OBJECTIVE: This study aimed to evaluate the treatment paradigm of a single dose of GSK-3 inhibitor administration at various time courses for the protection of the CNS from EAE.
MATERIALS AND METHODS: Effects of GSK-3 inhibition on intracellular cytokine levels were evaluated from in vitro naïve CD4+ T cell cultures. Immunized C57BL/6 female mice with MOG35-55 in conjunction with CFA and Ptx were used as a chronic inflammatory EAE disease model. Tideglusib (NP12), a Thiadiazolidinone class, selective, and non-ATP competitive GSK-3 inhibitor, was injected intraperitoneally at pre-EAE, same-day of immunization or disease onset. After 30 days post-immunization, brain, and spinal cord tissues were collected for inflammation and demyelination analysis by H&E and luxol fast blue staining, respectively, whereas cytokine profiles of the serum were assessed by cytokine beads array.
RESULTS: The inhibition of GSK-3 in CD4+ T cells increased IL-10 production. The administration of Tideglusib during pre-EAE and same-day, but not during disease onset, significantly reduced clinical symptoms and delayed disease onset. Histopathological analysis of spinal cord tissues showed a significant decline in the number of inflammatory cell infiltration with a concomitant reduction in demyelination through the blocking of GSK-3, especially during pre-EAE and sameday. Upregulation of IL-10 via GSK-3 inhibition coincided with the downregulation of cytokineassociated effector T cells, including IFN-γ, IL-9, IL-17A, IL-17F, IL-21, and IL-23. Increased IL-4 production, however, was only significant in the pre-EAE group.
CONCLUSION: The neuroprotective effects of Tideglusib against EAE are time-dependent. Downregulation of Th1 and Th17 hallmark cytokines by Tideglusib in EAE may be associated with IL-10 production.
METHODS: We analyzed data (2012-18) from the prospective cohort Dialysis Outcomes and Practice Patterns Study for 1544 GCC patients ≥18 years old and on dialysis >180 days.
RESULTS: Thirty-four percent of GCC HD patients had low Kt/V (<1.2) versus 5%-17% in Canada, Europe, Japan and the USA. Across the GCC countries, low Kt/V prevalence ranged from 10% to 54%. In multivariable logistic regression, low Kt/V was more common (P
OBJECTIVE: This study explored, assessed and compared the current status of medicines labeling, patient's counseling, and symptomatic diagnosis by general practitioners and community pharmacists.
MATERIAL AND METHODS: This study used trained Simulated Patients (SP), who participated in a scenario of common cold symptoms at private clinics and community pharmacies. SPs explored medication labeling, patients counseling and symptomatic diagnosis undertaken by general practitioners and community pharmacists. Later, study authors assessed and compared these practices. The study was conducted during June 2011 in Penang, Malaysia.
RESULTS: The study used descriptive statistics and Fisher-exact test to analyze data. Regarding patients counseling standard, among 100 visits by simulated patients, 64 (64%) from community pharmacists provided information about the medicine name, its indication, dosage and route of administration versus 17 (42.5%) general practitioners during 40 visits (p=0.024). Concerning adherence to labeling standard, for instance, only in one pharmacy visit, (1%) the pharmacist wrote the name of the patient on the medication label versus in 32 (80%) of doctors' visits, the doctors adhered to this labeling standard (p<0.001). In all doctors' visits (n=40, 100%), SPs were asked about symptoms, whereas in 87 (87%) CPs' visits, pharmacists fulfilled this counseling standard (p=0.02).
CONCLUSION: Although pharmacists showed less compliance to medicine labeling and symptomatic diagnosis compared to doctors, their counseling of patients was better. Separation will definitely contribute to more concentration of each provider on his/her roles and improve and direct the experiences and skills towards being more patient oriented.
BACKGROUND: The Arabian Gulf population is at high risk for atherosclerotic cardiovascular disease at younger ages. There is no up-to-date study regarding dyslipidemia management in this region, especially given the recent guideline-recommended LDL-C targets.
OBJECTIVE: Up-to-date comprehensive assessment of the current dyslipidemia management in the Arabian Gulf region, particularly in view of the recent evidence of the additive beneficial effects of ezetimibe and proprotein convertase subtilisin/kexin-9 (PCSK-9) inhibitors on LDL-C levels and cardiovascular outcomes.
METHODS: The Gulf Achievement of Cholesterol Targets in Out-Patients (GULF ACTION) is an ongoing national observational longitudinal registry of 3000 patients. In this study, adults ≥18 years on lipidlowering drugs for over three months from out-patients of five Gulf countries were enrolled between January 2020 and May 2022 with planned six-month and one-year follow-ups.
RESULTS: Of the 1015 patients enrolled, 71% were male, aged 57.9±12 years. In addition, 68% had atherosclerotic cardiovascular disease (ASCVD), 25% of these patients achieved the LDL-C target, and 26% of the cohort were treated using combined lipid-lowering drugs, including statins.
