Neuroprotective potential of topiramate, pregabalin and lacosamide combination in a rat model of acute SE and intractable epilepsy: Perspectives from electroencephalographic, neurobehavioral and regional degenerative analysis.

The lithium-pilocarpine model is commonly used to recapitulate characteristics of human intractable focal epilepsy. In the current study, we explored the impact of topiramate (TPM) alone and in combination with pregabalin and lacosamide administration for 6 weeks on the evolution of spontaneous recurrent seizures (SRS) and disease-modifying potential on associated neuropsychiatric comorbidities. In addition, redox impairments and neurodegeneration in hippocampus regions vulnerable to temporal lobe epilepsy (TLE) were assessed by cresyl violet staining. Results revealed that acute electrophysiological (EEG) profiling of the ASD cocktail markedly halted sharp ictogenic spikes as well as altered dynamics of brain wave oscillations thus validating the need for polytherapy vs. monotherapy. In TLE animals, pharmacological intervention for 6 weeks with topiramate 10 mg/kg in combination with PREG and LAC at the dose of 20 mg/kg exhibited marked protection from SRS incidence, improved body weight, offensive aggression, anxiety-like behavior, cognitive impairments, and depressive-like behavior (p < 0.05). Moreover, combination therapy impeded redox impairments as evidenced by decreased MDA and AchE levels and increased activity of antioxidant SOD, GSH enzymes. Furthermore, polytherapy rescued animals from SE-induced neurodegeneration with increased neuronal density in CA1, CA3c, CA3ab, hilus, and granular cell layer (GCL) of the dentate gyrus. In conclusion, early polytherapy with topiramate in combination with pregabalin and lacosamide prompted synergy and prevented epileptogenesis with associated psychological and neuropathologic alterations.

Neuroprotective Effect of Brivaracetam and Perampanel Combination on Electrographic Seizures and Behavior Anomalies in Pentylenetetrazole-Kindled Mice.

Pentylenetetrazole (PTZ)-induced kindling is a broadly used experimental model to study the anticonvulsive potential of new and existing chemical moieties with the aim of discovering drugs hindering seizure progression and associated neurological comorbidities. In the present study, the impact of brivaracetam (BRV) (10 and 20 mg/kg) as monotherapy as well as in combination with 0.25 mg/kg of perampanel (PRP) was investigated on seizure progression with simultaneous electroencephalographic changes in PTZ kindling mouse model. Subsequently, mice were experimentally analyzed for anxiety, cognition, and depression after which their brains were biochemically evaluated for oxidative stress. The outcomes demonstrated that BRV alone delayed the kindling process, but BRV + PRP combination significantly (p < 0.0001) protected the mice from seizures of higher severity and demonstrated an antikindling effect. The PTZ-kindled mice exhibited anxiety, memory impairment, and depression in behavioral tests, which were remarkably less (p < 0.001) in animals treated with drug combination (in a dose-dependent manner) as these mice explored central, illuminated, and exposed zones of open-field test, light/dark box, and elevated plus maze. Moreover, memory impairment was demonstrated by kindled mice, which was significantly (p < 0.001) protected by BRV + PRP as animal's spontaneous alteration, object discrimination, and step-through latencies were increased in various tests employed for the assessment of cognitive abilities. The brains of PTZ-kindled mice had increased malondialdehyde and reduced antioxidant enzymes while treatment with BRV + PRP combination prevented kindling-induced elevation in oxidative markers. The outcomes of this study demonstrate that combining the PRP at low dose augmented the antiseizure properties of BRV as both drugs when administered simultaneously hindered the process of kindling by reducing PTZ-induced excessive electrical activity and oxidative stress in the brain.

Impact of bevacizumab on clinical outcomes and its comparison with standard chemotherapy in metastatic colorectal cancer patients: a systematic review and meta-analysis.

