A Systematic Critical Review of Clinical Pharmacokinetics of Torasemide.

PURPOSE: Torasemide is a potassium-sparing loop diuretic used to treat fluid retention associated with congestive heart failure and kidney and hepatic diseases. This systematic review was conducted to combine all accessible data on the pharmacokinetics (PK) of torasemide in healthy and diseased populations, which may help clinicians avert adverse drug reactions and determine the correct dosage regimen. METHODS: Four databases were systematically searched to screen for studies associated with the PK of torasemide, and 21 studies met the eligibility criteria. The review protocol was registered in the PROSPERO database (CRD42023390178). RESULTS: A decrease in maximum plasma concentration (C max ) was observed for torasemide after administration of the prolonged-release formulation in comparison to that after administration of the immediate-release formulation, that is, 1.12 ± 0.17 versus 1.6 ± 0.2 mcg/mL. After administering an oral dose of torasemide, a 2-fold increase in the area under the concentration-time curve (AUC) was reported in patients with congestive heart failure compared with the healthy population. Moreover, the patients with renal failure (clearance < 30 mL/min) showed an increase in value of AUC 0-∞ that is, 42.9 versus 8.091 mcg.h -1 .mL -1 compared with healthy subjects. In addition, some studies have reported interactions with different drugs, in which irbesartan showed a slight increase in the AUC 0-∞ of torasemide, whereas losartan and empagliflozin did not. CONCLUSIONS: The current review summarizes all available PK parameters of torasemide that may be beneficial for avoiding drug-drug interactions in subjects with renal and hepatic dysfunction and for predicting doses in patients with different diseases.

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.

Clinical pharmacokinetics of nebivolol: a systematic review.

Nebivolol is a beta-1 receptor blocker used to treat hypertension, heart failure, erectile dysfunction, vascular disease, and diabetes mellitus. This review investigated the data regarding pharmacokinetic (PK) parameters, drug-drug interactions, dextrorotatory (D), and levorotatory (L) stereoisomers of nebivolol. The articles related to the PK of nebivolol were retrieved by searching the five databases; Google Scholar, PubMed, Cochrane Library, ScienceDirect, and EBSCO. A total of 20 studies comprising plasma concentration-time profile data following the nebivolol's oral and intravenous (IV) administration were included. The area under the concentration-time curve from zero to infinity (AUC0-∞) was 15 times greater in poor metabolizers (PMs) than in extensive metabolizers (EMs). In hypertensive patients, L-nebivolol expressed a higher maximum plasma concentration (Cmax) than D-nebivolol, i.e. 2.5 ng/ml vs 1.2 ng/ml. The AUC0-∞ of nebivolol was 3-fold greater in chronic kidney disease (CKD). The clearance (CL) was increased in obese than in controls from 51.6 ± 11.6 L/h to 71.6 ± 17.4 L/h when 0.5 mg/ml IV solution was infused. Nebivolol showed higher Cmax, AUC0-∞ and half-life (t1/2) when co-administered with bupropion, duloxetine, fluvoxamine, paroxetine, lansoprazole, and fluoxetine. This concise review of nebivolol would be advantageous in assessing all PK parameters, which may be crucial for clinicians to avoid drug-drug interactions, prevent adverse drug events and optimize the dosage regimen in diseased patients diagnosed with hypertension and cardiovascular disorders.

Determinants of anxiety and depression among university teachers during third wave of COVID-19.

