Strengthening regional commitment to ensuring access to medical abortion medicines in WHO's South-East Asia region: report of a participatory assessment and workshop.

BACKGROUND: In 2019, the World Health Organization identified improving access to safe abortion as an important priority toward improving sexual and reproductive health and rights and achieving Sustainable Development Goals. One strategy for addressing this priority is strengthening access to medicines for medical abortion. All 11 countries in the South-East Asia Region have some indications for legal abortion and permit post-abortion care. Therefore, strengthening access to medical abortion medicines is a reasonable strategy for improving access to safe abortion for the Region. METHODOLOGY: We applied an adapted version of an existing World Health Organization landscape assessment protocol for the availability of medical abortion medicines at the country-level in the South-East Asia Region. We collected publicly available data on the existence of national health laws, policies, and standard treatment guidelines; inclusion of medical abortion medicines in the national essential medicines list; and marketing authorization status for medical abortion medicines for each country and verified by Ministries of health. The findings were once more presented, discussed and recommendations were formulated during regional technical consultation workshop. Each country teams participated in the process, and subsequently, the suggestions were validated by representatives from Ministries of Health.. RESULTS: Few countries in the Region currently have national policies and guidelines for comprehensive safe abortion. However, either mifepristone-misoprostol in combination or misoprostol alone (for other indications) is included in national essential medicines lists in all countries except Indonesia and Sri Lanka. Few countries earmark specific public funds for procuring and distributing medical abortion commodities. In countries where abortion is legal, the private sector and NGOs support access to medical abortion information and medicines. Several countries only allow registered medical practitioners or specialists to administer medical abortion. CONCLUSION: Following this rapid participatory assessment and technical consultation workshop, the World Health Organization South-East Asia Regional Technical Advisory and Sexual and Reproductive Health and Rights technical committee recommended priority actions for policy and advocacy, service delivery, and monitoring and evaluation, and indicated areas for support.

Development of apigenin loaded gastroretentive microsponge for the targeting of Helicobacter pylori.

The goal of the present work was to invent an apigenin-stacked gastroretentive microsponge to target H. pylori. The quasi-emulsion technique was used to prepare microsponges, which were then tested for various physicochemical properties, in-vivo gastric retention, and in-vitro anti-H. pylori study. The microsponge that demonstrated a comparatively good product yield (76.23 ± 0.84), excellent entrapment efficiency (97.84 ± 0.85), sustained in-vitro gastric retention period, and prolonged drug release were chosen for further investigations. The microsponge's SEM analysis showed that it had a spherical form, porous surface, and interconnected spaces. No drug-polymer interactions were detected in the FTIR investigation. Apigenin was found to be dispersed in the microsponge's polymeric matrix according to DSC & XRD investigations. Moreover, the microsponge in the rat's stomach floated for 4 h, according to the ultrasonography. The antibacterial activity of apigenin against H. pylori was nearly two folds more than the pure apigenin and had a more sustained release in the best microsponge, according to the in vitro MIC data, when compared to pure apigenin. To sum up, the developed gastroretentive microsponge with apigenin offers a viable alternative for the efficient targeting of H. pylori. But more preclinical & clinical studies of our best microsponge would yield considerably more fruitful results.

Trio-Drug Combination of Sodium Valproate, Baclofen and Thymoquinone Exhibits Synergistic Anticonvulsant Effects in Rats and Neuro-Protective Effects in HEK-293 Cells.

