Administration of teclistamab in four patients with multiple myeloma requiring hemodialysis.

OBJECTIVE: Relapsed/refractory multiple myeloma (MM) has poor outcomes, especially in heavily pretreated patients. Limited data exists on the use of novel therapies in MM patients with renal dysfunction. This case series describes the successful initiation of teclistamab in four patients with heavily pre-treated MM on hemodialysis (HD). DATA SOURCES: The medical records of four adult MM patients on HD who received teclistamab were retrospectively reviewed. DATA SUMMARY: All patients completed teclistamab step-up dosing and received at least one full dose. HD runs were administered irrespective of teclistamab initiation. Patients tolerated therapy well, with only one patient experiencing grade 1 CRS, which was managed with supportive care. CONCLUSIONS: Due to the complexity of this patient population, close monitoring and multidisciplinary care are crucial. This approach is essential for effectively managing MM patients with renal dysfunction and for exploring novel treatment options.

Pectin nanoparticles loaded with nitric oxide donor drug: A potential approach for tissue regeneration.

The process of wound healing and tissue regeneration involves several key mechanisms to ensure the production of new tissues with similar cellular functions. This study investigates the impact of pectin, a natural polysaccharide, and nebivolol hydrochloride (NBV), a nitric oxide (NO) donor drug, on wound healing. Utilizing ionotropic gelation, NBV-loaded pectin nanoparticles were developed following a 2231 full factorial design. The optimized formulation, determined using Design expert® software, exhibited an encapsulation efficiency percentage of 70.68%, zeta potential of -51.4 mV, and a particle size of 572 nm, characterized by a spherical, discrete morphology. An in vivo study was conducted to evaluate the effectiveness of the optimal formulation in wound healing compared to various controls. The results demonstrated the enhanced ability of the optimal formulation to accelerate wound healing. Moreover, histopathological examination further confirmed the formulation's benefits in tissue proliferation and collagen deposition at the wound site 15 days post-injury. This suggests that the developed formulation not only promotes faster healing but does so with minimal side effects, positioning it as a promising agent for effective wound healing and tissue regeneration.

Formulation and optimization of ivermectin nanocrystals for enhanced topical delivery.

The increasing resistance to antiparasitic drugs and limited availability of new agents highlight the need to improve the efficacy of existing treatments. Ivermectin (IVM) is commonly used for parasite treatment in humans and animals, however its efficacy is not optimal and the emergence of IVM-resistant parasites presents a challenge. In this context, the physico-chemical characteristics of IVM were modified by nanocrystallization to improve its equilibrium water-solubility and skin penetration, potentially improving its therapeutic effectiveness when applied topically. IVM-nanocrystals (IVM-NC) were prepared using microfluidization technique. The impact of several process/formulation variables on IVM-NC characteristics were studied using D-optimal statistical design. The optimized formulation was further lyophilized and evaluated using several in vitro and ex vivo tests. The optimal IVM-NC produced monodisperse particles with average diameter of 186 nm and polydispersity index of 0.4. In vitro results showed an impressive 730-fold increase in the equilibrium solubility and substantial 24-fold increase in dissolution rate. Ex vivo permeation study using pig's ear skin demonstrated 3-fold increase in dermal deposition of IVM-NC. Additionally, lyophilized IVM-NC was integrated into topical cream, and the resulting drug release profile was superior compared to that of the marketed product. Overall, IVM-NC presents a promising approach to improving the effectiveness of topically applied IVM in treating local parasitic infections.

Analyzing Yemen's health system at the governorate level amid the ongoing conflict: a case of Al Hodeida governorate.

