Therapeutic Safety Research Articles

Pomegranate juice recuperates N’-Nitrosodiethylamine-induced kidney injury: evidence from biochemical and histological approaches

BackgroundPomegranate is considered as one of the oldest elixirs having various properties. Renal fibrosis is a preliminary sign of pathological degradation in most ailments related to kidney. Several efforts have been made for the discovery of cost-effective and safe therapeutics for the alleviation of renal diseases. There is a major dearth of studies on the action of pomegranate juice (PGJ) against NDEA-instigated kidney injury. This study investigates the protective and antifibrotic action of PGJ in restricting the occurrence of experimental renal fibrosis in Wistar rats. Renal injury was generated by a single intraperitoneal dose of 10 ml kg−1 b.wt. (1% NDEA stock), while fresh PGJ (i.p.) in doses of 2 ml kg−1 b.wt was administered thrice a week on alternate days for two weeks to observe amelioration. The renal function indices (blood urea, creatinine, and uric acid), SOD, CAT, LPO levels and renal anatomy (H&E, MT, Picrosirius and SEM) were investigated.ResultsThe assessment of renal function demonstrates augmented levels of blood urea, creatinine and uric acid in NDEA-administered groups in comparison with controls. SOD, CAT declined significantly in NDEA Day-7- and Day-14-treated animals, while the MDA levels raised by ~ 70.5% and ~ 76.3% in these groups, respectively. However, supplementation of PGJ provided recuperation from these elevated levels in injured groups. H&E staining of the controls exhibited normal renal structure with intact glomerulus and Bowman’s capsule, while NDEA generated congestion of glomerular tuft, convoluted tubules with cloudy swelling and multiple subsidence of the renal tissue. Noticeable presence of collagen fibers in the interstitium of cortex region of kidney was observed by MT staining along with gross ultrastructural deterioration in NDEA-administered animals by electron microscopy. PGJ supplementation exhibited restoration of renal anatomy and physiology.ConclusionsPomegranate may be considered as a potent nutraceutical to prevent NDEA-induced renal damage and may be included as a daily dietary supplement.

Intradermal Injection of a Thermoresponsive Polymeric Dexamethasone Prodrug (ProGel-Dex) Ameliorate Dermatitis in an Imiquimod (IMQ)-Induced Psoriasis-like Mouse Model.

Psoriasis is a chronic immune-mediated inflammatory skin disease, affecting ∼ 3% of the US population. Although multiple new systemic therapies have been introduced for the treatment of psoriatic skin disease, topical and intralesional glucocorticoids (GCs) continue to be used as effective psoriasis therapies. Their clinical utility, however, has been hampered by significant adverse effects, including skin atrophy and pigmentation as well as elevated blood glucose levels and hypertension. To mitigate these limitations, we have developed a N-(2-hydroxypropyl) methacrylamide (HPMA) copolymer-based thermoresponsive dexamethasone (Dex) prodrug (ProGel-Dex) and assessed its therapeutic efficacy and safety in an imiquimod (IMQ)-induced psoriasis-like (PL) mouse model. ProGel-Dex was intradermally administered once at three dosing levels: 0.5, 1.0, and 2.0 mg/kg/day Dex equivalent at the beginning of the study. PL mice were also treated with daily topical saline or Dex, which were used as control groups. Treatment of PL mice with ProGel-Dex dosed at 0.5 mg/kg/day resulted in a significant reduction in scaling and erythema. Improvement in gross pathology scores, skin histological scores, and serum cytokine levels was also observed. Interestingly, for mice treated with ProGel-Dex at 1.0 and 2.0 mg/kg/day Dex equivalent, only improvement in skin erythema was observed. GC-associated side effects, such as elevation of serum alanine aminotransferase (ALT) and amylase levels and body weight loss, were not observed in mice treated with ProGel-Dex at 0.5 and 1.0 mg/kg/day Dex equivalent. Collectively, these results demonstrate the efficacy and improved safety of ProGel-Dex in treating psoriatic skin lesions when compared to topical Dex treatment, supporting its translational potential for clinical management of lesional skin psoriasis.

