Evaluating the use of paracetamol to prevent fasting headache during the first week of Ramadan: A randomized, open-label, clinical trial.

BACKGROUND: Fasting headaches frequently occur during the first few days of Ramadan, and treatment is challenging because of fasting. OBJECTIVE: This study aimed to evaluate the effect of extended-release paracetamol on preventing fasting headaches. METHODS: A randomized, open-label clinical trial investigated the efficacy of extended-release paracetamol at a daily dose of 1330 mg in preventing fasting headache. Adults aged 18 years and older were recruited through the Clinical Trial Unit at the King Saud University Medical City. The eligible participants in the study fasted 13.5 h daily during the first week of Ramadan. Participants in the treatment and control arms were followed up to investigate the occurrence, severity, and timing of headache symptoms via self-reporting using a standardized headache diary scale with a daily online link or phone call. The primary outcome was the frequency of headache episodes while fasting during the first week of Ramadan. RESULTS: A total of 238 participants were enrolled and randomized. Of these, 173 followed the protocol (80 treated, 93 control) for at least the first day and were included in the analysis. Most participants were young and healthy, with a mean age of 32.2 ± 10.2 years. More men were included in the study (102/173; 59.0%), a small proportion of participants were smokers (31/173; 17.9%), and almost all participants reported being coffee drinkers (165/173; 95.4%); nonetheless, these characteristics were evenly distributed between the two groups in the study. The overall incidence of headache episodes was 33.0% (57/173) on day 1 and decreased to 11.3% (18/159) on day 7. On average over the 7 days, no significant effect was observed for the treatment on the incidence of headache, as the findings from the generalized estimating equation model indicated (ß = -0.398, p = 0.084; odds ratio = 0.67, 95% confidence interval [CI] 0.42-1.06). Moreover, there was initially no significant difference in the incidence of headache episodes between the treatment and control groups. However, the treatment group had significantly fewer headache episodes during fasting than the control group on day 3 (4/72 [5.6%] vs. 15/91 [16.5%], p = 0.031; relative risk [RR] = 0.34, 95% CI 0.12-0.97) and day 6 (5/69 [7.2%] vs. 20/90 [22.2%], p = 0.010; RR = 0.33, 95% CI 0.13-0.82). No adverse effects were observed during the study period. CONCLUSION: No significant differences were observed in the occurrence of fasting headaches between the two groups on most days during the study period. Additional studies are required to address fasting headaches during the first week of Ramadan.

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.

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

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

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

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

Liraglutide attenuates obese-associated breast cancer cell proliferation via inhibiting PI3K/Akt/mTOR signaling pathway.

This study aims to explore the anti-proliferative, pro-apoptotic, and anti-migration activities of liraglutide (LGT) in MCF-7 breast cancer (BC) cells in subjects with obesity, particularly its effects on the PI3K/Akt/mTOR/AMPK pathway. The role of AMPK/SIRT-1, an essential regulator of adipokine production, in the effect of LGT on the production of adipose-derived adipokine was also assessed. MCF-7 cells were incubated in conditioned medium (CM) generated from adipose-derived stem cells (ADSCs) of obese subjects. MCF-7 cells were then treated with LGT for 72 h. Anti-proliferative, pro-apoptotic, and anti-migration activities were investigated using alamarBlue, annexin V stain, and scratch assay, respectively. Protein levels of phosphorylated PI3K, p-Akt, p-mTOR, and p-AMPK were investigated using immunoblotting. Levels of adipokines in ADSCs were determined using RT-PCR before and after transfection of ADSCs using the specific small interference RNA sequences for AMPK and SIRT-1. LGT evoked anti-proliferative, apoptotic, and potential anti-migratory properties on MCF-7 cells incubated in CM from obese ADSCs and significantly mitigated the activity of the PI3K/Akt/mTOR survival pathway-but not AMPK-in MCF-7 cells. Furthermore, the anti-proliferative effects afforded by LGT were similar to those mediated by LY294002 (PI3K inhibitor) and rapamycin (mTOR inhibitor). Our results reveal that transfection of AMPK/SIRT-1 genes did not affect the beneficial role of LGT in the expression of adipokines in ADSCs. In conclusion, LGT elicits anti-proliferative, apoptotic, and anti-migratory effects on BC cells in obese conditions by suppressing the activity of survival pathways; however, this effect is independent of the AMPK/SIRT1 pathway in ADSCs or AMPK in BC cells.