Background: Yemen is regarded as one of the Middle East's poorest countries. Decades of political, economic, and social difficulties have culminated in the current protracted conflict. As a result, the globe experienced its worst humanitarian catastrophe. The ongoing war has affected several public services, notably the health sector, which is operating at less than half its capacity. This study aims to examine Yemen's health system at the governorate level (Al Hodeida) amidst the current conflict. It analyzes current challenges and produces suggestions for enhancement. Methods: The study used qualitative research methods such as Key Informant Interviews (KIIs) and document analysis. The study used WHO's health systems framework to measure health system performance. Twelve KIIs were conducted via Skype with several health stakeholders. In addition, documents were analyzed to inform the subject guide, generate themes, and aid in the triangulation of results. Results: According to the study findings, the governorate health system managed to offer a minimum level of healthcare services while making some advances in outbreak control jointly with other partners. One of the main difficulties confronting the governorate's health system is a severe lack of financial resources forcing it to rely entirely on external aid. Furthermore, other significant deficiencies include inadequate health system organogram, low reporting capacities, insufficient funding, and scarcity of health professionals. Conclusion: Yemen's frail health system has been weakened by almost eight years of insecurity and conflict. If the current scenario continues, most of Yemen's health system's operations and indicators will likely deteriorate. On the other hand, progress in some areas, such as primary healthcare (PHC) services and disease management, is remarkable. However, for better performance, Yemen's health system leadership and stakeholders should seek a holistic strategy to improve the entire dimensions of the health system.

Unmasking the enigma: An in-depth analysis of COVID-19 impact on the pediatric population.

OBJECTIVES: COVID-19, caused by the novel coronavirus, has had a profound and wide-reaching impact on individuals of all age groups across the globe, including children. This review article aims to provide a comprehensive analysis of COVID-19 in children, covering essential topics such as epidemiology, transmission, pathogenesis, clinical features, risk factors, diagnosis, treatment, vaccination, and others. By delving into the current understanding of the disease and addressing the challenges that lie ahead, this article seeks to shed light on the unique considerations surrounding COVID-19 in children and contribute to a deeper comprehension of this global health crisis affecting our youngest population. METHODS: A comprehensive literature search was conducted to gather the most recent and relevant information regarding COVID-19 in children. Multiple renowned databases, including MEDLINE, PubMed, Scopus, as well as authoritative sources such as the World Health Organization (WHO), the U.S. Food and Drug Administration (FDA), the European Medicines Agency (EMA), and the National Institutes of Health (NIH) websites and others were thoroughly searched. The search included articles, guidelines, reports, clinical trials results and expert opinions published within the past three years, ensuring the inclusion of the latest research findings on COVID-19 in children. Several relevant keywords, including "COVID-19," "SARS-CoV-2," "children," "pediatrics," and related terms were used to maximize the scope of the search and retrieve a comprehensive set of articles. RESULTS AND CONCLUSION: Three years since the onset of the COVID-19 pandemic, our understanding of its impact on children has evolved, but many questions remain unanswered. While SAR-CoV-2 generally leads to mild illness in children, the occurrence of severe cases and the potential for long-term effects cannot be overlooked. Efforts to comprehensively study COVID-19 in children must continue to improve preventive strategies, identify high-risk populations, and ensure optimal management. By unraveling the enigma surrounding COVID-19 in children, we can strive towards safeguarding their health and well-being in the face of future global health challenges.

Graphene Oxide/Chitosan Injectable Composite Hydrogel for Controlled Release of Doxorubicin: An Approach for Enhanced Intratumoral Delivery.