Efficacy and safety of Bacteroides fragilis BF839 for pediatric autism spectrum disorder: a randomized clinical trial.

The clinical utility of Bacteroides fragilis in treating autism spectrum disorder (ASD) remains unclear. Therefore, this randomized, double-blind, placebo-controlled study aimed to explore the therapeutic effects and safety of B. fragilis BF839 in the treatment of pediatric ASD. We examined 60 children aged 2-10 years diagnosed with ASD, and participants received either BF839 powder (10 g/bar with ≥106 CFU/bar of viable bacteria, two bars/day) or placebo for 16 weeks. The primary outcomes was Autism Behavior Checklist (ABC) score. The secondary outcomes were Childhood Autism Rating Scale (CARS), Social Responsiveness Scale (SRS), Normal Development of Social Skills from Infants to Junior High School Children (S-M), Gastrointestinal Symptom Rating Scale (GSRS) scores, and fecal microbiome composition. Assessments were performed on day 0 and at weeks 8 and 16. Compared with the placebo group, the BF839 group showed significant improvement in the ABC body and object use scores at week 16, which was more pronounced in children with ASD aged <4 years. Among children with a baseline CARS score ≥30, the BF839 group showed significant improvements at week 16 in the ABC total score, ABC body and object use score, CARS score, and GSRS score compared to the placebo group. Only two patients (6.67%) in the BF839 group experienced mild diarrhea. Compared with baseline and placebo group levels, the BF839 group showed a significant post-intervention increase in abundance of bifidobacteria and change in the metabolic function of neuroactive compounds encoded by intestinal microorganisms. BF839 significantly and safely improved abnormal behavior and gastrointestinal symptoms in children with ASD.

In-vivo Toxicity Evaluation of 3-(2-(3,4 dimethoxyphenyl)-2 oxoethylidene) Indolin-2-one (RAJI) in Zebrafish and Mice Model.

Breast cancer is a global health concern, with millions of cases reported annually worldwide, making it the most common cancer among women. In India, the incidence of breast cancer has been steadily rising, reflecting a growing public health challenge and hence in the development of new drug moieties. Toxicity analysis of such novel drug candidates play a critical role in drug development, ensuring the safety and efficacy of potential therapeutics. Animal models, especially mice and zebrafish in the recent days, have been extensively used for toxicity evaluation owing to their physiological and genetic similarities to humans. This study was hence conducted with an aim to assess the toxicity using animal models, particularly mice and zebrafish. In this study, 3-(2-(3,4-dimethoxyphenyl)-2-oxoethylidene)indolin-2-one (RAJI) - a chemically synthesised novel drug, was assessed for its toxicological potential in both zebrafish and mice models highlighting its survival, hatching, locomotor, neuromotor, behavioural abnormalities in zebrafish model and haematological and biochemical abnormalities in mice model. The results obtained emphasise that no significant damages were seen in both zebrafish (survival, hatching, locomotor, neuromotor, behavioural abnormalities) and mice (body weight, haematological and biochemical abnormalities) models when administered in low doses. All results obtained signifies that RAJI poses no harmful effects in the model organisms until administered in higher concentrations, thereby emphasising the fact that RAJI is a safe drug.

Role of Peripheral Parenteral Nutrition Composition on Clinical Outcomes in Patients Undergoing Gastrectomy or Colectomy: A Phase III Indian Clinical Trial.

