The effects of genetic polymorphism on toxicity and pharmacokinetics of methotrexate in Egyptian adult patients with leukaemia or lymphoma.

Polymorphisms in genes coding folate-metabolising enzymes might alter the pharmacokinetics and sensitivity for methotrexate "MTX".The aim of the study aimed to investigate the influence of MTHFR C677T, DHFR19 Ins/del, GGH -401 C > T, and MTR A2756G polymorphisms on MTX toxicity and pharmacokinetics in Egyptian patients with Acute lymphoblastic leukaemia (ALL) or Non-Hodgkin lymphoma (NHL).Fifty adult Egyptian patients with ALL and NHL, treated with high dose MTX, were prospectively enrolled in the study. Clinical and biochemical data was collected objectively from medical records after each cycle of MTX. Plasma concentrations of MTX were measured after 72 h of initiation of infusion. Genotyping was done with a PCR-ARMS and PCR-RFLP assays.The MTHFR C677T T variants significantly increased the risk of leukopoenia, whereas the genotype MTHFR 677 C > T TT significantly associated with lymphocytopenia, thrombocytopenia, and anaemia. The genotype GGH-401 TT was significantly correlated with anaemia. Plasma MTX level was significantly higher in patients with MTR A2756G G variants.MTHFR polymorphism played the main role in MTX toxicities. The pharmacokinetics of MTX was affected by MTR polymorphism. GGH mutation was mainly concerned with anaemia. Pharmacogenetic testing are recommended to optimise MTX therapy.

Clinical and Laboratory Factors Related to Seizure and Serotonin Toxicity in Tramadol Intoxication: An Egyptian Study.

BACKGROUND AND OBJECTIVES: Tramadol is a centrally acting analgesic with a lower risk of addiction compared to opioids. Tramadol overdose is becoming a health crisis in Egypt and is associated with serious and severe adverse effects. This study aims to identify clinical and laboratory findings associated with tramadol-induced seizure and serotonin toxicity in adult Egyptian patients with tramadol overdose. METHODS: This prospective study included adult patients admitted for tramadol overdose with or without symptoms of seizure or serotonin toxicity. Basic demographic information, clinical symptoms, laboratory measurements, and plasma tramadol concentrations were collected. RESULTS: A total of 71 patients (79% males) were included in the study. Seizure occurred in 38% of the subjects and was prevalent in male patients with metabolic acidosis or high tramadol concentrations. Serotonin toxicity occurred in 41% of the subjects and was prevalent in patients with hyperthermia, high pulse rate, and high tramadol levels. CONCLUSION: Seizure and serotonin toxicity are severe adverse effects of tramadol overdose that occur in high frequency among young Egyptians. High tramadol concentrations in plasma seem to play a key role in prevalence of seizure and serotonin syndrome in tramadol-intoxicated adult Egyptians.

Prevalence of Drug-Drug Interactions in Primary Care Prescriptions in Egypt: A Cross-Sectional Retrospective Study.

In clinical practice, drug-drug interactions (DDIs) pose significant risks to a large number of patients. Consequently, healthcare providers are required to diligently identify, monitor, and effectively handle these interactions in order to enhance patient outcomes. In Egypt, DDIs are poorly addressed, with no reports for DDIs in primary care. In our cross-sectional, retrospective, observational study, we collected a total of five thousand, eight hundred and twenty prescriptions across eight major governorates in Egypt. Prescriptions were collected over a span of 15 months between 1 June 2021 and 30 September 2022. These prescriptions were analyzed for potential DDIs using the Lexicomp® drug interactions tool. The prevalence of DDIs was found to be 18%, with 22% of the prescriptions having two or more potential DDIs. Moreover, we found 1447 DDIs of categories C (monitoring therapy recommended), D (therapy modification suggested), and X (avoid combination). The most commonly interacting drugs in our study were diclofenac, aspirin, and clopidogrel, while non-steroidal anti-inflammatory drugs (NSAIDs) were the most reported therapeutic class implicated in pharmacologic DDIs. Pharmacodynamic agonistic activity was the most common mechanism of interaction. Therefore, it is crucial to conduct screenings, detect early signs, and closely monitor drug-drug interactions (DDIs) to enhance patients' overall health outcomes, medication responses, and safety. In this regard, the clinical pharmacist assumes a vital role in implementing these preventive measures.

