Interrater and Intrarater Reliability of a Handheld Myotonometer in Measuring Mechanical Properties of the Neck and Orofacial Muscles.

OBJECTIVE: The purpose this study was to investigate the reliability of a handheld myotonometer in measuring the mechanical properties of the neck and orofacial muscles in asymptomatic individuals. METHODS: The study included 16 healthy participants. The mechanical properties (frequency, decrement, stiffness, relaxation time, and creep) of the selected muscles were measured with a MyotonPRO myotonometer (Mumeetria Ltd, Tallinn, Estonia). The sternocleidomastoid, upper trapezius, cervical extensor, and masseter muscles were selected to determine the reliability of the device. Measurements were performed by 2 examiners to determine interrater reliability; for intrarater reliability, an examiner repeated the measurements 1 week after the first measurements. RESULTS: The results revealed moderate to excellent intrarater and interrater reliability (intraclass correlation coefficients: 0.50-0.95) in measuring muscle mechanic properties. The standard error of measurement in the tested muscles ranged from 0.3 to 0.8 Hz for frequency, from 7.4 to 20.9 N/m for stiffness, from 0.1 to 0.2 for decrement, and from 0.8 to 1.4 ms for relaxation time. The minimum detectable change ranged from 0.8 to 2.2 Hz for frequency, from 20.5 to 57.9 N/m for stiffness, from 0.2 to 0.6 for decrement, from 2.2 to 3.9 ms for relaxation time, and from 0.2 to 0.3 for creep. In addition, the coefficients of variation were below 9.1% for all the assessed parameters. CONCLUSION: The obtained results demonstrate that the MyotonPRO device is a reliable and repeatable tool to quantify the frequency, stiffness, decrement, relation time, and creep of the neck and orofacial muscles in asymptomatic individuals.

The role of pharmacogenetics of cytochrome P450s in phenytoin-induced DRESS syndrome.

Anil et al. (2017) report a patient who presented with drug rash with eosinophilia and systemic symptom (DRESS) syndrome. It may be induced by various drugs. In the mentioned report DRESS syndrome has been attributed to phenytoin use. CYP2C9 is a genetically polymorphic enzyme, and decreased metabolism of many drugs has been reported in the subjects carrying variants of rs1799853 and rs1057910, which were designated as CYP2C9*2 and *3. rs3758581, the variant investigated by Anil et al., is a genetic variant of CYP2C19 (not that of CYP2C9, as stated and discussed in the report). CYP2C19 is also a highly genetically polymorphic enzyme, and rs3758581 may be present in 40 different haplotypes of CYP2C19 including *2 and *17 (for detailed information: www.pharmvar.org/gene/CYP2C19). Detection of rs3758581 is not sufficient because the patient presented by Anil H et al. may have CYP2C19*2, CYP2C19*17, or any other variant due to the co-appearance of other possible genetic variations. It is of importance to perform the correct genetic analysis because CYP2C19*2 is associated with low enzyme activity but CYP2C19*17 is associated with increased enzyme activity. CYP2C9 is a major enzyme responsible for the metabolism of phenytoin. CYP2C9*2 (rs1799853) and *3 (rs1057910) should be considered in a Caucasian subject. CYP2C19 (especially *2 and *17) and ABCB1 polymorphisms may also be considered for the evaluation of the patient. Additionally, serum phenytoin levels would be helpful to understand the contribution of genetic polymorphisms on the pharmacokinetics of phenytoin in the patients presenting side effects like DRESS syndrome.

Lower CYP2C9 activity in Turkish patients with Behçet's disease compared to healthy subjects: a down-regulation due to inflammation?

