Liraglutide's Effect on Weight Management in Subjects With Pre-diabetes: A Systematic Review & Meta-Analysis.

BACKGROUND: Despite the growing literature, the effectiveness of liraglutide in weight management among individuals with prediabetes and in preventing the disease remains controversial. This study aims to critically evaluate the extent of liraglutide's impact on weight management in this population and assess the heterogeneity among extant studies. METHODS: A systematic literature search was conducted across MEDLINE, Embase, ClinicalTrials.gov, and the reference list of retrieved studies to identify eligible English language randomized controlled trials evaluating liraglutide's effect on weight in individuals with pre-diabetes. Non-randomized studies, studies not reporting relevant outcomes, and those conducted on patients with type 2 diabetes were excluded from this review. Outcomes included a change from baseline in absolute body weight in kg, body mass index (BMI), waist circumference, glycosylated hemoglobin (HbA1c), and low-density lipoprotein cholesterol levels. Additional safety outcomes were also reported. Data were analyzed using R statistical software version 4.3.1. A fixed-effect model was used when pooling crude numbers for study outcomes. Moreover, a sensitivity analysis using random-effect model was performed and heterogeneity was assessed using I2 statistics. RESULTS: Five eligible studies were included, with a total of 1604 subjects in the liraglutide arm and 859 subjects in the control arm. Participants exposed to liraglutide showed a decrease in body weight (mean difference [MD] = -4.95 kg; 95% CI -5.16, -4.73; I2 = 93%), BMI (MD = -2.06 kg/m2; 95%CI -2.22, -1.89; I2 = 97%), waist circumference (MD = -4.61 cm; 95% CI -4.79, -4.43; I2 = 82%), HbA1c (MD = -0.33%; 95%CI -0.34, -0.31; I2 = 100%), and low-density lipoprotein cholesterol levels (MD = -0.36 mmol/L; 95% CI -0.39, -0.33; I2 = 99%). The overall effect size remained similar when using a random-effects model for all outcomes. In addition, the rate of adverse events was higher with liraglutide when compared to the control; however, the dropout rates were relatively lower in the former arm. CONCLUSION: While our meta-analysis suggests that liraglutide can reduce body weight, BMI, waist circumference, and HbA1c levels in individuals with pre-diabetes, the findings should be interpreted cautiously due to limitations such as the small number of trials and their short duration, and variability in dosages. Further randomized controlled trials examining long-term outcomes are essential to validate these findings and address the high heterogeneity among the studies included in this analysis.

Population pharmacokinetics of gentamicin in acute lymphoblastic leukemia pediatric patients compared to non-oncology patients.

Understanding the pharmacokinetics of gentamicin is essential in special populations, such as pediatric patients with acute lymphoblastic leukemia (ALL), in light of previous studies indicating that ALL patients have a lower volume of distribution than non-ALL patients. Furthermore, validation of such results is needed to ensure their clinical application. Accordingly, this single-center, retrospective, cross-sectional study compares the pharmacokinetic parameters of volume of distribution and clearance (Cl) of gentamicin between ALL and non-ALL patients. Inclusion criteria were pediatric patients aged between 1 and 14 years with or without ALL and receiving intravenous gentamicin for treatment courses > 72 h. Patients' characteristics, such as age, sex, height, serum albumin, diagnosis, serum creatinine (Scr) concentration, dosing, and pharmacokinetic information, including peak and trough concentrations, were retrieved. The study scrutinized a total of 115 pediatric patients, comprising toddlers (15.7 %), children (76.5 %), and adolescents (7.8 %). All patients received gentamicin every 8 h, with an average dose of 2.50 (0.64) mg/kg. Patients were divided into two groups based on disease state, with 45.2 % (n = 52) in the non-ALL group and 54.8 % (n = 63) in the ALL group. Both groups had similar characteristics in terms of gender, weight, body surface area, and dose. The only significant covariates identified were weight and creatinine clearance (Clcr) for volume of distribution (Vd). A significant difference was found in Scr, Clcr, and blood urea nitrogen (BUN); however, no significant difference between ALL and non-ALL patients emerged in the volume of distribution or Cl. In conclusion, the study findings indicate that dosing requirements were similar between the two groups. Further prospective studies with larger sample sizes are warranted.

The Impact of Cancer Relapse and Poor Patient Outcomes on Health Care Providers Practicing in the Oncology Field.