Intratumoral (IT) injection of chemotherapeutics into needle-accessible solid tumors can directly localize the anticancer drug in the tumor site, thus increasing its local bioavailability and reducing its undesirable effects compared to systemic administration. In this study, graphene oxide (GO)-based chitosan/ß-glycerophosphate (CS/GP) thermosensitive injectable composite hydrogels (CH) were prepared and optimized for the localized controlled delivery of doxorubicin (DOX). A quality-by-design (QbD) approach was used to study the individual and combined effects of several formulation variables to produce optimal DOX-loaded GO/CS/GP CH with predetermined characteristics, including gelation time, injectability, porosity, and swelling capacity. The surface morphology of the optimal formulation (DOX/opt CH), chemical interaction between its ingredients and in vitro release of DOX in comparison to GO-free CS/GP CH were investigated. Cell viability and cellular uptake after treatment with DOX/opt CH were studied on MCF 7, MDB-MB-231 and FaDu cell lines. The statistical analysis of the measured responses revealed significant effects of the concentration of GO, the concentration of CS, and the CS:GP ratio on the physicochemical characteristics of the prepared GO/CS/GP CH. The optimization process showed that DOX-loaded GO/CS/GP CH prepared using 0.1% GO and 1.7% CS at a CS: GO ratio of 3:1 (v/v) had the highest desirability value. DOX/opt CH showed a porous microstructure and chemical compatibility between its ingredients. The incorporation of GO resulted in an increase in the ability of the CH matrices to control DOX release in vitro. Finally, cellular characterization showed a time-dependent increase in cytotoxicity and cellular uptake of DOX after treatment with DOX/opt CH. The proposed DOX/opt CH might be considered a promising injectable platform to control the release and increase the local bioavailability of chemotherapeutics in the treatment of solid tumors.

Serum IgG4 level for malignancy prediction in indeterminate thyroid nodules among patients with or without autoimmune thyroid disease.

The incidence of thyroid nodules (TNs) has increased nowadays, and it is critical to properly differentiate between malignant and benign nodules to prevent unneeded thyroidectomy as well as complications related to surgery. IgG4 significantly contributes to various cancer-associated processes. The present study aimed to assess the value of serum IgG4 level in predicting malignancies in indeterminate thyroid nodules (ITN) among patients with and without autoimmune thyroid disease (AITD). A total of 67 patients with indeterminate cytology thyroid nodules (Bethesda III and IV, according to Bethesda system for reporting thyroid cytopathology) were selected. Preoperative serum thyroid profile, IgG4, anti-thyroglobulin (TG) and anti-thyroid peroxidase (TPO) antibody levels were determined. After total thyroidectomy, patients were categorized based on the postoperative histopathology outcome into two groups. Group (I): confirmed benign nodules (n=55) and Group (II): confirmed malignant TNs (n=12). IgG4 levels were significantly elevated among malignant TNs patients than in benign TNs patients, with a median (IQR) of 194.5 mg/dl (183 - 214) vs. 91 mg/dl (60 - 113), respectively (P=0.001). The cut-off value for differentiation between malignant and benign TNs was >180 mg/dl with a sensitivity of 75% and specificity of 100%. There was a significant positive correlation between thyroid antibodies and IgG4 levels (P=0.001). AITD patients had significantly higher level of IgG4 compared with those without AITD 189 mg/dl (153 - 208) vs 89 mg/dl (58 - 112), respectively (P =0.001). Eighty percent (12/15) of patients with AITD had malignant TNs with IgG4 >180 mg/dl, while 20% (3/15) of patients with benign TNs showed IgG4 levels < 180 mg/dl. In conclusion, IgG4 level can be proposed as a predictor of malignant TNs.

Women's cancers in Sudan with a focus on cervical cancer: turmoil, geopolitics and opportunities.

Cancer is the leading cause of death worldwide and the second leading cause of death in Sudanese women. However, despite proven interventions for primary, secondary and tertiary prevention and the World Health Organization's call to action toward eliminating cervical cancer, there has been little progress in addressing the cervical cancer burden in Sudan. This short communication intends to shed light on the challenges facing women's cancers in Sudan, taking cervical cancer as an example. It also discusses the opportunities and suggests ways to improve the outcomes of women's cancers in Sudan. Sudan's government should urgently implement a broad public health strategy to improve outcomes for women with cancer. The cancer control plan should be aligned with international, evidence-based recommendations and adapted to local circumstances. It should strengthen health literacy, augment different health care interventions, including vaccination, committed screening programmes, early detection and proper diagnosis of symptomatic cases, a programmatic approach to active management and palliative care and ensure robust referral pathways. Policies are also needed in collaboration with the international community in addressing the cancer care needs of internally displaced and refugee women in Sudan. The strategy should consider overcoming the existing challenges and making the most opportunities available.