BACKGROUND: We previously reported on a Swedish patient with Behçet's disease (BD) who was an ultra-rapid metaboliser of drugs catalysed by CYP2C9. Was this extreme metabolism caused by the disease? AIM: This study aims to compare the genotype/phenotype of CYP2C9 in patients with BD and healthy subjects. As the occurrence of BD is high in Turkey, all subjects were recruited from this country. METHODS: Genotyping of CYP2C9 was performed using standard PCR-RFLP and allele-specific PCR methods. Phenotyping of CYP2C9 was performed by administration of a 50-mg single oral dose of losartan and by calculating the urinary metabolic ratio (MR) of probe drug to its metabolite E-3174. Quantitation was performed by HPLC. RESULTS: The frequency of CYP2C9*2 and *3 was not significantly different between the Behçet's disease patients (12.5 and 8.7%) and the healthy subjects (8.9 and 8.2%). The geometric mean losartan MR was higher in the 52 patients (1.75) than in the 96 healthy subjects (1.02) (p = 0.002; t-test). Within the genotypes *1/*1, there was a significant difference of MR between patients and healthy subjects (P = 0.006). All but three of the Behçet's disease patients were treated with colchicine. In nine subsequent patients, we found no significant effect of 2 weeks of treatment with colchicine on the CYP2C9 MR. CONCLUSION: Contrary to expectation, the CYP2C9 activity was lower in Turkish BD patients compared to healthy subjects. As this seems not to be due to colchicine treatment, our hypothesis is that inflammation related to BD might have caused the down-regulation of the CYP2C9 activity due to immune cytokine reactions. The ultra-rapid metabolism of CYP2C9 substrate drugs in the Swedish patient was not due to her BD.

Association between ADH1C and ALDH2 polymorphisms and alcoholism in a Turkish sample.

BACKGROUND: Polymorphisms in the genes encoding alcohol metabolizing enzymes are associated with alcohol dependence. AIM: To evaluate the association between the alcohol dehydrogenase 1C (ADH1C) Ile350Val and aldehyde dehydrogenase 2 (ALDH2) Glu504Lys polymorphisms and alcohol dependence in a Turkish sample. METHODS: 235 individuals (115 alcohol-dependent patients and 120 controls) were genotyped for ADH1C and ALDH2 with PCR-RFLP (polymerase chain reaction-restriction fragment length polymorphism). Association between the polymorphisms and family history, daily and maximum amount of alcohol consumed was investigated. The associations between alcohol dependence, severity of consumption and family history and the polymorphisms were analyzed by chi-square or Fisher's exact test where necessary. Relationship between genotypes and dependence related features was evaluated using analysis of variance (ANOVA). RESULTS: The -350Val allele for ADH1C (ADH1C*2) was increased in alcohol-dependent patients (P = 0.05). In individuals with a positive family history, the genotype distribution differed significantly (P = 0.031) and more patients carried the Val allele compared with controls (P = 0.025). Genotyping of 162 participants did not reveal the -504Lys allele in ALDH2. CONCLUSIONS: These findings suggest that ADH1C*2 is associated with alcohol dependence in the Turkish population displaying a dominant inheritance model. ADH1C*2 allele may contribute to the variance in heritability of alcohol dependence. The ALDH2 -504Lys/Lys or Glu/Lys genotypes were not present in alcohol-dependent patients, similar to that seen in European populations and in contrast to the findings in the Asian populations.

Evaluation of lansoprazole as a probe for assessing cytochrome P450 2C19 activity and genotype-phenotype correlation in childhood.

PURPOSE: Lansoprazole, a cytochrome P450 2C19 (CYP2C19) substrate, has been widely used in children to manage acid-related diseases. CYP2C19 exhibits marked genetic polymorphisms, and distribution of these polymorphisms varies among different ethnic groups. There is limited data regarding the use of probe drugs for determining CYP2C19 activity in children. The aim of this study was to evaluate lansoprazole as an in vivo phenotyping probe for assessing CYP2C19 activity in children. METHODS: The CYP2C19*2, *3, and *17 variants were determined in 244 children. Three hours after a single oral dose of lansoprazole (n = 94) or omeprazole (n = 19), plasma lansoprazole and 5-hydroxy lansoprazole or omeprazole and 5-hydroxy omeprazole concentrations were analyzed by high-performance liquid chromatography. RESULTS: The CYP2C19*17 was the most frequent variant allele (24.4%). The group of patients with CYP2C19*17*17 genotype had a 70% lower (p < 0.05) mean lansoprazole plasma concentration compared with the CYP2C19*1*1 genotype group, whereas the CYP2C19*2*2 group had 6.9-fold higher (p < 0.01) mean lansoprazole plasma concentration. Lansoprazole metabolic ratios (lansoprazole/5-hydroxy-lansoprazole) were found to be significantly lower in the *17*17 [mean ± standard deviation (SD); 2.8 ± 2.1] group and higher in the *2*2 group (63.5 ± 12.2) compared with that of the *1*1 genotype group (6.1 ± 4.5). CONCLUSION: According to our results from a Turkish pediatric population, lansoprazole is a suitable probe drug for phenotyping CYP2C19. The CYP2C19*2 and *17 variants should be taken into consideration in predicting the clinical outcome of therapy with lansoprazole in the pediatric population.