Various types of parenteral nutritional products exist, each with specific formulations designed to meet the diverse nutritional needs of patient's post-abdominal surgery. Here, two different parenteral nutrition (PN) solutions BFLUID and NUTRIFLEX PERI are compared in terms of therapeutic efficacy and safety profile. A prospective, multi-center, randomized, parallel-group, non-inferiority Phase III clinical trial compared two PN solutions namely BFLUID (N = 78) and NUTRIFLEX PERI (N = 72) in 150 patients undergoing gastrectomy or colectomy. Primary endpoints included length of hospital stay while secondary endpoints included assessment and comparison of length of ICU/HDU stay, assessment of incidents of infections and mortality, change in blood levels of vitamin B1, change in nutritional parameters, thrombophlebitis, pain at the injection site, and recording of adverse events (AEs). There was no significant difference in terms of length of hospital stay, length of ICU/HDU stay as well as changes in nutritional parameters from baseline and change in blood levels of vitamin B1 from baseline. Both study groups exhibited comparability in terms of AEs, pain at the injection site, and the incidence of phlebitis. There was no significant difference in the number and severity of adverse events reported in both groups. Additionally, no signs of infection were observed in patients from either group. The trial successfully demonstrated the non-inferiority of BFLUID to NUTRIFLEX PERI. Moreover, the results indicated that PN enriched with high levels of branched-chain amino acids (BCAAs), essential amino acids (EAAs), and thiamine is both safe and efficacious for adult patients undergoing gastrectomy or colectomy. Goyal A, Pathak A, BS Madhu, Soni H, Bhatt K, Raju KVVN, et al. Role of Peripheral Parenteral Nutrition Composition on Clinical Outcomes in Patients Undergoing Gastrectomy or Colectomy: A Phase III Indian Clinical Trial. Indian J Crit Care Med 2024;28(9):871-878.

Traditional Medicine, Culture, and Psychedelic Science: New Pathways for Recovery From Substance Use Disorders.

This article provides an intercultural transdisciplinary perspective on the Indigenous roots of the resurging field of psychedelic science in the management of substance use disorders (SUDs). Ritual uses of entheogens (i.e., psychedelics of natural origin) are elaborate technologies for navigating, containing, and therapeutically directing non-ordinary states of consciousness induced by these compounds. A narrative review of the literature on the therapeutic potential of ayahuasca, peyote, psilocybin-containing mushrooms, Incilius alvarius-derived 5-MeO-DMT (5-methoxy-N,N-dimethyltryptamine), and iboga for the treatment of SUDs was conducted. This article also describes the application of some of these entheogens within a pilot intercultural clinical program implemented by the Yaqui tribe in Sonora, Mexico, for the treatment of SUDs and other mental health challenges. Observational research and preliminary clinical studies indicate the therapeutic potential and relative safety of these compounds in appropriate contexts, including the use of careful screening practices and complementary psychotherapeutic interventions. Preliminary research points to the potential therapeutic value of integrating entheogenic plant and fungi medicine with culturally attuned therapeutic strategies. Respectful intercultural dialogue across worldviews and scientific paradigms allows for the further development of new perspectives at the intersection of entheogens, addiction treatment, mental health, and traditional medicine. More interdisciplinary research is necessary in this field.

Unlocking the Potential of Drug Delivery Systems: A Comprehensive Review of Formulation Strategies and Technologies in the Field of Pharmaceutics

: The creation of innovative drug delivery systems to enhance therapeutic effectiveness, safety, and patient compliance has resulted in considerable developments in pharmaceutics in recent years. The most recent formulation techniques and technologies are reviewed in this article to improve medication distribution and accomplish specific therapeutic goals. : This article thoroughly summarizes the most recent formulation techniques and technologies used to enhance medication delivery and provide specific therapeutic effects. It discusses the variety of medication delivery methods, including nanoparticles, liposomes, micelles, and dendrimers, and explores the application of nanotechnology and biotechnology in drug delivery. Additionally, the paper emphasizes the significance of targeted drug delivery systems and their capacity to cross biological barriers including the blood-brain barrier and tumor microenvironment. : The review also addresses the challenges faced in developing and commercializing drug delivery systems and suggests potential solutions to overcome them. Furthermore, the article emphasizes the role of computational modeling and simulation in designing and optimizing drug delivery systems. : Overall, this review paper offers insightful information for pharmaceutics researchers, scientists, and practitioners that will help in the creation of novel drug delivery systems that improve patient outcomes and quality of life.

A retrospective evaluation of therapeutic efficacy and safety of chemoradiotherapy in older patients (aged ≥ 75 years) with limited-disease small cell lung cancer: insights from two institutions and review of the literature.