INTRODUCTION: Devastating cancer-related events are not uncommon, and these events have weakened communication performance and induced stress among health care providers (HCPs), particularly physicians. This study aimed to investigate the perspective of HCPs emotionally affected by poor clinical outcomes due to the failure of cancer therapy. METHODS: A cross-sectional, online survey was conducted over 3 months among HCPs practicing in the field of oncology in Saudi Arabia, comprising physicians, pharmacists, and nurses. Data were analyzed using Statistical Package for Social Sciences version 26.0. A P-value <.05 was considered statistically significant. RESULTS: This study demonstrated a positive correlation between HCPs' length of experience and emotional impact of treatment failure, albeit this was not statistically significant (P = .071). Analysis of their perspective toward failure of cancer therapies revealed a significant impact of occupation and sex (P = .014 and P = .047, respectively). Moreover, occupation played a significant role in shaping the viewpoint of HCPs toward the need for conducing further research to test the appropriateness of treatment protocols on local patients (P = .022). Despite the emotional responses of HCPs to suboptimal clinical outcomes, factors such as work burnout, lack of concentration and patience, work or personal problems, and under appreciation were frequently identified as triggers of such outcomes. CONCLUSION: Our results revealed that poor clinical outcomes observed among cancer patients are emotional triggers for HCPs practicing in the oncology field. The emotional response is often perceived negatively, and can potentially lead to a decline in the quality of care provided to these patients.

A practical method for oral administration of isotretinoin in pediatric oncology patient: A case study of neuroblastoma.

INTRODUCTION: Isotretinoin is a synthetic vitamin A derivative, administered off-label as maintenance therapy for neuroblastoma. This report addresses the challenge of administering isotretinoin to children, given its availability as soft gelatin capsules only. CASE REPORT: A 3-year-old boy diagnosed with stage IV neuroblastoma has undergone multimodal therapy, including six cycles of chemotherapy, followed by tumor resection and radiotherapy. Later, he was initiated on immunotherapy and prescribed isotretinoin 50 mg orally twice daily for two weeks, before each immunotherapy cycle. Isotretinoin is not available in liquid formulation and the patient could not swallow isotretinoin capsules. Therefore, pharmacist counseling was required to ensure appropriate administration of the drug. MANAGEMENT AND OUTCOMES: The patient's parents were instructed to pierce prescribed capsules, and empty and dilute their contents into a small glass containing olive oil after taking safety measures. Isotretinoin's stability in olive oil for 72 h was compared using high-performance liquid chromatography to its stability in soybean oil. The recovery rates were 98.62% and 98.3%, respectively. Drug miscibility was not an issue as isotretinoin is lipophilic. Therefore, it could be administered easily without considerable remaining on the interior wall of the glass. DISCUSSION: To the best of our knowledge, this is the first report that suggests a practical method for administering isotretinoin in liquid form, particularly in pediatric oncology patients. Isotretinoin was noted to be stable in olive oil and its exposure to light and oxygen would not be an issue given the short time from preparation to administration and the low emphasis on exposure by the manufacturer when such a method is recommended.

Solubility and Thermodynamic Analysis of Isotretinoin in Different (DMSO + Water) Mixtures.

The solubility and solution thermodynamics of isotretinoin (ITN) (3) in numerous {dimethyl sulfoxide (DMSO) (1) + water (H2O) (2)} combinations were studied at 298.2-318.2 K under fixed atmospheric pressure of 101.1 kPa. A shake flask methodology was used to determine ITN solubility, and correlations were made using the "van't Hoff, Apelblat, Buchowski-Ksiazczak λh, Yalkowsky-Roseman, Jouyban-Acree, and Jouyban-Acree-van't Hoff models". In mixtures of {(DMSO (1) + H2O (2)}, the solubility of ITN in mole fractions was enhanced with the temperature and DMSO mass fraction. The mole fraction solubility of ITN was highest in neat DMSO (1.02 × 10-1 at 318.2 K) and lowest in pure H2O (3.14 × 10-7 at 298.2 K). The output of computational models revealed good relationships between the solubility data from the experiments. The dissolution of ITN was "endothermic and entropy-driven" in all of the {(DMSO (1) + H2O (2)} mixtures examined, according to the positive values of measured thermodynamic parameters. Enthalpy was discovered to be the driving force behind ITN solvation in {(DMSO (1) + H2O (2)} combinations. ITN-DMSO displayed the highest molecular interactions when compared to ITN-H2O. The outcomes of this study suggest that DMSO has a great potential for solubilizing ITN in H2O.