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.

A Physiologically Based Pharmacokinetic Model to Predict Systemic Ondansetron Concentration in Liver Cirrhosis Patients.

INTRODUCTION: Ondansetron is a drug that is routinely prescribed for the management of nausea and vomiting associated with cancer, radiation therapy, and surgical operations. It is mainly metabolized in the liver, and it might accumulate in patients with hepatic impairment and lead to unwanted adverse events. METHODS: A physiologically based pharmacokinetic (PBPK) model was developed to predict the exposure of ondansetron in healthy and liver cirrhosis populations. The population-based PBPK simulator PK-Sim was utilized for simulating ondansetron exposure in healthy and liver cirrhosis populations. RESULTS: The developed model successfully described the pharmacokinetics of ondansetron in healthy and liver cirrhosis populations. The predicted area under the curve, maximum systemic concentration, and clearance were within the allowed twofold range. The exposure of ondansetron in the population of Child-Pugh class C has doubled in comparison to Child-Pugh class A. The dose has to be adjusted for liver cirrhosis patients to ensure comparable exposure to a healthy population. CONCLUSION: In this study, the developed PBPK model has described the pharmacokinetics of ondansetron successfully. The PBPK model has been successfully evaluated to be used as a tool for dose adjustments in liver cirrhosis patients.

Gastroprotective evaluation of Medicago sativa L. (Fabaceae) on diabetic rats.

Traditional uses for the plant Medicago sativa (M. sativa) (Alfalfa) (Family: Fabaceae) include liver protection, antioxidant activity, and the treatment of bleeding and digestive issues. This study aims to assess the effect of ethanol extract of M. sativa (EEMS) on experimental-induced ulcers in diabetic rats. By pylorus ligation and ethanol administration, gastric ulcers were induced in diabetic rats. Five groups each consisting of six rats in each model were used. All other groups except Group I were made diabetic by giving rats alloxan (140 mg/kg i.p.). Vehicles were given to Group I (normal control) and Group II (diabetes control) rats. Group III (positive control) received ranitidine 50 mg/kg, and Group IV and V received EEMS at doses of 100 and 400 mg/kg, respectively. In the pylorus ligation and ethanol-induced stomach ulcer model of rats, the findings demonstrated that EEMS (100 mg/kg) showed a decreased ulcer index of 2.01 ± 0.41 and was found statistically significant against the diabetes control group (p < 0.001) as well as, an ulcer index of 0.68 ± 0.22 by EEMS (400 mg/kg) with a significant reduction in the ulcer index (p < 0.001). EEMS (100 and 400 mg/kg) reduce free acidity by 13.16 ± 0.65 mEq/L and 9.83 ± 0.30 mEq/L, respectively. EEMS also showed a protective impact on the liver and kidneys of diabetic rats. Antihyperglycemic action was also discovered in diabetic animals. The findings of the current investigation demonstrated that ethanolic extract of M. sativa possesses anti-ulcer activity in diabetic rats. Ethanolic extract of M. sativa may be a treatment option for stomach ulcers that also have diabetes.

BALB/c and C57BL/6 mice differ in oxidant and antioxidant responses in innate and adaptive immune cells in an asthma model induced by cockroach allergens.