BACKGROUND: To estimate the determinants of anxiety and depression among university teachers in Lahore, Pakistan, during COVID-19. METHODS: A cross-sectional study was conducted by enrolling 668 teachers from the universities of Lahore, Pakistan. Data were collected using a questionnaire. Chi-square for significance and logistic regression for the association were used. RESULTS: Majorly, the university teachers, with an average age of 35.29 years, had regular jobs (72.8%), job experience of > 6 years (51.2%) and good self-reported health (55.4%). The majority of the teachers were working as lecturers (59.6%), lecturing in arts (33.5%) or general science (42.5%) departments, having MPhil (37.9%) or master (28.9%) degrees, and teaching via synchronous video (59.3%) mode. Anxiety and depression, severe and extremely severe, were higher among lecturers, MPhil or master degree holders, teachers lecturing arts and general science subjects, and in those on contract employment. Anxiety was significantly associated with academic departments; arts (OR;2.5, p = 0.001) and general science (OR;2.9, p = 0.001), poor health status (OR;4.4, p = 0.018), and contractual employment (OR;1.8, p = 0.003). Depression was associated with academic departments; arts (OR;2.7, p = 0.001) and general science (OR;2.5, p = 0.001), and health status (OR;2.3, p = 0.001). CONCLUSION: Among university teachers, anxiety and depression, severe and extremely severe, were prevalent among lecturers having MPhil or master degrees, belonging to arts and general science departments, and among contract employees. Anxiety and depression were significantly associated with academic disciplines, lower cadre, and poor health status.

Clinical pharmacokinetics of cefixime: a systematic review.

Cefixime is an antibiotic from the cephalosporin class used to treat various bacterial infections. The purpose of performing this review is to thoroughly evaluate the pharmacokinetic (PK) data on cefiximeFive databases were systematically searched to identify studies on the PK of cefixime.A total of 38 articles meeting the eligibility criteria were included that provide data on concentration-time profiles or PK parameters such as peak plasma and serum concentration (Cmax), area under the curve (AUC), clearance (CL), and time to reach Cmax (tmax). A dose-dependent increase in AUC and Cmax of cefixime was depicted in healthy volunteers. The clearance of cefixime decreased according to the degree of renal insufficiency among haemodialysis patients. A significant difference in CL was found in comparing fasted and fed states. A biphasic decline in serum concentrations of cefixime was reported when it was taken without probenecid.This review compiles all the reports on the PK of cefixime in healthy and really impaired patients; the summarised information can be used to optimise cefixime dosing in different disease states. Moreover, cefixime has increased time above MIC value suggesting that it may be an effective treatment for infections caused by certain pathogens.

Clinical pharmacokinetics of nadolol: A systematic review.

WHAT IS KNOWN AND OBJECTIVE: Nadolol is a non-selective beta-adrenergic antagonist that is used for the treatment of hypertension and angina. The primary route for its administration is oral. It is given once daily as it has a longer half-life (t½). The purpose of conducting this systematic review is to provide a comprehensive view of all the available pharmacokinetic (PK) data on nadolol in humans. This review aimed to systematically collate and analyze publish data on the clinical PK of nadolol in humans and this can be beneficial for the clinicians in dosage adjustments. METHODS: Two electronic databases PubMed and Google Scholar were used for conducting a systematic literature search. All the relevant articles containing PK data of nadolol in humans were retrieved. A total of 1275 articles were searched from both databases and after applying eligibility criteria finally, 22 articles were included for conducting the systematic review. RESULTS AND DISCUSSION: The area under the plasma concentration curve (AUC) and maximum plasma concentration (Cmax ) of nadolol increased in a dose-dependent manner. The t½ of nadolol was increased to double (18.2-68.6 h) in the patients with chronic kidney disease while the serum t½ became shorter (3.2-4.3 h) when administered to the children. The bioavailability of nadolol was greatly reduced by the coadministration of green tea. Nadolol can be effectively removed by hemodialysis. It undergoes enterohepatic circulation thus activated charcoal decreased its bioavailability. WHAT IS NEW AND CONCLUSION: Since, there is no previous report of a systematic review on the PK of nadolol, the current review encompasses all the relevant published articles on nadolol in humans. The analysis and understanding of PK parameters (AUC, Cmax , and t½) of nadolol may be helpful in the development and evaluation of PK models.

In vivo antioxidants, chemical characterization and biochemical and medicinal potential of Murraya koenigii in cisplatin-induced nephrotoxicity.