Background: Advances in targeted therapies have expanded the treatment options for colorectal cancer (CRC), allowing for more tailored and effective approaches to managing the disease. In targeted therapy, Bevacizumab is a commonly prescribed anti-VEGF monoclonal antibody that has a direct anti-vascular impact in cancer patients. Vascular Endothelial Growth Factors (VEGFs), especially VEGF-A, are significant agents in promoting tumour angiogenesis. Objective: To assess the impact of adding Bevacizumab to chemotherapy on progression-free survival (PFS) and overall survival (OS) in patients with metastatic colorectal cancer. Methodology: Comprehensive searches have been performed on electronic databases such as PubMed, and Google Scholar using the following terms: colorectal cancer, adenocarcinoma, Bevacizumab, chemotherapy, and monoclonal antibody. Results: In the meta-analysis, 16 out of the 24 included studies were analysed. In the final analysis, incorporating Bevacizumab with chеmothеrapy demonstrated favourable outcomes for OS with a hazard ratio (HR = 0.689,95%CI: 0.51-0.83, I² = 39%, p <0.01) and for PFS with a hazard ratio (HR = 0.77 95% CI: 0.60-0.96, I² = 54%, p < 0.01). The subgroup analysis of PFS, categorised by study dеsign (prospеctivе vs rеtrospеctivе), reveals that the Hazard Ratio (HR = 0.82, 95% CI: 0.62-0.97, I² = 21%, p < 0.01) and for OS with a hazard ratio (HR = 0.73, 95% CI: 0.52-0.86, I² = 17%, p < 0.01). Conclusion: Our findings indicate that combining Bevacizumab with chemotherapy enhances clinical outcomes and results in a significant increase in PFS and OS in patients with metastatic colorectal cancer. Positive outcomes are demonstrated by a substantial 23% increase in PFS and 31% increase in OS in patients with metastatic colorectal cancer who undergo Bevacizumab in conjunction with chemotherapy.

Investigating clinical pharmacokinetics of brivaracetam by using a pharmacokinetic modeling approach.

The development of technology and the processing speed of computing machines have facilitated the evaluation of advanced pharmacokinetic (PK) models, making modeling processes simple and faster. The present model aims to analyze the PK of brivaracetam (BRV) in healthy and diseased populations. A comprehensive literature review was conducted to incorporate the BRV plasma concentration data and its input parameters into PK-Sim software, leading to the creation of intravenous (IV) and oral models for both populations. The developed physiologically based pharmacokinetic (PBPK) model of BRV was then assessed using the visual predictive checks, mean observed/predicted ratios (Robs/pre), and average fold error for PK parameters including the maximum systemic concentration (Cmax), the area under the curve at time 0 to t (AUC0-∞), and drug clearance (CL). The PBPK model of BRV demonstrated that mean Robs/pre ratios of the PK parameters remained within the acceptable limits when assessed against a twofold error margin. Furthermore, model predictions were carried out to assess how AUC0-∞ is affected following the administration of BRV in individuals with varying degrees of liver cirrhosis, ranging from different child-pugh (CP) scores like A, B, and C. Moreover, dose adjustments were recommended by considering the variations in Cmax and CL in various kidney disease stages (mild to severe).

Electrolyte disturbances in patients hospitalized for COVID-19 infection: An observational study.

There are multiple mechanisms by which The Coronavirus-19 (COVID-19) infection can cause electrolyte abnormalities, which may not be the case for bacterial causes of pneumonia. This study aimed to assess the differences in electrolyte levels between patients suffering from COVID-19 and bacterial pneumonia. This is an original, retrospective study. Two cohorts of hospitalized patients were included, 1 suffering from COVID-19 and the other from bacterial pneumonia. Their day 1 and day 3 levels of sodium, potassium, magnesium, and phosphorus, as well as their outcomes, were extracted from the charts. Statistical analysis was subsequently performed. Mean admission levels of sodium, potassium, phosphorus, and magnesium were 135.64 ±â€…6.13, 4.38 ±â€…0.69, 3.53 ±â€…0.69, and 2.03 ±â€…0.51, respectively. The mean day 3 levels of these electrolytes were 138.3 ±â€…5.06, 4.18 ±â€…0.59, 3.578 ±â€…0.59, and 2.11 ±â€…0.64, respectively. Patients suffering from bacterial pneumonia were significantly older (N = 219, mean = 64.88 ±â€…15.99) than patients with COVID-19 pneumonia (N = 240, mean = 57.63 ±â€…17.87). Bacterial pneumonia group had significantly higher serum potassium (N = 211, mean = 4.51 ±â€…0.76), and magnesium (N = 115, mean = 2.12 ±â€…0.60) levels compared to COVID-19 group (N = 227, mean = 4.254 ±â€…0.60 for potassium and N = 118, mean = 1.933 ±â€…0.38 for magnesium). Only magnesium was significantly higher among day 3 electrolytes in the bacterial pneumonia group. No significant association between electrolyte levels and outcomes was seen. We found that COVID-19 patients had lower potassium and magnesium levels on admission, possibly due to the effect of COVID-19 on the renin-angiotensin-aldosterone system as well as patient characteristics and management. We did not find enough evidence to recommend using electrolyte levels as a determinator of prognosis, but more research is needed.