The standard treatment for patients in good general condition with limited-disease small cell lung cancer (LD-SCLC) is concurrent platinum/etoposide chemotherapy and thoracic radiotherapy (TRT). However, the efficacy and safety of chemoradiotherapy (CRT) in older patients with LD-SCLC has not been fully explored; moreover, the optimal treatment for this patient group remains unclear. This study aimed to investigate the feasibility and efficacy of CRT in older patients with LD-SCLC. From April 2007 to June 2021, consecutive older patients (aged ≥ 75 years) with stage I to III SCLC who received concurrent or sequential CRT at two institutions were retrospectively evaluated for efficacy and toxicity of CRT. A total of 32 older patients underwent concurrent (n = 19) or sequential (n = 13) CRT for LD-SCLC. The median ages of the patients in the concurrent and sequential CRT groups were 77 (range: 75-81) years and 79 (range: 76-92) years, respectively. The median number of chemotherapeutic treatment cycles was four (range, 1-5), and the response rate was 96.9% in all patients (94.7% in concurrent and 100% in sequential CRT groups). The median progression-free survival (PFS) and median overall survival (OS) for all patients were 11.9 and 21.1 months, respectively. The median PFS was 13.0 and 9.0 months in the concurrent CRT and sequential CRT groups, respectively, with no statistically significant difference (p = 0.67). The median OS from the initiation of CRT was 19.2 and 23.5 months in the concurrent and sequential CRT groups, respectively (p = 0.46). The frequencies of Grade ≥ 3 hematological adverse events were as follows: decreased white blood cell count, 20/32 (62.5%); decreased neutrophil count, 23/32 (71.9%); anemia, 6/32 (18.8%); decreased platelet count, 7/32 (21.9%); and febrile neutropenia, 3/32 (9.4%). Treatment-related deaths occurred in one patient from each group. Although hematological toxicities, particularly reduced neutrophil count, were severe, CRT showed favorable efficacy in both concurrent and sequential CRT groups. However, concurrent CRT may not be feasible for all older patients with LD-SCLC; accordingly, sequential CRT may be considered as a treatment of choice for these patients. Further prospective trials are warranted to identify optimal treatment strategies for this patient group.

S20-02 Maternal and maternal-fetal PBPK models for estimating therapeutic efficacy and safety in pregnancy

S20-02 Maternal and maternal-fetal PBPK models for estimating therapeutic efficacy and safety in pregnancy

A Comparative Analysis of Botulinum Toxin Use Versus Other Therapies for Temporomandibular Disorders: A Systematic Review.

Existing literature regarding the efficacy of Botulinum toxin A (BoNT-A) therapy in improving the clinical outcomes of temporomandibular disorders (TMDs) is ambiguous and lacks consistency. Thus, this study aimed to evaluate the efficacy of BoNT-A in reducing pain, occlusal force, electromyographic (EMG) changes, and maximum mouth opening compared with placebo and other interventions. An electronic database search was conducted using MEDLINE, PubMed, Google Scholar, the Cochrane Library, and ClinicalTrials.gov from January 2000 to June 2024 to identify randomized controlled trials (RCTs). A manual search complemented the electronic search. The Risk of Bias 2 (RoB 2) assessment was used to evaluate the internal validity of the included studies. A total of 1719 studies were identified, of which 23 fulfilled the inclusion criteria. Nineteen of these studies evaluated pain levels (primary outcome) after BoTN-A therapy, with six of them observing a decrease. In terms of secondary outcomes, seven of 10 studies noted an increase in maximum mouth opening, while all six reported a drop in EMG activity, and all four found a decrease in occlusal force following BoNT-A therapy.Muscle activity and biting force were significantly reduced in the therapeutic groups. Clinicians must consider these adverse events before treating patients with BoNT-A therapy. Additional regulatory guidelines and standardization of injection protocols are essential in improving therapeutic outcomes and patient safety. These findings suggest that BoNT-A may be a feasible option for TMD management but should be used with caution in clinical settings.

Current Pharmaceutical Strategies in the Management of Persistent Pulmonary Hypertension of the Newborn (PPHN): A Comprehensive Review of Therapeutic Agents.