Murraya koenigii (Mk) is an old plant with a significant therapeutic value throughout Africa, Asia, and Latin America. The excessive use of cisplatin (Cis> 50 mg/m2) is associated with nephrotoxicity, ototoxicity, gastrotoxicity, myelosuppression, and allergic reactions. Remedial measures are needed for the protection of nephrotoxicity against cisplatin. Thus, we have investigated Mk leaf extract's nephroprotective effects to prevent cisplatin-induced nephrotoxicity in Wistar albino rats. The presence of polyphenols, phenolic compounds, tannins, and saponins was revealed during phytochemical investigation, and antioxidant activity was recorded. There were no toxicological symptoms in the treated rats, and no anatomical, physiological, or histological abnormalities were found compared to the control rats. The results of correcting cisplatin-induced nephrotoxicity revealed that the extract has a significant ability to treat kidney damage, with most parameters returning to normal after only three weeks of therapy. It was concluded that co-administered cisplatin with Mk leaves extract showed exceptional nephroprotective effects at a 400 mg/kg dose ratein Cis-induced nephrotoxicity.

Impact of the COVID-19 outbreak on mental health status and associated factors among general population: a cross-sectional study from Pakistan.

The recent outbreak of coronavirus disease (COVID-19) has significantly affected the mental health of people globally. This study aimed to investigate the mental health status and associated factors among residents of Pakistan. An online questionnaire survey was conducted from April 3 to May 7, 2020, using convenience and snowball sampling techniques. Data regarding demographics, physical health status and contact history during the last 2 weeks were collected. Furthermore, the Depression, Anxiety, and Stress scales (DASS-21) were utilized to measure the mental health of the participants. The analyses included descriptive statistics and regression analysis. Of the 1663 participants who completed this survey, 1598 met the inclusion criteria. The results revealed mild to moderate depression among 390 participants (24.4%), mild to moderate anxiety among 490 participants (30.7%) and mild to moderate stress among 52 participants (3.3%). A majority of the participants rated their health as good (n = 751, 47.0%). Moreover, students reported significantly higher scores on depression (B = 1.29, 95% CI = 0.71-1.88; p < 0.05), anxiety (B = 0.56, 95% CI = -0.06 to 1.18; p < 0.05) and stress (B = 0.56, 95% CI = -0.12 to 1.23; p < 0.05). Physical symptoms, including fever, cough and myalgia, and contact history in the last 14 days reported significant associations with depression, anxiety and stress (p < 0.05). The mental health status of the people was noted to be affected during the COVID-19 outbreak. Assessment of several factors with significant associations with depression, anxiety and stress may aid in developing psychological interventions for vulnerable groups.

Chronically administered Agave americana var. marginata extract ameliorates diabetes mellitus, associated behavioral comorbidities and biochemical parameters in alloxan-induced diabetic rats.

Introduction: Diabetes mellitus causes hyperglycemia and associated complications to the brain. In current study, the traditionally reported remedial claims of Agave americana var. marginata has been scientifically investigated in diabetic rats. Methodology: The methanolic extract of leaves of Agave americana var. marginata (Aa.Cr) was characterized for total phenols, flavonoids, and antioxidant potential through in-vitro testing. The rats chronically pre-treated with Aa.Cr (400 and 600 mg/kg) for 45 days were challenged with alloxan-induced hyperglycemia. The dose-dependent effects of Aa.Cr on blood glucose levels and body weights were compared with diabetic rats using glibenclamide (0.6 mg/kg) as a standard. The animals were tested for diabetes-associated neurological comorbidities through behavioral and biochemical evaluation. Results: The phenols and flavonoids enriched Aa.Cr caused a significant dose-dependent hypoglycemic effect. Aa.Cr showed protection from comorbid anxiety, depression and cognitive impairment as compared to diabetic rats. The alanine aminotransferase, total cholesterol, triglycerides and low-density lipoprotein were prominently reduced, and high-density lipoprotein was increased in rats treated with Aa.Cr. Moreover, the oxidative stress in isolated brains was reduced by Aa.Cr. Conclusion: These findings suggest that Aa.Cr is enriched with antioxidant and anti-inflammatory phytoconstituents valuable for diabetes and related neurological complications.