Changes in dietary habits during Covid-19 lockdown in Egypt: the Egyptian COVIDiet study.

PURPOSE: COVID-19 lockdown changed social habits and lifestyle, including dietary habits, of people worldwide. However, limited information is available about these changes in Egypt. This cross-sectional study investigates the effects of COVID-19 lockdown on dietary habits among the Egyptian populations. METHODS: An online questionnaire, based on sociodemographic data and dietary adherence in accordance with the validated PREDIMED MedDiet Adherence Screener (MEDAS), was used all over the Egyptian governorates. The dietary changes were statistically evaluated for significance in relation to age, gender, body mass index (BMI), education level and governorates. RESULTS: A total of 1010 participants (76% aged below 36 years, 77% female, 22% obese, and 62% university-level education) answered the questionnaire. Respondents ≤ 20 years had a significant increase in weight and consumption of carbonated beverages, commercial pastries, fried and fast food. Egyptians > 50 years old had a significant decrease in physical activity. Underweight people (less than 3% of participants) increased their fast food intake with a prominent rise in weight. However, obese people increased cooking frequency and increased eating times with a decrease in physical activity. Male participants reported increased intake of carbonated beverages and fast food, while female participants increased the intake of homemade pastries with a significant decrease in physical activity. Approximately 50% of participants with postgraduate education reported decreased intake of fast food and carbonated beverages as well as decreased body weight. Residents of Cairo showed a significant increase in vegetable intake, and fried food intake with a decrease in seafood consumption. Participants from the Delta region had a significant increase in pastries intake. CONCLUSION: The findings of this study explored the need for increasing awareness about healthy lifestyle in future lockdown periods.

Simple HPLC-UV Method for Piperacillin/Tazobactam Assay in Human Plasma.

BACKGROUND: Piperacillin (Pip)/tazobactam (Taz) is a broad-spectrum antimicrobial agent that has been commonly used in the intensive care unit for severe and life-threatening infections. Recent evidence suggests that therapeutic drug monitoring (TDM) for Pip could be beneficial in clinical practice to facilitate dose optimization and increase the odds of treatment success. The aim was to develop and validate a sensitive and simple high-performance liquid chromatography (HPLC) method for the simultaneous quantification of Pip and Taz in human plasma. METHODS: Samples (0.3 mL) were deproteinized with acetonitrile. The supernatant was evaporated and then reconstituted and injected into the HPLC. The chromatographic analysis was carried out by using the C18 column and gradient elution with the acetonitrile:water mobile phase mixture with 0.1% trifluoracetic acid at a flow rate of 0.8 mL/min using a UV detector at 218 nm. RESULTS: The method had acceptable linearity (r2 > 0.99) over the concentration ranges of 0.5-400 µg/mL and 1-100 µg/mL for Pip and Taz, respectively. The method demonstrated acceptable inter- and intra-day precision and accuracy within ±20% with adequate stability results. CONCLUSION: The developed method is sensitive and simple and utilizes simple sample preparation and elution steps, making it suitable and practical for Pip/Taz TDM.

The promising role of CCL2 as a noninvasive marker for nonalcoholic steatohepatitis diagnosis in Egyptian populations.

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is a common liver problem, including both nonalcoholic fatty liver (NAFL) and nonalcoholic steatohepatitis (NASH). In this study, we investigated the role of CCL2 and IL6 as a noninvasive tool for the diagnosis of NASH in clinical practice and to establish criteria for discrimination NASH from NAFL in Egyptian populations with NAFLD. METHOD: In addition to 30 healthy controls, serum samples from 66 NAFLD patients histologically diagnosed by biopsy (32 NAFL and 34 NASH) were analyzed for serum IL6, CCL2, liver biomarkers, complete blood count and lipid profile. Serum IL6 or CCL2 levels were tested for correlation with the NASH activity score (NAS score). RESULT: Both IL6 and CCL2 were significantly upregulated in NASH patients compared with NAFL patients or control. Serum CCL2 was significantly correlated with the degree of hepatocytes ballooning (the diagnostic endpoint for NASH) without any significant correlation with steatosis or lobular inflammation. Serum IL6 was not correlated with the NAS score. The ROC curve analysis of CCL2 for NASH diagnosis revealed an area under curve (AUROC) of 0.959 at cutoff ≥227 pg/ml. While IL6 revealed an (AUROC) of 0.790. CONCLUSION: Serum CCL2 but not IL6 is a promising noninvasive tool for NASH diagnosis and CCL2 can provide a reliable, validated scoring system to discriminate NAFL from NASH in the Egyptian population confirming the role of CCL2 in NASH pathogenesis. These findings will aid in the development of innovative NASH treatment strategies in Egypt and improve the quality of clinical care.