Persistent Pulmonary Hypertension of the Newborn (PPHN) is a life-threatening condition characterized by the failure of normal circulatory transition after birth, leading to sustained pulmonary hypertension and severe hypoxemia. Despite advancements in neonatal care, PPHN remains a significant cause of morbidity and mortality among newborns, particularly in full-term and near-term infants. This review provides a comprehensive overview of current pharmaceutical strategies for managing PPHN, focusing on various therapeutic agents' mechanisms, efficacy, and safety. Key interventions include inhaled nitric oxide, which has become the standard treatment for reducing pulmonary vascular resistance, alongside prostacyclin analogs, phosphodiesterase inhibitors, and endothelin receptor antagonists. Additionally, extracorporeal membrane oxygenation (ECMO) is highlighted as a critical intervention for severe, refractory cases. The review also discusses emerging therapies and the potential role of personalized medicine in improving treatment outcomes. Despite the progress made, challenges remain, including the timely diagnosis of PPHN and the need for accessible treatments in resource-limited settings. As research continues to uncover the underlying pathophysiology of PPHN, it is crucial to develop more targeted and effective pharmaceutical strategies. This review aims to inform clinicians and researchers of the current state of PPHN management and the ongoing advancements that may shape future therapeutic approaches.

More efficient endoscopic submucosal dissection with deep endotracheal intubation for superficial cervical esophageal carcinoma: a dual-center, prospective, randomized controlled study

Deep endotracheal intubation (DET) has been proposed to improve cervical esophageal endoscopic submucosal dissection (ESD) because of the limited space and visibility. We aimed to evaluate the efficacy and safety of DET. In the current dual-center trial, patients were randomized into DET or conventional endotracheal intubation (CET) groups. Complete resection rate, operation time, and adverse events were measured and compared. Fifty-nine patients (60 lesions) were assigned to the groups, showing comparable baseline characteristics. The complete resection rates were similarly high in both groups. However, DET significantly reduced ESD operation time (52.2 minutes vs 71.1 minutes, P< .001) and postoperative pain scores (3.1 vs 4.7, P< .01). Severe stenosis occurred more frequently in the CET patients (20% vs 0%, P= .035). No significant differences were observed in other adverse events. DET can overcome technical challenges to improve therapeutic efficiency and safety. (Clinical trial registration number: NCT06420258.).

Systematic Review of the Efficacy and Safety of RSV-Specific Monoclonal Antibodies and Antivirals in Development.

Respiratory syncytial virus (RSV) is a leading cause of acute respiratory infection amongst all ages, causing a significant global health burden. Preventative and therapeutic options for RSV infection have long been under development, and recently, several widely-publicised vaccines targeting older adult and maternal populations have become available. Promising monoclonal antibody (mAb) and antiviral (AV) therapies are also progressing in clinical trials, with the prophylactic mAb nirsevimab recently approved for clinical use in infant populations. A systematic review on current progress in this area is lacking. We performed a systematic literature search (PubMed, Embase, Web of Science, ClinicalTrials.gov, EudraCT, ANZCTR-searched Nov 29th, 2023) to identify studies on all RSV-specific mAbs and AV therapies that has undergone human clinical trials since year 2000. Data extraction focused on outcomes related to the therapeutic efficacy and safety of the intervention on trial, and all studies were graded against the OCEBM Levels of Evidence Table. Results from 59 studies were extracted, covering efficacy and safety data on six mAbs (motavizumab, motavizumab-YTE, nirsevimab, ALX-0171, suptavumab, clesrovimab) and 12 AV therapies (ALN-RSV01, RSV604, presatovir, MDT-637, lumicitabine, IFN-α1b, rilematovir, enzaplatovir, AK0529, sisunatovir, PC786, EDP-938). Of the mAbs reviewed, nirsevimab and clesrovimab hold considerable promise. The timeline for RSV-specific AV availability is less advanced, although EDP-938 and AK0529 have reported promising phase 2 efficacy and safety data. Moving forward, passive immunisation and treatment options for RSV infection will play a significant role in reducing the health burden of RSV, complementing recent advancements in vaccine development. TRIAL REGISTRATION: PROSPERO registration: CRD42022376633.

Advancements in the use of nanopharmaceuticals for cancer treatment.