CONCLUSION: The preliminary results of this cohort revealed that only one-fourth of ASCVD patients achieved LDL-C targets. Therefore, GULF ACTION shall improve our understanding of current dyslipidemia management and "guideline gaps" in the Arabian Gulf region.
TRIAL DESIGN: The study is a randomized, placebo-controlled, adaptive clinical trial with parallel group design, superiority framework with an allocation ratio of 1:1 among experimental (HNS) and placebo group. An interim analysis will be done when half of the patients have been recruited to evaluate the need to adapt sample size, efficacy, and futility of the trial.
PARTICIPANTS: All asymptomatic patients with hospital or community based COVID-19 exposure will be screened if they have had 4 days exposure to a confirmed case. Non-pregnant adults with significant exposure level will be enrolled in the study High-risk exposure (<6 feet distance for >10min without face protection) Moderate exposure (<6 feet distance for >10min with face protection) Subjects with acute or chronic infection, COVID-19 vaccinated, and allergy to HNS will be excluded from the study. Recruitment will be done at Shaikh Zayed Post-Graduate Medical Institute, Ali Clinic and Doctors Lounge in Lahore (Pakistan).
INTERVENTION AND COMPARATOR: In this clinical study, patients will receive either raw natural honey (0.5 g) and encapsulated organic Nigella sativa seeds (40 mg) per kg body weight per day or empty capsule with and 30 ml of 5% dextrose water as a placebo for 14 days. Both the natural products will be certified for standardization by Government College University (Botany department). Furthermore, each patient will be given standard care therapy according to version 3.0 of the COVID-19 clinical management guidelines by the Ministry of National Health Services of Pakistan.
MAIN OUTCOMES: Primary outcome will be Incidence of COVID-19 cases within 14 days of randomisation. Secondary endpoints include incidence of COVID-19-related symptoms, hospitalizations, and deaths along with the severity of COVID-19-related symptoms till 14th day of randomization.
RANDOMISATION: Participants will be randomized into experimental and control groups (1:1 allocation ratio) via the lottery method. There will be stratification based on high risk and moderate risk exposure.
BLINDING (MASKING): Quadruple blinding will be ensured for the participants, care providers and outcome accessors. Data analysts will also be blinded to avoid conflict of interest. Site principal investigator will be responsible for ensuring masking.
NUMBERS TO BE RANDOMISED (SAMPLE SIZE): 1000 participants will be enrolled in the study with 1:1 allocation.
TRIAL STATUS: The final protocol version 1.4 was approved by institutional review board of Shaikh Zayed Post-Graduate Medical Complex on February 15, 2021. The trial recruitment was started on March 05, 2021, with a trial completion date of February 15, 2022.
TRIAL REGISTRATION: Clinical trial was registered on February 23, 2021, www.clinicaltrials.gov with registration ID NCT04767087 .
FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). With the intention of expediting dissemination of this trial, the conventional formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol. The study protocol has been reported in accordance with the Standard Protocol Items: Recommendations for Clinical Interventional Trials (SPIRIT) guidelines.
METHODS: The title amides (4a-j) were obtained by simple nucleophilic substitution reaction of dexibuprofen acid chloride with substituted amines in good yield and chemical structures were confirmed by FTIR, 1H NMR, 13C NMR and mass spectral data.
RESULTS: The brine shrimp lethality assay results showed that all of the synthesized compounds are non-toxic to shrimp larvae. The inhibitory effects on tumor growth were evaluated and it was observed that N-(2,5-dichlorophenyl)-2-(4-isobutylphenyl) propionamide (4e) and N-(2-chlorophenyl)-2-(4-isobutylphenyl) propionamide (4g) exhibited excellent antitumor activity compared to all other derivatives. The compound 4e bearing 2,5-dichloro substituted phenyl ring and 4g possesses 2-chloro substituted phenyl ring exhibited 100% inhibition of the tumor growth. The anticancer activity was evaluated against breast carcinoma cell line (MCF-7) and it was observed that derivative 4e exhibited excellent growth inhibition of cancer cells with IC50 value of 0.01±0.002 µm, which is better than the standard drugs. The docking studies against breast cancer type 1 susceptibility protein BRCA1 (PDBID 3K0H) exhibited good binding affinities, which are in good agreement with the wet lab results. The compounds 4e and 4g showed the binding energy values of -6.39 and -6.34 Kcal/mol, respectively. The molecular dynamic (MD) simulation was also carried out to evaluate the residual flexibility of the best docking complexes of compounds 4e and 4g. The MD simulation analysis assured that the 4e formed a more stable complex with the target protein than the 4g. The synthesized amide derivatives exhibited were devoid of gastrointestinal side effects and no cytotoxic effects against human normal epithelial breast cell line (MCF-12A) were found.
CONCLUSION: Based upon our wet lab and dry lab findings we propose that dexibuprofen analogue 4e may serve as a lead structure for the design of more potent anticancer drugs.