Yolande B. Saab

Objective The study aims to verify the usage of mathematical modeling in predicting patients’ medication doses in association with their genotypes versus real-world data. Methods The work relied on collecting, extracting, and using real-world data on dosing and patients’ genotypes. Drug metabolizing enzymes, i.e., cytochrome CYP 450, were the focus. A total number of 1914 subjects from 26 studies were considered, and CYP2D6 and CYP2C19 gene polymorphisms were used for the verification. Results Results show that the mathematical model was able to predict the reported optimal dosing of the values provided in the considered studies. Predicting patients’ optimal doses circumvents trial and error in patients’ treatments. Discussion The authors discussed the advantages of using a mathematical model in patients’ dosing and identified multiple issues that would hinder the usability of raw data in the future, especially in the era of artificial intelligence (AI). The authors recommend that researchers and healthcare professionals use simple descriptive metabolic activity terms for patients and use allele activity scores for drug dosing rather than phenotype/genotype classifications. Conclusion The authors verified that a mathematical model could assist in providing data for better-informed decision-making in clinical settings and drug research and development.

Codeine is metabolized by the CYP2D6 enzyme, and individuals with certain genetic variations of the CYP2D6 gene may metabolize codeine differently, leading to variable efficacy and toxicity. Drug-drug interactions can also affect the metabolism of codeine. A tool to adjust codeine dose based on these factors does not currently exist. Healthcare providers should use their clinical judgment and reference different established dosing guidelines to determine the appropriate dose of codeine for individual patients. The study provides a tool that assists prescribers in adjusting codeine dose based on CYP2D6 gene-pair polymorphisms and drug-drug interactions. Highlighted is the need to consider pharmacogenetics and drug-drug interactions when determining the appropriate dosing of codeine and provide a framework for implementing individualized dosing based on these factors.

Objective: The aim of the study was to investigate the gene polymorphisms of angiotensin-converting enzyme (ACE), angiotensinogen (AGT), and angiotensin type 1 receptor (AT1R) in association with coronavirus disease 2019 (COVID-19) mortality rates worldwide. Methods: The prevalence of ACE I/D, AGT M235T, and AT1R A1166C alleles’ frequencies in different populations was assessed. Data on COVID-19-related cases and deaths were acquired from the European Center for Disease Prevention and Control, which included weekly reports by country and continent. An Excel tool was developed to visualize the acquired data of mortality and incidence by classifying them by continent/country across specific periods of time. Spearman’s nonparametric correlation was used to evaluate the association between country-based frequencies in RAS gene polymorphisms and COVID-19-related deaths. Results: While China constituted the initial reservoir of COVID-19, incidence/mortality rates in Europe and America outnumbered the figures in the former. A clear association was identified between death rates and ACE D/I (r = 0.3659; P = 0.033), as well as AGT A/G variants (r = 0.7576; P = 0.015). Data on AT1R polymorphisms suggested no correlation with mortality rates. Conclusion: Our results demonstrated a significant disparity in COVID-19-related susceptibility and mortality among different populations and corroborate the importance of gene polymorphisms in predicting and consequently improving patients’ outcomes.

Phthalate esters (PAEs) are plasticizers associated with multiple toxicities; however, no strict regulations have been implemented to restrict their use in medical applications in Lebanon. Our study aimed at assessing the potential risks correlated with phthalate exposure from IV bags manufactured in Lebanon. GC–MS analysis showed that di-(2-ethylhexyl) phthalate (DEHP) is the predominant phthalate found in almost all samples tested with values ranging from 32.8 to 39.7% w/w of plastic. DEHP concentrations in the IV solutions reached up to 148 µg/L, as measured by SPME-GC–MS/MS, thus resulting in hazard quotients greater than 1, specifically in neonates. The toxicity of DEHP is mainly attributed to its metabolites, most importantly mono-(2-ethylhexyl) phthalate (MEHP). The IV bag solution with the highest content in DEHP was therefore used to extrapolate the amounts of urinary MEHP. The highest concentrations were found in neonates having the lowest body weight, which is concerning, knowing the adverse effects of MEHP in infants. Our study suggests that the use of IV bags manufactured in Lebanon could pose a significant risk in hospitalized patients, especially infants in neonatal care. Therefore, Lebanon, as well as other countries, should start imposing laws that restrict the use of phthalates in medical IV bags and substitute them with less toxic plasticizers.