Attitudes toward COVID-19 vaccination among urogynecology patients.

Objective: Urogynecology patients skew older and often require intimate exams to treat non-life-threatening conditions, thus making care particularly susceptible to the effects of COVID-19. We aim to understand COVID-19 vaccination attitudes amongst urogynecology patients during the pandemic, which has adversely affected healthcare delivery, to identify measures that can be undertaken to improve care going forward. Study design: Cross-sectional surveys of urogynecology patients were conducted in three different states (Delaware, New Jersey, and Pennsylvania) between March and August 2021. Demographics, vaccination status, and COVID-19 attitudes were analyzed. Chi-square tests investigated group differences between vaccine-hesitant and unhesitant subjects. Results: Out of 158 surveys, eighty-three percent of respondents were vaccinated or planning to get vaccinated. Older age and regular flu vaccination predicted COVID-19 vaccination. Ninety-three percent of subjects were comfortable attending in-person visits. However, vaccine-hesitant individuals were less comfortable attending in-person and were significantly less likely to be comforted by clinic interventions, such as masking. Hesitant and unhesitant groups trusted doctors or medical professionals most for their source of COVID-19 information. Conclusions: Urogynecology patients mirror the general older population's COVID-19 vaccination attitudes, with distinct differences between hesitant and unhesitant groups. Vaccine-hesitant subjects appear less comfortable coming to in-person visits and less comforted by possible interventions, posing a difficult obstacle for clinics to overcome. High levels of patient trust suggest healthcare providers can play a crucial role in encouraging COVID-19 vaccination and combating misinformation.

Correction: Zaman et al. Synthesis and Evaluation of Thiol-Conjugated Poloxamer and Its Pharmaceutical Applications. Pharmaceutics 2021, 13, 693.

In the original publication, there was a mistake in one author name, Mohammed Alasmari should be Mohammed S [...].

Resolution of severe gastroparesis induced by parasympathetic surge following facial trauma: a case report.

BACKGROUND: Gastroparesis is a condition that affects the motility of the gastrointestinal (GI) tract, causing a delay in the emptying process and leading to nausea, vomiting, bloating, and upper abdominal pain. Motility treatment along with symptom management can be done using antiemetics or prokinetics. This study highlights the diagnostic and therapeutic challenges of gastroparesis and suggests a potential link between facial trauma and symptom remission, indicating the need for further investigation. CASE PRESENTATION: A 46-year-old Hispanic man with hypertension, type 2 diabetes (T2D), and hyperlipidemia on amlodipine 10 mg, lisinopril 5 mg, empagliflozin 25 mg, and insulin glargine presented with a diabetic foot ulcer with probable osteomyelitis. During hospitalization, the patient developed severe nausea and vomiting. The gastroenterology team advised continuing antiemetic medicine and trying very small sips of clear liquids. However, the patient didn't improve. Therefore, the gastroenterology team was contacted again. They advised having stomach emptying tests to rule out gastroparesis as the source of emesis. In addition, they recommended continuing metoclopramide, and starting erythromycin due to inadequate improvement. Studies found a 748-min stomach emptying time. Normal is 45-90 min. An uneventful upper GI scope was done. Severe gastroparesis was verified, and the gastroenterology team advised a percutaneous jejunostomy or gastric pacemaker for gastroparesis. Unfortunately, the patient suffered a mechanical fall resulting in facial trauma. After the fall, the patient's nausea eased, and emesis stopped. He passed an oral liquids trial after discontinuation of erythromycin and metoclopramide. CONCLUSION: This case exemplifies the difficulties in diagnosing and treating gastroparesis. An interesting correlation between parasympathetic surges and recovery in gastroparesis may be suggested by the surprising remission of symptoms following face injuries.

Levofloxacin loaded chitosan and poly-lactic-co-glycolic acid nano-particles against resistant bacteria: Synthesis, characterization and antibacterial activity.

