Pharmacokinetics of Dasatinib in Rats: a Potential Food-Drug Interaction with Naringenin.

BACKGROUND AND OBJECTIVES: The novel tyrosine kinase inhibitor (TKI) dasatinib, a multitarget inhibitor of Bcr-Abl and Src family kinases, has been licensed for the treatment of Ph+ acute lymphoblastic leukemia and chronic myeloid leukemia. Many citrus-based foods include the flavonoid naringenin, which is commonly available. Dasatinib is a Cyp3a4, P-gp, and Bcrp1 substrate, which makes it sensitive to potential food-drug interactions. The concurrent use of naringenin may change the pharmacokinetics of dasatinib, which could result in adverse effects and toxicity. The present investigation examined the impact of naringenin on the pharmacokinetics interactions of DAS and proposes a possible interaction mechanism in Wistar rats. METHODS: Rats were provided with a single oral dose of dasatinib (25 mg/kg) with or without naringenin pretreatment (150 mg/kg p.o. daily for 7 days, n = 6 in each group). Dasatinib was quantified in plasma by UHPLC MS/MS assay. Noncompartmental analysis was used to compute the pharmacokinetic parameters, and immunoblot was used to assess the protein expression in the hepatic and intestinal tissues. RESULTS: Following 7 days of naringenin pretreatment, the plasma mean concentration of dasatinib was enhanced compared with without pretreatment. In rats that were pretreated with naringenin, the pharmacokinetics of the orally administered dasatinib (25 mg/kg) was shown to be significantly different from that of dasatinib given without pretreatment (p < 0.05). There was a significant enhancement in pharmacokinetic parameters elimination half-life (T1/2), time to maximum concentration ( Tmax), maximum concentration )Cmax), area under the concentration-time curve (AUC0-t), area under the moment curve (AUMC0-∞), and mean residence time (MRT) by 28.41%, 50%, 103.54%, 72.64%, 115.08%, and 15.19%, respectively (p < 0.05) and suppression in elimination rate constant (Kel), volume of distribution (Vd), and clearance (CL) by 21.09%, 31.13%, and 46.25%, respectively, in comparison with dasatinib alone group (p < 0.05). The enhancement in dasatinib bioavailability and systemic exposure resulted from the significant inhibition of Cyp3a2, Mdr1/P-gp, and Bcrp1 expression and suppression of the dasatinib hepatic and intestinal metabolism, which enhanced the rate of dasatinib absorption and decreased its elimination. CONCLUSION: Concurrent use of naringenin-containing supplements, herbs, or foods with dasatinib may cause serious and potentially life-threatening drug interactions. Further studies are necessary to determine the clinical significance of these findings.

Herb-drug interaction: Effect of sinapic acid on the pharmacokinetics of dasatinib in rats.

Dasatinib (DAS) is a narrow therapeutic index drug and novel oral multitarget inhibitor of tyrosine kinase and approved for the first-line therapy for chronic myelogenous leukemia (CML) and Philadelphia chromosome (Ph + ) acute lymphoblastic leukemia (ALL). DAS, a known potent substrate of cytochrome (CYP) 3A, P-glycoprotein (Pgp) and breast cancer resistance protein (BCRP) and is subject to auto-induction. The dietary supplementation of sinapic acid (SA) or concomitant use of SA containing herbs/foods may alter the pharmacokinetics as well as pharmacodynamics of DAS, that may probably lead to potential interactions. Protein expression in rat hepatic and intestinal tissues, as well as the in vivo pharmacokinetics of DAS and the roles of CYP3 A2 and drug transporters Pgp-MDR1 and BCPR/ABCG2, suggested a likely interaction mechanism. The single dose of DAS (25 mg/kg) was given orally to rats with or without SA pretreatment (20 mg/kg p.o. per day for 7 days, n = 6). The plasma concentration of DAS was estimated by using Ultra-High-Performance Liquid Chromatography Mass spectrometry (UHPLC-MS/MS). The in vivo pharmacokinetics and protein expression study demonstrate that SA pretreatment has potential to alter the DAS pharmacokinetics. The increase in Cmax, AUC and AUMC proposes increase in bioavailability and rate of absorption via modulation of CYP3 A2, PgP-MDR1 and BCPR/ABCG2 protein expression. Thus, the concomitant use of SA alone or with DAS may cause serious life-threatening drug interactions.

