In Vivo Bioavailability and Therapeutic Assessment of Host-Guest Inclusion Phenomena for the Hydrophobic Molecule Etodolac: Pharmacodynamic and Pharmacokinetic Evaluation

The aim of present investigation was 1) to evaluate the in vivo bioavailability of an Etodolac (ETD)-β-cyclodextrin (β-CD) inclusion complex system prepared by kneading and spray drying techniques in rats, 2) to study the pharmacodynamic parameters in various animal models for analyzing the therapeutic response and, 3) to evaluate the pharmacokinetic profile of the drug administered. Inclusion complexation with β-CD enhanced the solubility of the drug, improved bioavailability and reduced ulcerogenicity of ETD in rats. Pharmacodynamic studies were carried out in normal LACA mice and pharmacokinetic evaluation was done in male Wistar rats. Pharmacokinetic parameters evaluated for the inclusion complexes revealed good correlation. The minimum dose necessary to produce analgesic or anti-arthritic activity was also decreased, indicating that the host-guest strategy that uses β-CD and ETD was very effective and could be successfully employed in the preparation of pharmaceutical formulations of anti-arthritics and analgesics

Paradoxical effect of coating on natural guar gum blended carbomer matrix systems for the neurological depressive disorders

Oral extended release products offer potential advantages in patient compliance and therapeutic outcomes like sustained blood levels with attenuation of adverse effects. In neuropsychiatric disorders like depression, most of the formulations serve a marketing objective rather than a clinical objective. The present investigation was aimed to develop a once daily sustained release formulation for delivery of an acid-labile, water soluble antidepressant, duloxetine HCl. The formulation was pragmatically designed using blend of natural and synthetic polymeric biomaterials that it releases the drug at alkaline pH in a sustained manner. The basic intention was to develop a tablet formulation with hydrophilic matrix core, using blend of release retarding natural biodegradable polymers such as guar gum, carbopol 71G-NF (a synthetic carbomer) and C-Pharm® gel. Barrier coating using HPMC-E5 was given to retard the initial release followed by enteric coating with HPMC-AS to prevent exposure of drug in acidic mileau of the stomach. The formulation exhibited desired release pattern and was described best-fit by Hixon-Crowell model. Stability analysis under stress conditions up to one month displayed good reproducibility. The matrix tablets successfully decreased the symptoms of depression (significant decrease in immobility time) in a rat forced swimming model. Pharmacokinetic data of the formulation revealed (tmax ~ 6 h, Cmax ~ 1157.58 ng/ml, mean AUCt~11145.04 ng*h/ml, and Ka~1.07h-1) good correlation in all animals.Keywords: Matrix tablets; Duloxetine HCl; Sustained release; Enteric coating; Hixon-crowell mode

Paradoxical effect of coating on natural guar gum blended carbomer matrix systems for the neurological depressive disorders

Oral extended release products offer potential advantages in patient compliance and therapeutic outcomes like sustained blood levels with attenuation of adverse effects. In neuropsychiatric disorders like depression, most of the formulations serve a marketing objective rather than a clinical objective. The present investigation was aimed to develop a once daily sustained release formulation for delivery of an acid-labile, water soluble antidepressant, duloxetine HCl. The formulation was pragmatically designed using blend of natural and synthetic polymeric biomaterials that it releases the drug at alkaline pH in a sustained manner. The basic intention was to develop a tablet formulation with hydrophilic matrix core, using blend of release retarding natural biodegradable polymers such as guar gum, carbopol 71G-NF (a synthetic carbomer) and C-Pharm® gel. Barrier coating using HPMC-E5 was given to retard the initial release followed by enteric coating with HPMC-AS to prevent exposure of drug in acidic mileau of the stomach. The formulation exhibited desired release pattern and was described best-fit by Hixon-Crowell model. Stability analysis under stress conditions up to one month displayed good reproducibility. The matrix tablets successfully decreased the symptoms of depression (significant decrease in immobility time) in a rat forced swimming model. Pharmacokinetic data of the formulation revealed (tmax ~ 6 h, Cmax ~ 1157.58 ng/ml, mean AUCt~11145.04 ng*h/ml, and Ka~1.07h-1) good correlation in all animals.Keywords: Matrix tablets; Duloxetine HCl; Sustained release; Enteric coating; Hixon-crowell mode

Dizajniranje sustava isporuke 5-fluorouracila u kolon tabletama obloženima miješanim filmom