Dynamics of Choline-Containing Phospholipids in Traumatic Brain Injury and Associated Comorbidities.

The incidences of traumatic brain injuries (TBIs) are increasing globally because of expanding population and increased dependencies on motorized vehicles and machines. This has resulted in increased socio-economic burden on the healthcare system, as TBIs are often associated with mental and physical morbidities with lifelong dependencies, and have severely limited therapeutic options. There is an emerging need to identify the molecular mechanisms orchestrating these injuries to life-long neurodegenerative disease and a therapeutic strategy to counter them. This review highlights the dynamics and role of choline-containing phospholipids during TBIs and how they can be used to evaluate the severity of injuries and later targeted to mitigate neuro-degradation, based on clinical and preclinical studies. Choline-based phospholipids are involved in maintaining the structural integrity of the neuronal/glial cell membranes and are simultaneously the essential component of various biochemical pathways, such as cholinergic neuronal transmission in the brain. Choline or its metabolite levels increase during acute and chronic phases of TBI because of excitotoxicity, ischemia and oxidative stress; this can serve as useful biomarker to predict the severity and prognosis of TBIs. Moreover, the effect of choline-replenishing agents as a post-TBI management strategy has been reviewed in clinical and preclinical studies. Overall, this review determines the theranostic potential of choline phospholipids and provides new insights in the management of TBI.

Investigating the Role of Altered Systemic Albumin Concentration on the Disposition of Theophylline in Adult and Pediatric Patients with Asthma by Using the Physiologically Based Pharmacokinetic Approach.

Theophylline is commonly used for the treatment of asthma and has a low hepatic clearance. The changes in plasma albumin concentration occurring in asthma may affect the exposure of theophylline. The aim of the presented work was to predict theophylline pharmacokinetics (PK) after incorporating the changes in plasma albumin concentration occurring in patients with asthma into a physiologically based pharmacokinetic (PBPK) model to see whether these changes can affect the systemic theophylline concentrations in asthma. The PBPK model was developed following a systematic model building approach using Simcyp. The predictions were performed initially in healthy adults after intravenous and oral drug administration. Only when the developed adult PBPK model had adequately predicted theophylline PK in healthy adults, the changes in plasma albumin concentrations were incorporated into the model for predicting drug exposure in patients with asthma. After evaluation of the developed model in the adult population, it was scaled to children on physiologic basis. The model evaluation was performed by using visual predictive checks and comparison of ratio of observed and predicted (Robs/Pre) PK parameters along with their 2-fold error range. The developed PBPK model has effectively described theophylline PK in both healthy and diseased populations, as Robs/Pre for all the PK parameters were within the 2-fold error limit. The predictions in patients with asthma showed that there were no significant changes in PK parameters after incorporating the changes in serum albumin concentration. The mechanistic nature of the developed asthma-PBPK model can facilitate its extension to other drugs. SIGNIFICANCE STATEMENT: Exposure of a low hepatic clearance drug like theophylline may be susceptible to plasma albumin concentration changes that occur in asthma. These changes in systemic albumin concentrations can be incorporated into a physiologically based pharmacokinetic model to predict theophylline pharmacokinetics in adult and pediatric asthma populations. The presented work is focused on predicting theophylline absorption, distribution, metabolism, and elimination in adult and pediatric asthma populations after incorporating reported changes in serum albumin concentrations to see their impact on the systemic theophylline concentrations.

Non-pharmacological Interventions for Intractable Epilepsy.

