In Vivo Antidiarrheal and Cytotoxic Potential of Different Fractions of Pandanus Foetidus Leaves

Abstract This study investigated the antidiarrheal and cytotoxic effects of methanol, petroleum ether, chloroform and aqueous fractions of Pandanus foetidus leaf extract. Antidiarrheal effect was measured in castor oil induced-diarrhea, -enteropooling and -gastrointestinal motility (GI) test models in albino mice. Cytotoxicity was investigated in brine shrimp lethality bioassay. All data were analyzed by the software, statistical package for social science (SPSS), Version 18.0. The extracts (200 mg/kg) showed a remarkable antidiarrheal activity by reducing the number of defecation and maintaining the consistency of feces. The petroleum ether, chloroform and aqueous fraction of the extract significantly (p < 0.05) inhibited the diarrheal incidence at the dose of 200 mg/kg. Castor oil induced enteropooling and fluid accumulation was significantly reduced by methanol and chloroform fraction, whereas gastrointestinal motility was shrunk by the aqueous fraction only. Loperamide was used as a reference drug in the above mentioned models. In cytotoxicity test, the lowest LC 50 was found to be 106.97 μg/ml by the chloroform fraction of the extract. The results demonstrated that Pandanus foetidus extract could be used as pharmaceutical preparation of antidiarrheal and cytotoxic agent obtained from appropriate solvent system

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

ANTIDIARRHEAL ACTIVITY OF LEAVES EXTRACT OF MICROCOS PANICULATA LINN IN MICE

The experiment of methanolic extract of Microcos paniculata leaves showed significant (p<0.001) inhibitor activity against castor oil induced diarrhea and castor oil induced enteropooling in mice at dose of 400 mg/kg body weight. There was also significant (p<0.01) reduction in gastrointestinal motility in the charcoal meal test. Loperamide (5 mg/kg b. wt) was used as positive control. These results revealed that the leaves extract possess pharmacological activity against diarrhea and may possibly explain the use of the plant in traditional medicine

Evaluation of antidiarrheal activity of methanolic extract of Maranta arundinacea Linn. leaves

Diarrhea is one of the most common causes for thousands of deaths every year. Therefore, identification of new source of antidiarrheal drugs becomes one of the most prominent focuses in modern research. Our aim was to investigate the antidiarrheal and cytotoxic activities of methanolic extract of Maranta arundinacea linn. (MEMA) leaves in rats and brine shrimp, respectively. Antidiarrheal effect was evaluated by using castor oil-induced diarrhea, enteropooling, and gastrointestinal motility tests at 200 mg/kg and 400 mg/kg body weight in rats where the cytotoxic activity was justified using brine shrimp lethality bioassay at different concentrations of MEMA. The extract showed considerable antidiarrheal effect by inhibiting 42.67% and 57.75% of diarrheal episode at the doses of 200 and 400 mg/kg, respectively. MEMA also significantly (p < 0.01) reduced the castor oil-induced intestinal volume (2.14 +/- 0.16 to 1.61 +/- 0.12 mL) in enteropooling test as well as intestinal transit (33.00 to 43.36%) in GI motility test, compared to their respective control. These observed effects are comparable to that of standard drug loperamide (5 mg/kg). On the other hand, in brine shrimp lethality test after 24 h, surviving brine shrimp larvae were counted and LD50 was assessed. Result showed that MEMA was potent against brine shrimp with LD50 value of 420 mu g/mL. So the highest dose of 400 mu g/mL of MEMA was not toxic to mice. So these results indicate that bioactive compounds are present in methanolic extract of Maranta arundinacea leaves including significant antidiarrheal activity and could be accounted for pharmacological effects

Investigation of in vivo neuropharmacological effect of Alpinia nigra leaf extract

Objective: To analyze in vivo neuro-pharmacological effects of Alpinia nigra as anxiety is a particular form of behavioral inhibition that occurs in response to novel environmental events. Methods: In present study, the extract of Alpinia nigra was evaluated for its central nervous system depressant effect using mice behavioral models, such as hole cross, open field and thiopental sodium induced sleeping time tests for its sedative properties and an elevated plus-maze test for its anxiolytic potential, respectively. Results: In anxiolytic study, the extract displayed increased percentage of entry into open arm at the dose of 400 and 200 mg/kg. The extract produced a significant (P<0.01) increase in sleeping duration and reduction of onset of sleep compared to sodium thiopental at both doses (200 and 400 mg/kg). The extract (200 and 400 mg/kg) also showed a dose-dependent suppression of motor activity and exploratory activity of the mice in both open field and hole cross test. Conclusion: This study demonstrates that the treated extract has significant central nervous system depressant effect. Further studies on active constituent of the extract can provide approaches for therapeutic intervention

Sedative and Anxiolytic Activities of Geodorum densiflorum Roots in Swiss Albino Mice