Acenocoumarol sensitivity and pharmacokinetic characterization of CYP2C9 *5/*8,*8/*11,*9/*11 and VKORC1*2 in black African healthy Beninese subjects.

This study aimed at investigating the contribution of CYP2C9 and VKORC1 genetic polymorphisms to inter-individual variability of acenocoumarol pharmacokinetics and pharmacodynamics in Black Africans from Benin. Fifty-one healthy volunteers were genotyped for VKORC1 1173C>T polymorphism. All of the subjects had previously been genotyped for CYP2C9*5, CYP2C9*6, CYP2C9*8, CYP2C9*9 and CYP2C9*11 alleles. Thirty-six subjects were phenotyped with a single 8 mg oral dose of acenocoumarol by measuring plasma concentrations of (R)- and (S)-acenocoumarol 8 and 24 h after the administration using chiral liquid-chromatography tandem mass-spectrometry. International normalized ratio (INR) values were determined prior to and 24 h after the drug intake. The allele frequency of VKORC1 variant (1173C>T) was 1.96% (95% CI 0.0-4.65%). The INR values did not show statistically significant difference between the CYP2C9 genotypes, but were correlated with body mass index and age at 24 h post-dosing (P < 0.05). At 8 h post dose, the (S)-acenocoumarol concentrations in the CYP2C9*5/*8 and CYP2C9*9/*11 genotypes were about 1.9 and 5.1 fold higher compared with the CYP2C9*1/*1 genotype and 2.2- and 6.0-fold higher compared with the CYP2C9*1/*9 group, respectively. The results indicated that pharmacodynamic response to acenocoumarol is highly variable between the subjects. This variability seems to be associated with CYP2C9*5/*8 and *9/*11 variant and demographic factors (age and weight) in Beninese subjects. Significant association between plasma (S)-acenocoumarol concentration and CYP2C9 genotypes suggested the use of (S)-acenocoumarol for the phenotyping purpose. Larger number of subjects is needed to study the effect of VKORC1 1173C>T variant due to its low frequency in Beninese population.

Association between the Glu298Asp and T(-786)C polymorphisms of the endothelial nitric oxide synthase gene and respiratory distress in preterm neonates.

Genetic polymorphisms in the gene that codes for endothelial nitric oxide synthase (eNOS) have been associated with less nitric oxide availability and with various cardiovascular diseases in humans. The objective of this study was to analyze the genotype distributions and allele frequencies for the Glu298Asp (G894T) and T(-786)C polymorphisms of the eNOS gene among neonates with respiratory distress in comparison to healthy control subjects. Fifty premature neonates with respiratory distress and 55 neonates without any respiratory problem were included in the study. Genomic DNA from all the neonates was analyzed by polymerase chain reaction. A polymerase chain reaction-restriction fragment length polymorphism analysis of eNOS gene polymorphisms was performed, and the results were compared. There were no significant differences between the groups regarding either genotype distributions or the allele frequencies for the Glu298Asp and T(-786)C polymorphisms. These results suggest that eNOS Glu298Asp and T(-786)C polymorphisms are not associated with development of respiratory distress.

Multidrug resistance in patients undergoing resective epilepsy surgery is not associated with C3435T polymorphism in the ABCB1 (MDR1) gene.

PURPOSE: The C3435T polymorphism in the gene coding for P-glycoprotein (ABCB1) has been correlated with drug resistance in patients with epilepsy. However, replication studies have revealed conflicting results and the reason for this is not clear. We investigated the frequency of C3435T polymorphism in epileptic Turkish patients who underwent resective epilepsy surgery and compared our results with healthy controls. METHODS: DNA samples were obtained from 100 healthy controls and 89 consecutive adult patients who underwent resective brain surgery due to refractory seizures at our epilepsy center. Genotypes for the C3435T polymorphism were determined by PCR and restriction analysis. RESULTS: Comparison of drug-resistant patients and healthy controls revealed no significant difference in allele frequency (C vs. T; chi(2)=0.015, p=0.90) and genotype frequency (chi(2)=2.05, p=0.36). The findings in the pure hippocampal sclerosis (HS) group (n=73) were not significantly different from control subjects, either (allele frequency: chi(2)=0.29, p=0.59; genotype frequency: chi(2)=2.14, p=0.34). CONCLUSIONS: Our findings failed to prove an association between C3435T polymorphism and drug resistance in a sample of Turkish patients with refractory epilepsy who underwent resective brain surgery.