Effects of Apigenin on Pharmacokinetics of Dasatinib and Probable Interaction Mechanism.

Dasatinib (DAS), a narrow-therapeutic index drug, Bcr-Abl, and Src family kinases multitarget inhibitor have been approved for chronic myelogenous leukemia (CML) and Ph-positive acute lymphocytic leukemia (Ph+ ALL). Apigenin (APG) has a long history of human usage in food, herbs, health supplements, and traditional medicine, and it poses low risk of damage. The concomitant use of APG containing herbs/foods and traditional medicine may alter the pharmacokinetics of DAS, that probably lead to possible herb-drug interactions. The pharmacokinetic interaction of APG pretreatment with DAS in rat plasma following single and co-oral dosing was successfully deliberated using the UPLC-MS/MS method. The in vivo pharmacokinetics and protein expression of CYP3A2, Pgp-MDR1, and BCPR/ABCG2 demonstrate that APG pretreatment has potential to drastically changed the DAS pharmacokinetics where escalation in the Cmax, AUC(0-t), AUMC(0-inf_obs), T1/2, Tmax, and MRT and reduction in Kel, Vd, and Cl significantly in rats pretreated with APG 40 mg/kg, thus escalating systemic bioavailability and increasing the rate of absorption via modulation of CYP3A2, Pgp-MDR1, and BCPR/ABCG2 protein expression. Therefore, the concomitant consumption of APG containing food or traditional herb with DAS may cause serious life-threatening drug interactions and more systematic clinical study on herb-drug interactions is required, as well as adequate regulation in herbal safety and efficacy.

Thymoquinone Attenuates Retinal Expression of Mediators and Markers of Neurodegeneration in a Diabetic Animal Model.

BACKGROUND: Diabetic retinopathy (DR) is a slow eye disease that affects the retina due to a long-standing uncontrolled diabetes mellitus. Hyperglycemia-induced oxidative stress can lead to neuronal damage leading to DR. OBJECTIVE: The aim of the current investigation is to assess the protective effects of thymoquinone (TQ) as a potential compound for the treatment and/or prevention of neurovascular complications of diabetes, including DR. METHODS: Diabetes was induced in rats by the administration of streptozotocin (55 mg/kg intraperitoneally, i.p.). Subsequently, diabetic rats were treated with either TQ (2 mg/kg i.p.) or vehicle on alternate days for three weeks. A healthy control group was also run in parallel. At the end of the treatment period, animals were euthanized, and the retinas were collected and analyzed for the expression levels of brain-derived neurotrophic factor (BDNF), tyrosine hydroxylase (TH), nerve growth factor receptor (NGFR), and caspase-3 using Western blotting techniques in the retina of diabetic rats and compared with the normal control rats. In addition, dichlorofluorescein (DCF) levels in the retina were assessed as a marker of reactive oxygen species (ROS), and blood-retinal barrier breakdown (BRB) was examined for vascular permeability. The systemic effects of TQ treatments on glycemic control, kidney and liver functions were also assessed in all groups. RESULTS: Diabetic animals treated with TQ showed improvements in the liver and kidney functions compared with control diabetic rats. Normalization in the levels of neuroprotective factors, including BDNF, TH, and NGFR, was observed in the retina of diabetic rats treated with TQ. In addition, TQ ameliorated the levels of apoptosis regulatory protein caspase-3 in the retina of diabetic rats and reduced disruption of the blood-retinal barrier, possibly through a reduction in reactive oxygen species (ROS) generation. CONCLUSION: These findings suggest that TQ harbors a significant potential to limit the neurodegeneration and retinal damage that can be provoked by hyperglycemia in vivo.