Epilepsy is a chronic brain disorder, with anti-epileptic drugs (AEDs) providing relief from hyper-excitability of neurons, but largely failing to restrain neurodegeneration. We investigated a progressive preclinical trial in rats, whereby the test drugs; sodium valproate (SVP; 150 and 300 mg/kg), baclofen (BFN; 5 and 10 mg/kg), and thymoquinone (THQ; 40 and 80 mg/kg) were administered (i.p, once/day for 15 days) alone, and as low dose combinations, and subsequently tested for antiseizure and neuroprotective potential using electrical stimulation of neurons by Maximal electroshock (MES). The seizure stages were monitored, and hippocampal levels of m-TOR, IL-1ß, IL-6 were measured. Hippocampal histopathology was also performed. Invitro and Insilco studies were run to counter-confirm the results from rodent studies. We report the synergistic effect of trio-drug combination; SVP (150 mg/kg), BFN (5 mg/kg) and THQ (40 mg/kg) against generalized seizures. The Insilco results revealed that trio-drug combination binds the Akt active site as a supramolecular complex, which could have served as a delivery system that affects the penetration and the binding to the new target. The potential energy of the ternary complex in the Akt active site after dynamics simulation was found to be -370.426 Kcal/mol, while the supramolecular ternary complex alone was -38.732 Kcal/mol, with a potential energy difference of -331.694 Kcal/mol, which favors the supramolecular ternary complex at Akt active site binding. In addition, the said combination increased cell viability by 267% and reduced morphological changes induced by Pentylenetetrazol (PTZ) in HEK-293 cells, which indicates the neuroprotective property of said combination. To conclude, we are the first to report the anti-convulsant and neuroprotective potential of the trio-drug combination.

Evaluation and docking of indole sulfonamide as a potent inhibitor of α-glucosidase enzyme in streptozotocin -induced diabetic albino wistar rats.

We have synthesized new hybrid class of indole bearing sulfonamide scaffolds (1-17) as α-glucosidase inhibitors. All scaffolds were found to be active except scaffold 17 and exhibited IC50 values ranging from 1.60 to 51.20 µM in comparison with standard acarbose (IC50 = 42.45 µM). Among the synthesized hybrid class scaffolds 16 was the most potent analogue with IC50 value 1.60 µM, showing many folds better potency as compared to standard acarbose. Whereas, synthesized scaffolds 1-15 showed good α-glucosidase inhibitory potential. Based on α-glucosidase inhibitory effect, Scaffold 16 was chosen due to highest activity in vitro for further evaluation of antidiabetic activity in Streptozotocin induced diabetic rats. The Scaffold 16 exhibited significant antidiabetic activity. All analogues were characterized through 1H, 13CNMR and HR MS. Structure-activity relationship of synthesized analogues was established and confirmed through molecular docking study.

Synthesis, in vitro antiurease, in vivo antinematodal activity of quinoline analogs and their in-silico study.

Synthesis of quinoline analogs and their urease inhibitory activities with reference to the standard drug, thiourea (IC50 = 21.86 ± 0.40 µM) are presented in this study. The inhibitory activity range is (IC50 = 0.60 ± 0.01 to 24.10 ± 0.70 µM) which displayed that it is most potent class of urease inhibitor. Analog 1-9, and 11-13 emerged with many times greater antiurease potential than thiourea, in which analog 1, 2, 3, 4, 8, 9, and 11 (IC50 = 3.50 ± 0.10, 7.20 ± 0.20, 1.30 ± 0.10, 2.30 ± 0.10, 0.60 ± 0.01, 1.05 ± 0.10 and 2.60 ± 0.10 µM respectively) were appeared the most potent ones among the series. In this context, most potent analogs such as 1, 3, 4, 8, and 9 were further subjected for their in vitro antinematodal study against C. elegans to examine its cytotoxicity under positive control of standard drug, Levamisole. Consequently, the cytotoxicity profile displayed that analogs 3, 8, and 9 were found with minimum cytotoxic outline at higher concentration (500 µg/mL). All analogs were characterized through 1H NMR, 13C NMR and HR-EIMS. The protein-ligand binding interaction for most potent analogs was confirmed via molecular docking study.

Formulation of carteolol chitosomes for ocular delivery: formulation optimization, ex-vivo permeation, and ocular toxicity examination.