Molecular diagnosis and clinical characterization of pseudohypoparathyroidism type-Ib in a patient with mild Albright's hereditary osteodystrophy-like features, epileptic seizures, and defective renal handling of uric acid.

We describe a patient who presented with epileptic seizures unresponsive to anticonvulsive treatment. Laboratory investigations demonstrated epileptiform seizure activity in the brain but also revealed severe hypocalcemia, hyperphosphatemia, and elevated serum parathyroid hormone. In addition, the patient showed a reduced serum level of 25-[OH]-vitamin D. The diagnosis of pseudohypoparathyroidism type-Ib (PHP-Ib) was made based on these clinical findings and upon identification of a 3-kb deletion within the STX16 locus, a genetic defect frequently associated with autosomal dominant PHP-Ib. This mutation was also present in the patient's unaffected mother and her affected sister. Despite the molecular diagnosis of PHP-Ib, which is characterized by parathyroid hormone resistance in the absence of Albright's hereditary osteodystrophy (AHO), the patient had a round face, slightly short stature, and short fourth metacarpals, which were consistent with mild AHO. The patient and her affected sister, who lacked AHO-like features, showed reduced serum levels of uric acid and increased fractional excretion of uric acid, a finding that was reported only once previously for PHP-Ib. Unlike the previous report, the fractional uric acid excretion and serum uric acid levels returned to normal in our patient and her sister after 3 months of treatment period. These findings underscore several important points with respect to the pathogenesis and clinical presentation of PHP-Ib. Furthermore, the findings in the index case present interesting novel aspects, including a previously undescribed coexistence of the 3-kb STX16 deletion and AHO-like features and a clinical course complicated by concomitant 25-[OH]-vitamin D deficiency, which may have resulted, at least partly, from long-term use of antiepileptic drugs.

Inhibitory effect of valproic acid on cytochrome P450 2C9 activity in epilepsy patients.

Drug interactions constitute a major problem in the treatment of epilepsy because drug combinations are so common. Valproic acid is a widely used anticonvulsant drug with a broad therapeutic spectrum. Case reports suggest interaction between valproic acid and other drugs metabolized mainly by cytochrome P450 isoforms. The aim of this study was to evaluate the inhibitory effect of valproic acid on cytochrome P450 2C9 (CYP2C9) activity by using losartan oxidation as a probe in epilepsy patients. Patients were prescribed sodium valproate (mean 200 mg/day for the first week and 400 mg/day in the following period) according to their clinical need. A single oral dose of 25 mg losartan was given to patients before and after the first dose, first week and 4 weeks of valproic acid treatment. Losartan and E3174, the CYP2C9-derived carboxylic acid metabolite of losartan in 8 hr urine were assayed by using high pressure liquid chromatography. Urinary losartan/E3174 ratio did not change significantly on the first day (0.9, 0.3-3.5; median, range), and first week (0.6, 0.2-3.8; median, range), while a significant increase was observed after 4 weeks of valproic acid treatment (1.1, 0.3-5.7; median, range) as compared to that of measured before valproic acid administration (0.6, 0.1-2.1; median, range) (P = 0.039). The degree of inhibition was correlated with the steady-state plasma concentrations of valproic acid (r(2) = 0.70, P = 0.04). The results suggest an inhibitory effect of valproic acid on CYP2C9 enzyme activity in epilepsy patients at steady state. The risk of pharmacokinetic drug-drug interactions should be taken into account during concomitant use of valproic acid and CYP2C9 substrates.

Successful treatment of propafenone, digoxin and warfarin overdosage with plasma exchange therapy and rifampicin.