Quality assessment of different brands of atorvastatin tablets available in Riyadh, Saudi Arabia.

BACKGROUND: Hypolipidemic agents have been shown to be helpful in the primary and secondary prevention of cardiovascular disease. Most often, statins are prescribed to treat hyperlipidemia. There are a number of statins available in the market today, but atorvastatin is the most widely prescribed. It is essential that the drugs should have the appropriate amount of active pharmaceutical ingredient and meet the necessary physical properties. The main purpose of the study was to evaluate the quality of different marketed brands of atorvastatin calcium tablets available in Saudi Arabia. METHODS: In this study, innovator product coded as (AS-1) and five generics brands (coded as AS-2 to AS-6) of atorvastatin tablets 20 mg available in Saudi Arabia were evaluated for in vitro dissolution test, weight variations, friability and hardness tests. The analysis of drug was carried out by "high-performance liquid chromatography" (HPLC) method using C18 column (4.6 × 150 mm, 5 µm). The mobile phase was consisted of acetonitrile and HPLC water (pH 2.1, adjusted with orthophosphoric acid) in ratio of 52:48 v/v, the flow rate was 1.0 ml/min. Atorvastatin was detected at a wavelength of 254 nm. RESULTS: According to the results of the dissolution study, the investigated products released more than 90% of atorvastatin in 15 min. Within 60 min, the brands AS-1, AS-3, AS-5, and AS-6 depicted nearly 100% atorvastatin release, while the brand AS-2 displayed 91.69% drug release. According to our findings, the investigated atorvastatin innovator (AS-1) and generic brands such as AS-2 to AS-6 were of good pharmaceutical quality. CONCLUSIONS: All generic brands of atorvastatin tablets available in the Saudi Arabian market met the pharmacopoeia's consistency checks such as weight variation, friability, hardness and in vitro dissolution. Hence, focusing on their in vitro release properties, it was determined that these brands could be used interchangeably.

Sinapic Acid Ameliorates Acetic Acid-Induced Ulcerative Colitis in Rats by Suppressing Inflammation, Oxidative Stress, and Apoptosis.

Background: Ulcerative colitis (UC) is a long-term condition which results in inflammation and ulcers of the colon and rectum. The key indications of active disease are abdominal pain and diarrhea mixed with blood. Aims: We explore the underlying colon protective mechanism of sinapic acid (SA) against acetic acid (AA) induced ulcerative colitis in rats. The implications of inflammation, oxidative stress, and apoptosis are studied. Methodology: Twenty-four rats were distributed into four categories, normal control (NC), ulcerative colitis (UC), ulcerative Colitis with SA 40 mg/kg (SA 40 mg/kg + AA), and ulcerative colitis with prednisolone (PRDL 10 mg/kg + AA), and were pretreated orally with saline, saline and SA (40 mg/kg/day) or PRDL (10 mg/kg/day) respectively, for 7 days. UC was prompted by trans-rectal administration of 4% AA on the 5th day, colon tissues were surgically removed for gross morphology and histological inspection, oxidative stress, and inflammatory markers and immunoblot analysis of Bax, caspase-3, and Bcl-2. Results: Macroscopic and histological inspection demonstrated that both SA 40 mg/kg and PRDL (10 mg/kg/day) significantly ameliorates colonic injuries. In addition, both pretreatments significantly ameliorates AA-induced UC, oxidative stress, as indicated by suppressed malondialdehyde (MDA), nitric oxide (NO) levels and restoring antioxidant/oxidant balance as indicated by catalase and glutathione levels, suppressed inflammation via inhibiting cytokines TNF-α, IL-6, inflammatory markers MPO, PGE2, COX-2 and NF-κB and inhibiting the protein expression of Bax and caspase-3 apoptotic protein and increasing the anti-apoptotic protein, Bcl-2 thereby inhibiting apoptosis. Conclusion: Sinapic acid significantly ameliorates AA induced UC in rats by suppressing inflammation, oxidative stress, and apoptosis in colonic tissues which exhibits its potential for the management of UC.