Level of knowledge and quality of life among Saudi caregivers of Parkinson's disease patients: A study from a tertiary hospital in Riyadh, Saudi Arabia.

Purpose: We aimed to assess the family caregivers' level of knowledge and attitudes about Parkison's disease (PD), identify factors affecting their knowledge, evaluate their quality of life (QoL) and factors influencing it and to define the effect of PD on activities of daily living (ADLs) of PD patients. Method: We developed and validated a questionnaire to assess the level of knowledge and attitudes of family caregivers toward PD, effects of PD on caregivers' QoL as well as its effects on activities of daily living (ADLs) of patients from the caregivers' perspective. A scoring system was utilized and SPSS was used to evaluate the differences in responses between the groups; p < 0.05 indicated statistical significance. Results: 69 caregivers and their corresponding patients were included in the study. Family caregivers had a low level of knowledge, as reflected by a mean score of 3.45 out of 8. However, 62.3% were aware of all medications used by their patients. Additionally, the level of knowledge was associated with caregivers' gender as 57.1% of the female caregivers had medium PD knowledge scores while 58.5% of the male had low scores (p = 0.038). The level of knowledge was also associated with daily caregiving hours as only 44.5% of caregivers whom spending 0-5 h/day had medium and high knowledge scores while greater proportions with same scoring levels were found among those providing care > 5 h/day (75.0% in > 5-10 hrs; 52.4% in > 10-24 hrs; p = 0.024). Most caregivers confirmed their QoL had declined, yet the male caregivers had better QoL than females (p = 0.026). Longer caregiving time was associated with decline (p = 0.016) and severe effect on QoL of caregivers (p = 0.04). Conclusion: Caregivers of PD patients had a low level of knowledge. Female caregivers had significantly higher level of PD knowledge than their male counterparts. Low level of PD knowledge was significantly associated with shorter caregiving time per day. Longer caregiving time was significantly associated with a decline in caregivers' QoL. Increasing awareness and knowledge among caregivers is necessary to ensure better treatment outcomes and improve the QoL of both caregivers and patients.

Androgen deprivation therapy and depression in the prostate cancer patients: review of risk and pharmacological management.

Purpose: Despite the effectiveness of androgen deprivation therapy in advanced prostate cancer, serious neuropsychiatric consequences in androgen deprivation therapy (ADT)-treated patients, mainly depression, have been concerning and gained more attention recently. This narrative review aims to shed light on the risk and pharmacological management of ADT-induced depression in PCa patients.Methods: We searched PubMed, Scopus and Google Scholar databases using MESH keywords "Prostate cancer OR prostate neoplasm" AND "Depression" AND "Androgen Deprivation Therapy" AND "antidepressants". Search was limited to English and studies conducted on humans. Studies' titles and abstracts were screened, and further information were obtained from the text, if necessary, to decide whether studies are to be included in this review.Results: Our review revealed 23 studies confirming the occurrence and worsening of depressive symptoms in ADT-treated patients, which frequently require pharmacological interventions; whereas 10 studies indicated otherwise. All studies were prospective, retrospective, cross-sectional or case reports. Based on the incidence of depression provided by the observational studies, the average among ADT-treated patients was 18.23% (range: 2.1-46.9%), while it was 8.42% (range: 1.4-23.3%) in the non-ADT patients. Although several treatments have been used for depression in cancer patients, current knowledge lacks observational and controlled studies as well as clinical guidelines that demonstrate efficacy and safety of antidepressants and guide clinicians to the appropriate treatment in these patients, respectively. On the other side, a few clinical studies have been published regarding the efficacy of selective serotonin reuptake inhibitors, selective serotonin and norepinephrine reuptake inhibitors and/or saftey on other ADT associated adverse effects.Conclusions: Our work supports the recent attention towards mood issues as an adverse effect of ADT, and that greater awareness of this is warranted among clinicians. Clinical studies published regarding the use of antidepressants for other ADT associated adverse effects established the foundation that can be adopted to examine these therapies on ADT-induced depression.

A comprehensive review program to prepare pharmacy students for the Saudi Pharmacist Licensure Examination (SPLE).