In 30% of epileptic individuals, intractable epilepsy represents a problem for the management of seizures and severely affects the patient's quality of life due to pharmacoresistance with commonly used antiseizure drugs (ASDs). Surgery is not the best option for all resistant patients due to its post-surgical consequences. Therefore, several alternative or complementary therapies have scientifically proven significant therapeutic potential for the management of seizures in intractable epilepsy patients with seizure-free occurrences. Various non-pharmacological interventions include metabolic therapy, brain stimulation therapy, and complementary therapy. Metabolic therapy works out by altering the energy metabolites and include the ketogenic diets (KD) (that is restricted in carbohydrates and mimics the metabolic state of the body as produced during fasting and exerts its antiepileptic effect) and anaplerotic diet (which revives the level of TCA cycle intermediates and this is responsible for its effect). Neuromodulation therapy includes vagus nerve stimulation (VNS), responsive neurostimulation therapy (RNS) and transcranial magnetic stimulation therapy (TMS). Complementary therapies such as biofeedback and music therapy have demonstrated promising results in pharmacoresistant epilepsies. The current emphasis of the review article is to explore the different integrated mechanisms of various treatments for adequate seizure control, and their limitations, and supportive pieces of evidence that show the efficacy and tolerability of these non-pharmacological options.

Predicting Stereoselective Disposition of Carvedilol in Adult and Pediatric Chronic Heart Failure Patients by Incorporating Pathophysiological Changes in Organ Blood Flows-A Physiologically Based Pharmacokinetic Approach.

Chronic heart failure (CHF) is a systemic low perfusion syndrome resulting from impairment in the pumping function of the heart. The decrease in blood supply to body organs can potentially affect the pharmacokinetics (PK) of the drugs being administered. Carvedilol is administered as a racemic mixture and undergoes extensive stereoselective first pass metabolism. For such a drug, the pathophysiological changes occurring in CHF can have a profound impact on PK, and thus the resulting pharmacodynamic response, of both enantiomers. The aim of the current work was to predict stereoselective disposition of carvedilol after incorporating the pathophysiological changes in CHF into a whole-body physiologically based PK model using Simcyp, and to scale that model to pediatric CHF patients on a physiologic basis to investigate whether the same changes in the adult model can also be adopted for children. The developed model has successfully described PK of carvedilol enantiomers in healthy adults and in patients after the incorporation of reduced organ blood flows, as seen by the visual predictive checks and the calculated observed/predicted ratios for all PK parameters of interest. In contrast to adults, pediatric patients up to 12 years of age were better described without the reductions in organ blood flow, whereas older pediatric patients were better described after incorporating organ blood flow reductions. These findings indicate that the incorporated blood flow reductions in the adult model cannot be directly adopted in pediatrics, at least for the young ones; however, to draw definite conclusions, more data are still needed.

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.

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.

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.

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).

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.

Unveiling the potential of perampanel and pregabalin in addressing pentylenetetrazole-induced electrographic alterations and neurobehavioral anomalies.

Chemical kindling is broadly used experimental model to investigate novel treatments on the process of epileptogenesis and coexisting behavioral comorbidities. The current study aimed to investigate the low dose perampanel (PER) (0.125 and 0.5 mg/kg) and pregabalin (PG) (15 mg/kg) as standalone treatments and in combination on kindling-induced seizure progression with concurrent electroencephalographic alterations. Mice were subjected to pentylenetetrazole (PTZ)-induced kindling followed by neurobehavioral assessment for anxiety-like activity and cognitive deficit through behavioral experiments. The monotherapy with PER at 0.5 mg/kg and PG at 15 mg/kg delayed the kindling process but PRP+PG yielded pronounced benefits and hindered the development of seizures of higher severity. PER+PG combination relieved the animals from anxiety-like behavior in various employed anxiogenic tests. Furthermore, the kindling-associated cognitive deficit was protected by PER+PG combination as increased alteration behavior, discrimination index and latencies to enter the dark zone were noted in y-maze, object recognition and passive avoidance tests, respectively while shorter escape latencies were noted in water maze. The brain samples of kindled mice had elevated malondialdehyde and reduced catalase, superoxide dismutase and glutathione peroxidase enzymes while treatment with PER and PG combination shielded the mice from heightened kindling-associated oxidative stress. Overall, the findings of the present study illustrate that concurrent administration of PER and PG effectively hindered the process of epileptogenesis by protecting neuronal excitability and brain oxidative stress. The results predict the dominance of PER and PG combination over monotherapy which might serve as an effective novel combination to combat drug resistance and behavioral disorders in epileptic patients.