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Papers by Yolande Saab

Objective: Genetic, environmental, physiological and pathophysiological factors contribute to the... more Objective: Genetic, environmental, physiological and pathophysiological factors contribute to the interindividual variability in drug metabolism and response. Among the different cytochromes responsible for drug disposition, cytochrome P450 2D6 (CYP2D6) is a polymorphic enzyme accountable for the clearance of 25% to 30% of medications used including cardiovascular and neuroactive drugs. Severe clinical implications can result from CYP2D6 polymorphism, hence the significance of studying the incidence of different phenotypes in the white Lebanese population. Methods: A 30-mg dose of dextromethorphan hydrobromide was administered to 156 volunteers. Urine samples were collected 8 hours after dextromethorphan administration then stored at-80°C until analysis for dextromethorphan levels and its metabolites using a sensitive, simple high-performance liquid chromatography assay. Results: The distribution frequency histogram of CYP2D6 metabolic ratios (MRs) showed a bimodal distribution with a gap between the metabolic ratios of 0.14 and 0.31 corresponding to log MR between-0.85 and-0.51. This gap correlates well with the antimode of MR=0.3 reported by previous studies in white populations. Sixteen subjects were classified as poor metabolizers accounting for 10.25% of the whole population sample with metabolic ratios ranging from 0.31 to 25.77; in contrast, 140 (89.75%) volunteers were found to be extensive metabolizers exhibiting MRs between 0.000439 and 0.139. Conclusions: The findings demonstrated the presence of a high proportion of CYP2D6 poor metabolizers in the white Lebanese population and hence the sig

EThOS - Electronic Theses Online ServiceGBUnited Kingdo

Pharmacogenetics and Genomics

Objective The aim of the study was to investigate the gene polymorphisms of angiotensin-convertin... more 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 outnum...

Toxics

Phthalate esters (PAEs) are plasticizers associated with multiple toxicities; however, no strict ... more 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,...

Objective: Genetic, environmental, physiological and pathophysiological factors contribute to the... more Objective: Genetic, environmental, physiological and pathophysiological factors contribute to the interindividual variability in drug metabolism and response. Among the different cytochromes responsible for drug disposition, cytochrome P450 2D6 (CYP2D6) is a polymorphic enzyme accountable for the clearance of 25% to 30% of medications used including cardiovascular and neuroactive drugs. Severe clinical implications can result from CYP2D6 polymorphism, hence the significance of studying the incidence of different phenotypes in the white Lebanese population.

EThOS - Electronic Theses Online ServiceGBUnited Kingdo

Journal of the Renin-Angiotensin-Aldosterone System, 2011

Aim: The study objective was to examine the association of hypertension in the Lebanese populatio... more Aim: The study objective was to examine the association of hypertension in the Lebanese population with three renin–angiotensin system gene polymorphisms (RAS): angiotensin-converting enzyme (ACE), angiotensinogen (AGT) and angiotensin-receptor type 1 (AT1R). Methods: A total of 270 subjects (124 hypertensive vs 146 normotensive) were genotyped for ACE insertion (I)/deletion (D), AGT (M235T), and AT1R (A1166C) gene polymorphisms by polymerase chain reaction and restriction fragment length polymorphism. Results: The studied genes showed no deviation from Hardy–Weinberg equilibrium. No association could be reported with the ACE I/D polymorphism, although the D allele frequency was high (77%) in patients. AGT TT genotype prevalence was found to be lower in hypertensive versus normotensive subjects ( p < 0.0001). AT1R CC and AC genotypes were significantly more frequent in hypertensive than normotensive subjects ( p < 0.0001). Conclusion: The first conducted study on the RAS gene ...

The Pharmacogenomics Journal

Human cytochrome P450 2C9(CYP2C9) accounts for ~20%of hepatic total cytochrome P450 content and m... more Human cytochrome P450 2C9(CYP2C9) accounts for ~20%of hepatic total cytochrome P450 content and metabolizes～15% clinical drugs,especially the drugs with a narrow therapeutic index.CYP2C9 is highly polymorphism.Many results have shown that the genetic polymorphisms of CYP2C9 have close relationship with drug metabolism and adverse drug reaction.According to CYP2C9 enzyme activity,CYP2C9 could be classified as extensive metabolizers,intermedia metabolizers and poor metabolizers.The relationship between genetic polymorphisms and phenotypes,have become the prevalent research topics in the area of pharmacogenetics.In this paper,we reviewed the genetic polymorphisms of CYP2C9 in four areas:the mechanism,metabolic phenotype,drug metabolism and disease susceptibility.