Background:Conventional delivery systems like solution and suspension are commonly used for the treatment of ocular diseases but have low corneal residence time and hence the duration of effect is limited. These drawbacks of conventional systems can be reduced by preparing bioadhesive chitosan (CH) coated noisome.Methods: Niosomes (NIM) of carteolol (CT) were developed by the thin-film hydration method and optimised by the Box-Behnken statistical design. Further, the optimised CT-NIM was coated with CH to enhance the ocular residence time . The optimised formulation was evaluated for vesicle size, entrapment efficiency, and in-vitro drug release and transcorneal permeation, histopathology, etc.Results: CT-NIM-opt showed the vesicle size and entrapment efficiency of 235 ± 3.54 nm, and 70.45 ± 0.87%, respectively. DSC spectra exhibited that CT was completely encapsulated into the CH-CT-NIM matrix. Drug release from CH-CT-NIM-opt was more sustained (68.28 ± 4.2%) than CT-NIM (75.69 ± 4.5% in 12 h) and CT solution (99.89 ± 2.8% in 4 h). The CH-CT-NIM-opt represented a strong bio-adhesion (89.76 ± 3.6%) than CT-NIM-opt (15.65 ± 3.4%). The permeation flux exhibited 1.13-fold higher permeation than CT-NIM and 3.23 fold than CT solution. The corneal hydration was found to be within the limit value. The histopathology study exhibited no structural damage to the cornea . HET-CAM results showed zero scores indicating no bleeding or haemorrhage. CH-CT-NIM-opt was found to be isotonic and exhibited good stability when stored at 4 °C for the stated duration of time.Conclusion: The above findings suggested that NIM can be a potential carrier for the delivery of CT with better ocular residence time.

Combined HIV-1 Tat and oxycodone activate the hypothalamic-pituitary-adrenal and -gonadal axes and promote psychomotor, affective, and cognitive dysfunction in female mice.

The majority of HIV+ patients present with neuroendocrine dysfunction and ~50% experience co-morbid neurological symptoms including motor, affective, and cognitive dysfunction, collectively termed neuroHIV. In preclinical models, the neurotoxic HIV-1 regulatory protein, trans-activator of transcription (Tat), promotes neuroHIV pathology that can be exacerbated by opioids. We and others find gonadal steroids, estradiol (E2) or progesterone (P4), to rescue Tat-mediated pathology. However, the combined effects of Tat and opioids on neuroendocrine function and the subsequent ameliorative capacity of gonadal steroids are unknown. We found that conditional HIV-1 Tat expression in naturally-cycling transgenic mice dose-dependently potentiated oxycodone-mediated psychomotor behavior. Tat increased depression-like behavior in a tail-suspension test among proestrous mice, but decreased it among diestrous mice (who already demonstrated greater depression-like behavior); oxycodone reversed these effects. Combined Tat and oxycodone produced apparent behavioral disinhibition of anxiety-like responding which was greater on diestrus than on proestrus. These mice made more central entries in an open field, but spent less time there and demonstrated greater circulating corticosterone. Tat increased the E2:P4 ratio of circulating steroids on diestrus and acute oxycodone attenuated this effect, but repeated oxycodone exacerbated it. Corticotropin-releasing factor was increased by Tat expression, acute oxycodone exposure, and was greater on diestrus compared to proestrus. In human neuroblastoma cells, Tat exerted neurotoxicity that was ameliorated by E2 (1 or 10 nM) or P4 (100, but not 10 nM) independent of oxycodone. Oxycodone decreased gene expression of estrogen and κ-opioid receptors. Thus, neuroendocrine function may be an important target for HIV-1 Tat/opioid interactions.

Migraine screen questionnaire: further psychometric evidence from categorical data methods.