The Antihypertensive Effect of Quercetin in Young Spontaneously Hypertensive Rats; Role of Arachidonic Acid Metabolism.

Hypertension affects almost 50% of the adult American population. Metabolites of arachidonic acid (AA) in the kidney play an important role in blood pressure regulation. The present study investigates the blood pressure-lowering potential of quercetin (QR), a naturally occurring polyphenol, and examines its correlation to the modulation of AA metabolism. Spontaneously hypertensive rats (SHR) were randomly divided into four groups. Treatment groups were administered QR in drinking water at concentrations of 10, 30, and 60 mg/L. Blood pressure was monitored at seven-day intervals. After a total of seven weeks of treatment, rats were killed and kidney tissues were collected to examine the activity of the two major enzymes involved in AA metabolism in the kidney, namely cytochrome P450 (CYP)4A and soluble epoxide hydrolase (sEH). Medium- and high-dose QR resisted the rise in blood pressure observed in the untreated SHR and significantly inhibited the activity of the CYP4A enzyme in renal cortical microsomes. The activity of the sEH enzyme in renal cortical cytosols was significantly inhibited only by the high QR dose. Our data not only demonstrate the antihypertensive effect of QR, but also provide a novel mechanism for its underlying cardioprotective properties.

Effects of Green Tea Extract on Atorvastatin Pharmacokinetics in Healthy Volunteers.

BACKGROUND AND OBJECTIVES: Green tea catechins were recently reported to inhibit drug transporters such as organic anion-transporting polypeptides (OATPs) and metabolic enzymes, affecting the bioavailability of many drugs. This study aimed to evaluate the clinical significance of the effects of different doses of green tea extract on the pharmacokinetic parameters of atorvastatin and to rationalize the associated interaction mechanism. METHODS: A randomized, double-blind, three-phase crossover study involving 12 healthy volunteers was performed. Participants received a single dose of atorvastatin 40 mg alone (control group), atorvastatin 40 mg plus a capsule containing 300 mg of dry green tea extract, or atorvastatin 40 mg plus a capsule containing 600 mg of dry green tea extract. Plasma samples taken from the volunteers were analyzed for atorvastatin using liquid chromatography-tandom mass spectrometry (LC/MS/MS). RESULTS: Compared to atorvastatin alone, the administration of 300 mg or 600 mg of the green tea extract along with atorvastatin decreased the peak plasma concentration (Cmax) of atorvastatin by 25% and 24%, respectively (P < 0.05), and the area under the plasma concentration-time curve (AUC0-∞) of atorvastatin by 24% and 22%, respectively (P < 0.05). Additionally, administration of 300 mg or 600 mg of the green tea extract increased the apparent oral clearance (CL/F) of atorvastatin by 31% and 29%, respectively. The time to Cmax (Tmax) and the elimination half-life (t1/2) of atorvastatin did not differ among the three phases. The effects of 600 mg of the green tea extract on the pharmacokinetic parameters of atorvastatin were not significantly different from the effects of 300 mg of the green tea extract. CONCLUSION: Green tea extract decreases the absorption but not the elimination of atorvastatin, possibly by inhibiting OATP, albeit not in a dose-dependent manner. Coadministration of green tea extract with atorvastatin may necessitate the monitoring of the plasma concentration of atorvastatin in clinical practice.

Effect of Dietary Doses of Quercetin on Hepatic Drug Metabolizing Enzymes in Spontaneously Hypertensive Rats.

