Significant (p &lt; 0.05) increase in the level of malondialdehyde, decrease in superoxide dismutase level and histopathological abnormalities were observed in the testes at 2000 mg/kg. Upon cessation of treatment with T. occidentalis for 30 days, the observed effects were reversed. Conclusions: The findings showed that the hydroethanolic leaf extract of Telfairia occidentalis is relatively non-toxic on acute and sub-chronic exposures at low to moderate doses, with the potential to elicit anti-anemic effects, reduce the risk of atherosclerosis and cardiovascular disease, and enhance antioxidant status in the brain and liver. Although possibly beneficial at low to moderate doses, the extract could be harmful to the testes with prolonged oral exposure at high dose

Antinociceptive and anti-inflammatory activities of ethanolic extract of Alafia barteri

This study analyzes the antinociceptive and anti-inflammatory properties of ethanolic leaf extract of Alafia barteri Oliv., Apocynaceae, based on its medicinal use in the treatment of toothaches, inflammation and fevers. The antinociceptive effect was assessed in mice using acetic acid-induced writhing, tail clip, tail immersion and formalin assays. Anti-inflammatory activity was evaluated on carrageenan-induced paw oedema in rats, and xylene-induced ear oedema in mice. In acetic acid-induced writhing test, the extract at different doses (50, 100 and 200 mg/kg, p.o.) significantly (p < 0.05) and dose-dependently reduced pain by 35.04, 56.49 and 84.25%, respectively. The extract also significantly inhibited both the early and late phases of formalin-induced nociception in mice. In the tail immersion test, the extract caused a significant inhibition of pain (34.43% inhibition, after 90 min) at a dose of 200 mg/kg, while the effect of the extract in the tail clip test was only significant at the 100 mg/kg dose. A. barteri caused a significant inhibition of paw oedema development in the carrageenan and xylene-induced oedema tests. There was no mortality recorded following treatment with the extract (5 g/kg, p.o.). The results support the traditional use of A. barteri in the treatment of various diseases associated with pain and inflammation