BACKGROUND: Psychometric investigations of tools used in the screening of migraine including the migraine screen questionnaire (MS-Q), using an adequate statistical approach is needed. We assessed the psychometric properties of the migraine screen questionnaire (MS-Q) using categorical data methods. MATERIAL AND METHODS: A total of 343 students at Mizan-Tepi University, Ethiopia, age range = 18-35 years were selected by a simple random sampling method to participate in a cross-sectional study. The respondents completed the MS-Q, a semi-structured socio-demographic questionnaire, and a visual analog scale for attention (VAS-A). RESULTS: The cumulative variance rule (> 40%), the Kaiser's criteria (Eigenvalue> 1), the Scree test and, the parallel analysis (minimum rank) identified a 1-factor model for the MS-Q with the factor loadings in the range of 0.78 to 0.84. Fit indices favored a 1-factor model of the MS-Q as indicated by comparative fit index (0.993), weighted root mean square residual (0.048), root mean square error of approximation (0.067), the goodness of fit index (1.00), and non-normed fit index (0.987). The values of the Factor Determinacy Index (0.953), marginal reliability (0.909), H-latent (0.909), H-observed (0.727), explained common variance (0.906) and the mean item residual absolute loadings (0.225) further complimented finding of the 1-Factor model. McDonald's Omega (0.903) suggested adequate internal consistency. Discriminative validity was supported by significantly higher scores for the total and all the MS-Q items except one among those with complaints of attention. CONCLUSION: The categorical methods support the psychometric validity of the MS-Q in the study population.

Prevalence of poor sleep quality in the Ethiopian population: a systematic review and meta-analysis.

BACKGROUND: Only a limited amount of data is available from lower-income countries regarding the prevalence of poor quality of sleep. This meta-analysis of the scientific literature was performed to estimate the pooled prevalence of poor sleep quality in the Ethiopian population. METHODS: The study protocol followed was the Preferred Reporting of Items for Systematic Review and meta-analysis (PRISMA) statement. RESULTS: The nine studies which met the inclusion criteria provided data based on a total of 9103 participants who were studied at various health and academic institutions. The incidences of self-reported poor sleep quality ranged from 26 to 66.2%. The pooled estimate of poor sleep quality was 53%.There was a high prevalence of reported poor quality of sleep among younger subjects and among those who were studied in community (noninstitutional) settings. CONCLUSION: The pooled prevalence of poor sleep quality is quite high among Ethiopians.

HIV-1 Tat Dysregulates the Hypothalamic-Pituitary-Adrenal Stress Axis and Potentiates Oxycodone-Mediated Psychomotor and Anxiety-Like Behavior of Male Mice.

Human immunodeficiency virus (HIV) is associated with co-morbid affective and stress-sensitive neuropsychiatric disorders that may be related to dysfunction of the hypothalamic-pituitary-adrenal (HPA) stress axis. The HPA axis is perturbed in up to 46% of HIV patients, but the mechanisms are not known. The neurotoxic HIV-1 regulatory protein, trans-activator of transcription (Tat), may contribute. We hypothesized that HPA dysregulation may contribute to Tat-mediated interactions with oxycodone, a clinically-used opioid often prescribed to HIV patients. In transgenic male mice, Tat expression produced significantly higher basal corticosterone levels with adrenal insufficiency in response to a natural stressor or pharmacological blockade of HPA feedback, recapitulating the clinical phenotype. On acute exposure, HIV-1 Tat interacted with oxycodone to potentiate psychomotor and anxiety like-behavior in an open field and light-dark transition tasks, whereas repeated exposure sensitized stress-related psychomotor behavior and the HPA stress response. Pharmacological blockade of glucocorticoid receptors (GR) partially-restored the stress response and decreased oxycodone-mediated psychomotor behavior in Tat-expressing mice, implicating GR in these effects. Blocking corticotrophin-releasing factor (CRF) receptors reduced anxiety-like behavior in mice that were exposed to oxycodone. Together, these effects support the notion that Tat exposure can dysregulate the HPA axis, potentially raising vulnerability to stress-related substance use and affective disorders.

Psychometric properties of the Insomnia Severity Index in Ethiopian adults with substance use problems.