Advances in nanotechnology make it possible to specifically target therapies to cancer cells and neoplasms, guide the surgical resection of tumors, and optimize the effectiveness of radiological treatments. This research article provides a concise synthesis of current knowledge in the field of galenic pharmacy focused on targeted drug delivery in oncology. This research article synthesizes current knowledge in galenic pharmacy, focusing on targeted drug delivery in oncology and reviewing recent advancements in nanopharmaceuticals for cancer treatment. The data for this review are derived from a comprehensive analysis of the most cited scientific literature (Pubmed). Recent studies, clinical trials, and technological breakthroughs related to nanopharmaceuticals have been rigorously examined. This diverse source ensures a comprehensive representation of the latest developments in the field. The results highlight the emergence of nanopharmaceuticals as a promising approach to cancer treatment. The most common in oncology remain liposomes, nanopolymers, and nanocrystals. From a galenic point of view, these three forms offer a wide range of improvements compared to conventional forms such as improvement in solubility as well as stability. The same observation is in the clinic where treatment response rates are significantly improved. The most advantageous form will depend on the specific characteristics of each patient and each type of cancer. The precise design of nanocarriers allows for targeted drug delivery, enhancing therapeutic efficacy while reducing side effects. Concrete examples of clinical applications are presented, illustrating the practical potential of these advancements. In conclusion, this review provides a holistic overview of recent developments in galenic pharmacy for targeted drug delivery in oncology. The stability of nanocarriers is a crucial challenge because it conditions the effectiveness and safety of the drugs transported. Environmental and biological variations encountered in the body can compromise this stability, jeopardizing the therapeutic effectiveness and safety of treatments. Likewise, personalized approaches are essential to address interindividual variations in treatment response, as well as patients' pharmacogenomic profiles, in order to optimize therapeutic effectiveness and minimize adverse effects.

Using Quality by Design Tools to Study Gel Formulation from Brassica juncea Leaves and Conducting its In vitro, In vivo, Molecular Docking, and ADMET Analyses.

This research aims to create a gel formulation of Brassica juncea leaf extract and assess its anti-inflammatory properties using an in silico study. The anti-inflamma-tory activity has been compared with Diclofenac molecules in PDB id: 4Z69. Further, the Ab-sorption, Distribution, Metabolism, Excretion, and Toxicity analysis has been performed to en-sure the therapeutic potential and safety of the drug development process. The Quality by De-sign tool has been applied to optimize formulation development. The extracted gel is characterized by performing Fourier transformer infrared, zeta potential, particle size, Scanning Electron Microscope, and entrapment efficiency. Further, the formulation is evaluated by examining its viscosity, spreadability, and pH measurement. An In-vitro study of all nine extract suspensions was conducted to determine the drug contents at 276 nm. The optimized suspension has shown the maximum percentage of drug release (82%) in 10 hours of study. Animal study for anti-inflammatory activity was performed, and results of all five groups of animals compared the % inhibition of paw edema at three hours; gel (56.70 %), standard (47.86 %), and (39.72 %) were found. The research could conclude that the anti-inflammatory activity of gel formulation is high compared to extract, and a molecular docking study validates the anti-inflammatory ther-apeutic effects. ADMET analysis ensures the therapeutic effects and their safety.

Therapeutic efficacy and safety of artemether-lumefantrine combination therapy for the treatment of uncomplicated Plasmodium falciparum malaria at Teda Health Centre, Northwest Ethiopia, 2022/23