Environmental risk assessment of anti-cancer drugs and their transformation products is a major c... more 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, Ca...

Environmental Science and Pollution Research

Water contamination with pharmaceutical products is a well-studied problem. Numerous studies have... more Water contamination with pharmaceutical products is a well-studied problem. Numerous studies have demonstrated the presence of anticancer drugs in different water resources that failed to be eliminated by conventional wastewater treatment plants. The purpose of this report was to conduct a systematic review of anticancer drugs in the aquatic environment. The methodology adopted was carried out in compliance with the PRISMA guidelines. From the 75 studies that met the specific requirements for inclusion, data extracted showed that the most common anticancer drugs studied are cyclophosphamide, tamoxifen, ifosfamide and methotrexate with concentrations measured ranging between 0.01 and 86,200 ng/L. There was significant variation in the methodologies employed due to lack of available guidelines to address sampling techniques, seasonal variability and analytical strategy. The most routinely used technique for quantitative determination was found to be solid-phase extraction followed by ...

Pharmacogenomics and Personalized Medicine

Variability in response to warfarin is one of the main obstacles challenging its use in clinical ... more Variability in response to warfarin is one of the main obstacles challenging its use in clinical practice. Vitamin K epoxide reductase complex (VKORC) is the target enzyme of warfarin, and variations in the form of single nucleotide polymorphisms (SNPs) in VKORC1, coding for this enzyme, are known to cause resistance to warfarin treatment. This study aimed to explore VKORC1 variants in Emirati patients receiving warfarin treatment and to correlate their genotypes at the studied SNPs to their maintenance warfarin dose. Patients and methods: Sanger sequencing of the majority of the VKORC1 gene was applied to samples from 90 patients and 117 normal individuals recruited from Tawam Hospital, Al-Ain, UAE. Genotypes at the following variants were determined (rs9923231, rs188009042, rs61742245, rs17708472, rs9934438, rs8050894, rs2359612, rs7294). Statistical analysis was applied, including ANOVA, cross-tabulation, and multiple linear regression analysis, to determine the ability of nongenetic factors (age and gender) and genetic factors (VKORC1 genotypes) to explain variability in warfarin dose in patients. Results: Different frequencies of minor alleles were detected in the selected SNPs. Significant variation among genotypes at six VKORC1 variants were identified (rs9923231, rs9934438, rs8050894, rs2359612, rs7294). The main predictors for warfarin dose were rs9923231, age, and rs61742245 with 50.7% of the average warfarin dose in our sample could be explained by a regression model built on these three factors. Conclusion: This is the first report of the explanatory power of VKORC1 genotypes and nongenetic factors (age and gender) on warfarin dose among Emiratis. Also, this study highlighted the positive effect of considering rare pharmacogenomic variants on explaining warfarin dose variability.

Journal of Pharmacy Practice and Research

... Yolande B. Saab*, Leyla Sharaf, Ismail Zeidan, Abdelrahman Bizri ... McQuaker IG, Hunter AE, ... more ... Yolande B. Saab*, Leyla Sharaf, Ismail Zeidan, Abdelrahman Bizri ... McQuaker IG, Hunter AE, Pacey S, Haynes AP, Iqbal A, Russell NH (1997) Low-dose filgrastim significantly enhances neutrophil recovery following autologous peripheral blood stem-cell transplantation in ...

Phytother Res, 2004

The methanol extract of the leaves of Centaurium erythraea L. (Gentianaceae) was evaluated for he... more The methanol extract of the leaves of Centaurium erythraea L. (Gentianaceae) was evaluated for hepatoprotective activity against acetaminophen-induced liver toxicity in rats. An oral dose of 300 mg/kg/day for 6 days or a single dose of 900 mg/kg for 1 day exhibited a significant protective effect by lowering serum glutamate oxaloacetate transaminase (SGOT), glutamate pyruvate transaminase (SGPT) and lactate dehydrogenase (LDH). The activity of the extract was supported by histopathological examination of liver sections.