Pharmaceutical equivalency of locally and regionally manufactured generic pharmaceutical products in UAE.

Generic drugs or generic medicines are pharmaceutical products manufactured to be equivalent to the brand/innovator drug products. They represent the majority of worldwide prescribed medicines; therefore, their quality is critical to maximize patients' therapeutic outcomes. This study aimed to evaluate the pharmaceutical equivalency of locally and regionally manufactured generic pharmaceutical products being sold in the United Arab Emirates (UAE) market to enhance public confidence, promote their utilization, and reduce treatment costs. Three drugs (tadalafil, rosuvastatin, and acetaminophen) from three different pharmacological classes were selected from the UAE market as representatives for generic drugs. At least two generic products for each locally (L) and regionally (R) manufactured generic were evaluated according to the USP criteria in comparison to the brand (B) comparator product. All comparative tests were performed before storage and 3 and 6 months after storage during the accelerated stability study performed under the conditions for climatic zone IV (40 °C ± 2 °C /75% RH ± 5% RH). Although results were statistically different from the comparators using ANOVA and Tukey's Kremer post hoc tests, all tests were within the USP acceptance limits, except one, for friability, disintegration, content uniformity, and dissolution. Significant changes were observed following their storage over 6 months during accelerated stability studies, however, without failing the USP limits. Only one locally manufactured acetaminophen generic failed the USP dissolution tests before and after its storage and failed the disintegration test following its storage under accelerated conditions for zone IV. In conclusion, the majority of the locally and regionally manufactured generic products being sold in the UAE market were of good quality and performed similarly to their comparators. However, a continuous independent quality evaluation for the marketed generic drugs is essential to enhance public confidence.

Repurposing Potential of the Antiparasitic Agent Ivermectin for the Treatment and/or Prophylaxis of COVID-19.

Due to the rapid, vast, and emerging global spread of the Coronavirus Disease 2019 (COVID-19) pandemic, many drugs were quickly repurposed in a desperate attempt to unveil a miracle drug. Ivermectin (IVM), an antiparasitic macrocyclic lactone, was tested and confirmed for its in vitro antiviral activity against severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) in early 2020. Along with its potential antiviral activity, the affordability and availability of IVM resulted in a wide public interest. Across the world, trials have put IVM to test for both the treatment and prophylaxis of COVID-19, as well as its potential role in combination therapy. Additionally, the targeted delivery of IVM was studied in animals and COVID-19 patients. Through this conducted literature review, the potential value and effectiveness of the repurposed antiparasitic agent in the ongoing global emergency were summarized. The reviewed trials suggested a value of IVM as a treatment in mild COVID-19 cases, though the benefit was not extensive. On the other hand, IVM efficacy as a prophylactic agent was more evident and widely reported. In the most recent trials, novel nasal formulations of IVM were explored with the hope of an improved optimized effect.

A Nano-Liposomal Formulation of Caffeic Acid Phenethyl Ester Modulates Nrf2 and NF-κß Signaling and Alleviates Experimentally Induced Acute Pancreatitis in a Rat Model.