BackgroundThe emergence of Plasmodium falciparum drug resistance against artemisinin-based combination therapy has threatened malaria control efforts. Since malaria control and elimination plans are dependent on these drugs, they must remain efficacious. However, resistance to these drugs was detected in low-transmission settings and is predicted to emerge in high-transmission settings, including in unspecified areas of Ethiopia. Therefore, this study aimed to assess the therapeutic efficacy and safety of artemether-lumefantrine for the treatment of uncomplicated P. falciparum malaria.MethodsA single-arm prospective observational study was conducted at Teda Health Centre, Northwest Ethiopia, by following the 2009 World Health Organization efficacy study guidelines from September 2022 to February 2023. Patients with uncomplicated falciparum malaria were conveniently selected and treated with a standard dose of artemether-lumefantrine, along with a single low dose of primaquine. Then clinical and parasitological responses and haemoglobin levels were assessed during the 28-day scheduled follow-up. Blood films were examined and asexual parasites were quantified; axillary temperature was measured; and drug adverse events were assessed throughout the follow-up. Finally, the drug efficacy (adequate clinical and parasitological response) was determined by Kaplan–Meier and per-protocol analyses. The data were analysed using the WHO Excel spreadsheet and SPSS version 25 software.ResultsThe success rates of PCR uncorrected and corrected Kaplan–Meier analysis on day 28 were 95.8% (95% CI 87.5–98.6) and 97.3% (95% CI 89.4–99.3), respectively. The per-protocol PCR uncorrected and corrected adequate clinical and parasitological responses were 95.5% (95% CI 87.5–99.1) and 97% (95% CI 89.5–99.6), respectively. On day-3, 97% of study participants were free of asexual parasitaemia, and all of them were fever-free on day-2. All of the gametocyte-positive patients at baseline were found to be negative for gametocytes on day-2. Moreover, the baseline mean hemoglobin of 13.10 g/dl increased slightly on day-14 to 13.27 g/dl but significantly on day-28 to 13.69 g/dl in a paired sample t test. All adverse events reported were mild.ConclusionArtemether-lumefantrine continued to be an efficacious and safe drug for the treatment of uncomplicated Plasmodium falciparum malaria at the Teda Health Centre.Trial registration: unique ID# PACTR202309773069812 at https://pactr.samrc.ac.za on September 1, 2023.

Synthesis and In-Vitro and In-Silico Investigation of Pyrazole Derivatives as Antibacterial and Antifungal Agents

Background: Heterocyclic compounds with O, N, and/or S atoms are highly valuable in drug discovery and development. Their pyrazole moieties find applications in various fields, such as herbicides, corrosion inhibitors, electron transport materials, polymers, and luminescent materials. Consequently, there is a pressing need in medicinal chemistry to develop new antibacterial agents to enhance therapeutic efficacy and safety. Methods: A newer biologically active 1-(4-substitutedphenyl)-5-chloro-3-methyl-1Hpyrazole-4-carboxylic acid analogue was synthesized by the para-substituted phenylhydrazine. All the synthesized compounds were characterized by NMR, mass spectral, and IR spectrum examinations, as well as C, H, and N analyses. The synthesized compounds were screened for antibacterial and antifungal activities. Furthermore, a molecular docking study was performed to elucidate the binding modes of synthesized ligands in the active pockets of DNA gyrase and CYP51 (PDB IDs: 4uro and 5tz1, respectively) for exhibiting the binding modes and predicting the mechanism of action of synthesized ligands. Results: Five compounds (2Rb, 2Re, 2Rg, 2Rh, and 2Ri) demonstrated significant antibacterial action against gram-positive B. subtilis and gram-negative E. coli and antifungal activity against C. albicans and A. niger compared to the standard drugs cefixime and ketoconazole. Furthermore, molecular docking was employed to reveal how the newly synthesized ligands bind within the active pockets. It was found that compound 2Rb demonstrated significant antibacterial activity, and compound 2Rg had good antifungal activity. Conclusion: The current study highlights the unique structural characteristics and significant biological activity of the synthesized compounds. In the pursuit of novel antibacterial and antifungal molecules, these compounds could prove beneficial to society.

Polymer-locking fusogenic liposomes for glioblastoma-targeted siRNA delivery and CRISPR-Cas gene editing.