This study investigated the psychometric properties of the Insomnia Severity Index (ISI) in substance-using Ethiopian adults. A simple random sampling of houses and a purposive sampling selection was performed in Mizan city, Ethiopia (n = 406). Participants completed the ISI and a meta-cognition questionnaire and sociodemographic information. IBM SPSS software with Amos was used for data analysis. There was no major ceiling or floor effect in the ISI scores. The internal consistency (Cronbach's alpha = 0.68 and 0.78) and internal homogeneity (moderate to strong item-total ISI score correlations; r ≥ 0.47) were adequate. All of the ISI (item as well as total) scores correlated with the meta-cognition total scores (r = 0.16-0.44; p < .01). The exploratory factor analysis results were heterogeneous. However, the confirmatory factor analysis favored a 2-factor model. The ISI has good psychometric validity among Ethiopian adults with substance use.

Psychometric properties of the Epworth sleepiness scale in Ethiopian university students.

BACKGROUND: Daytime sleepiness is highly prevalent across the globe. The Epworth sleepiness scale (ESS) is the most widely used tool for screening daytime sleepiness. The psychometric properties of the ESS have not been comprehensively examined in African populations. MATERIAL AND METHODS: A cross-sectional design with simple random sampling was used in the present study. The study recruited 600 students from Mizan-Tepi University, Ethiopia, of which 329 (age = 18-28 years and body mass index = 21.19 ± 3.17 kg/m2) completed the study. ESS, a semi-structured socio-demographics questionnaire and a clinical interview to diagnose insomnia according to the International Classification of Sleep Disorders were employed. RESULTS: All except one item of the ESS showed a floor effect, while only one item score showed ceiling effect. However, no ceiling/floor effect was observed in the ESS total score. The Cronbach's alpha (0.75) and composite reliability (0.75), indicated good internal consistency, while a moderate item-total score correlation (r = 0.55-0.67) implied favorable internal homogeneity. The known-group validity was established by significantly higher scores for all the ESS item scores and the ESS total scores among those with symptoms of insomnia than among non-symptomatic students. Fit indices along with the consideration of inter-factor correlation coefficient, measures of item retention favored the unidimensional structure of the ESS. CONCLUSION: The ESS has excellent psychometric validity for screening daytime sleepiness in Ethiopian university students.

Psychometric properties of the perceived stress scale in Ethiopian university students.

BACKGROUND: Stress is a common psychological condition usually associated with many psycho-physical disorders. Stress and its risk factors are frequently seen in Ethiopians including university students. In such circumstances, a valid measure to screen for stress in Ethiopians is necessary. Therefore, we assessed the psychometric properties of the Perceived Stress Scale (PSS) in Ethiopian university students. METHODS: A cross-sectional study with a simple random sampling method was performed on students of Mizan-Tepi University, Mizan-Aman, Ethiopia. The study presents a psychometric investigation on a sample of 387 students (age = 21.8 ± 3.8 years, and body mass index = 20.8 ± 3.2 kg/m2) who completed PSS, Generalized anxiety disorder-7 scale (GAD-7), and a socio-demographics tool. McDonald's Omega (internal consistency), factor validity for ordinal data and convergent validity (Spearman's correlation) were assessed. RESULTS: No ceiling/floor effect was seen for the total or factor scores of the PSS-10 and PSS-4. Two factor model of the PSS-10 was favored by fit indices with Comparative Fit Index> 0.95, Weighted root mean square residual<.05 and root mean square error of approximation<.08. McDonald's Omega was 0.78 and 0.68 for the PSS-10: Factor-1 and PSS-10: Factor-2, respectively. McDonald's Omega was 0.70 and 0.54 for the PSS-4: Factor-1 and PSS-4: Factor-2, respectively. There were moderate-strong correlations (r = 0.62-0.83) between PSS factors and respective items loading on them. PSS scores were correlated with GAD-7 (r = .27-.40, p < .01). CONCLUSION: The psychometric measures support the validity of the PSS-10 in Ethiopian university students.