Fresh root of Geodorum densiflorum (Lam.) (Orchidaceae) has applications in regularizing menstrual cycle and as topical aids in insect bites and wounds. The tuber extracts of some plants belonging to Geodorum have folkloric reputation in the management of transient anxiety. The current study was undertaken to investigate the sedative/ anxiolytic effects of G. densiflorum root extracts using rodent behavioral models, such as open field, hole cross, thiopental sodium-induced hypnosis and elevated plus maze test. Present data shows that the organic extracts of G. densiflorum root increase the thiopental sodium induced sleeping time and reduce the time for the onset of sleep. A statistically significant reduction in motor activity and exploratory behavior were observed in the open field and hole cross tests. The results of the current studies provide scientific evidence for its uses in traditional medicines as sedative and anxiolytic agents

Sedative and Anxiolytic Activities of Geodorum densiflorum Roots in Swiss Albino Mice

Fresh root of Geodorum densiflorum (Lam.) (Orchidaceae) has applications in regularizing menstrual cycle and as topical aids in insect bites and wounds. The tuber extracts of some plants belonging to Geodorum have folkloric reputation in the management of transient anxiety. The current study was undertaken to investigate the sedative/ anxiolytic effects of G. densiflorum root extracts using rodent behavioral models, such as open field, hole cross, thiopental sodium-induced hypnosis and elevated plus maze test. Present data shows that the organic extracts of G. densiflorum root increase the thiopental sodium induced sleeping time and reduce the time for the onset of sleep. A statistically significant reduction in motor activity and exploratory behavior were observed in the open field and hole cross tests. The results of the current studies provide scientific evidence for its uses in traditional medicines as sedative and anxiolytic agents

In Vitro and In Vivo Inhibition of MATE1 by Tyrosine Kinase Inhibitors

The membrane transport of many cationic prescription drugs depends on facilitated transport by organic cation transporters of which several members, including OCT2 (SLC22A2), are sensitive to inhibition by select tyrosine kinase inhibitors (TKIs). We hypothesized that TKIs may differentially interact with the renal transporter MATE1 (SLC47A1) and influence the elimination and toxicity of the MATE1 substrate oxaliplatin. Interactions with FDA-approved TKIs were evaluated in transfected HEK293 cells, and in vivo pharmacokinetic studies were performed in wild-type, MATE1-deficient, and OCT2/MATE1-deficient mice. Of 57 TKIs evaluated, 37 potently inhibited MATE1 function by &gt;80% through a non-competitive, reversible, substrate-independent mechanism. The urinary excretion of oxaliplatin was reduced by about 2-fold in mice with a deficiency of MATE1 or both OCT2 and MATE1 (p &lt; 0.05), without impacting markers of acute renal injury. In addition, genetic or pharmacological inhibition of MATE1 did not significantly alter plasma levels of oxaliplatin, suggesting that MATE1 inhibitors are unlikely to influence the safety or drug-drug interaction liability of oxaliplatin-based chemotherapy

Contribution of MATE1 to Dofetilide-Induced Proarrhythmia

Dofetilide is a rapid delayed rectifier potassium current inhibitor widely used to prevent the recurrence of atrial fibrillation and flutter. The clinical use of this drug is associated with increases in QTc interval, which predisposes to ventricular cardiac arrhythmias. The mechanisms involved in the disposition of dofetilide, including its movement in and out of cardiomyocytes, remain unknown. Using a xenobiotic transporter screen, we identified MATE1 (SLC47A1) as an efflux transporter of dofetilide and found that genetic knockout or pharmacological inhibition of MATE1 in mice was associated with enhanced retention of dofetilide in cardiomyocytes and increased QTc prolongation. The urinary excretion of dofetilide was also dependent on MATE1 genotype, and we found that this transport mechanism provides a mechanistic basis for previously recorded drug-drug interactions of dofetilide with various contraindicated drugs, including bictegravir, cimetidine, ketoconazole, and verapamil. The translational significance of these observations was examined with a physiologically-based pharmacokinetic model that adequately predicted the drug-drug interaction liabilities in humans. These findings support the thesis that MATE1 serves a conserved cardioprotective role by restricting excessive cellular accumulation and warrant caution against the concurrent administration of potent MATE1 inhibitors and cardiotoxic substrates with a narrow therapeutic window

MATE1 Deficiency Exacerbates Dofetilide-Induced Proarrhythmia

Dofetilide is a rapid delayed rectifier potassium current inhibitor widely used to prevent the recurrence of atrial fibrillation and flutter. The clinical use of this drug is associated with increases in QTc interval, which predispose patients to ventricular cardiac arrhythmias. The mechanisms involved in the disposition of dofetilide, including its movement in and out of cardiomyocytes, remain unknown. Using a xenobiotic transporter screen, we identified MATE1 (SLC47A1) as a transporter of dofetilide and found that genetic knockout or pharmacological inhibition of MATE1 in mice was associated with enhanced retention of dofetilide in cardiomyocytes and increased QTc prolongation. The urinary excretion of dofetilide was also dependent on the MATE1 genotype, and we found that this transport mechanism provides a mechanistic basis for previously recorded drug-drug interactions of dofetilide with various contraindicated drugs, including bictegravir, cimetidine, ketoconazole, and verapamil. The translational significance of these observations was examined with a physiologically-based pharmacokinetic model that adequately predicted the drug-drug interaction liabilities in humans. These findings support the thesis that MATE1 serves a conserved cardioprotective role by restricting excessive cellular accumulation and warrant caution against the concurrent administration of potent MATE1 inhibitors and cardiotoxic substrates with a narrow therapeutic window