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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 (β = −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. Plain Language Summary: Ramadan is a month in which millions of Muslims fast from dawn to dusk; however, fasting during the day (e.g., for 13 hours) may cause headache and discourage individuals from this spiritual practice and can impact normal productivity, especially during the first week as the body adapts. We tested whether taking extended‐release paracetamol before fasting in the morning could avert fasting‐induced headache. Extended‐release paracetamol can be partially beneficial in delaying, but not necessarily preventing, fasting‐induced headache. [Correction added on 12th September 2024, after the first online publication: The Plain Language Summary has been updated.] [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

The article explores the effects of preemptive extended-release paracetamol on fasting-induced headaches during Ramadan, finding that it reduced headache occurrence on certain days and delayed the onset of headaches. Topics include fasting-induced headaches, the use of paracetamol during Ramadan, and strategies to prevent fasting-related discomfort.

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. [ABSTRACT FROM AUTHOR]

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 itmay 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 bythe 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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Purpose: Despite the effectiveness of androgen deprivation therapy in advanced prostate cancer, serious neuropsychiatric consequences in androgen deprivation therapy (ADT)-treated patients, mainly depression, have been concerning and gained more attention recently. This narrative review aims to shed light on the risk and pharmacological management of ADT-induced depression in PCa patients. Methods: We searched PubMed, Scopus and Google Scholar databases using MESH keywords "Prostate cancer OR prostate neoplasm" AND "Depression" AND "Androgen Deprivation Therapy" AND "antidepressants". Search was limited to English and studies conducted on humans. Studies' titles and abstracts were screened, and further information were obtained from the text, if necessary, to decide whether studies are to be included in this review. Results: Our review revealed 23 studies confirming the occurrence and worsening of depressive symptoms in ADT-treated patients, which frequently require pharmacological interventions; whereas 10 studies indicated otherwise. All studies were prospective, retrospective, cross-sectional or case reports. Based on the incidence of depression provided by the observational studies, the average among ADT-treated patients was 18.23% (range: 2.1–46.9%), while it was 8.42% (range: 1.4–23.3%) in the non-ADT patients. Although several treatments have been used for depression in cancer patients, current knowledge lacks observational and controlled studies as well as clinical guidelines that demonstrate efficacy and safety of antidepressants and guide clinicians to the appropriate treatment in these patients, respectively. On the other side, a few clinical studies have been published regarding the efficacy of selective serotonin reuptake inhibitors, selective serotonin and norepinephrine reuptake inhibitors and/or saftey on other ADT associated adverse effects. Conclusions: Our work supports the recent attention towards mood issues as an adverse effect of ADT, and that greater awareness of this is warranted among clinicians. Clinical studies published regarding the use of antidepressants for other ADT associated adverse effects established the foundation that can be adopted to examine these therapies on ADT-induced depression. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: Despite the common use of acetaminophen and its safety profile, cases of acetaminophen-induced hepatic toxicities have been reported due to unintentional duplication that mostly results from the public significant lack of knowledge. This research aims to assess the public awareness towards the safe use of acetaminophen in Saudi Arabia. Methods: A cross-sectional study that targeted the adults in Saudi Arabia that was carried out using self-administered questionnaire. The data obtained included sociodemographic characteristics, the pattern of use, the attitude, as well as the knowledge of the general public towards acetaminophen. Results: Data presented in this study showed that a significant majority of the respondents (84.11%) used acetaminophen without their physician's prescription as needed, (66%) denied the development of side effects after using acetaminophen. In terms of the participants' knowledge and awareness towards the usage of acetaminophen and its safety, a pronounced proportion of the respondents (53.65%) incorrectly identified the maximum daily dose of acetaminophen and only (16.2%) could. A significant minority of the participants (27%) admitted relying on their own knowledge as the primary source of information. Among the participants (54.69%) denied receiving education on acetaminophen from health care professionals. A marked distinction was observed between the respondents with higher educational level as well as younger individuals regarding the identification of the maximum daily dose (p = 0.0034) and (p = 0.039), respectively. Conclusion: There is a concerning inadequacy of the public awareness about the appropriate use of acetaminophen. [ABSTRACT FROM AUTHOR]

Purpose: The aim of the study was to evaluate physicians' perception of the concept of pharmacokinetics and therapeutic drug monitoring (PK/TDM) and their use in clinical practice. Methods: A novel, structured, self-administered questionnaire was designed, validated and distributed to physicians in 3 major cities in Saudi Arabia (Riyadh, Jeddah, Dammam) during a 4-month period. Data were collected on demographics, knowledge and practice of PK/TDM. Attitudes toward integrating these skills into daily clinical practice were also investigated. Results: A total of 724 physicians completed the survey and included in the study. European and North American physicians were found to be more exposed to PK/TDM than other physicians. About 70% of the participants stated that they have applied PK/TDM in their practice, at least, once and most of these were consultants. Only 4.3% of respondents had never checked organ function prior to prescribing narrow therapeutic index drugs. Although the majority (78.4%) perceived PK/TDM as very important to their practice, only 35.3% have tried to calculate drug PK parameters for their patients when necessary. Conclusion: The result of this study showed that the knowledge of physicians about PK/TDM was inadequate. Moreover, the utilization of competent clinical pharmacists trained in PK/TDM was low. An interdisciplinary educational program between the physicians and pharmacist in PK/TDM will lead to a better health care outcome. [ABSTRACT FROM AUTHOR]