Therapeutics and Clinical Risk Management, 2015

Response to clopidogrel varies widely with nonresponse rates ranging from 4% to 30%. A reduced fu... more 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.

International Journal of Pharmacy and Pharmaceutical Sciences

Pharmacology & Pharmacy, 2011

Background: There is little knowledge about genotyping of cytochrome P450s in the Middle East, an... more Background: There is little knowledge about genotyping of cytochrome P450s in the Middle East, and there has not been any report on the genotype of CYP2C9 allelic variants in Lebanese population. Aims and objectives: The purpose of the study was to determine and compare the frequencies of the cytochrome P450 CYP2C9 variants in the Lebanese population with the frequencies in other ethnic populations. Methods: CYP2C9 genotypes were determined in a total of 146 samples of unrelated, healthy Lebanese individuals residing in different areas in Lebanon. Following DNA extraction from buccal cells and polymerase chain reaction, genotyping was performed by Pyrosequencing method. CYP2C9 genotypes results were compared to other populations'; i.e., Middle Easterns, Europeans, Asians, and African Americans. Results and discussion: The frequencies of the CYP2C29*2, CYP2C9*3, and CYP2C9*4 alleles were 11.305%, 11.645%, and 1.025% respectively. No CYP2C9*5 allele variants were found among the Lebanese study sample. Volunteers could be divided into three CYP2C9 genotype groups: subjects (76.71%) with no mutated alleles (CYP2C9*1*1; homozygous extensive metabolizers, EM), 21.23% with one mutated allele (CYP 2C9*1*2, *1*3, *1*4, and *1*5; heterozygous intermediate metabolizers IM), and 2.06% with two mutated alleles, homozygous variants as poor metabolizers, PM). The comparative analysis using genotype groups of different populations showed differences among Lebanese and other Caucasians. Conclusion: This is the first report from Lebanon on CYP2C9 variants; it highlights a higher frequency of CYP2C9 extensive metabolizers compared to other populations including Caucasians. The results serve as a database on CYP 2C9 polymorphisms and baseline clinical data for dosing and avoiding adverse drug reactions of drugs metabolised by CYP2C9 in Lebanese patients.

Objective: Genetic, environmental, physiological and pathophysiological factors contribute to the... more Objective: Genetic, environmental, physiological and pathophysiological factors contribute to the interindividual variability in drug metabolism and response. Among the different cytochromes responsible for drug disposition, cytochrome P450 2D6 (CYP2D6) is a polymorphic enzyme accountable for the clearance of 25% to 30% of medications used including cardiovascular and neuroactive drugs. Severe clinical implications can result from CYP2D6 polymorphism, hence the significance of studying the incidence of different phenotypes in the white Lebanese population. Methods: A 30-mg dose of dextromethorphan hydrobromide was administered to 156 volunteers. Urine samples were collected 8 hours after dextromethorphan administration then stored at-80°C until analysis for dextromethorphan levels and its metabolites using a sensitive, simple high-performance liquid chromatography assay. Results: The distribution frequency histogram of CYP2D6 metabolic ratios (MRs) showed a bimodal distribution with a gap between the metabolic ratios of 0.14 and 0.31 corresponding to log MR between-0.85 and-0.51. This gap correlates well with the antimode of MR=0.3 reported by previous studies in white populations. Sixteen subjects were classified as poor metabolizers accounting for 10.25% of the whole population sample with metabolic ratios ranging from 0.31 to 25.77; in contrast, 140 (89.75%) volunteers were found to be extensive metabolizers exhibiting MRs between 0.000439 and 0.139. Conclusions: The findings demonstrated the presence of a high proportion of CYP2D6 poor metabolizers in the white Lebanese population and hence the sig

EThOS - Electronic Theses Online ServiceGBUnited Kingdo

Pharmacogenetics and Genomics

Objective The aim of the study was to investigate the gene polymorphisms of angiotensin-convertin... more 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 outnum...

Toxics

Phthalate esters (PAEs) are plasticizers associated with multiple toxicities; however, no strict ... more 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,...