Thymoquinone modulates the expression of sepsis-related microRNAs in a CLP model.

Sepsis is a clinical syndrome common in critical care settings. In the present study, the therapeutic effect of thymoquinone (TQ) on the expression of sepsis-related microRNAs (miRNAs/miRs), levels of inflammatory markers, organ dysfunction and mortality were investigated in a cecal ligation and puncture (CLP) rat model. A single dose of TQ (1 mg/kg) was administered to animals 24 h after CLP and the mortality rate was assessed up to 7 days following the induction of sepsis. In addition, blood samples were collected at different time points and the expression levels of miRNAs (i.e. miR-16, miR-21, miR-27a and miR-34a) were examined, along with the levels of inflammatory cytokines (i.e. TNF-α, IL-1α, IL-2, IL-6 and IL-10) and sepsis markers (i.e. C-reactive protein, endothelial cell-specific molecule-1, VEGF, procalcitonin and D-dimer). Liver, kidney and lung tissues were also collected for further histological examination. Treatment with TQ significantly downregulated the miRNA expression levels, as well as the levels of inflammatory cytokines and early-stage sepsis biomarkers by 30-70% at 12-36 h (P<0.05). Furthermore, CLP model rats treated with TQ exhibited an ~80% increase in survival rate compared with that in the untreated CLP group. In addition, TQ induced the preservation of organ function and structure. In conclusion, the present study demonstrated a promising therapeutic effect of TQ against the sequelae of sepsis.

Myricetin (3,3',4',5,5',7-Hexahydroxyflavone) Prevents 5-Fluorouracil-Induced Cardiotoxicity.

5-Fluorouracil (5-FU) is a strong anti-cancer drug used to manage numerous cancers. Cardiotoxicity, renal toxicity, and liver toxicity are some of the adverse effects which confine its clinical use to some extent. 5-FU-induced organ injuries are associated with redox imbalance, inflammation, and damage to heart functioning, particularly in the present study. Myricetin is an abundant flavonoid, commonly extracted from berries and herbs having anti-oxidative and anti-cancer activities. We planned the current work to explore the beneficial effects of myricetin against 5-FU-induced cardiac injury in Wistar rats through a biochemical and histological approach. Prophylactic myricetin treatment at two doses (25 and 50 mg/kg) was given to rats orally for 21 days against cardiac injury induced by a single injection of 5-FU (150 mg/kg b.wt.) given on the 20th day intraperitoneally. The 5-FU injection induced oxidative stress, inflammation, and extensive cardiac damage. Nevertheless, myricetin alleviated markers of inflammation, apoptosis, cardiac toxicity, oxidative stress, and upregulated anti-oxidative machinery. The histology of heart further supports our biochemical findings mitigated by the prophylactic treatment of myricetin. Henceforth, myricetin mitigates 5-FU-induced cardiac damage by modulating oxidative stress, inflammation, and cardiac-specific markers, as found in the present study.

Protective effect of chrysin, a flavonoid, on the genotoxic activity of carboplatin in mice.