Purpose: The Saudi Pharmacist Licensure Examination (SPLE) has been mandated by the Saudi Commission for Health Specialties (SCFHS) for three and a half years; however, colleges of pharmacy and/or pharmacy organizations in Saudi Arabia have yet to implement a comprehensive review program to help prospective graduates to succeed. The aim of this study was to assess the impact of an integrated program designed to enhance students' performance on the SPLE. Methods: A cross-sectional study was conducted to determine the impact of integrating SPLE review activities (clinical review quizzes (CRQs), disease state presentations (DSPs), a Capstone OSCE, and a mock SPLE) on students' SPLE results and perceptions of their SPLE preparation and performance. Student scores from the review activities were analyzed and an anonymous, voluntary survey was used to assess the impact of these activities on student readiness levels and performance on the SPLE. Results: A total of 127 Doctor of Pharmacy (Pharm.D.) students were included in the study. The average scores for the mock SPLE, DSPs, and Capstone OSCE were (55.8% ± 8.55), (91.3% ± 7.17), and (95.2% ± 6.90), respectively. Approximately 50% of the students responded to the survey. Most students had taken and passed the SPLE on the first attempt (94.6%) with an average score of 635.7 ± 39.4 (∼79%). Over 60% and 70% of students recommended the SPLE CRQs activity and the DSP activity, respectively. With respect to mock SPLE, 60.9% believed that it provided an idea of what to expect on the SPLE and 54.7% recommended to add the Capstone OSCE into the curriculum. Overall, the majority of students would recommend these activities be incorporated in the college of pharmacy curriculum in order to better prepare pharmacy graduates for the SPLE. Conclusion: Prospective graduates from Saudi universities may benefit from college of pharmacy-organized SPLE reviews. Based on this study's findings, a comprehensive review course including a mock SPLE and disease state presentations is recommended. In addition, SPLE review lectures, CRQs, and a Capstone OSCE may provide additional benefit.

Aspirin Use among Saudi Adults: The Prevalence and Users' Characteristics.

Introduction: Despite the public routine use of aspirin as cardio-prophylaxis agent, its use is only recommended in particular situations, and not as usual primary prevention. Only few local studies investigate the use of aspirin in patients with certain diseases, but not within the public population. The purpose of this study was to evaluate the prevalence of aspirin use and identify the demographic and clinical characteristics among Saudi users. Methodology: A cross-sectional study targeting Saudi adults in Saudi Arabia was conducted over a period of four months in 2021 using online Google forms. The study collected data to assess the prevalence of use, use of aspirin according to prevention type, users' characteristics and comorbidities. Additionally, a self-assessment of knowledge, perception, reasons and attitude towards aspirin use among Saudi adults was conducted. A chi-square test was used to determine the association between the variables. A P-value ≤ 0.05 was considered statistically significant. Results: The prevalence of aspirin use was 47%. Regarding the self-assessed aspirin knowledge, the majority of the respondents (n = 481; 62.4 %) found to have good knowledge. Less than half of the participants (n = 341; 44%) use aspirin as primary prevention agent while only 23 participants (2.9%) use aspirin as secondary prevention agent. There was a significant difference between gender and user type (p = 0.001). With regards to comorbidities, hypertension, hyperlipidemia, diabetes, and obesity were common among the primary users of aspirin. Significant associations were found (p = 0.001) between participant's user type and the following characteristics such as smoking status, past medical history, presence of comorbidities. Conclusion: Aspirin use is commonly prevalent Saudi population with good level of knowledge of the therapy; however, its popular use as primary preventive agent for CVD may necessitate medical advice based on the level of cardiovascular risk.

Does Ramadan fasting disrupt international normalised ratio control in warfarin-treated medically stable patients?

AIM: Warfarin is commonly used in patients with thrombotic diseases. This study aimed to evaluate the impact of Ramadan fasting on warfarin efficacy by investigating international normalised ratio (INR) stability in medically stable patients. METHODS: A retrospective observational study was conducted at King Khalid University Hospital during Ramadan 2016 on fasting adult patients aged above 18 years and receiving warfarin. The INR values during pre-Ramadan, Ramadan and post-Ramadan periods were collected after satisfying the inclusion criteria. Time within the therapeutic range (TTR) during the whole period was estimated using the conventional method. RESULTS: In total, 101 patients were included in the study. The mean age (SD) was 55.8 ± 15.5 years, and 52.4% were females. The target INR range for 62.4% was 2-3, while 37.6% had a target INR range of 2.5-3.5. An upward trend in the proportion of patients with therapeutic INR was noticed during Ramadan (59.4%) as compared to pre- (56.4%) and post-Ramadan periods (53.5%) respectively. Additionally, the proportions of patients with supratherapeutic and sub-therapeutic INR were the highest and lowest, 23% and 24% respectively post-Ramadan as compared to other periods. Based on target INR categorisation, achieving therapeutic INR during Ramadan was more feasible with the low INR (2-3) compared to the high INR (2.5-3.5) target patients, 63.5% vs 52.6% respectively. TTR estimation revealed 62.4% and 37.6% of the patients had good and poor, respectively, anticoagulation status throughout the study period. CONCLUSION: Despite the changes in mean INR and proportion of patients with therapeutic INR during Ramadan compared to other non-fasting months, our results confirmed that short-term fasting during Ramadan has no significant influence on INR stability and, consequently, therapeutic efficacy in warfarin-treated medically stable patients.