Asthma is a complex and heterogenous disease affected by a multitude of factors. Several phenotypes of asthma exist which are influenced by various molecular mechanisms that include presence of antioxidant and oxidant enzymes in different immune cells such as dendritic cells (DCs), alveolar macrophages (AMs), neutrophils, and T cells. Close interaction between epithelial cells and dendritic cells initiates complex pathogenesis of asthma followed by involvement of other innate and adaptive immune cells. In chronic phase of the disease, these immune cells support each other in amplification of airway inflammation where oxidant-antioxidant balance is known to be an important contributing factor. Genetic variability in antioxidant response may influence the development of airway inflammation, however it has not been studied in mice yet. The two most studied mice strains, i.e. BALB/c and C57BL/6 are reported to have dissimilar airway responses to the same allergens due to their genetic makeup. In this investigation, we explored whether these strains had any differences in pulmonary oxidant-antioxidant system (Nrf2, SOD2, iNOS, HO-1, nitrotyrosine) in different immune cells (DCs, AMs, neutrophils, T cells), airway inflammation (presence of eosinophils and/or neutrophils) and mucus production in response to repeated cockroach allergen extract (CE) mouse model of asthma. Our data show that C57BL/6 mice had better induction of antioxidant system than BALB/c mice. Consequently, iNOS/nitrotyrosine levels were much exaggerated in BALB/c than C57BL/6 mice. As a result, BALB/c mice developed mixed granulocytic airway inflammation, whereas C57BL/6 developed mostly eosinophilic airway inflammation. Our data suggest that an exaggerated oxidant generation along with a weak antioxidant induction in response to a natural allergen on a susceptible genetic background may determine development of severe asthma phenotype such as mixed granulocyte inflammation.

Auranofin Modulates Thioredoxin Reductase/Nrf2 Signaling in Peripheral Immune Cells and the CNS in a Mouse Model of Relapsing-Remitting EAE.

Multiple sclerosis (MS) is one of the most prevalent chronic inflammatory autoimmune diseases. It causes the demyelination of neurons and the subsequent degeneration of the central nervous system (CNS). The infiltration of leukocytes of both myeloid and lymphoid origins from the systemic circulation into the CNS triggers autoimmune reactions through the release of multiple mediators. These mediators include oxidants, pro-inflammatory cytokines, and chemokines which ultimately cause the characteristic plaques observed in MS. Thioredoxin reductase (TrxR) and nuclear factor erythroid 2-related factor 2 (Nrf2) signaling plays a crucial role in the regulation of inflammation by modulating the transcription of antioxidants and the suppression of inflammatory cytokines. The gold compound auranofin (AFN) is known to activate Nrf2 through the inhibition of TrxR; however, the effects of this compound have not been explored in a mouse model of relapsing-remitting MS (RRMS). Therefore, this study explored the influence of AFN on clinical features, TrxR/Nrf2 signaling [heme oxygenase 1 (HO-1), superoxide dismutase 1 (SOD-1)] and oxidative/inflammatory mediators [IL-6, IL-17A, inducible nitric oxide synthase (iNOS), myeloperoxidase (MPO), nitrotyrosine] in peripheral immune cells and the CNS of mice with the RR type of EAE. Our results showed an increase in TrxR activity and a decrease in Nrf2 signaling in SJL/J mice with RR-EAE. The treatment with AFN caused the amelioration of the clinical features of RR-EAE through the elevation of Nrf2 signaling and the subsequent upregulation of the levels of antioxidants as well as the downregulation of oxidative/pro-inflammatory mediators in peripheral immune cells and the CNS. These data suggest that AFN may be beneficial in the treatment of RRMS.

Protective role of Dodonaea viscosa extract against streptozotocin-induced hepatotoxicity and nephrotoxicity in rats.

Previous investigations have shown that D. viscosa herbal extract is often used to treat a variety of diseases. Therefore, the purpose of this study was to investigate any additional potential impacts on rat liver and kidney damage induced by diabetes. Streptozotocin (STZ) (60 mg/kg/day) was given as a single dosage to cause type 1 diabetes. After then, diabetic rats received oral doses of D. viscosa for four weeks at 150 and 300 mg/kg/day. Blood, liver, and kidney tissues were collected at the end of the treatment and examined. Analysis was made of the serum lipid profile, liver, and kidney functions, as well as blood biochemistry. Moreover, the levels of tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), interleukin-1 beta (IL-1ß), prostaglandin E-2 (PGE-2), and nitric oxide (NO) were estimated in serum. In liver and kidney samples, thiobarbituric acid reactive substances (TBARs) and reduced glutathione (GSH), as well as the pro-inflammatory cytokines and enzymatic activities of glutathione peroxidase (GPx), glutathione reeducates (GR), glutathione-S-transferase (GST), catalase (CAT), and superoxide dismutase (SOD) were analyzed. Histological changes in liver and kidney cross-sections were also observed. Our findings demonstrated that D. viscosa dramatically decreased pro-inflammatory indicators in blood, kidney, and liver tissues as well as blood glucose, and restored insulin levels, and lipid profiles. Additionally, it significantly raises the antioxidant enzyme activity SOD, CAT, GPx, and GST, while significantly lowering TBARs levels. The above-mentioned biochemical changes that took place in tissues were further supported by histological alterations. These findings imply that D. viscosa protects against STZ-induced hyperglycemia, aberrant lipid synthesis, and oxidative stress and that these benefits may be mediated by interacting with various targets to increase the levels of antioxidant enzymes in the liver and kidneys. Its mode of action and safety for use as medicine against various metabolic problems caused by diabetes require more research.