Carboplatin is amongst the most commonly used anticancer drugs for the management of several human malignancies. However, it has displayed genotoxic properties against normal cells. Evaluation of natural products for their protective effects against chemotherapeutic drug induced toxicity has been growing in recent years. A naturally occurring flavonoid, chrysin, has strong antioxidant abilities and protects against DNA impairment. This study used multiple assays to evaluate the levels of damage to DNA in normal cells and to examine any possible protective role of chrysin against such damage. Male BALB/c mice were administered chrysin orally in two doses of 20 and 40 mg/kg for 10 consecutive days and then a single injection of carboplatin [90 mg/kg body weight (b.w.)] was administered intraperitoneally to induce carboplatin toxicity. 24 h after the carboplatin injection, mice were sacrificed. DNA damage was evaluated using several genotoxicity tests (8-Hydroxydeoxy-guanosine marker, comet assay, micronucleus test, and chromosomal aberration assay) to identify diverse types of damage to the DNA. The results suggest that pretreatment with chrysin significantly decreased the level of DNA damage caused by carboplatin probably due to its potent antioxidant traits. Therefore, chrysin can be considered to be developed as a chemoprotective agent against chemotherapy associated side-effects.

Sinapic acid ameliorates cardiac dysfunction and cardiomyopathy by modulating NF-κB and Nrf2/HO-1 signaling pathways in streptozocin induced diabetic rats.

Hyperglycemia and hyperlipidemia-arbitrated mitochondrial oxidative insult is key reason for cardiac dysfunction and cardiomyopathy. Sinapic acid (SA) is a hydroxycinnamic acid (a polyphenolic acid) present in multiple plants and possesses several pharmacological activities. In this study, we examined the cardio protective effects of SA on streptozotocin (STZ)-induced cardiac insults. STZ and both STZ induced diabetes and normal control rats were administered with 20 and 40 mg/kg SA for 12 weeks. STZ rats demonstrated hyperglycemia and hyperlipidemia. Additionally, STZ administered rats exhibited various histological changes in the cardiac muscles and significantly enhanced CK-MB and LDH. The significant enhancement of oxidative stress, inflammation, and apoptotic markers, and the capacity to curb oxidative stress was significantly abridged in the STZ induced diabetic heart. Chronic treatment with SA (20-40 mg/kg) ameliorated the increased level of glucose, lipid, and cardiac function markers and curtailed histological changes in the cardiac muscles. Chronic treatment also repressed inflammation, oxidative stress and apoptosis thereby and restoring antioxidant defenses in the myocardium of STZ induced diabetic rats. STZ induced cardiac dysfunction and cardiomyopathy by promoting inflammation and oxidative stress. Sinapic acid ameliorates cardiac dysfunction and cardiomyopathy via improvement of hyperglycemia, hyperlipidemia, inflammation, oxidative stress, and apoptosis. Thus, SA possesses possible therapeutic value for the prevention of diabetic cardiac dysfunction and cardiomyopathy via the NRF2/HO-1 and NF-κB pathways.

Eudragit-Coated Sporopollenin Exine Microcapsules (SEMC) of Phoenix dactylifera L. of 5-Fluorouracil for Colon-Specific Drug Delivery.

In this study, 5-fluorouracil (5-FU)-loaded pollens of Phoenix dactylifera and their coating with ERS was done and evaluated for the colon-targeted delivery of 5-FU to treat colon cancer. Sporopollenin exine microcapsules (SEMC) from the pollens of Phoenix dactylifera were extracted by the reflux method and 5-FU into SEMC was encapsulated by the vacuum-assisted loading method. 5-FU loaded SEMC was coated with Eudragit® RS-100 (ERS) by the organic solvent-evaporation technique under vacuum to avoid the discharge of 5-FU in the stomach and small intestine. Morphological and physicochemical characterization of drug-loaded SEMC (coated/uncoated) was performed by scanning electron microscopy (SEM), FTIR, XRD, and DSC. The encapsulation and drug loading were determined by the direct method, and an in vitro release study was performed in simulated gastric and intestinal fluids (SGF/SIF). The colon-specific delivery of 5-FU from the SEMC was assessed in terms of pharmacokinetics and gastrointestinal tract distribution after oral administration in rats. The successful encapsulation and loading of 5-FU into SEMC by a vacuum-assisted loading technique and its coating with ERS by a solvent-evaporation technique were achieved. SEM images of uncoated SEMC have shown porous structures, and coating with ERS reserved their morphology with a smooth surface and discrete microstructures and the 5% w/v ERS acetone solution. ERS-coated SEMC sustained the release of 5-FU until 24 h in SIF, while it was up to 12 h only from uncoated SEMC. The maximum plasma concentration (Cmax) of 5-FU from uncoated SEMC was 102.82 µg/mL after 1 h, indicating a rapid release of 5-FU in the upper gastrointestinal tract. This concentration decreased quickly with a half-life of 4 h, AUC0-t was 264.1 µg/mL.h, and MRT0-inf was 5.2 h. The Cmax of 5-FU from ERS-coated SEMC was 19.47 µg/mL at 16 h. The Cmax of 5-FU in small intestines was 406.2 µg/g at 1 h from uncoated SEMC and 1271.5 µg/g at 12 h from coated SEMC. Conclusively, a 249.9-fold higher relative bioavailability of 5-FU was achieved with the ERS-coated SEMC in colon tissues than that from uncoated SEMC.