Validation of the adapted Leeds sleep evaluation questionnaire in Ethiopian university students.

BACKGROUND: Current evidence supports the applicability of the Leeds Sleep Evaluation Questionnaire (LSEQ) in screening for insomnia. The psychometric properties of the LSEQ have never been investigated in an African population. Therefore, this study aimed to validate the adapted version of the LSEQ-Mizan (LSEQ-M) in Ethiopian university students. METHODS: Of a preliminary sample of 750 (random sampling), 424 students (age = 21.87 ± 4.13 years and body mass index = 20.84 ± 3.18 kg/m2) from Mizan-Tepi University, Mizan-Aman, South-west Ethiopia completed the LSEQ-M, the General Anxiety Disorder Scale-7 and a semi-structured questionnaire for socio-demographics. Insomnia was screened in accordance with the International Classification of Sleep Disorders as a measure of concurrent validity. RESULTS: Although, individual items showed ceiling and floor effect, the LSEQ-M as a scale did not have these effects. Good internal consistency (Cronbach's alpha of 0.84) and strong internal homogeneity as measured by the correlation coefficient between items scores and the LSEQ-M global score was found. The LSEQ-M showed excellent screening applicability for insomnia with optimal cut-off scores of 52.6 (sensitivity 94%, specificity 80%), and the area under the curve, 0.95 (p < 0.0001). The original 4-Factor model was valid in Ethiopian university students for screening for insomnia. CONCLUSION: The LSEQ-M has excellent psychometric validity in screening for insomnia among Ethiopian university students.

Validation of the Pittsburgh sleep quality index in community dwelling Ethiopian adults.

BACKGROUND: The applicability of the Pittsburgh Sleep Quality Index (PSQI) in screening of insomnia is demonstrated in various populations. But, the tool has not been validated in a sample of Ethiopians. Therefore, this study aimed to assess its psychometric properties in community dwelling Ethiopian adults. MATERIAL AND METHODS: Participants (n = 311, age = 25.5 ± 6.0 years and body mass index = 22.1 ± 2.3 kg/m2) from Mizan-Aman town, Southwest Ethiopia completed the PSQI and a semi-structured questionnaire for socio-demographics. Clinical interview for screening of insomnia according to the International Classification of Sleep Disorders was carried out as a concurrent validation measure. RESULTS: Overall, the PSQI scale did not have floor effect and ceiling effects. Moderate internal consistency (Cronbach's alpha was 0.59) and sufficient internal homogeneity as indicated by correlation coefficient between component scores and the global PSQI score was found. The PSQI was of good value for screening insomnia with optimal cut-off scores of 5.5 (sensitivity 82%, specificity 56.2%) and the area under the curve, 0.78 (p < 0.0001). The PSQI has unidimensional factor structure in the Ethiopian community adults for screening insomnia. CONCLUSION: The PSQI has good psychometric validity in screening for insomnia among Ethiopians adults.

Sleep correlates of substance use in community-dwelling Ethiopian adults.

PURPOSE: The relationship between sleep disturbances and substance use can have harmful effects. Evidence shows widespread use of substances, including khat, in the Ethiopian population. However, to the best of our knowledge, no study has investigated the sleep correlates of substance use in community-dwelling Ethiopian adults. MATERIALS AND METHODS: A cross-sectional study using simple random sampling was performed on community-dwelling adults (n = 371, age = 25.5 ± 5.7 years, body mass index = 22.0 ± 2.2 kg/m2) in Mizan-Aman, Ethiopia. Dichotomized sleep measures (sleep quality and sleep latency) assessed by the Pittsburgh Sleep Quality Index (PSQI) were used in association analysis using binary logistic regression with substance use (khat, smoking, and alcohol). RESULT: Sleep latency was associated with khat chewing (adjusted odds ratio (AOR) = 2.8, 95% confidence interval (CI) 1.7-4.4) and tobacco smoking (AOR = 2.1, 95% CI 1.4-3.0). Sleep quality was associated with khat chewing (AOR = 3.1, 95% CI 1.8-5.2), tobacco smoking (AOR = 1.7, 95% CI 1.2-2.5), and alcohol intake (AOR = 1.9, 95% CI 1.1-3.1). CONCLUSION: Sleep correlates of substance use were found in community-dwelling Ethiopians. These findings may aid in the development of targeted strategies to manage substance use-related sleep disturbances.