The currently available management strategies for acute pancreatitis are inadequately effective which calls for exploration of new approaches to treat this condition. Caffeic acid phenethyl ester (CAPE) is a major bioactive constituent of honeybee propolis with promising therapeutic and preventive applications. However, its pharmaceutical potential and clinical use are hindered by its poor water solubility and limited plasma stability. In this study, we aimed to prepare, characterize and evaluate a CAPE-loaded nanoliposomal formulation to improve the efficacy of CAPE for the management of acute pancreatitis. The CAPE-loaded nanoliposomes (CAPE-loaded-NL) were prepared by a thin layer evaporation technique and were optimized using three edge activators. CAPE-loaded-NL were characterized for their vesicle size (VS), zeta potential (ZP), encapsulation efficiency (EE), polydispersity index (PDI), crystalline state and morphology. The protective effect of the optimal CAPE-loaded-NL was evaluated in a rat model of acute pancreatitis induced by administering a single intraperitoneal injection of L-ornithine. Oral pretreatment with CAPE-loaded-NL significantly counteracted ornithine-induced elevation in serum activities of pancreatic digestive enzymes and pancreatic levels of malondialdehyde, nuclear factor kappa B (NF-κB) p65, tumor necrosis factor-alpha, nitrite/nitrate, cleaved caspase-3 and myeloperoxidase activity. Moreover, pretreatment with CAPE-loaded-NL significantly reinstated the ornithine-lowered glutathione reductase activity, glutathione, nuclear factor erythroid 2-related factor 2 (Nrf2), heme oxygenase-1 levels and ATP/ADP ratio, and potentiated the Bcl-2/Bax ratio in pancreatic tissue. CAPE-loaded-NL displayed superior antioxidant, anti-inflammatory and anti-apoptotic effects compared to free CAPE oral suspension and achieved a more potent correction of the derangements in serum amylase and pancreatic myeloperoxidase activities. The histological observations were in line with the biochemical findings. Our results suggest that CAPE-loaded-NL provide a promising interventional approach for acute pancreatitis mainly through the enhancement of the exerted antioxidant, anti-inflammatory and anti-apoptotic effects which may be mediated, at least in part, through modulation of Nrf2 and NF-κß signaling.

Optimization, characterization and in vivo evaluation of mupirocin nanocrystals for topical administration.

Treatment of infectious skin conditions resulting from wounds and burns with topical antibiotics is challenging, particularly those caused by methicillin-resistant Staphylococcus aureus bacteria (MRSA). This is due to the formation of bacterial biofilms characterized by antimicrobial resistance. Mupirocin (MP), a widely used topical antibiotic, is active against gram-positive bacteria including MRSA. However, MP suffers from sub-optimal therapeutic efficacy due to its poor water-solubility and the significant rise in MP-resistant S. aureus. In this study, the physico-chemical characteristics of MP were modified through nanocrystallization to improve its therapeutic efficacy for the treatment of skin infections. Mupirocin-nanocrystals (MP-NC) were prepared using a nanoprecipitation technique and optimized using a D-optimal response surface design. The optimization of MP-NC produced ultra-small monodisperse spherical particles with a mean diameter of 70 nm and a polydispersity index of 0.2. The design resulted in two optimal MP-NC formulations that were evaluated by performing series of in vitro, ex vivo, microbiological, and in vivo studies. In-vitro results showed a 10-fold increase in the saturation solubility and a 9-fold increase in the dissolution rate of MP-NC. Ex vivo permeation studies, using pig ears skin, showed a 2-fold increase in the dermal deposition of MP-NC with the highest drug deposition occurring at 500-µm skin depth. Moreover, the optimal MP-NC formulations were lyophilized and incorporated into a 2% w/w cream. Microbiological studies revealed a 16-fold decrease in the minimum inhibitory concentration and the minimum bactericidal concentration of MP-NC. In vivo studies, using a rat excision burn wound model, demonstrated rapid and complete healing of infected burn wounds in rats treated with MP-NC cream in comparison to marketed Avoban ointment. Our results suggest that nanocrystallization of MP may provide an avenue through which higher levels of a topically applied MP can be permeated into the skin to reach relevant infectious areas and exert potential local antibacterial effects.

Assessment of the non-communicable diseases kit for humanitarian emergencies in Yemen and Libya.