Tocilizumab and Systemic Corticosteroids in the Management of Patients with COVID-19: A Systematic Review and Meta-Analysis.

BACKGROUND: To date, there is no effective treatment for the new coronavirus disease (COVID-19). We aimed to systematically review the literature on the association between the combination of tocilizumab (TCZ) and systemic corticosteroid therapy (SCT) on outcomes of COVID-19 patients. METHODS: We searched MEDLINE, Cochrane Central, and preprints, for studies in which health outcomes were compared between adults with severe COVID-19 who received TCZ and SCT and those who received standard of care without TCZ. Record screening, data extraction, and risk of bias assessment were performed in duplicate. Random effect models were used when pooling crude numbers and adjusted effect estimates of study outcomes. RESULTS: Our search identified seventeen studies. The pooled crude mortality rate was lower in the combination arm (relative risk, RR=0.62, 95% confidence interval [CI]=0.42 - 0.91; I2=60%). The adjusted mortality rates were also lower in the combination arm (RR=0.58, 95% CI=0.42 - 0.81; I2=71%). The rate of superinfections did not differ between the two interventions. CONCLUSIONS: The findings of this study show that combination of TCZ and SCT compared to SOC has lower mortality rates. There is an urgent need for well-designed randomized trials to assess the safety and efficacy of this combination in subjects with severe COVID-19.

The potential role of thymoquinone in preventing the cardiovascular complications of COVID-19.

A new virus strain detected in late 2019 and not previously described in humans is the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which causes corona virus disease (COVID-19). While potential therapeutic approaches for COVID-19 are being investigated, significant initiatives are being made to create protective drugs and study various antiviral agents to cure the infection. However, an effective treatment strategy against COVID-19 is worrisome inadequate. The objective of the present manuscript is to discuss the potential role of thymoquinone (TQ) in preventing the cardiovascular complications of COVID-19, focusing on viral inhibition, antioxidant potential, vascular effect, and cardiac protection. The multifunctional properties of TQ could potentially synergize with the activity of current therapeutic interventions and offer a basis for managing COVID-19 disease more effectively. Even though the experimental evidence is positive, a translational application of TQ in COVID-19 is timely warranted.

Gastroprotective Effect of Sinapic Acid on Ethanol-Induced Gastric Ulcers in Rats: Involvement of Nrf2/HO-1 and NF-κB Signaling and Antiapoptotic Role.