In patients with glioblastoma (GBM), upregulated midkine (MDK) limits the survival benefits conferred by temozolomide (TMZ). RNA interference (RNAi) and CRISPR-Cas9 gene editing technology are attractive approaches for regulating MDK expression. However, delivering these biologics to GBM tissue is challenging. Here we demonstrate a polymer-locking fusogenic liposome (Plofsome) that can be transported across the blood-brain barrier (BBB) and deliver short interfering RNA or CRISPR-Cas9 ribonucleoprotein complexes into the cytoplasm of GBM cells. Plofsome is designed by integrating a 'lock' into the fusogenic liposome using a traceless reactive oxygen species (ROS)-cleavable linker so that fusion occurs only after crossing the BBB and entering the GBM tissue with high ROS levels. Our results showed that MDK suppression by Plofsomes significantly reduced TMZ resistance and inhibited GBM growth in orthotopic brain tumour models. Importantly, Plofsomes are effective only at tumour sites and not in normal tissues, which improves the safety of combined RNAi and CRISPR-Cas9 therapeutics.

Comparison of obinutuzumab and rituximab for treating primary membranous nephropathy.

This study compared the effectiveness and safety profiles of obinutuzumab and rituximab in the treatment of patients with primary membranous nephropathy. Patients with primary membranous nephropathy who had urine protein ≥ 3.5 g/24 hours and estimated glomerular filtration rate (eGFR) ≥30 mL/min/1.73 m2 despite six months of angiotensin-converting enzyme inhibitor/angiotensin II receptor blocker and treatment with obinutuzumab or rituximab were included and matched by propensity score (ratio: 1:2) based on age, sex, urine protein, eGFR, and titers of Anti-Phospholipase A2 receptor (PLA2R) antibody. The primary outcome was defined as a combination of partial or complete remission at 12 months. Logistic regression models, Kaplan Meier curves, and absolute risk differences were employed to compare the therapeutic effectiveness and safety profiles of obinutuzumab and rituximab. Sixty-three patients with primary membranous nephropathy were included in the study, with 21 patients receiving obinutuzumab and 42 patients receiving rituximab. At 12 months, the primary outcome was achieved in 20 of 21 patients in the obinutuzumab group and 28 of 42 patients in the rituximab group (obinutuzumab vs. rituximab: 95% vs. 67%; odds ratio (OR): 10.00, 95% confidence intervals (CI):1.21-82.35, P=0.03). Moreover, patients in the obinutuzumab group acquired more complete remission (obinutuzumab vs. rituximab: 38% vs. 14%; OR: 3.69, 95% CI:1.08-12.68, P=0.04). In PLA2R-associated primary membranous nephropathy subgroup analyses, patients in obinutuzumab group sustained lower CD19 B cell counts (CD19 B cell counts: median (IQR) 0 (0-6) cells/ul vs. 20 (3-58) cells/ul, P=0.002) and were more prone to achieve immunological remission (defined as PLA2R antibody <2 RU/ml) at six months [obinutuzumab vs. rituximab: 92% (12 out of 13) vs. 64% (16 out of 25), P=0.06] than rituximab. Both treatment regimens were well tolerated. Our study demonstrated that obinutuzumab is associated with higher odds of clinical remission compared to rituximab at 12 months which may be due to higher immunological remission at six months with a similar safety profile in patients with primary membranous nephropathy.

An oil-in-gel type of organohydrogel loaded with methylprednisolone for the treatment of secondary injuries following spinal cord traumas

The secondary injuries following traumatic spinal cord injury (SCI) is a multiphasic and complex process that is difficult to treat. Although methylprednisolone (MP) is the only available pharmacological regime for SCI treatment, its efficacy remains controversial due to its very narrow therapeutic time window and safety concerns associated with high dosage. In this study, we have developed an oil-in-gel type of organohydrogel (OHG) in which the binary oleic-water phases coexist, for the local delivery of MP. This new OHG is fabricated by a glycol chitosan/oxidized hyaluronic acid hydrophilic network that is uniformly embedded with a biocompatible oil phase, and it can be effectively loaded with MP or other hydrophobic compounds. In addition to spatiotemporally control MP release, this biodegradable OHG also provides a brain tissue-mimicking scaffold that can promote tissue regeneration. OHG remarkably decreases the therapeutic dose of MP in animals and extends its treatment course over 21 d, thereby timely manipulating microglia/macrophages and their associated with signaling molecules to restore immune homeostasis, leading to a long-term functional improvement in a complete transection SCI rat model. Thus, this OHG represents a new type of gel for clinical treatment of secondary injuries in SCI.