BACKGROUND: Administration of quercetin (QR) has shown several health benefits in clinical and pre-clinical studies. OBJECTIVE: This study investigates the effect of dietary doses of QR on hepatic drug metabolizing enzymes in spontaneously hypertensive rats in order to investigate the potential for herb-drug interactions. METHODS: The activity and/or protein expression of selected cytochrome P450 (CYP) enzymes and microsomal epoxide hydrolase were measured in hepatic microsomes using specific probe substrates and/or polyclonal antibodies. Cytosolic fraction was utilized to measure protein level and activity of major antioxidant systems. RESULTS: The doses employed in our study did not cause any significant alterations in the activity and/or protein level of CYP1A1, CYP2A6, CYP2E, and glutathione (GSH). While the activity and apoprotein levels of CYP1A2 and CYP2B1/2 were significantly reduced by the medium and high doses of QR, the activity and/or protein level of microsomal CYP3A and cytosolic GSH-S-transferase, GSH reductase, and GSH peroxidase were significantly enhanced. Activity and protein level of CYP2C9 were significantly inhibited by all doses. Only the high-dose QR resulted in significant inhibition of both microsomal and soluble epoxide hydrolase as well as induction of the antioxidant enzymes, catalase and superoxide dismutase. CONCLUSION: This study demonstrates that dietary doses of QR may offer chemoprevention through stimulation of the endogenous antioxidant systems and inhibition of CYP enzymes involved in bioactivation of procarcinogens. However, modulation of drug metabolizing enzymes by QR could have potential for herb-drug interactions with the possibility of serious complications.

Studying the Inhibitory Effect of Quercetin and Thymoquinone on Human Cytochrome P450 Enzyme Activities.

BACKGROUND: Quercetin (QR) and thymoquinone (TQ) are herbal remedies that are currently extensively used by the general population to prevent and treat various chronic conditions. Therefore, investigating the potential of pharmacokinetic interactions caused by the concomitant use of these herbal remedies and conventional medicine is warranted to ensure patient safety. PURPOSE OF THE STUDY: This study was conducted to determine the inhibitory effect of QR and TQ, two commonly used remedies, on the activities of selected cytochrome P450 (CYP) enzymes that play an important role in drug metabolism and/or toxicology. MATERIALS AND METHODS: The in vitro studies were conducted using fluorescence-based high throughput assays using human c-DNA baculovirus expressed CYP enzymes. For measuring CYP2E1 activity, a validated High-performance liquid chromatography (HPLC) assay was utilized to measure the formation of 6-hydroxychlorzoxazone. RESULTS: The obtained half-maximum inhibitory concentration values with known positive control inhibitors of this study were comparable to the published values indicating accurate experimental techniques. Although QR did not show any significant effect on CYP1A2 and CYP2E1, it exhibited a strong inhibitory effect against CYP2D6 and a moderate effect against CYP2C19 and CYP3A4. On the other hand, TQ demonstrated a strong and a moderate inhibitory effect against CYP3A4 and CYP2C19, respectively. CONCLUSIONS: The findings of this study may indicate that consumption of QR or TQ, in the form of food or dietary supplements, with drugs that are metabolized by CYP2C19, CYP2D6, or CYP3A4 may cause significant herb-drug interactions. SUMMARY: Neither QR nor TQ has any significant inhibitory effect on the activity of CYP1A2 or CYP2E1 enzymesBoth QR and TQ have a moderate to strong inhibitory effect on CYP3A4 activityQR has a moderate inhibitory effect on CYP2C19 and a strong inhibitory effect on CYP2D6Both QR and TQ are moderate inhibitors of the CYP2C9 activity. Abbreviations used: ABT: Aminobenztriazole, BZF: 7,8 Benzoflavone, CYP: Cytochrome P450, GB: Gingko Biloba, IC50: Half-maximum inhibitory concentration, KTZ: Ketoconazole, QND: Quinidine, QR: Quercetin, TCP: Tranylcypromine, TQ: Thymoquinone.

Pharmacokinetics and Pharmacodynamics of Promising Arginase Inhibitors.