We report here the successful treatment of a 16-year-old female who ingested 20 tablets of digoxin each containing 0.25 mg (total dose ingested equivalent to 0.1 mg/kg), 32 tablets of warfarin each containing 5mg (equivalent to 3.2 mg/kg), and approximately 15 tablets of propafenone each containing 300 mg (equivalent to 90 mg/kg). The patient developed hypotension and sinus bradycardia necessitating external cardiac pacing 17 hours after drug ingestion. In addition to gastric lavage, activated charcoal, blood alkalinisation, administration of vitamin K and temporary cardiac pacing, the authors performed plasma exchange for drug removal and administered rifampicin in order to increase the metabolism of digoxin, propafenone and warfarin. The patient was discharged without any sequelae. Plasma exchange may be lifesaving in drug ingestions where there is a low volume of distribution and high plasma protein binding. Rifampicin, an inducer of cytochrome p450, may be used in intoxications for elimination of drugs with inactive metabolites.

Effect of raloxifene on cerebral vasospasm following experimental subarachnoid hemorrhage in rats.

The effect of raloxifene on cerebral vasospasm following experimental subarachnoid hemorrhage (SAH) was investigated in a rat model. Seven groups of seven rats underwent no SAH, no treatment; SAH only; SAH plus vehicle; SAH plus 3 days intraperitoneal raloxifene treatment; SAH plus 4 days intraperitoneal raloxifene treatment; SAH plus 3 days intrathecal raloxifene treatment; and SAH plus 4 days intrathecal raloxifene treatment. The basilar artery cross-sectional areas were measured at 72 or 96 hours following SAH. The results showed raloxifene decreased SAH-induced cerebral vasospasm in all treatment groups, and suggested no difference between intraperitoneal and intrathecal application, or between 3 days and 4 days of raloxifene treatment. The present study demonstrates that raloxifene is a potential therapeutic agent against cerebral vasospasm after SAH.

Effects of Genetic Polymorphisms of Cytochrome P450 Enzymes and MDR1 Transporter on Pantoprazole Metabolism and Helicobacter pylori Eradication.

Pantoprazole is a proton pump inhibitor that is commonly used in the treatment of peptic ulcer disease (PUD) and metabolized by cytochrome P450 (CYP) enzymes CYP2C19 and CYP3A4. Pantoprazole is a substrate for multi-drug resistance protein 1 (MDR1). Single nucleotide polymorphisms (SNPs) in CYP2C19, CYP3A4 and MDR1 affect enzyme activity or gene expression of proteins and may alter plasma pantoprazole concentrations and treatment success in PUD. In this study, we aimed to investigate the association between genetic polymorphisms in CYP2C19, CYP3A4 and MDR1 and pharmacokinetics of pantoprazole and therapeutic outcome in patients with either Helicobacter pylori-associated [H.P.(+)]-PUD or [H.P.(+)]-gastritis. The plasma pantoprazole concentrations were determined by using an HPLC method at the third hour after a 40-mg tablet of pantoprazole administration in 194 newly diagnosed patients with either [H.P.(+)]-PUD or [H.P.(+)]-gastritis. Genotyping was performed by using PCR-RFLP and DNA sequencing. Among patients appearing for follow-up examination (n = 105), the eradication rate for H. pylori was 82.8% (n = 87). The median pantoprazole plasma concentrations in poor metabolizers (PM), rapid metabolizers (RM) and ultrarapid metabolizers (URM) were 2.07, 1.69 and 1.28 µg/ml, respectively (p = 0.04). CYP3A4*1G and *22 polymorphisms did not affect plasma pantoprazole concentrations and H. pylori eradication rate. The MDR1 genetic polymorphisms did not affect plasma pantoprazole concentrations. MDR1 3435CC-2677GG-1236CC haplotype carriers had lower H. pylori eradication rate (60%) than the remaining subjects (84.9%) while the difference was not statistically significant (p = 0.07). In conclusion, while CYP2C19 genetic polymorphisms significantly affected plasma pantoprazole concentrations, polymorphisms of CYP2C19, CYP3A4 and MDR1 did not affect H. pylori eradication rates.

Decreased Activity and Genetic Polymorphisms of CYP2C19 in Behçet's Disease.