BACKGROUND: With the global increase in antibacterial resistance, the challenge faced by developing countries is to utilize the available antibiotics, alone or in combination, against resistant bacterial strains. We aimed to encapsulate the levofloxacin (LVX) into polymeric nanoparticles using biodegradable polymers i.e. Chitosan and PLGA, estimating their physicochemical characteristics followed by functional assessment as nanocarriers of levofloxacin against the different resistant strains of bacteria isolated from biological samples collected from tertiary care hospital in Lahore, Pakistan. METHODS: LVX-NPs were synthesized using ion gelation and double emulsion solvent-evaporation method employing chitosan (CS) and poly-lactic-co-glycolic acid (PLGA), characterized via FTIR, XRD, SEM, and invitro drug release studies, while antibacterial activity was assessed using Kirby-Bauer disc-diffusion method. RESULTS: Data revealed that the levofloxacin-loaded chitosan nanoparticles showed entrapment efficiency of 57.14% ± 0.03 (CS-I), 77.30% ± 0.08(CS-II) and 87.47% ± 0.08 (CS-III). The drug content, particle size, and polydispersity index of CS-I were 52.22% ± 0.2, 559 nm ± 31 nm, and 0.030, respectively, whereas it was 66.86% ± 0.17, 595 nm ± 52.3 nm and 0.057, respectively for CS-II and 82.65% ± 0.36, 758 nm ± 24 nm and 0.1, respectively for CS-III. The PLGA-levofloxacin nanoparticles showed an entrapment efficiency of 42.80% ± 0.4 (PLGA I) and 23.80% ± 0.4 (PLGA II). The drug content, particle size and polydispersity index of PLGA-I were 86% ± 0.21, 92 nm ± 10 nm, and 0.058, respectively, whereas it was 52.41% ± 0.45, 313 nm ± 32 nm and 0.076, respectively for PLGA-II. The XRD patterns of both polymeric nanoparticles showed an amorphous nature. SEM analysis reflects the circular-shaped agglomerated nanoparticles with PLGA polymer and dense spherical nanoparticles with chitosan polymer. The in-vitro release profile of PLGA-I nanoparticles showed a sustained release of 82% in 120 h and it was 58.40% for CS-III. Both types of polymeric nanoparticles were found to be stable for up to 6 months without losing any major drug content. Among the selected formulations, CS-III and PLGA-I, CS-III had better antibacterial potency against gram+ve and gram-ve bacteria, except for K. pneumonia, yet, PLGA-I demonstrated efficacy against K. pneumonia as per CSLI guidelines. All formulations did not exhibit any signs of hemotoxicity, nonetheless, the CS-NPs tend to bind on the surface of RBCs. CONCLUSION: These data suggested that available antibiotics can effectively be utilized as nano-antibiotics against resistant bacterial strains, causing severe infections, for improved antibiotic sensitivity without compromising patient safety.

Recent developments in targeting breast cancer stem cells (BCSCs): a descriptive review of therapeutic strategies and emerging therapies.

Despite recent advancements in the diagnosis and treatment of breast cancer (BC), patient outcomes in terms of survival, recurrence, and disease progression remain suboptimal. A significant factor contributing to these challenges is the cellular heterogeneity within BC, particularly the presence of breast cancer stem cells (BCSCs). These cells are thought to serve as the clonogenic nexus for new tumor growth, owing to their hierarchical organization within the tumor. This descriptive review focuses on the evolving strategies to target BCSCs, which have become a pivotal aspect of therapeutic development. We explore a variety of approaches, including targeting specific tumor surface markers (CD133 and CD44), transporters, heat shock proteins, and critical signaling pathways like Notch, Akt, Hedgehog, KLF4, and Wnt/ß-catenin. Additionally, we discuss the modulation of the tumor microenvironment through the CXCR-12/CXCR4 axis, manipulation of pH levels, and targeting hypoxia-inducible factors, vascular endothelial growth factor, and CXCR1/2 receptors. Further, this review focuses on the roles of microRNA expression, strategies to induce apoptosis and differentiation in BCSCs, dietary interventions, dendritic cell vaccination, oncolytic viruses, nanotechnology, immunotherapy, and gene therapy. We particularly focused on studies reporting identification of BCSCs, their unique properties and the efficacy of various therapeutic modalities in targeting these cells. By dissecting these approaches, we aim to provide insights into the complex landscape of BC treatment and the potential pathways for improving patient outcomes through targeted BCSC therapies.