A physiologically based pharmacokinetic model of cefepime to predict its pharmacokinetics in healthy, pediatric and disease populations.

The physiologically based pharmacokinetic modeling (PBPK) approach can predict drug pharmacokinetics (PK) by combining changes in blood flow and pathophysiological alterations for developing drug-disease models. Cefepime hydrochloride is a parenteral cephalosporin that is used to treat pneumonia, sepsis, and febrile neutropenia, among other things. The current study sought to identify the factors that impact cefepime pharmacokinetics (PK) following dosing in healthy, diseased (CKD and obese), and pediatric populations. For model construction and simulation, the modeling tool PK-SIM was utilized. Estimating cefepime PK following intravenous (IV) application in healthy subjects served as the primary step in the model-building procedure. The prediction of cefepime PK in chronic kidney disease (CKD) and obese populations were performed after the integration of the relevant pathophysiological changes. Visual predictive checks and a comparison of the observed and predicted values of the PK parameters were used to verify the developed model. The results of the PK parameters were consistent with the reported clinical data in healthy subjects. The developed PBPK model successfully predicted cefepime PK as observed from the ratio of the observed and predicted PK parameters as they were within a two-fold error range.

Physiologically-based pharmacokinetic modeling for single and multiple dosing regimens of ceftriaxone in healthy and chronic kidney disease populations: a tool for model-informed precision dosing.

Introduction: Ceftriaxone is one of commonly prescribed beta-lactam antibiotics with several label and off-label clinical indications. A high fraction of administered dose of ceftriaxone is excreted renally in an unchanged form, and it may accumulate significantly in patients with impaired renal functions, which may lead to toxicity. Methods: In this study, we employed a physiologically-based pharmacokinetic (PBPK) modeling, as a tool for precision dosing, to predict the biological exposure of ceftriaxone in a virtually-constructed healthy and chronic kidney disease patient populations, with subsequent dosing optimizations. We started developing the model by integrating the physicochemical properties of the drug with biological system information in a PBPK software platform. A PBPK model in an adult healthy population was developed and evaluated visually and numerically with respect to experimental pharmacokinetic data. The model performance was evaluated based on the fold error criteria of the predicted and reported values for different pharmacokinetic parameters. Then, the model was applied to predict drug exposure in CKD patient populations with various degrees of severity. Results: The developed PBPK model was able to precisely describe the pharmacokinetic behavior of ceftriaxone in adult healthy population and in mild, moderate, and severe CKD patient populations. Decreasing the dose by approximately 25% in mild and 50% in moderate to severe renal disease provided a comparable exposure to the healthy population. Based on the simulation of multiple dosing regimens in severe CKD population, it has been found that accumulation of 2 g every 24 h is lower than the accumulation of 1 g every 12 h dosing regimen. Discussion: In this study, the observed concentration time profiles and pharmacokinetic parameters for ceftriaxone were successfully reproduced by the developed PBPK model and it has been shown that PBPK modeling can be used as a tool for precision dosing to suggest treatment regimens in population with renal impairment.

Mechanism Underlying Triple VEGFR Inhibitor Tivozanib-Induced Hypertension in Mice Model.