Behçet's disease (BD) is a systemic autoimmune disorder. Cytochrome P450 enzymes (CYPs) are responsible for various drug metabolism reactions as well as those of endogenous substances which may be associated with autoimmune disease susceptibility. Recently, we reported that in patients with BD, CYP2C9 seems to be down-regulated due to inflammation. In the same Turkish patients with BD, we investigated whether also CYP2C19 activity is decreased. Lansoprazole (30 mg) was given as a probe drug to evaluate CYP2C19 activity in 59 patients with BD and 27 healthy control volunteers. An HPLC method was used to determine plasma lansoprazole and its metabolite, 5-hydroxy lansoprazole, concentrations. The genotyping for CYP2C19 *2, *3 and *17 polymorphisms was made using PCR-RFLP. The median lansoprazole/5-hydroxy lansoprazole metabolic ratio (MR) in patients with BD was 2.6-fold higher as compared to the healthy control group (p = 0.001, 22.6 (1.3-26) and 8.8 (0.5-140) as median and range, respectively). The CYP2C19*17*17 genotype frequency was found to be significantly less in the BD group as compared to the healthy controls (1.7% versus 14.8% in controls, p = 0.01). Additionally, colchicine treatment did not affect the CYP2C19 enzyme activity in six patients (p = 0.43). In conclusion, the patients with BD had lower CYP2C19 enzyme activity and lower frequency of the CYP2C19*17 allele as compared to those of the healthy controls. Further studies are warranted on the mechanisms underlying this relation. This study should also be applied to other autoimmune diseases similarly characterized by local or systemic inflammation.

Pharmacogenetics of cyclophosphamide in patients with hematological malignancies.

PURPOSE: A high degree of interindividual variation in cyclophosphamide (CPA) pharmacokinetics was reported in certain cancer patient groups. To better understand the mechanisms underlying the variation in CPA metabolism, we have investigated the pharmacokinetics of CPA and its active metabolite 4-hydroxycyclophosphamide (4-OH-CPA) in patients with hematological tumors. The pharmacokinetics of CPA and its active metabolite were related to the genotype of CYP2B6, CYP2C9 and CYP2C19. The influence of liver function on CPA metabolism was also evaluated. METHODS: Twenty-nine patients with hematological malignancies (MM, ALL or NHL) treated with a conventional CPA dose (1g/m(2)) were recruited to this study. Blood samples were collected before, during and after CPA treatment. HPLC was used to measure plasma concentrations of CPA and 4-OH-CPA. Patients were genotyped for the CYP2B6 G516T, CYP2C9*2, CYP2C9*3, CYP2C19*2 and CYP2C19*3 alleles. Serum bilirubin levels were measured before the treatment. Data was analyzed individually and by population pharmacokinetic methods, using non-linear mixed effect modeling. RESULTS: The interindividual variability in exposure to CPA, 4-OHCPA and 4-OH-CPA/CPA was 5.8-, 3.3- and 10.3-fold, respectively. A positive correlation between half-lives of CPA and 4-OH-CPA was found while a significant negative correlation between AUCs of CPA and 4-OH-CPA was detected. In the population analysis, the CYP2B6 G516T variant allele contribution to CPA clearance was about twice as the contribution from the wild type gene while the genotype of CYP2C9 and CYP2C19 did not influence clearance. A negative correlation was observed between bilirubin level and CPA bioactivation. CONCLUSION: This study demonstrates for the first time that the presence of the CYP2B6 G516T mutation increases the rate of 4-OH-CPA formation in patients with hematological malignancies. The liver function prior therapy as assessed by s-bilirubin influences CPA metabolism.

Inhibitory effect of 5-fluorouracil on cytochrome P450 2C9 activity in cancer patients.

Drug interactions have been reported between 5-fluorouracil and cytochrome P450 2C9 (CYP2C9) substrates, S-warfarin and phenytoin. This study was performed to determine the influence of 5-fluorouracil on cytochrome P450 2C9 (CYP2C9) activity in colorectal cancer patients (n=17) receiving 5-fluorouracil. Losartan was used as a marker to assess CYP2C9 activity. Losartan and its CYP2C9 dependent metabolite, E-3174, were determined in urine. The ratios of urinary losartan/E-3174 before and after the 5-fluorouracil treatment were compared for each patient. Genotyping was performed to detect the CYP2C9*2 and CYP2C9*3. At the end of the first cycle of 5-fluorouracil, losartan/E-3174 ratio was increased by 28.0% compared to the pre-treatment values (P=0.15). In five patients recruited for phenotyping after three 5-fluorouracil cycles, the metabolic ratio was increased significantly by 5.3 times (P=0.03). The results suggest that in most patients 5-fluorouracil inhibited CYP2C9 activity. This inhibition was more pronounced when the total administered dose increased. This finding may help explain the mechanism of interaction between 5-fluorouracil and CYP2C9 substrates.