Role of pharmacist during COVID-19 pandemic: A retrospective study focused on critically ill COVID-19 patients.

BACKGROUND AND AIM: During the Coronavirus 2019 (COVID-19) crisis, there has been a huge demand for medications and unprecedented utilization of intensive care unit (ICU) services that subsequently and profoundly impacted the quality of medical care provided to COVID-19 patients. This study aimed to shed light on the role of pharmacists on the health care provided to critically ill COVID-19 patients. METHODS: A retrospective study, was conducted in Diriyah hospital in Riyadh, Saudi Arabia on all COVID-19 patients admitted to the ICU between June 27th and August 15th, 2020 until patients were transferred to the medical ward, discharged, or deceased. All medication related interventions performed by pharmacists have been documented electronically, collected and subsequently categorized and analyzed. RESULTS: The mean age of patients was 58.8 years (±12.98 SD), with age of >64 years in approximately 37%. Four hundred and seventy interventions (470) were made by pharmacists of which 32%, 11.7%, 4%, 2.6%, 2.1% were due to error in dosing regimens, drug duplication, missing drug information, drugs requiring prior authorization, and missing critical information, respectively; while 40.6% were due to medication shortage of which 40.3% were substituted with alternative medications. Based on the analysis of drugs involved in interventions, medication groups that were mainly associated with interventions included antibiotics (16.8%), electrolytes/minerals (11.7%) and vitamins (9.4%). CONCLUSION: During health crises such as COVID-19 pandemic, the role of pharmacists in the ICU services becomes extremely crucial for providing better patients' outcomes. Further studies should be conducted to follow up these findings in the context of COVID-19 pandemic.

Pharmacokinetic profile of sildenafil citrate in healthy Middle Eastern Males: Comparison with other ethnicities.

AIM: 1) To investigate the pharmacokinetic profile of sildenafil citrate in Middle Eastern males and, 2) To highlight the impact of ethnicity on its pharmacokinetics parameters through comparing Middle Eastern data to the data estimated from different ethnic groups. METHOD: The study was conducted on 24 Middle Eastern healthy male volunteers. Pharmacokinetic data including Cmax, Tmax, t1/2, AUC0-t, AUC0-∞ were estimated from blood samples collected at several time points within 24 h post-administration of a single 100-mg tablet of sildenafil citrate (Viagra®). Pharmacokinetic data of sildenafil generic 100-mg tablet (product B) was determined in the volunteers using the same analytical method. Pharmacokinetic data of other studies published on different ethnicities were obtained and compared to our Viagra®-related data. RESULTS: Analysis of Middle Eastern data (mean ± SD) revealed Cmax = 398.9 ± 107.7 ng/ml; Tmax = 1.84 ± 0.22 h; t1/2 = 2.66 ± 0.97 h; AUC0-24 = 1475 ± 515.3 ng.h/ml; AUC0-∞ = 1556 ± 567.58 ng.h/ml. There was no significant difference between Viagra® and product B, confirming the bioequivalence of the two preparation as well as the reliability of utilized analytical method. Data comparisons between Middle Eastern and other ethnicities indicated that Iranian, Mexican, and Thai would potentially have twice the effect observed in Arabs and Caucasians, considering the same prescribed drug formulation and dose. CONCLUSION: There is a considerable difference in the pharmacokinetic profile of sildenafil citrate between Middle Eastern and other ethnic groups. Ethnicity may predispose individuals to unwanted prolonged activity of sildenafil and adverse events. Thus, it should be taken in consideration by clinicians when recommending sildenafil dose.

Delayed Akt suppression in the lipopolysaccharide-induced acute lung injury promotes resolution that is associated with enhanced effector regulatory T cells.