Relation of poverty with treatment-seeking behavior and antibiotic misuse among UTI patients in Pakistan.

Objective: The current study aimed to assess the relation between multi-dimension poverty, treatment-seeking behavior, and antibiotic misuse among urinary tract infection (UTI) patients. Method: A cross-sectional approach was utilized to recruit patients who had a history of UTI in the previous month from two provinces of Pakistan. The treatment-seeking behavior and antibiotic misuse data were collected on a self-developed questionnaire, whereas the poverty data were collected on a modified multi-dimension poverty index (MPI). Descriptive statistics were applied to summarize the data. The logistic regression analysis was carried out to assess the association of multi-dimension poverty with patient treatment-seeking behavior and antibiotic misuse. Results: A total of 461 participants who had UTI symptoms in the previous month were recruited. Most of the participants in the severely deprived stage treated the UTI (p < 0.001); however, there was a high proportion of the participants who consulted with friends and family for UTI treatment (p < 0.001). The patients with deprivation status (deprived and severely deprived) were less associated with formal consultation. The poorer subgroups were less likely to practice antibiotic course completion. Conclusion: The current study highlighted that poverty plays an important role in antibiotic misuse. Poorer subgroups were associated with informal consultations and the incompletion of the antibiotic course. Further studies are needed to explore the potential role of poverty in treatment-seeking behavior and antibiotic misuse.

Landiolol for Treating Arrhythmias: A State-of-The-Art Review.

This article provides a state-of-the-art review on landiolol, a medication that was recently submitted for 7 approvals. Focusing on its pharmacology, pharmacokinetics, and pharmacodynamics, the analysis underscores landiolol's unique attributes compared to conventional beta-blockers, particularly esmolol. As a sympatholytic agent, landiolol exhibits a short half-life, high cardioselectivity, and minimal impact on blood pressure, setting it apart in the realm of arrhythmia treatment. The review explores landiolol's potential applications, emphasizing scenarios where other beta-blockers may be limited. A detailed examination of its efficacy in preventing postoperative atrial fibrillation reveals promising results from clinical trials, suggesting its utility in diverse surgical settings. Additionally, the article delves into landiolol's role in rate control for atrial fibrillation/flutter, treatment of ventricular tachycardia/fibrillation, and its use in managing sepsis-related tachyarrhythmias. The evolving landscape of landiolol's applications extends beyond cardiac care, including potential anti-inflammatory, antioxidative, analgesic, and anticancer effects. While the outcomes from various studies are promising, challenges persist, requiring further research to optimize dosing strategies, identify optimal patient populations, and elucidate mechanisms underlying its diverse effects. The potential expansion of landiolol's applications highlights the importance of ongoing clinical investigation, offering a promising avenue for enhancing arrhythmia management and addressing broader medical needs.

Exploring the pharmacokinetics of second-generation cephalosporin, cefaclor: a systematic review in healthy and diseased populations.

Cefaclor is a bactericidal antibiotic recommended for treating diverse types of infections. This review aims to comprehensively assess the pharmacokinetic (PK) data on cefaclor in humans.Google Scholar, PubMed, Cochrane Library, and EBSCO databases were systematically performed to identify all the relevant studies containing at least one reported PK parameter of cefaclor.Cefaclor shows the linear PK profile as the area under the plasma concentration-time curve from 0 to t (AUC0-t) and maximum plasma concentration (Cmax) increase in a dose-dependent manner. The AUC0-t of cefaclor in the rice diet was found to be higher than that of bread food, i.e. 19.9 ± 2.6 ug/ml.hr vs 15.4 ± 4 ug/ml.hr. The AUC in paediatrics during the fed state was significantly higher compared to that in adults. Patients with renal impairments showed a Cmax 2.2 times higher than that of normal subjects. A significant increase in Cmax was depicted among individuals following a vegetarian diet in comparison with the non-vegetarian diet. Moreover, cefaclor exhibits time-dependent killing above the minimum inhibitory concentration (MIC < 2 ug), favouring its use in treating infections caused by specific pathogens.This systematic review summarises all the reported PK parameters of cefaclor in healthy and diseased subjects in the literature. This data can help practitioners in adjusting cefaclor doses among different diseases and populations to avoid drug interactions and adverse effects.