Emergency health kits are a vital way of providing essential medicines and supplies to health clinics during humanitarian crises. The WHO non-communicable diseases (NDCs) kit was developed 5 years ago, recognising the increasing challenge of providing continuity of care and secondary prevention of NCDs and exacerbations, in such settings. Monitoring and evaluation of emergency health kits is an important process to ensure the contents are fit for purpose and to assess usability and utility. However, there are also challenges and limitations in collecting the relevant data to do so.This Practice paper provides a summary of the key methodologies, findings and limitations of NCD kit assessments conducted in Libya and Yemen. Methodologies included a combination of semistructured interviews, surveys with healthcare workers, NCD knowledge tests and quantifying the remaining contents.The kit was able to support the vital delivery of NCD patient care in some complex humanitarian settings and was appreciated by health facilities. However, there were also some challenges affecting kit use. Some kit contents were found to be in greater or lesser quantities than required, and medicine brands and country of origin affected acceptability. Supply chains were affected by the humanitarian situations, with some kits being held up for months prior to arrival. Furthermore, healthcare staff had received limited NCD training and were unable to dispense certain medicines, such as psychotropics, at the primary care level. Further granularity of kit modules, predeployment facility assessments, increased NCD training opportunities and a monitoring system could improve the utility of the kits.

A real world analysis of first line treatment of advanced EGFR mutated non-small cell lung cancer: A multi-center, retrospective study.

INTRODUCTION: The recently published FLAURA trial demonstrated that osimertinib has remarkable efficacy in front-line setting for non-small cell lung cancer (NSCLC). While this has transformed current practice, there are no effective treatments following progression on osimertinib. The aim of our study was to compare progression-free survival (PFS) and overall survival (OS) between patients initiated on osimertinib to those started on other EGFR TKIs. METHODS: This was a multicenter, retrospective study conducted at two large academic centers. Adult patients with EGFR-mutated non-small cell lung cancer (NSCLC) who received EGFR therapy between 2014 and 2019 were included. Patients were dichotomized based on front-line TKI (osimertinib vs. other). PFS, OS, and time-to-discontinuation were evaluated. RESULTS: One-hundred seventy-two patients were included in the final analysis. Fifty-two (30.2%) patients received osimertinib and 120 (69.8%) patients received another EGFR TKI. The PFS rates at 6, 12, and 18 months were 86.3%, 79.5%, 69.8% in the osimertinib group and 86.6%, 64.2%, 39.3% in the other EGFR TKI group, respectively (p < 0.0036).Estimated OS at 6, 12, and 18 months was similar for both groups: 94.2%, 94.2%, 80.2% and 95.7%, 93.9%, 84.1%, respectively [Adjusted HR = 0.95 (95% CI, 0.37-2.44; p < 0.9128]. CONCLUSION: Osimertinib demonstrated greater 12 and 18 month PFS compared to other EGFR TKIs. This finding is consistent with results of the FLAURA trial. However, unlike FLAURA, there were no differences in estimated OS between the two groups in our study. Further research to evaluate optimal sequencing strategies in the real world of first, second and third generation TKIs is needed.

Modulation of the sublingual microenvironment and pH-dependent transport pathways to enhance atropine sulfate permeability for the treatment of organophosphates poisoning.

Atropine sulfate (AS) auto-injectors are the only approved antidote for out-of-hospital emergency treatment of organophosphates (OP) toxicity. However, they are only available for military use and require the administration of multiple auto-injectors. Therefore, an alternative, patient-friendly and more affordable fast-disintegrating sublingual tablets (FDSTs) of AS were previously developed. In this article, the effect of modifying the microenvironment's pH and/or using penetration enhancers on AS sublingual transport pathways were evaluated in an attempt to further enhance AS sublingual permeability. Ten different AS FDST formulations with or without the incorporation of alkalizer and various penetration enhancers were manufactured and characterized. AS permeability was investigated through excised porcine sublingual membrane using Franz cells. Results showed that the incorporation of either a transcellular enhancer or alkalizer achieved a significantly higher AS permeability enhancement (twofold). Combining sodium bicarbonate (Na Bicarb) 2% as alkalizer with sodium dodecyl sulfate (SDS) 1% as a transcellular enhancer resulted in the greatest synergistic enhancement in AS sublingual permeability (up to twelvefold). In conclusion, the modified AS FDST developed in this work has the potential to improve the pharmacokinetic parameters of AS following sublingual administration for the first-aid treatment of OP toxicity in future animal bioequivalency studies.