The adaptive immune response could play a major role in the resolution of lung injury. Although regulatory T cells (Tregs) have been implicated in promoting the resolution of lung injury, therapeutic strategies to enhance Treg quantity and activity at the site of injury need further exploration. In the current study, Akt inhibition using triciribine (TCBN), given 48 h after lipopolysaccharide (LPS) administration, increased Tregs-promoted resolution of acute lung injury (ALI). TCBN treatment enhanced the resolution of LPS-induced ALI on day 7 by reducing pulmonary edema and neutrophil activity associated with an increased number of CD4+/FoxP3+/CD103+ and CTLA4+ effector Tregs, specifically in the injured lungs and not in the spleen. Treatment of EL-4 T-lymphocytes with two Akt inhibitors (TCBN and MK-2206) for 72 h resulted in increased FoxP3 expression in vitro. On the other end, Treg-specific PTEN knockout (PTENTreg KO) mice that have a higher Akt activity in its Tregs exhibited a significant impairment in ALI resolution, increased edema, and neutrophil activity associated with a reduced number of CD4+/FoxP3+/CD103+ and CTLA4+ effector Tregs as compared with the control group. In conclusion, our study identifies a potential target for the treatment of late-stage ALI by promoting resolution through effector Treg-mediated suppression of inflammation.

Prevalence and severity of dyspepsia in Saudi Arabia: A survey-based study.

BACKGROUND AND AIM: Dyspepsia is one of the gastrointestinal diseases that is very common worldwide. Despite its prevalence globally, which ranges between 1.8% and 57%, no study has assessed the prevalence in Saudi Arabia. This study was aimed to investigate the prevalence and severity of dyspepsia in the general population of Saudi Arabia. METHODS: A modified Short-Form Leeds Dyspepsia Questionnaire (SF-LDQ) was utilized to conduct our study. The questionnaire score ranges between 0 and 32, where zero indicated no dyspepsia, a score of 1-8 indicated mild dyspepsia, a score of 9-15 indicated moderate dyspepsia and a score of higher than 15 represented severe dyspepsia. Socio-demographic data of the participants including age, gender, marital status, BMI, job description, insurance, and education level were collected. Using Statistical Package for Social Sciences version 21.0 (SPSS), a univariate analysis was performed to assess the association of participants characteristics with the prevalence of dyspepsia, whereas logistic regression analysis was used to correlate their characteristics with the severity of dyspepsia. RESULTS: During a period of one month, March 1st to 31st 2019, a total of 778 participants have completed the survey. Most of them were females accounting for 68% of the population, married (63.9%), middle aged (range 34-51 years old) and literate with high school education (72.3%). Ninety two percent (92%) of the study population were found to experience dyspepsia. However, there is no significant association between socio-demographic characteristics and dyspepsia or its severity as well. CONCLUSION: The prevalence of dyspepsia in Saudi Arabia is the highest in the gulf region which would potentially lead to more GI complications, and associate to poor health and economic outcomes. Education programs are essential to raise the people awareness of dyspepsia and the appropriate ways to prevent it.

Modulation of the p75 neurotrophin receptor using LM11A-31 prevents diabetes-induced retinal vascular permeability in mice via inhibition of inflammation and the RhoA kinase pathway.

AIMS/HYPOTHESIS: Breakdown of the inner blood-retinal barrier (BRB) is an early event in the pathogenesis of diabetic macular oedema, that eventually leads to vision loss. We have previously shown that diabetes causes an imbalance of nerve growth factor (NGF) isoforms resulting in accumulation of its precursor proNGF and upregulation of the p75 neurotrophin receptor (p75NTR), with consequent increases in the activation of Ras homologue gene family, member A (RhoA). We also showed that genetic deletion of p75NTR in diabetes preserved the BRB and prevented inflammatory mediators in retinas. This study aims to examine the therapeutic potential of LM11A-31, a small-molecule p75NTR modulator and proNGF antagonist, in preventing diabetes-induced BRB breakdown. The study also examined the role of p75NTR/RhoA downstream signalling in mediating cell permeability. METHODS: Male C57BL/6 J mice were rendered diabetic using streptozotocin injection. After 2 weeks of diabetes, mice received oral gavage of LM11A-31 (50 mg kg-1 day-1) or saline (NaCl 154 mmol/l) for an additional 4 weeks. BRB breakdown was assessed by extravasation of BSA-AlexaFluor-488. Direct effects of proNGF were examined in human retinal endothelial (HRE) cells in the presence or absence of LM11A-31 or the Rho kinase inhibitor Y-27632. RESULTS: Diabetes triggered BRB breakdown and caused significant increases in circulatory and retinal TNF-α and IL-1ß levels. These effects coincided with significant decreases in retinal NGF and increases in vascular endothelial growth factor and proNGF expression, as well as activation of RhoA. Interventional modulation of p75NTR activity through treatment of mouse models of diabetes with LM11A-31 significantly mitigated proNGF accumulation and preserved BRB integrity. In HRE cells, treatment with mutant proNGF (10 ng/ml) triggered increased cell permeability with marked reduction of expression of tight junction proteins, zona occludens-1 (ZO-1) and claudin-5, compared with control, independent of inflammatory mediators or cell death. Modulating p75NTR significantly inhibited proNGF-mediated RhoA activation, occludin phosphorylation (at serine 490) and cell permeability. ProNGF induced redistribution of ZO-1 in the cell wall and formation of F-actin stress fibres; these effects were mitigated by LM11A-31. CONCLUSIONS/INTERPRETATION: Targeting p75NTR signalling using LM11A-31, an orally bioavailable receptor modulator, may offer an effective, safe and non-invasive therapeutic strategy for treating macular oedema, a major cause of blindness in diabetes.