Design and Evaluation of Pegylated Large 3D Pore Ferrisilicate as a Potential Insulin Protein Therapy to Treat Diabetic Mellitus.

An iron-based SBA-16 mesoporous silica (ferrisilicate) with a large surface area and three-dimensional (3D) pores is explored as a potential insulin delivery vehicle with improved encapsulation and loading efficiency. Fe was incorporated into a framework of ferrisilicate using the isomorphous substitution technique for direct synthesis. Fe3+ species were identified using diffuse reflectance spectroscopy. The large surface area (804 m2/g), cubic pores (3.2 nm) and insulin loading were characterized using XRD, BET surface area, FTIR and TEM analyses. For pH sensitivity, the ferrisilicate was wrapped with polyethylene glycol (MW = 400 Daltons) (PEG). For comparison, Fe (10 wt%) was impregnated on a Korea Advanced Institute of Science and Technology Number 6 (KIT-6) sieve and Mesocellular Silica Foam (MSU-F). Insulin loading was optimized, and its release mechanism was studied using the dialysis membrane technique (MWCO = 14,000 Da) at physiological pH = 7.4, 6.8 and 1.2. The kinetics of the drug's release was studied using different structured/insulin nanoformulations, including Santa Barbara Amorphous materials (SBA-15, SBA-16), MSU-F, ultra-large-pore FDU-12 (ULPFDU-12) and ferrisilicates. A different insulin adsorption times (0.08-1 h), insulin/ferrisilicate ratios (0.125-1.0) and drug release rates at different pH were examined using the Korsmeyer-Peppas model. The rate of drug release and the diffusion mechanisms were obtained based on the release constant (k) and release exponent (n). The cytotoxicity of the nanoformulation was evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay using human foreskin fibroblast (HFF-1) cells. A low cytotoxicity was observed for this nanoformulation starting at the highest concentrations used, namely, 400 and 800 µg. The hypoglycemic activity of insulin/ferrisilicate/PEG on acute administration in Wistar rats was studied using doses of 2, 5 and 10 mg/kg body weight. The developed facile ferrisilicate/PEG nanoformulation showed a high insulin encapsulation and loading capacity with pH-sensitive insulin release for potential delivery through the oral route.

Alleviation of Cocaine Withdrawal and Pertinent Interactions between Salvinorin-Based Antagonists and Kappa Opioid Receptor.

The kappa opioid receptor (KOR) is involved in the regulation of both the reward and mood processes. Recent reports find that the use of drugs of abuse increases the production of dynorphin and the overall activation of KOR. Long-acting KOR antagonists, such as norbinaltorphimine (nor-BNI), JDTic, and 5'-guanidinonaltrindole (GNTI), have been shown to stop depressive and anxiety-related disorders, which are the common side effects of withdrawal that can lead to a relapse in drug use. Unfortunately, these prototypical KOR antagonists are known to induce selective KOR antagonism that is delayed by hours and extremely prolonged, and their use in humans comes with serious safety concerns because they possess a large window for potential drug-drug interactions. Furthermore, their persistent pharmacodynamic activities can hinder the ability to reverse unanticipated side effects immediately. Herein, we report our studies of the lead selective, salvinorin-based KOR antagonist (1) as well as nor-BNI on C57BL/6N male mice for spontaneous cocaine withdrawal. Assessment of pharmacokinetics showed that 1 is a short-acting compound with an average half-life of 3.75 h across different compartments (brain, spinal cord, liver, and plasma). Both 1 (5 mg/kg) and nor-BNI (5 mg/kg) were shown to reduce spontaneous withdrawal behavior in mice, with 1 producing additional anti-anxiety-like behavior in a light-dark transition test (however, no mood-related effects of 1 or nor-BNI were observed at the current dosing in an elevated plus maze or a tail suspension test). Our results support the study of selective, short-acting KOR antagonists for the treatment of psychostimulant withdrawal and the associated negative mood states that contribute to relapse. Furthermore, we identified pertinent interactions between 1 and KOR via computational studies, including induced-fit docking, mutagenesis, and molecular dynamics simulations, to gain insight into the design of future selective, potent, and short-acting salvinorin-based KOR antagonists.