Mind the gap: an analysis of core capacities of the international health regulations (2005) to respond to outbreaks in Yemen.

BACKGROUND: Yemen that has been devastated by war is facing various challenges to respond to the recent potential outbreaks and other public health emergencies due to lack of proper strategies and regulations, which are essential to public health security. The aim of this study is to assess the implementation of the International Health Regulations (IHR 2005) core capacities under the current ongoing conflict in Yemen. METHODS: The study simulated the World Health Organization (WHO) Joint External Evaluation (JEE) tool to assess the IHR core capacities in Yemen. Qualitative research methods were used, including desk reviews, in-depth interviews with key informants and analysis of the pooled data. RESULT: Based on the assessment of the three main functions of the IHR framework (prevention, detection, and response), Yemen showed a demonstrated or developed capacity to detect outbreaks, but nevertheless limited or no capacity to prevent and respond to outbreaks. CONCLUSION: This study shows that there has been poor implementation of IHR in Yemen. Therefore, urgent interventions are needed to strengthen the implementation of the IHR core capacities in Yemen. The study recommends 1) raising awareness among national and international health staff on the importance of IHR; 2) improving alignment of INGO programs with government health programs and aligning both towards better implementation of the IHR; 3) improving programmatic coordination, planning and implementation among health stakeholders; 4) increasing funding of the global health security agenda at country level; 5) using innovative approaches to analyze and address gaps in the disrupted health system, and; 6) addressing the root cause of the collapse of the health services and overall health system in Yemen by ending the protracted conflict situation.

In Situ-Forming Microparticles for Controlled Release of Rivastigmine: In Vitro Optimization and In Vivo Evaluation.

In this work, sucrose acetate isobutyrate (SAIB) and polylactic co-glycolic acid (PLGA) were used alone or in combination as a matrix-former (MF) to prepare long-acting injectable rivastigmine (RV) in situ-forming microparticles (ISM). RV-ISM were prepared by the emulsification of an internal phase, containing the drug and the matrix former(s), into an external oily phase containing a stabilizer. The statistical design, Central Composite Design (CCD), was adopted as a quality by design (QbD) approach to optimize the formulation of RV-ISM systems. The fabricated RV-ISM systems was designed to minimize the initial burst drug release and maximize the sustainment of RV release from the ISM and ease of injection. The influence of critical formulation variables such as the matrix-former to drug (MF/D) ratio and SAIB to PLGA (S/P) ratio in the internal phase with respect to critical quality attributes (CQAs), such as the percentage drug release within the first day (Q1), the time required for 50% drug release (T50%) and the rate of injection, were studied using the CCD. The optimal RV-ISM system with the highest desirability value (0.74) was predicted to have an MF/D ratio of 11.7:1 (w/w) and an S/P ratio of 1.64:1 (w/w). The optimal RV-ISM system was assessed for its release profile, injectability, rheological properties, morphology, effect on cell viability, tolerance to γ-sterilization and in vivo performance in male albino rabbits. In vitro release studies revealed that the optimal RV-ISM system released 100% of its drug content throughout a release period of 30 days with only 15.5% drug release within the first day (Q1) and T50% of 13.09 days. Moreover, the optimal system showed a high injection rate of 1.012 mL/min, pseudoplastic flow, uniform spherical globules with homogenous particle size, minimal cytotoxicity and high tolerability to γ-sterilization. In vivo pharmacokinetic (PK) studies revealed that the rate of absorption of RV from the optimal RV-ISM system was controlled compared to a drug solution following either intramuscular (IM) or subcutaneous (SC) injection. Furthermore, the optimal RV-ISM was found to follow flip-flop PK with poor correlation between in vitro release and in vivo findings. These findings suggest that the optimal RV-ISM is a promising tool to achieve a sustained release therapy for RV; however, further investigation is still required to optimize the in vivo performance of RV-ISM.