Tivozanib is a triple vascular endothelial growth factor receptor inhibitor, recently approved for the treatment of refractory advanced renal cell carcinoma. Clinical studies showed that around 46% of patients who received tivozanib suffer from hypertension in all grades. Thus, the present study was conducted to identify the role of angiotensin-II (AngII) in the mechanism underlying tivozanib-induced vascular toxicity and hypertension. C57BL/6 male mice received tivozanib (1 mg/kg) with or without losartan (10 or 30 mg/kg) for 3 weeks. Blood pressure was recorded every 3 days, and proteinuria was measured every week. On day 21, all mice were euthanized, and samples were harvested for further analysis. Tivozanib elevated blood pressure until systolic blood pressure reached 163 ± 6.6 mmHg on day 21 of treatment with low urination and high proteinuria. AngII and its receptors, endothelin-1, and oxidative stress markers were significantly increased. While nitric oxide (NO) levels were reduced in plasma and aortic tissues. AngII type 1 receptor blockade by losartan prevented these consequences caused by tivozanib and kept blood pressure within normal range. The results showed that AngII and ET-1 might be potential targets in the clinical studies and management of hypertension induced by tivozanib.

Predicting Hydroxychloroquine Clearance in Healthy and Diseased Populations Using a Physiologically Based Pharmacokinetic Approach.

Hydroxychloroquine (HCQ), a congener of chloroquine, is widely used in prophylaxis and the treatment of malaria, and also as a cure for rheumatoid arthritis, systemic lupus erythematosus, and various other diseases. Physiologically based pharmacokinetic modeling (PBPK) has attracted great interest in the past few years in predicting drug pharmacokinetics (PK). This study focuses on predicting the PK of HCQ in the healthy population and extrapolating it to the diseased populations, i.e., liver cirrhosis and chronic kidney disease (CKD), utilizing a systematically built whole-body PBPK model. The time vs. concentration profiles and drug-related parameters were obtained from the literature after a laborious search and in turn were integrated into PK-Sim software for designing healthy intravenous, oral, and diseased models. The model's evaluation was performed using observed-to-predicted ratios (Robs/Rpre) and visual predictive checks within a 2-fold error range. The healthy model was then extrapolated to liver cirrhosis and CKD populations after incorporating various disease-specific pathophysiological changes. Box-whisker plots showed an increase in AUC0-t in liver cirrhosis, whereas a decrease in AUC0-t was seen in the CKD population. These model predictions may assist clinicians in adjusting the administered HCQ doses in patients with different degrees of hepatic and renal impairment.

Development and Evaluation of a Physiologically Based Pharmacokinetic Model of Labetalol in Healthy and Diseased Populations.

Labetalol is a drug that exhibits both alpha and beta-adrenergic receptor-blocking properties. The American Heart Association/American Stroke Association (AHA/ASA) has recommended labetalol as an initial treatment option for the management of severe hypertension. The physiologically based pharmacokinetic (PBPK) model is an in silico approach to determining the pharmacokinetics (PK) of a drug by incorporating blood flow and tissue composition of the organs. This study was conducted to evaluate the primary reasons for the difference in PK after intravenous (IV) and oral administration in healthy and diseased (renal and hepatic) populations. A comprehensive literature search was done using two databases, PubMed and Google Scholar. Various PK parameters were screened for the development of the PBPK model utilizing a population-based PK-Sim simulator. Simulations were performed after creating building blocks firstly in healthy individuals and then in diseased patients after IV and oral administration. The disposition of labetalol after IV and oral administration occurring in patients with the hepatic and renal disease was predicted. The model was evaluated by calculating the Robs/pred ratio and average fold error (AFE), which was in the two-fold error range. Moreover, Box-whisker plots were made to compare the overall concentration of the drug in the body at various stages of disease severity. The presented model provides useful quantitative estimates of drug dosing in patients fighting against severe chronic diseases.

Prevalence, knowledge and attitude toward electronic cigarette use among male health colleges students in Saudi Arabia-A cross-sectional study.