Angiotensin II type 2 receptor stimulation with compound 21 improves neurological function after stroke in female rats: a pilot study.

The angiotensin II type 2 receptor (AT2R) agonist, compound 21 (C21), has been shown to be neurovascularly protective after ischemic stroke in male rats. In the current study, we aim to study the impact of C21 treatment on female rats. Young female Wistar rats were subjected to different durations of middle cerebral artery occlusion (MCAO) (3 h, 2 h, and 1 h) using a silicone-coated monofilament, treated at reperfusion with 0.03 mg/kg ip of C21 and followed up for different times (1, 3, and 14 days) after stroke. Behavioral tests were performed (Bederson, paw grasp, beam walk, and rotarod), and animals were euthanized for infarct size analysis and Western blot analysis. In vitro, primary male and female brain microvascular endothelial cells (ECs) were grown in culture, and the expression of the AT2R was compared between males and females. At 1 day, C21 treatment resulted in an improvement in Bederson scores. However, at 3 days and 14 days, the impact of C21 on stroke outcomes was less robust. In vitro, the expression of the AT2R was significantly higher in female ECs compared with male ECs. In conclusion, C21 improves Bederson scores after stroke in female rats when administered early at reperfusion. The ability of C21 to exert its neuroprotective effects might be affected by fluctuating levels of female hormones. NEW & NOTEWORTHY The present study shows the neuroprotective impact of C21 on ischemic stroke in female rats and how the protective effects of C21 can be influenced by the hormonal status of female rodents.

The unconventional role of Akt1 in the advanced cancers and in diabetes-promoted carcinogenesis.

Decades of research have elucidated the critical role of Akt isoforms in cancer as pro-tumorigenic and metastatic regulators through their specific effects on the cancer cells, tumor endothelial cells and the stromal cells. The pro-cancerous role of Akt isoforms through enhanced cell proliferation and suppression of apoptosis in cancer cells and the cells in the tumor microenvironment is considered a dogma. Intriguingly, studies also indicate that the Akt pathway is essential to protect the endothelial-barrier and prevent aberrant vascular permeability, which is also integral to tumor perfusion and metastasis. To complicate this further, a flurry of recent reports strongly indicates the metastasis suppressive role of Akt, Akt1 in particular in various cancer types. These reports emanated from different laboratories have elegantly demonstrated the paradoxical effect of Akt1 on cancer cell epithelial-to-mesenchymal transition, invasion, tumor endothelial-barrier disruption, and cancer metastasis. Here, we emphasize on the specific role of Akt1 in mediating tumor cell-vasculature reciprocity during the advanced stages of cancers and discuss how Akt1 differentially regulates cancer metastasis through mechanisms distinct from its pro-tumorigenic effects. Since Akt is integral for insulin signaling, endothelial function, and metabolic regulation, we also attempt to shed some light on the specific effects of diabetes in modulating Akt pathway in the promotion of tumor growth and metastasis.

Endothelial stromelysin1 regulation by the forkhead box-O transcription factors is crucial in the exudative phase of acute lung injury.