Allopregnanolone and neuroHIV: Potential benefits of neuroendocrine modulation in the era of antiretroviral therapy.

Forty years into the HIV pandemic, approximately 50% of infected individuals still suffer from a constellation of neurological disorders collectively known as 'neuroHIV.' Although combination antiretroviral therapy (cART) has been a tremendous success, in its present form, it cannot eradicate HIV. Reservoirs of virus reside within the central nervous system, serving as sources of HIV virotoxins that damage mitochondria and promote neurotoxicity. Although understudied, there is evidence that HIV or the HIV regulatory protein, trans-activator of transcription (Tat), can dysregulate neurosteroid formation potentially contributing to endocrine dysfunction. People living with HIV commonly suffer from endocrine disorders, including hypercortisolemia accompanied by paradoxical adrenal insufficiency upon stress. Age-related comorbidities often onset sooner and with greater magnitude among people living with HIV and are commonly accompanied by hypogonadism. In the post-cART era, these derangements of the hypothalamic-pituitary-adrenal and -gonadal axes are secondary (i.e., relegated to the brain) and indicative of neuroendocrine dysfunction. We review the clinical and preclinical evidence for neuroendocrine dysfunction in HIV, the capacity for hormone therapeutics to play an ameliorative role and the future steroid-based therapeutics that may have efficacy as novel adjunctives to cART.

Poor Sleep in Community-Dwelling Polysubstance Users: Association With Khat Dependence, Metacognition, and Socio-Demographic Factors.

Purpose: Poor sleep and cognitive deficits are often associated with increased drug use. However, no study has addressed the relationship between poor sleep, substance dependence, and metacognitive deficit in polysubstance users. Methods: This was a cross-sectional study with a simple random sampling involving community-dwelling polysubstance users (n = 326, age = 18-43 years) in Mizan, Ethiopia. Participants completed a brief sleep questionnaire, severity of dependence on khat (SDS-Khat), a brief meta-cognition questionnaire, and a socio-demographic survey. Results: Majority (56.4%) of the polysubstance users had sleep disturbance. Chronic health conditions [adjusted odds ratio (AOR) = 2.52, 95% confidence interval (CI) 1.31-4.85], chronic conditions in the family (AOR = 2.69, 95% CI 1.40-5.20), illiterate-primary level of educational status (AOR = 2.40, 95% CI 1.30-4.04), higher SDS-Khat score (AOR = 1.39, 95% CI 1.13-1.72), and lower meta-cognition score (AOR = 0.90, 95% CI 0.84-0.97) predicted poor sleep in the polysubstance users. Moreover, low metacognition score and high SDS score also predicted additional sleep disturbances like chronic sleep insufficiency, lethargy and restlessness after nighttime sleep, socio-occupational dysfunctions, and daytime disturbances in polysubstance users. Conclusion: Poor sleep, severe khat dependence, and metacognitive deficits are common in community polysubstance users. Moreover, poor sleep is associated with higher khat dependence, lower metacognitive ability, lower educational status, and the presence of chronic conditions in polysubstance users or their families.