Background: In the current study, we evaluated the therapeutic potential of sinapic acid (SA) in terms of the mechanism underlying its gastroprotective action against ethanol-induced gastric ulcers in rats. Methods: These effects were examined through gross macroscopic evaluation of the stomach cavity [gastric ulcer index (GUI)], alteration in pH, gastric juice volume, free acidity, total acidity, total gastric wall mucus, and changes in PGE2. In addition, we evaluated lipid peroxidation (malondialdehyde), antioxidant systems (catalase and glutathione), inflammatory markers [tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6), and myeloperoxidase (MPO)], apoptotic markers (caspase-3, Bax, and Bcl-2), nuclear factor-κB [NF-κB (p65)], NO levels, and histopathological staining (H and E and PAS). Results: In rats with ethanol-induced ulcers, pre-treatment with SA (40 mg/kg p. o.) decreased the sternness of ethanol-induced gastric mucosal injuries by decreasing the GUI, gastric juice volume, free acidity, and total acidity. In addition, the pH and total gastric mucosa were increased, together with histopathological alteration, neutrophil incursion, and increases in PGE2 and NO2. These effects were similar to those observed for omeprazole, a standard anti-ulcer drug. SA was shown to suppress gastric inflammation through decreasing TNF-α, IL-6, and MPO, as well as curbing gastric oxidative stress through the inhibition of lipid peroxidation (MDA) and restoration of depleted glutathione and catalase activity. SA inhibited Bcl-2-associated X (Bax) and caspase-3 activity, and restored the antiapoptotic protein Bcl-2; these findings indicate the antiapoptotic potential of SA, leading to enhanced cell survival. SA also repressed NF-κB signaling and increased IκBα. Moreover, SA upregulated the nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1), thereby restoring depleted antioxidant defense enzymes and implicating the NRF2/HO-1 signaling pathways. Conclusion: These results suggest that the prophylactic administration of SA (40 mg/kg) can ameliorate ethanol-induced gastric ulcers in rats primarily via the modulation of Nrf2/HO-1 and NF-κB signaling and subsequent enhancement of cell viability.

Enriched pharmacokinetic behavior and antitumor efficacy of thymoquinone by liposomal delivery.

Background: Thymoquinone (TQ) has potential anti-inflammatory, immunomodulatory and anticancer effects but its clinical use is limited by its low solubility, poor bioavailability and rapid clearance. Aim: To enhance systemic bioavailability and tumor-specific toxicity of TQ. Materials & methods: Cationic liposomal formulation of TQ (D1T) was prepared via ethanol injection method and their physicochemical properties, anticancer effects in orthotopic xenograft pancreatic tumor model and pharmacokinetic behavior of D1T relative to TQ were evaluated. Results: D1T showed prominent inhibition of pancreatic tumor progression, significantly greater in vivo absorption, approximately 1.5-fold higher plasma concentration, higher bioavailability, reduced volume of distribution and improved clearance relative to TQ. Conclusion: Encapsulation of TQ in cationic liposomal formulation enhanced its bioavailability and anticancer efficacy against xenograft pancreatic tumor.

Sinapic acid mitigates methotrexate-induced hepatic injuries in rats through modulation of Nrf-2/HO-1 signaling.

The present research has been investigated to study the protective outcomes of sinapic acid (SA) against methotrexate (MTX) encouraged liver damage in rats by modulating the Nrf2/HO-1 and NF-κB signaling pathways. The animals were arbitrarily allocated into four groups: group I rats administered a 0.5% carboxymethyl cellulose (CMC) vehicle orally for 15 consecutive days with a single intravenous standard saline injection (0.9% NaCl) on day seven. Groups II, III, and IV were injected intraperitoneally with 20 mg MTX/kg on 7th day. Animals in group III and IV were treated orally for 14 days with 20 mg of SA/kg dissolved daily in 0.5% CMC respectively. In all experimental groups, liver function, biochemical, histopathological and molecular changes were evaluated. MTX-induced changes in liver function indices like ALT, AST, and ALP are substantially restored with SA pretreatment. Moreover, antioxidant defense mechanisms (GSH, SOD, and CAT) and oxidative/nitrostative stress (MDA and NO) and inflammatory cytokine (TNF-α, IL-ß and MPO) were also substantially restored. Furthermore, the conclusions indicate that SA prevents the hepatic damage caused by MTX through apoptosis inhibition and stimulation of Nrf2/HO-1-medial antioxidant enzymes by NF-κB inhibition. Histological findings have shown that SA therapy has greatly protected liver damage caused by MTX.