Background: Health care professionals have an important role in increasing awareness about smoking harms and serving as role models. This study aims to assess knowledge, attitude and perception toward electronic cigarettes (ECs) as well as prevalence of ECs use among male health colleges students. Method: This is a cross-sectional survey-based study conducted among students in the male campus of five different health colleges over a 4-month period from February 2020 to May 2020. Descriptive analysis was used to assess the knowledge, perception and attitude, and inferential testing was used to evaluate the association of different participant's variables and knowledge toward ECs usage using SPSS. Results: A total of 333 students were included in the analysis. Most of students (n = 205; 61.6%) had never used ECs, while 22.8 and 15.6% used them for recreational and smoking cessation purposes, respectively. Focusing on ECs users from each college individually, medical students had the highest prevalence followed by dental, pharmacy and nursing students (47.4, 40.7, 34.5, and 32%, respectively). Many students had misconceptions and a low level of knowledge about ECs, such as recognizing them as smoking-cessation tools and not knowing whether toxic and carcinogenic components levels in ECs are similar to conventional cigarettes, respectively. Medical students had significantly higher knowledge compared to dental students [3 (2) vs. 2 (1); p = 0.033]. Moreover, smokers were less knowledgeable than non-smokers [2.5 (1) vs. 2.1 (1), p = 0.027]. At least 62.8% of students perceived using ECs as a fashionable alternative smoking method and 59.2% believed that they may become a gateway for smoking addiction. Only 120 (36.0%) health colleges students were confidently able to advise smokers regarding ECs. Conclusion: Our study highlights an increased trend of ECs use accompanied with insufficient knowledge and several misconceptions about ECs among health colleges students. This was associated with a negative influence on their attitude toward ECs use, which would potentially lead to negative consequences on public health.

Development and Evaluation of a Physiologically Based Pharmacokinetic Model for Predicting Haloperidol Exposure in Healthy and Disease Populations.

The physiologically based pharmacokinetic (PBPK) approach can be used to develop mathematical models for predicting the absorption, distribution, metabolism, and elimination (ADME) of administered drugs in virtual human populations. Haloperidol is a typical antipsychotic drug with a narrow therapeutic index and is commonly used in the management of several medical conditions, including psychotic disorders. Due to the large interindividual variability among patients taking haloperidol, it is very likely for them to experience either toxic or subtherapeutic effects. We intend to develop a haloperidol PBPK model for identifying the potential sources of pharmacokinetic (PK) variability after intravenous and oral administration by using the population-based simulator, PK-Sim. The model was initially developed and evaluated to predict the PK of haloperidol and its reduced metabolite in adult healthy population after intravenous and oral administration. After evaluating the developed PBPK model in healthy adults, it was used to predict haloperidol-rifampicin drug-drug interaction and was extended to tuberculosis patients. The model evaluation was performed using visual assessments, prediction error, and mean fold error of the ratio of the observed-to-predicted values of the PK parameters. The predicted PK values were in good agreement with the corresponding reported values. The effects of the pathophysiological changes and enzyme induction associated with tuberculosis and its treatment, respectively, on haloperidol PK, have been predicted precisely. For all clinical scenarios that were evaluated, the predicted values were within the acceptable two-fold error range.

Angiotensin II type 1 receptor blockade attenuates gefitinib-induced cardiac hypertrophy via adjusting angiotensin II-mediated oxidative stress and JNK/P38 MAPK pathway in a rat model.

Gefitinib is a tyrosine kinase inhibitor (TKI) of the epidermal growth factor receptor (EGFR), used for the treatment of advanced or metastatic non-small cell lung cancer. Recently, studies proved that Gefitinib-induced cardiotoxicity through induction of oxidative stress leads to cardiac hypertrophy. The current study was conducted to understand the mechanisms underlying gefitinib-induced cardiac hypertrophy through studying the roles of angiotensin II (AngII), oxidative stress, and mitogen-activated protein kinase (MAPK) pathway. Male Wistar albino rats were treated with valsartan, gefitinib, or both for four weeks. Blood samples were collected for AngII and cardiac markers measurement, and hearts were harvested for histological study and biochemical analysis. Gefitinib caused histological changes in the cardiac tissues and increased levels of cardiac hypertrophy markers, AngII and its receptors. Blocking of AngII type 1 receptor (AT1R) via valsartan protected hearts and normalized cardiac markers, AngII levels, and the expression of its receptors during gefitinib treatment. valsartan attenuated gefitinib-induced NADPH oxidase and oxidative stress leading to down-regulation of JNK/p38-MAPK pathway. Collectively, AT1R blockade adjusted AngII-induced NADPH oxidase and JNK/p38-MAPK leading to attenuation of gefitinib-induced cardiac hypertrophy. This study found a pivotal role of AngII/AT1R signaling in gefitinib-induced cardiac hypertrophy, which may provide novel approaches in the management of EGFRIs-induced cardiotoxicity.