A Comprehensive Physiologically Based Pharmacokinetic Model of Nadolol in Adults with Renal Disease and Pediatrics with Supraventricular Tachycardia.

Nadolol is a long-acting non-selective ß-adrenergic antagonist that helps treat angina and hypertension. The current study aimed to develop and validate the physiologically based pharmacokinetic model (PBPK) of nadolol in healthy adults, renal-compromised, and pediatric populations. A comprehensive PBPK model was established by utilizing a PK-Sim simulator. After establishing and validating the model in healthy adults, pathophysiological changes i.e., blood flow, hematocrit, and GFR that occur in renal failure were incorporated in the developed model, and the drug exposure was assessed through Box plots. The pediatric model was also developed and evaluated by considering the renal maturation process. The validation of the models was carried out by visual predictive checks, calculating predicted to observed (Rpre/obs) and the average fold error (AFE) of PK parameters i.e., the area under the concentration-time curve (AUC0-t), the maximum concentration in plasma (Cmax), and CL (clearance). The presented PBPK model successfully simulates the nadolol PK in healthy adults, renal-impaired, and pediatric populations, as the Rpre/obs values of all PK parameters fall within the acceptable range. The established PBPK model can be useful in nadolol dose optimization in patients with renal failure and children with supraventricular tachycardia.

Intrapericardial Diaphragmatic Hernia Following the Convergence Procedure for Atrial Fibrillation.

This case report highlights a very rare variant of diaphragmatic hernia, namely, an intrapericardial diaphragmatic hernia, which can arise as a complication of the convergence procedure. A 77-year-old man, presenting with chronic shortness of breath and fatigue, was unexpectedly found to have herniation of the transverse colon into the pericardial cavity through a diaphragmatic-pericardial defect. The diaphragmatic defect was repaired with mesh via robotic surgery. The patient reported resolution of his symptoms at the six-month follow-up.

A Systematic Review of the Economic Burden of Diabetes in Eastern Mediterranean Region Countries.

Diabetes Mellitus (DM) is a highly prevalent non-communicable disease with high mortality and morbidity, which imposes a significant financial impact on individuals and the healthcare system. The identification of various cost components through cost of illness analysis could be helpful in health-care policymaking. The current systematic review aims to summarize the economic burden of DM in the Eastern Mediterranean Region (EMR) countries. The original studies published in the English language between January 2010 and June 2023 reported the cost of DM was identified by searching four different databases (Google Scholar, PubMed, Science Direct, and Cochrane Central). Two reviewers independently screened the search results and extracted the data according to a predefined format, whereas the third reviewer's opinion was sought to resolve any discrepancies. The costs of DM reported in the included studies were converted to USD dates reported in the studies. After the systematic search and screening process, only 10 articles from EMR countries met the eligibility criteria to be included in the study. There are substantial variations in the reported costs of DM and the methodologies used in the included studies. The mean annual cost per patient of DM (both direct and indirect cost) ranged from 555.20 USD to 1707.40 USD. The average annual direct cost ranged from 155.8 USD to 5200 USD and indirect cost ranged from 93.65 USD to 864.8 USD per patient. The studies included in the review obtained a median score of 8.65 (6.5 ─ 11.5) on the quality assessment tool based on Alison's checklist for evaluation of cost of illness studies. There is a significant economic burden associated with DM, which directly affects the patients and healthcare system. Future research should focus on refining cost estimation methodologies, improving the understanding of study findings, and making it easier to compare studies.

Tuberculosis (TB) treatment challenges in TB-diabetes comorbid patients: a systematic review and meta-analysis.