Saudi Arabia, pharmacists and COVID-19 pandemic.

The latest outbreak of Covid-19 pandemic has placed a significant effect on health care system around the world. This article discusses the role of pharmacists in Saudi Arabia during the current Covid-19 pandemic. Pharmacists are an important part of everyday healthcare in Saudi Arabia. Pharmacists helped to protect the public from Covid-19 pandemic disease by participating in various initiatives including health education and promotion, medication dispensing, medication reconciliation, medication and patient counselling, training for self-management in current outbreak and emergency preparedness. Full utilization of skills of pharmacists boosted the safety response of Saudi Arabia to Covid-19 pandemic.

A Sensitive Rapid and Environmentally Friendly UHPLC Assay Method for the Determination of Thymoquinone in Plasma Samples and Its Analytical Application.

A precise, swift and environmental-friendly reverse phase ultra-high performance liquid chromatographic assay for the determination of thymoquinone (TQ) in plasma samples using thymol (TM) as an internal standard was developed and validated. The method used a high strength silica C18 1.7 µm column (100 × 2.1 mm) with an isocratic mobile phase consisting of a blend of methanol and 20 mM potassium dihydrogen ortho-phosphate (90:10 v/v; pH of 4.2). The selected eluent provided a short run time (≤2 min), better peak symmetry, lower limit of quantification of 10 ng/mL and satisfactory values of other chromatographic parameters including resolution (Rs = 1), capacity factor (k = 21.5 and 14.5 for TQ and TM, respectively), selectivity (α = 1.482) and number of theoretical plates (N = 1653 and 784 for TQ and TM, respectively). The method was efficiently applied to a pharmacokinetic study of TQ following an intraperitoneal administration of 2 mg/kg in mice. The concentrations of TQ in plasma were measurable up to 12 h with Cmax of 404.08 ± 28.91 ng/mL, T1/2 of 2.31 ± 0.10 h and area under plasma concentration-time curve of 1527.00 ± 46.61 ng/mL × h.

Gender effect on the pharmacokinetics of thymoquinone: Preclinical investigation and in silico modeling in male and female rats.

Thymoquinone is the most biologically active constituent of Nigella sativa (black seed). A monoterpene compound chemically known as 2-methyl-5-isopropyl-1, 4-quinone. In this study, the gender-dependent pharmacokinetic behavior of thymoquinone in rats was investigated. Thymoquinone was administered orally (20 mg/kg) and intravenously (5 mg/kg) to male and female rats and blood samples were collected at specific time points. Plasma concentration-time curves were plotted and pharmacokinetic parameters were determined using the non-compartmental analysis. In addition, simulations of steady state concentrations of thymoquinone in male and female rats were performed using GastroPlus PK software. After oral administration, the maximum plasma concentration (Cmax) of thymoquinone was 4.52 ±â€¯0.092 µg/ml in male rats and 5.22 ±â€¯0.154 µg/ml in female rats (p = 0.002). Similarly, after intravenous administration, the Cmax was 8.36 ±â€¯0.132 µg/ml in males and 9.51 ±â€¯0.158 µg/ml in females (p = 0.550). The area under the plasma concentration-time curve (AUC)0-∞ following oral dosing was 47.38 ±â€¯0.821 µg/ml·h in females and 43.63 ±â€¯0.953 µg/ml·h in males (p = 0.014). Pharmacokinetics and plasma concentration vs. time profiles for multiple oral doses of thymoquinone in rats were predicted using a simulation model to compare the simulation results with the experimental plasma pharmacokinetic data. The differences observed in thymoquinone pharmacokinetics between male and female rats after a single dose were not evident for the simulated steady-state parameters. The findings suggest that the gender difference does not seem to play a significant role in thymoquinone disposition at steady state.