Purpose: To investigate the preventative activity of benzyl isothiocyante and S-carvone against high-fat diet-induced obesity and metabolic complications. Methods: Ten-week-old C57BL/6 male mice were fed a high-fat diet and injected intraperitoneally twice per week with benzyl isothiocyante, S-carvone, or vehicle for 8 weeks. The body weight, food intake, and body composition were monitored, and glucose tolerance and insulin tolerance tests were performed at the end of the experiment. Serum and tissue samples were studied using serum biochemistry, histological, and gene expression analysis to define the effects of benzyl isothiocyante and S-carvone treatments on lipid and glucose metabolism and inflammatory responses. Results: Benzyl isothiocyante and S-carvone blocked high-fat diet-induced weight gain, fat accumulation in the liver, and insulin resistance. The beneficial effects were found to be associated with an improvement of expression of macrophage marker genes in white adipose tissue, including F4/80, Cd11b, Cd11c, Cd206, and Tnf-α, and reduced expression of genes ( Pparγ2, Scd1, Cd36) responsible for lipid synthesis and transport in the liver. Conclusion: Benzyl isothiocyante and S-carvone block high-fat diet-induced obesity and metabolism disorders and can be considered for management of the obesity epidemic that affects approximately 36% of adults and 17% of children in the USA. [ABSTRACT FROM AUTHOR]

Reactive oxygen species generated as a by-product in metabolism play a central role in the development of obesity and obesity-related metabolic complications. The objective of the current study is to explore the possibility to block obesity and improve metabolic homeostasis via phloretin, a natural antioxidant product from apple tree leaves and Manchurian apricot. Both preventive and therapeutic activities of phloretin were assessed using a high-fat diet-induced obesity mouse model. Phloretin was injected intraperitoneally twice weekly into regular and obese mice fed a high-fat diet. The effects of phloretin treatment on body weight and composition, fat content in the liver, glucose and lipid metabolism, and insulin resistance were monitored and compared to the control animals. Phloretin treatment significantly blocks high-fat diet-induced weight gain but did not induce weight loss in obese animals. Phloretin improved glucose homeostasis and insulin sensitivity and alleviated hepatic lipid accumulation. RT-PCR analysis showed that phloretin treatment suppresses expression of macrophage markers ( F4/80 and Cd68) and pro-inflammatory genes ( Mcp-1 and Ccr2) and enhances adiponectin gene expression in white adipose tissue. In addition, phloretin treatment elevated the expression of fatty acid oxidation genes such as carnitine palmitoyltransferase 1a and 1b ( Cpt1a and Cpt1b) and reduced expression of monocyte chemoattractant protein-1 ( Mcp-1), de novo lipogenesis transcriptional factor peroxisome proliferator-activated receptor-γ 2 ( Pparγ2), and its target monoacylglycerol O-acyltransferase ( Mgat-1) genes. These results provide direct evidence to support a possible use of phloretin for mitigation of obesity and maintenance of metabolic homeostasis. [ABSTRACT FROM AUTHOR]

Background and objectives: Neural tube defects are congenital anomalies which canlead to infant death and serious disability. They are initiated during embryogenesis, between the 23rd and 27th day of fetal life, and can be prevented by the administration of folic acid. Therefore, this study aims to evaluate the knowledge and practice of Saudi women at childbearing age regarding NTDs and FA supplementation. Methodology: This is a cross-sectional study on Saudi women of reproductive age who were asked to complete an online survey to examine their knowledge and practice regarding folic acid supplementation and neural tube defects. Descriptive and simple linear regression analyses were conducted using SPSS v.26 (SPSS Inc., Chicago, IL, USA). Results: A total of 613 women have completed the questionnaire, from which the majority (46.7%) were aged between 36 and 40 years. About 94% of women heard about folic acid and 80% indicated that its deficiency has some relation to neural tube defects. Approximately 37%, 25.3%, and 23.2% of women reported the proper time for folic acid intake to be during first trimester of pregnancy, before pregnancy, or throughout pregnancy, respectively. Linear regression analysis revealed that increase age and education were significantly correlated with a decrease in folic acid administration (p = 0.008) and (p = 0.001), respectively. However, there was no association between time of folic acid administration and income or number of parities. Conclusion: Despite the acceptable level of awareness about the relation of folic acid and neural tube defects, our results revealed that more education is required towards the proper time of supplementation among Saudi childbearing women. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Cannabis use has been growing recently and it is legally consumed in many countries. Cannabis has a variety of phytochemicals including cannabinoids, which might impair the peripheral systems responses affecting inflammatory and immunological pathways. However, the exact signaling pathways that induce these effects need further understanding. The objective of this study is to investigate the serum proteomic profiling in patients diagnosed with cannabis use disorder (CUD) as compared with healthy control subjects. The novelty of our study is to highlight the differentially changes proteins in the serum of CUD patients. Certain proteins can be targeted in the future to attenuate the toxicological effects of cannabis. Blood samples were collected from 20 male individuals: 10 healthy controls and 10 CUD patients. An untargeted proteomic technique employing two-dimensional difference in gel electrophoresis coupled with mass spectrometry was employed in this study to assess the differentially expressed proteins. The proteomic analysis identified a total of 121 proteins that showed significant changes in protein expression between CUD patients (experimental group) and healthy individuals (control group). For instance, the serum expression of inactive tyrosine protein kinase PEAK1 and tumor necrosis factor alpha-induced protein 3 were increased in CUD group. In contrast, the serum expression of transthyretin and serotransferrin were reduced in CUD group. Among these proteins, 55 proteins were significantly upregulated and 66 proteins significantly downregulated in CUD patients as compared with healthy control group. Ingenuity pathway analysis (IPA) found that these differentially expressed proteins are linked to p38MAPK, interleukin 12 complex, nuclear factor-κB, and other signaling pathways. Our work indicates that the differentially expressed serum proteins between CUD and control groups are correlated to liver X receptor/retinoid X receptor (RXR), farnesoid X receptor/RXR activation, and acute phase response signaling. [ABSTRACT FROM AUTHOR]