Up-regulation of arginase activity in several chronic disease conditions, including cancer and hypertension, may suggest new targets for treatment. Recently, the number of new arginase inhibitors with promising therapeutic effects for asthma, cancer, hypertension, diabetes mellitus, and erectile dysfunction has shown a remarkable increase. Arginase inhibitors may be chemical substances, such as boron-based amino acid derivatives, α-difluoromethylornithine (DMFO), and Nω-hydroxy-nor-L-arginine (nor-NOHA) or, of plant origin such as sauchinone, salvianolic acid B (SAB), piceatannol-3-O-ß-D-glucopyranoside (PG) and obacunone. Despite their promising therapeutic potential, little is known about pharmacokinetics and pharmacodynamics of some of these agents. Several studies were conducted in different animal species and in vitro systems and reported significant differences in pharmacokinetics and pharmacodynamics of arginase inhibitors. Therefore, extra caution should be considered before extrapolating these studies to human. Physicochemical and pharmacokinetic profiles of some effective arginase inhibitors make it challenging to formulate stable and effective formulation. In this article, existing literature on the pharmacokinetics and pharmacodynamics of arginase inhibitors were reviewed and compared together with emphasis on possible drug interactions and solutions to overcome pharmacokinetics challenges and shortage of arginase inhibitors in clinical practice.

A new validated HPLC method for the determination of quercetin: Application to study pharmacokinetics in rats.

A simple, accurate, and reproducible high-performance liquid chromatography (HPLC) method has been developed and validated for the quantification of quercetin (QR) in rat plasma. The method involves a simple protein precipitation procedure to extract both QR and thymoquinone (TQ), the internal standard. The chromatographic analysis was achieved on a Shimadzu LC 20 A HPLC system equipped with a Supelcosil LC-18 T C18 column and an isocratic mobile phase consisting of 0.3% trichloroacetic acid in water and acetonitrile HPLC-grade (50:50, v/v) run at a flow rate of 0.9 mL/min for 13 min. The UV detection wavelength was set at 254 nm. The method exhibited good linearity (R2 > 0.994) over the assayed concentration range (0.10-25 µg/mL) and demonstrated good intra-day and inter-day precision and accuracy (relative standard deviations and the deviation from predicted values were <20%). This method was also successfully applied for studying the pharmacokinetics of QR in rats following a single oral dose of QR to evaluate its pharmacokinetic parameters in rats.

Effects of Lemon and Seville Orange Juices on the Pharmacokinetic Properties of Sildenafil in Healthy Subjects.

PURPOSE: Several severe drug interactions have been reported when sildenafil, a potent drug for the treatment of erectile dysfunction, is co-administered with drugs or herbal remedies that inhibit cytochrome P450 (CYP) 3A4. This study evaluates the effects of two citrus fruit juices, lemon and Seville orange, on the pharmacokinetics of sildenafil in male healthy subjects following a single oral dose. METHODS: We conducted an open-label, three-way crossover study in nine healthy male volunteers. Participants received a single oral dose of sildenafil (50 mg) after pretreatment with 250 mL of either water (control), undiluted lemon juice, or Seville orange juice for 3 consecutive days. All subjects were monitored for adverse effects during the study period. Plasma samples were collected for 12 h after dosing and analyzed for sildenafil concentration. RESULTS: Compared with pretreatment with water, Seville orange juice significantly increased the area under the plasma concentration-time curve from time zero to infinity and the peak plasma concentration of sildenafil by 44 % (90 % confidence interval [CI] 30-60) and 18 % (90 % CI 108-129), respectively, without affecting the time to reach peak plasma concentration. Additionally, Seville orange juice significantly reduced the apparent oral clearance of sildenafil by 30 % (90 % CI 63-75) without affecting its elimination half-life. In contrast, lemon juice did not cause any significant alterations in the pharmacokinetics of sildenafil. There was no significant treatment-related adverse effects reported during the study. CONCLUSIONS: Although it is considered as a moderate CYP3A4 inhibitor, Seville orange only caused a mild increase in exposure to sildenafil after a single oral dose, without manifestation of any adverse effects. The enhanced bioavailability of sildenafil by Seville orange may be attributed to inhibition of its intestinal first-pass effect (CYP3A4 and or p-glycoprotein). Lemon juice, in contrast, had no effects on the pharmacokinetics of sildenafil.