Environmental risks imposed by anti-cancer drugs and their degradation products are a major concern worldwide. The consumption of anticancer drugs is increasing throughout the years and conventional water treatment processes seem to be ineffective for their removal. The aim of this study is to analyze the consumption of anticancer drugs in Lebanon and assess their potential health hazard as contaminants of the Lebanese surface waters. Anticancer drugs consumption data between the years 2013 and 2018 were collected and the following parameters were calculated: yearly consumption of single active ingredients, yearly consumption of drug equivalents (for drugs belonging to the same pharmacologic class having the same active ingredient) and Predicted Environmental Concentrations (PECs). The obtained PEC values were used to stratify compounds into risk categories. The top five most commonly consumed drugs are Mycophenolate mofetil, Hydroxycarbamide, Capecitibine, Mycophenolic acid and Azathioprine. Based on the calculated PEC values of single active ingredients as well as their equivalents, six high-risk priority compounds were identified: Mycophenolate mofetil, Hydroxycarbamide, Capecitibine, Mycophenolic acid, Azathioprine and 5-Fluorouracil. The impact of these micropollutants on animals as well as humans was analyzed. This research stresses the importance of further analysis of chemotherapy micropollutants with major focus on high-risk drugs. Additionally, regulations should be set in place to ensure proper management of wastewater and the development of efficient wastewater treatment plants.

Environmental risk assessment of anti-cancer drugs and their transformation products is a major concern worldwide due to two main factors: the consumption of chemotherapeutic agents is increasing throughout the years and conventional water treatment processes seem to be ineffective. The aim of the study is to investigate the consumption of anticancer drugs and assess their potential health hazard as contaminants of the Lebanese surface waters. Data on yearly consumption of 259 anti-neoplastic drugs over the years 2013 to 2018 were collected and the following parameters were calculated: yearly consumption of single active ingredients, yearly consumption of drug equivalents (for drugs belonging to the same pharmacologic class/ having the same active ingredient) and Predicted Environmental Concentrations (PECs). The classification of compounds into risk categories was based on exposure using PECs. The top five most commonly consumed drugs are Mycophenolate mofetil, Hydroxycarbamide, Capecitibine, Mycophenolic acid and Azathioprine. Based on the calculated PEC values of single active ingredients as well as their equivalents, six high risk priority compounds were identified: Mycophenolate mofetil, Hydroxycarbamide, Capecitibine, Mycophenolic acid and Azathioprine and 5-Fluorouracil. The impact of these micropollutants on animals as well as humans was analyzed. This research paper stresses the importance of further analysis of chemotherapy micropollutants with major focus on high risk drugs. Additionally, regulations should be set in place to ensure proper management of waste water and the development of efficient waste water treatment plants.

Purpose: Response to clopidogrel varies widely with nonresponse rates ranging from 4% to 30%. A reduced function of the gene variant of the CYP2C19 has been associated with lower drug metabolite levels, and hence diminished platelet inhibition. Drugs that alter CYP2C19 activity may also mimic genetic variants. The aim of the study is to investigate the cumulative effect of CYP2C19 gene polymorphisms and drug interactions that affects clopidogrel dosing, and apply it into a new clinical-pharmacogenetic algorithm that can be used by clinicians in optimizing clopidogrel-based treatment. Method: Clopidogrel dose optimization was analyzed based on two main parameters that affect clopidogrel metabolite area under the curve: different CYP2C19 genotypes and concomitant drug intake. Clopidogrel adjusted dose was computed based on area under the curve ratios for different CYP2C19 genotypes when a drug interacting with CYP2C19 is added to clopidogrel treatment. A clinical-pharmacogenetic algorithm was developed based on whether clopidogrel shows 1) expected effect as per indication, 2) little or no effect, or 3) clinical features that patients experience and fit with clopidogrel adverse drug reactions. Results: The study results show that all patients under clopidogrel treatment, whose genotypes are different from *1*1, and concomitantly taking other drugs metabolized by CYP2C19 require clopidogrel dose adjustment. To get a therapeutic effect and avoid adverse drug reactions, therapeutic dose of 75 mg clopidogrel, for example, should be lowered to 6 mg or increased to 215 mg in patients with different genotypes. Conclusion: The implementation of clopidogrel new algorithm has the potential to maximize the benefit of clopidogrel pharmacological therapy. Clinicians would be able to personalize treatment to enhance efficacy and limit toxicity.

Simple and cost-effective methods are needed to extract DNA in order to use it in large-scale studies. Blood is an excellent DNA source; however, it is costly and invasive thus an alternative is needed. Several kits and chemical protocols using buccal cells have been proposed for DNA extraction. The objective of the study is to evaluate buccal NaOH chemical protocol and Nucleospin^® Tissue Kit (BD Biosciences, Macery-Nagel, Germany) for DNA extraction. DNA swab samples were collected from 300 voluntary participants. DNA yields and purity were measured by NaOH and Nucleospin^® Tissue Kit techniques; the cost and time consumption for DNA extraction per sample were assessed as well. Results have shown that DNA amount and purity extracted by NaOH procedure was compared to that of the kit (p = 0.164; p = 0.249, respectively). NaOH method was considered cheaper and less time consuming (0.06 versus 3.80 USD, and 1.33 versus 3.59 minutes per sample, p < 0.001). Buccal cell derived DNA extracted by NaOH protocol can be considered a feasible substitute for more expensive and time-consuming kits.