Objective: Genetic, environmental, physiological and pathophysiological factors contribute to the... more Objective: Genetic, environmental, physiological and pathophysiological factors contribute to the interindividual variability in drug metabolism and response. Among the different cytochromes responsible for drug disposition, cytochrome P450 2D6 (CYP2D6) is a polymorphic enzyme accountable for the clearance of 25% to 30% of medications used including cardiovascular and neuroactive drugs. Severe clinical implications can result from CYP2D6 polymorphism, hence the significance of studying the incidence of different phenotypes in the white Lebanese population.

EThOS - Electronic Theses Online ServiceGBUnited Kingdo

Journal of the Renin-Angiotensin-Aldosterone System, 2011

Aim: The study objective was to examine the association of hypertension in the Lebanese populatio... more Aim: The study objective was to examine the association of hypertension in the Lebanese population with three renin–angiotensin system gene polymorphisms (RAS): angiotensin-converting enzyme (ACE), angiotensinogen (AGT) and angiotensin-receptor type 1 (AT1R). Methods: A total of 270 subjects (124 hypertensive vs 146 normotensive) were genotyped for ACE insertion (I)/deletion (D), AGT (M235T), and AT1R (A1166C) gene polymorphisms by polymerase chain reaction and restriction fragment length polymorphism. Results: The studied genes showed no deviation from Hardy–Weinberg equilibrium. No association could be reported with the ACE I/D polymorphism, although the D allele frequency was high (77%) in patients. AGT TT genotype prevalence was found to be lower in hypertensive versus normotensive subjects ( p < 0.0001). AT1R CC and AC genotypes were significantly more frequent in hypertensive than normotensive subjects ( p < 0.0001). Conclusion: The first conducted study on the RAS gene ...

The Pharmacogenomics Journal

Human cytochrome P450 2C9(CYP2C9) accounts for ~20%of hepatic total cytochrome P450 content and m... more Human cytochrome P450 2C9(CYP2C9) accounts for ~20%of hepatic total cytochrome P450 content and metabolizes～15% clinical drugs,especially the drugs with a narrow therapeutic index.CYP2C9 is highly polymorphism.Many results have shown that the genetic polymorphisms of CYP2C9 have close relationship with drug metabolism and adverse drug reaction.According to CYP2C9 enzyme activity,CYP2C9 could be classified as extensive metabolizers,intermedia metabolizers and poor metabolizers.The relationship between genetic polymorphisms and phenotypes,have become the prevalent research topics in the area of pharmacogenetics.In this paper,we reviewed the genetic polymorphisms of CYP2C9 in four areas:the mechanism,metabolic phenotype,drug metabolism and disease susceptibility.

Environmental risk assessment of anti-cancer drugs and their transformation products is a major c... more 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, Ca...

Environmental Science and Pollution Research

Water contamination with pharmaceutical products is a well-studied problem. Numerous studies have... more Water contamination with pharmaceutical products is a well-studied problem. Numerous studies have demonstrated the presence of anticancer drugs in different water resources that failed to be eliminated by conventional wastewater treatment plants. The purpose of this report was to conduct a systematic review of anticancer drugs in the aquatic environment. The methodology adopted was carried out in compliance with the PRISMA guidelines. From the 75 studies that met the specific requirements for inclusion, data extracted showed that the most common anticancer drugs studied are cyclophosphamide, tamoxifen, ifosfamide and methotrexate with concentrations measured ranging between 0.01 and 86,200 ng/L. There was significant variation in the methodologies employed due to lack of available guidelines to address sampling techniques, seasonal variability and analytical strategy. The most routinely used technique for quantitative determination was found to be solid-phase extraction followed by ...