BACKGROUND: The Directly Observed Treatment-Short Course (DOTS) Programme was implemented by WHO and includes a combination of four anti-tuberculosis (TB) drugs (isoniazid, pyrazinamide, ethambutol and rifampicin) for a period of six months to eradicate the TB infection completely. Diabetes mellitus (DM) is recognized as one of a strong contributor of TB according to World Health Organization (WHO). The presence of diabetes mellitus type 2 (DM type 2) makes TB treatment complicated. Thus, the objective of the current meta-analysis was to identify and quantify the impact of type 2 DM on treatment outcomes of TB patients treated under the DOTS Programme. METHODS: This meta-analysis was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Through a systematic review of relevant literature, we focused on studies investigating treatment outcomes including extended treatment duration and recurrence for individuals with both TB and DM undergoing DOTS therapy. The extracted information included study designs, sample sizes, patient characteristics and reported treatment results. RESULTS: In 44 studies from different parts of the world, the pooled HR for the impact of DM on extended treatment duration and reoccurrence were HR 0.72, 95% CI 0.56-0.83, p < .01 and HR 0.93, 95% CI 0.70-1.04, p = .08, respectively. The pooled HR for impact of DM on composite TB treatment outcomes was calculated as 0.76 (95% CI 0.60-0.87), p < .01 with an effect size of 41.18. The heterogeneity observed among the included studies was moderate (I2 = 55.79%). CONCLUSIONS: A negative impact of DM was found on recurrence and extended treatment duration in TB patients treated with DOTS therapy. DM type 2 is responsible for the TB treatment prolongation and TB recurrence rates. By implementing effective management strategies and advancing research, the challenges can be mitigated, arising due to the complex interaction between DM and TB.

Chronic kidney disease and physiologically based pharmacokinetic modeling: a critical review of existing models.

INTRODUCTION: Physiologically based pharmacokinetic (PBPK) modeling is a paradigm shift in this era for determining the exposure of drugs in pediatrics, geriatrics, and patients with chronic diseases where clinical trials are difficult to conduct. AREAS COVERED: This review has collated data regarding published PBPK models on chronic kidney disease (CKD), including the drug and system-specific input model parameters and model evaluation criteria. Four databases were used from 13th June 2023 to 10th July 2023 for identifying the relevant studies that met the inclusion/exclusion criteria. Alterations in plasma protein (albumin/alpha-1 acid glycoprotein), gastric emptying time, hematocrit, small intestinal transit time, the abundance of cytochrome (CYP) 450 enzymes, glomerular filtration rate, and physicochemical parameters for different drugs were explicitly elaborated from earlier reported studies. Moreover, model evaluation depicted that models in CKD for most of the included drugs were within the allowed two-fold error range. EXPERT OPINION: This review will provide insights for researchers on applying PBPK models in managing patients with different levels of CKD to prevent undesirable side effects and increase the effectiveness of drug therapy.

Perampanel increases seizure threshold in pentylenetetrazole-kindled mice and improves behavioral dysfunctions by modifying mRNA expression levels of BDNF/TrkB and inflammatory markers.

Perampanel (PER), a novel 3rd-generation antiseizure drug that modulates altered post-synaptic glutamatergic storming by selectively inhibiting AMPA receptors, is recently approved to treat intractable forms of seizures. However, to date, presumably consequences of long-term PER therapy on the comorbid deleterious psychiatric disturbances and its correlation with neuroinflammatory parameters are not fully investigated in chronic models of epilepsy. Therefore, we investigated the real-time effect of PER on brain electroencephalographic (EEG) activity, behavioral alterations, redox balance, and relative mRNA expression in pentylenetetrazole (PTZ) induced kindling. Male BALB/c mice were pretreated with PER (0.125, 0.25, and 0.5 mg/kg) for 3 weeks and challenged with 11 injections of PTZ at the sub-threshold dose of 40 mg/kg every other day. vEEG from implanted cortical electrodes was monitored to elucidate seizure propagation and behavioral manifestations. Recorded EEG signals exhibited that PER 0.5 mg/kg pretreatment exceptionally impeded the onset of sharp epileptic spike-wave discharges and associated motor symptoms. Additionally, qEEG analysis showed that PER prevented alterations in absolute mean spectral power and reduced RMS amplitude of epileptogenic spikes vs PTZ control. Furthermore, our outcomes illustrated that PER dose-dependently attenuated PTZ-evoked anxiety-like behavior, memory deficits, and depressive-like behavior that was validated by a series of behavioral experiments. Moreover PER, significantly reduced lipid peroxidation, AChE, and increased levels of SOD and total thiol in the mice brain via AMPAR antagonism. Post-PTZ kindling provoked overstimulation of BDNF/TrkB signaling and increased release of pro-inflammatory cytokines that were reversed by PER with suppression of iNOS in brain immune cells. In conclusion, our findings highlight that PER might play an auspicious preventive role in the proepileptic transformation of brain circuits via suppression of BDNF/TrkB signaling and reduced transcriptional levels of neuroinflammatory markers leading to improvised epilepsy-induced neurobehavioral and neurochemical effects.