The study was carried out to establish the effectiveness of a mixed film composed of ethyl cellulose/Eudragit S100 for colonic delivery of 5-flourouracil (5-FU). Tablets cores containing 5-FU were prepared by direct compression method by coating at different levels (2–9 %, m/m) with a non-aqueous solution containing ethylcellulose/Eudragit S100. Coated tablets were studied for the in vitro release of 5-FU and the samples were analyzed spectrophotometrically at 266 nm. Drug release from coated systems depended on the thickness of the mixed film and the composition of the core. Channel formation was initiated in the coat by dissolution of the Eudragit S 100 fraction at higher pH in the colonic region. The release was found to be higher in tablets containing Avicel as filler owing to its wicking action compared to that from lactose containing cores. Furthermore, batches containing superdisintegrant (1 %, m/m Cross-PVP) along with Avicel in the core released approximately 81.1 % drug during the colonic transit time. Kinetic studies indicated that all the formulations followed first-order release kinetics. The developed delivery system will expectedly deliver the drug to the colon.Cilj rada bio je pripraviti miješane filmove od etilceluloze i Eudragita S100 za isporuku 5-flourouracil (5-FU) u kolon. Jezgre tableta s 5-FU pripravljene su metodom izravne kompresije koristeći nevodenu otopinu etilceluloze/Eudragita S100 (2–9 %, m/m). Iz obloženih tableta proučavano je in vitro oslobađanje 5-FU koristeći speckrofotometrijsku analizu na 266 nm. Oslobađanje lijeka iz obloženog sustava ovisilo je o debljini filma i sastavu jezgre tablete. Stvaranje kanala u ovojnici potaknuto je otapanjem frakcije s Eudragitom S 100 pri višim pH u debelom crijevu. Jače oslobađanje bilo je iz tableta s Avicelom kao punilom nego iz tableta s laktozom zahvaljujući kapilarnom djelovanju Avicela. Nadalje, pripravci sa superdezintegratorom (1 %, m/m Cross-PVP) i Avicelom oslobađali su približno 81,1 % lijeka u vremenu koje je potrebno za prolaz tableta kroz kolon. Kinetička ispitivanja pokazuju da svi pripravci slijede kinetiku prvog reda. Razvijeni sustavi trebali bi biti pogodni za isporuku lijeka u kolon

Fizičkokemijska karakterizacija inkluzijskih kompleksa celekoksiba s beta-ciklodekstrinom i oslobađanje celekoksiba in vitro

In this study, attempts were made to investigate the effects of betha-cyclodextrin (betha-CD) on the aqueous solubility and dissolution rate of celecoxib. Inclusion complexes were prepared by the kneading method and characterized by SEM, NMR, IR, DSC, and X-ray powder diffraction. Dissolution rate of the complexes was significantly greater than that of the corresponding physical mixtures and pure drug, indicating that the formation of inclusion complex increased the solubility of the poorly soluble drug celecoxib.U radu je ispitivan utjecaj beta-ciklodekstrina (beta-CD) na vodotopljivost i oslobađanje celekoksiba iz inkluzijskih kompleksa. Kompleksi su priređeni metodom gnječenja i karakterizirani pomoću SEM, NMR, IR, DSC i difrakcijom rentgenskim zračenjem. Oslobađanje iz kompleksa bilo je značajno bolje nego iz fizičke smjese što ukazuje da je stvaranje inkluzijskog kompleksa povećalo topljivost teško topljivog celekoksiba

Canagliflozin and renal outcomes in type 2 diabetes and nephropathy

BACKGROUND Type 2 diabetes mellitus is the leading cause of kidney failure worldwide, but few effective long-term treatments are available. In cardiovascular trials of inhibitors of sodium–glucose cotransporter 2 (SGLT2), exploratory results have suggested that such drugs may improve renal outcomes in patients with type 2 diabetes. METHODS In this double-blind, randomized trial, we assigned patients with type 2 diabetes and albuminuric chronic kidney disease to receive canagliflozin, an oral SGLT2 inhibitor, at a dose of 100 mg daily or placebo. All the patients had an estimated glomerular filtration rate (GFR) of 30 to <90 ml per minute per 1.73 m2 of body-surface area and albuminuria (ratio of albumin [mg] to creatinine [g], >300 to 5000) and were treated with renin–angiotensin system blockade. The primary outcome was a composite of end-stage kidney disease (dialysis, transplantation, or a sustained estimated GFR of <15 ml per minute per 1.73 m2), a doubling of the serum creatinine level, or death from renal or cardiovascular causes. Prespecified secondary outcomes were tested hierarchically. RESULTS The trial was stopped early after a planned interim analysis on the recommendation of the data and safety monitoring committee. At that time, 4401 patients had undergone randomization, with a median follow-up of 2.62 years. The relative risk of the primary outcome was 30% lower in the canagliflozin group than in the placebo group, with event rates of 43.2 and 61.2 per 1000 patient-years, respectively (hazard ratio, 0.70; 95% confidence interval [CI], 0.59 to 0.82; P=0.00001). The relative risk of the renal-specific composite of end-stage kidney disease, a doubling of the creatinine level, or death from renal causes was lower by 34% (hazard ratio, 0.66; 95% CI, 0.53 to 0.81; P<0.001), and the relative risk of end-stage kidney disease was lower by 32% (hazard ratio, 0.68; 95% CI, 0.54 to 0.86; P=0.002). The canagliflozin group also had a lower risk of cardiovascular death, myocardial infarction, or stroke (hazard ratio, 0.80; 95% CI, 0.67 to 0.95; P=0.01) and hospitalization for heart failure (hazard ratio, 0.61; 95% CI, 0.47 to 0.80; P<0.001). There were no significant differences in rates of amputation or fracture. CONCLUSIONS In patients with type 2 diabetes and kidney disease, the risk of kidney failure and cardiovascular events was lower in the canagliflozin group than in the placebo group at a median follow-up of 2.62 years

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