Pharmacogenomics and Personalized Medicine

Variability in response to warfarin is one of the main obstacles challenging its use in clinical ... more Variability in response to warfarin is one of the main obstacles challenging its use in clinical practice. Vitamin K epoxide reductase complex (VKORC) is the target enzyme of warfarin, and variations in the form of single nucleotide polymorphisms (SNPs) in VKORC1, coding for this enzyme, are known to cause resistance to warfarin treatment. This study aimed to explore VKORC1 variants in Emirati patients receiving warfarin treatment and to correlate their genotypes at the studied SNPs to their maintenance warfarin dose. Patients and methods: Sanger sequencing of the majority of the VKORC1 gene was applied to samples from 90 patients and 117 normal individuals recruited from Tawam Hospital, Al-Ain, UAE. Genotypes at the following variants were determined (rs9923231, rs188009042, rs61742245, rs17708472, rs9934438, rs8050894, rs2359612, rs7294). Statistical analysis was applied, including ANOVA, cross-tabulation, and multiple linear regression analysis, to determine the ability of nongenetic factors (age and gender) and genetic factors (VKORC1 genotypes) to explain variability in warfarin dose in patients. Results: Different frequencies of minor alleles were detected in the selected SNPs. Significant variation among genotypes at six VKORC1 variants were identified (rs9923231, rs9934438, rs8050894, rs2359612, rs7294). The main predictors for warfarin dose were rs9923231, age, and rs61742245 with 50.7% of the average warfarin dose in our sample could be explained by a regression model built on these three factors. Conclusion: This is the first report of the explanatory power of VKORC1 genotypes and nongenetic factors (age and gender) on warfarin dose among Emiratis. Also, this study highlighted the positive effect of considering rare pharmacogenomic variants on explaining warfarin dose variability.

Journal of Pharmacy Practice and Research

... Yolande B. Saab*, Leyla Sharaf, Ismail Zeidan, Abdelrahman Bizri ... McQuaker IG, Hunter AE, ... more ... Yolande B. Saab*, Leyla Sharaf, Ismail Zeidan, Abdelrahman Bizri ... McQuaker IG, Hunter AE, Pacey S, Haynes AP, Iqbal A, Russell NH (1997) Low-dose filgrastim significantly enhances neutrophil recovery following autologous peripheral blood stem-cell transplantation in ...

Phytother Res, 2004

The methanol extract of the leaves of Centaurium erythraea L. (Gentianaceae) was evaluated for he... more The methanol extract of the leaves of Centaurium erythraea L. (Gentianaceae) was evaluated for hepatoprotective activity against acetaminophen-induced liver toxicity in rats. An oral dose of 300 mg/kg/day for 6 days or a single dose of 900 mg/kg for 1 day exhibited a significant protective effect by lowering serum glutamate oxaloacetate transaminase (SGOT), glutamate pyruvate transaminase (SGPT) and lactate dehydrogenase (LDH). The activity of the extract was supported by histopathological examination of liver sections.

Therapeutics and Clinical Risk Management, 2015

Response to clopidogrel varies widely with nonresponse rates ranging from 4% to 30%. A reduced fu... more 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.

International Journal of Pharmacy and Pharmaceutical Sciences

Pharmacology & Pharmacy, 2011

Background: There is little knowledge about genotyping of cytochrome P450s in the Middle East, an... more Background: There is little knowledge about genotyping of cytochrome P450s in the Middle East, and there has not been any report on the genotype of CYP2C9 allelic variants in Lebanese population. Aims and objectives: The purpose of the study was to determine and compare the frequencies of the cytochrome P450 CYP2C9 variants in the Lebanese population with the frequencies in other ethnic populations. Methods: CYP2C9 genotypes were determined in a total of 146 samples of unrelated, healthy Lebanese individuals residing in different areas in Lebanon. Following DNA extraction from buccal cells and polymerase chain reaction, genotyping was performed by Pyrosequencing method. CYP2C9 genotypes results were compared to other populations'; i.e., Middle Easterns, Europeans, Asians, and African Americans. Results and discussion: The frequencies of the CYP2C29*2, CYP2C9*3, and CYP2C9*4 alleles were 11.305%, 11.645%, and 1.025% respectively. No CYP2C9*5 allele variants were found among the Lebanese study sample. Volunteers could be divided into three CYP2C9 genotype groups: subjects (76.71%) with no mutated alleles (CYP2C9*1*1; homozygous extensive metabolizers, EM), 21.23% with one mutated allele (CYP 2C9*1*2, *1*3, *1*4, and *1*5; heterozygous intermediate metabolizers IM), and 2.06% with two mutated alleles, homozygous variants as poor metabolizers, PM). The comparative analysis using genotype groups of different populations showed differences among Lebanese and other Caucasians. Conclusion: This is the first report from Lebanon on CYP2C9 variants; it highlights a higher frequency of CYP2C9 extensive metabolizers compared to other populations including Caucasians. The results serve as a database on CYP 2C9 polymorphisms and baseline clinical data for dosing and avoiding adverse drug reactions of drugs metabolised by CYP2C9 in Lebanese patients.