The impact of vitamin D supplementation on peripheral neuropathy in a sample of Egyptian prediabetic individuals.

Background: Vitamin D deficiency is seen more frequently in diabetic patients with distal symmetrical polyneuropathy. Unfortunately, there is a shortage of data concerning prediabetic individuals with peripheral neuropathy (PN). Therefore, we aimed to study the association of vitamin D deficiency with PN severity and to determine the effect of vitamin D supplementation on PN in prediabetics. Methods: A case-control study was conducted consisting of 89 prediabetic individuals with PN and a control group of prediabetics without PN, recruited from the outpatient department of the National Institute of Diabetes and Endocrinology, Cairo, Egypt. All patients were screened for PN using clinical examination and Douleur Neuropathique 4 diagnostic questionnaire (DN4). Group A (with PN) was assessed for neuropathic severity using the Short-Form McGill Pain Questionnaire (SF-MPQ). In addition, 25-hydroxyvitamin D, ionized calcium, phosphorus, parathyroid hormone (PTH), glycated hemoglobin (HbA1c), fasting blood glucose (FBG), 2-hour post 75g glucose (2h-PPBG) and lipid profile were measured for both groups. Prediabetic patients with PN were given vitamin D3 200.000 IU IM monthly for three months. After three months, clinical assessment, DN4, SF-MPQ and all laboratory measures were repeated. Results: Vitamin D was not associated with the severity of PN patients. However, supplementation of vitamin D resulted in a highly significant improvement in glycemic parameters , p≤0.001. Interestingly, neuropathy score and severity before vitamin D supplementation were (6.4±1.6 and 28.3±7.2) and after became (2.5±0.9 and 17±6.3, p≤0.001). Conclusion: Correction of vitamin D deficiency in prediabetics with PN as well as hypovitaminosis D, improves glycemic parameters, PN score and severity.

Efficacy and safety of doravirine in treatment-naive HIV-1-infected adults: a systematic review and meta-analysis.

This research aims to study the safety and efficacy of doravirine in the treatment of HIV-1 (human immunodeficiency virus) patients. We conducted an electronic search in eight databases for the inclusion of eligible studies. We have only included randomized controlled trials (RCTs) that study the safety and efficacy of doravirine in the treatment of HIV-1 adult patients. Six papers were included in this meta-analysis. For network (direct and indirect) estimates, the doravirine 100 mg treatment strategy found to have the highest efficacy (P score = 0.786) followed by doravirine 25 mg (P score = 0.684), efavirenz 600 mg (P score = 0.574), doravirine 200 mg (P score = 0.532), 100 mg ritonavir and plus 800 mg darunavir (P score = 0.416), and placebo (P score = 0.009), respectively. Regarding drug-related AE, the placebo group found to have the highest safety profile with the least AE rates (P score = 0.927) followed by doravirine 100 mg (P score = 0.720), 100 mg ritonavir and plus 800 mg darunavir (P score = 0.717), doravirine 25 mg (P score = 0.336), doravirine 200 mg (P score = 0.258), and efavirenz 600 mg (P score = 0.043), respectively. Nevertheless, there was no significant difference between DOR 100 mg in comparison with 100 mg ritonavir and plus 800 mg darunavir (OR = 1.14; 95% CI = 0.23-5.74), DOR 25 mg (OR = 0.37; 95% CI = 0.06-2.34), DOR 200 mg (OR = 0.89; 95% CI = 0.17-4.59), or efavirenz 600 mg (OR = 0.58; 95% CI = 0.17-1.98). Moreover, the pairwise (direct only) comparisons did not show a significant difference between doravirine (all doses) and other treatment groups. Doravirine could be counted as an efficacious, safe, and well-tolerated treatment option that is preferable to other regimens for the initial therapy of individuals with HIV-1 infection.