Enhanced vascular permeability is associated with inflammation and edema in alveoli during the exudative phase of acute respiratory distress syndrome (ARDS). Mechanisms leading to the endothelial contribution on the early exudative stage of ARDS are not precise. We hypothesized that modulation of endothelial stromelysin1 expression and activity by Akt1-forkhead box-O transcription factors 1/3a (FoxO1/3a) pathway could play a significant role in regulating pulmonary edema during the initial stages of acute lung injury (ALI). We utilized lipopolysaccharide (LPS)-induced mouse ALI model in vivo and endothelial barrier resistance measurements in vitro to determine the specific role of the endothelial Akt1-FoxO1/3a-stromelysin1 pathway in ALI. LPS treatment of human pulmonary endothelial cells resulted in increased stromelysin1 and reduced tight junction claudin5 involving FoxO1/3a, associated with decreased trans-endothelial barrier resistance as determined by electric cell-substrate impedance sensing technology. In vivo, LPS-induced lung edema was significantly higher in endothelial Akt1 knockdown (EC-Akt1-/-) compared to wild-type mice, which was reversed upon treatment with FoxO inhibitor (AS1842856), stromelysin1 inhibitor (UK356618) or with shRNA-mediated FoxO1/3a depletion in the mouse lungs. Overall, our study provides the hope that targeting FoxO and styromelysin1 could be beneficial in the treatment of ALI.

Endothelial Akt1 loss promotes prostate cancer metastasis via ß-catenin-regulated tight-junction protein turnover.

BACKGROUND: Cancer research, in general, is focused on targeting tumour cells to limit tumour growth. These studies, however, do not account for the specific effects of chemotherapy on tumour endothelium, in turn, affecting metastasis. METHODS: We determined how endothelial deletion of Akt1 promotes prostate cancer cell invasion in vitro and metastasis to the lungs in vivo in endothelial-specific Akt1 knockdown mice. RESULTS: Here we show that metastatic human PC3 and DU145 prostate cancer cells invade through Akt1-deficient human lung endothelial cell (HLEC) monolayer with higher efficiency compared to control HLEC. Although the endothelial Akt1 loss in mice had no significant effect on RM1 tumour xenograft growth in vivo, it promoted metastasis to the lungs compared to the wild-type mice. Mechanistically, Akt1-deficient endothelial cells exhibited increased phosphorylation and nuclear translocation of phosphorylated ß-catenin, and reduced expression of tight-junction proteins claudin-5, ZO-1 and ZO-2. Pharmacological inhibition of ß-catenin nuclear translocation using compounds ICG001 and IWR-1 restored HLEC tight-junction integrity and inhibited prostate cancer cell transendothelial migration in vitro and lung metastasis in vivo. CONCLUSIONS: Here we show for the first time that endothelial-specific loss of Akt1 promotes cancer metastasis in vivo involving ß-catenin pathway.

Evaluation of the Efficacy and Safety of Quetiapine in the Treatment of Delirium in Adult ICU Patients: A Retrospective Comparative Study.

Background: Quetiapine is commonly prescribed off-label to manage delirium in intensive care unit (ICU) patients. However, limited studies comparing its efficacy and safety to those of other antipsychotics exist in the literature. Method: A retrospective, single-center chart review study was conducted on adults admitted to the ICU between January 2017 and August 2022, who were diagnosed with delirium and treated with a single antipsychotic and had no neurological medical conditions, active alcohol withdrawal, or prior use of antipsychotics. Data were analyzed using SPSS software version 28, with p-values of <0.05 indicating statistical significance. Results: In total, 47 patients were included, of whom 22 (46.8%), 19 (40.4%), 4 (8.5%), and 2 (4.3%) were on quetiapine, haloperidol, risperidone, and olanzapine, respectively. The median number of hours needed to resolve delirium were 12 (21.5), 23 (28), 13 (13.75), and 36 (10) (p = 0.115) for quetiapine, haloperidol, risperidone, and olanzapine, respectively, with haloperidol being used for a significantly shorter median number of days than quetiapine (3 (2.5) days vs. 7.5 (11.5) days; p = 0.007). Of the medication groups, only quetiapine-treated patients received a significantly higher median maintenance compared to the initiation dose (50 (50) mg vs. 50 (43.75) mg; p = 0.039). For the length of stay in the ICU and hospital, delirium-free days, % of ICU time spent in delirium, ventilator-free days, the difference between the highest and baseline QTc intervals, and ICU and hospital mortalities, no significant difference was observed between the groups. Conclusions: Overall, the use of quetiapine in our retrospective study seems to not be advantageous over the other drugs in terms of efficacy and safety outcomes.