[µ-Opioid Receptor Gene (OPRM1) Polymorphisms A118G and C17T in Alcohol Dependence: A Turkish Sample]. / Türkiye'de Alkol Bagimliliginda µ-Opioid Reseptör Geni (OPRM1) A118G ve C17T Polimorfizmleri.

OBJECTIVES: Previous investigations on opioid system genetics have identified polymorphisms of the OPRM1 gene expressing µ-opioid receptors to be significantly associated with some features of alcohol dependence (AD). In the present study, we evaluated the relationship between single nucleotide polymorphisms (SNP) in the OPRM1 gene, A118G (rs1799971, Asn40Asp) and C17T (rs1799972, Arg6Val), and AD diagnosis, level of alcohol consumption, and AD severity in a Turkish sample. METHODS: 121 AD patients and 117 healthy male subjects were included in the study. OPRM1 A118G (N40D) and C17T (A6V) polymorphisms were evaluated using PCR - RFLP (polymerase chain reaction - restriction fragment length polymorphism) method. We evaluated the association between the presence of SNPs and AD diagnosis, family history of AD, AD severity evaluated via the Michigan Alcoholism Screening Test (MAST), the daily average and maximum quantity of alcohol consumed. RESULTS: There was no significant difference in OPRM1 A118G genotype frequencies between the AD and control groups. T allele frequency for the OPRM1 C17T SNP was very low (0.006) in the sample population. OPRM1 A118G SNP G118 allele carriers showed significantly higher levels of AD severity as indicated by the MAST. CONCLUSION: The OPRM1 G118 allele was significantly associated with more severe AD in the Turkish population. Similar to other European populations, the frequency of the OPRM1 T17 allele was very low.

Improved anti-emetic efficacy of 5-HT3 receptor antagonists in cancer patients with genetic polymorphisms of ABCB1 (MDR1) drug transporter.

Chemotherapy-induced nausea and vomiting (CINV) remains a major adverse effect decreasing quality of life in patients with cancer. Genetic variations among patients may be responsible for part of the lack of efficacy of anti-emetic drugs. The aim of this study was to investigate how the genetic variants of the drug transporter ABCB1 (MDR1) gene affect anti-emetic treatment with 5-HT3 receptor antagonists. Patients (n = 239) receiving moderately or highly emetogenic chemotherapy and ondansetron or granisetron were included in the study. Anti-emetic responses were recorded daily. The primary end-point of the assessment was the total control rates of CINV in the acute and delayed phases after chemotherapy. Genotyping was performed by PCR-RFLP. In the acute phase, patients with ABCB13435TT, 1236TT or 2677TT genotypes had a higher control rate of CINV than other genotype groups: (64.7% in 3435TT versus 45.7% in 3435CC+CT, p = 0.016; 65.1% in 1236TT versus 46.4% in 1236CC+CT, p = 0.027; 66.7% in 2677TT versus 46.5% in other genotypes, p = 0.021). Subjects carrying homozygous variant alleles together (TT-TT-TT) showed a significantly higher protection from nausea and vomiting (67.7% in TT-TT-TT versus 47.1% in other genotypes, p = 0.032). After the logistic regression analysis with adjustment for other known covariates, the total control rate was significantly higher in the 3435TT genotype group during the acute phase (p = 0.021). No significant change was found between the total control rates among genotypes in the delayed phase. Each of three 3435TT, C1236TT, 2677TT genotypes of ABCB1 and their combination was associated with about 50% higher anti-emetic response to 5-HT3 receptor antagonists in the acute phase of chemotherapy in patients with cancer receiving moderately or highly emetogenic chemotherapy. ABCB1 (MDR1) genotypes may contribute to predict the anti-emetic efficacy of 5-HT3 antagonists.