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.

[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.

Investigation of 1377C/T polymorphism of the Toll-like receptor 3 among patients with chronic hepatitis B.

The immunopathogenesis of chronic hepatitis B (CHB) has not been clarified yet. Toll-like receptors (TLR) are a receptor family that initiates immunity with exogenous-endogenous ligands and plays a role in the pathogenesis of infections. In this study, we aimed to investigate the frequency of TLR 3 1377C/T (rs3775290) polymorphism and its role in patients with CHB. We included 50 healthy individuals as control group and 73 active and 43 inactive hepatitis B patients. All DNA samples were isolated from blood samples. For the detection of TLR 3 1377C/T single-nucleotide polymorphism, restriction fragment length polymorphism was used. A statistically significant difference was determined in Hepatitis B virus (HBV) DNA levels of CHB patients with the CC, CT, and TT genotypes (p = 0.013). The highest levels of HBV DNA were detected in individuals with TT genotypes. Additionally, the frequency of CC genotype was higher in the active CHB patients compared with that of the inactive CHB patients (p = 0.044). No statistically significant difference in TLR 3 1377C/T polymorphism was detected between healthy controls and the hepatitis B patients (p = 0.342). In conclusion, HBV DNA level was higher in the individuals with TT genotype, and CC genotype was more frequent in the active CHB patients. These results suggest a possible association between CHB and TLR 3 gene (1377C/T) polymorphism.

Relation of the Allelic Variants of Multidrug Resistance Gene to Agranulocytosis Associated With Clozapine.

Clozapine use is associated with leukopenia and more rarely agranulocytosis, which may be lethal. The drug and its metabolites are proposed to interact with the multidrug resistance transporter (ABCB1/MDR1) gene product, P-glycoprotein (P-gp). Among various P-glycoprotein genetic polymorphisms, nucleotide changes in exons 26 (C3435T), 21 (G2677T), and 12 (C1236T) have been implicated for changes in pharmacokinetics and pharmacodynamics of many substrate drugs. In this study, we aimed to investigate the association between these specific ABCB1 polymorphisms and clozapine-associated agranulocytosis (CAA). Ten patients with a history of CAA and 91 control patients without a history of CAA, despite 10 years of continuous clozapine use, were included. Patient recruitment and blood sample collection were conducted at the Hacettepe University Faculty of Medicine, Department of Psychiatry, in collaboration with the members of the Schizophrenia and Other Psychotic Disorders Section of the Psychiatric Association of Turkey, working in various psychiatry clinics. After DNA extraction from peripheral blood lymphocytes, genotyping was performed using polymerase chain reaction and endonuclease digestion. Patients with CAA had shorter duration of clozapine use but did not show any significant difference in other clinical, sociodemographic characteristics and in genotypic or allelic distributions of ABCB1 variants and haplotypes compared with control patients. Among the 10 patients with CAA, none carried the ABCB1 all-variant haplotype (TT-TT-TT), whereas the frequency of this haplotype was approximately 12% among the controls. Larger sample size studies and thorough genetic analyses may reveal both genetic risk and protective factors for this serious adverse event.

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.

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.

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.

Ocular pharmacokinetics, safety and efficacy of intracameral moxifloxacin 0.5% solution in a rabbit model.

PURPOSE: This study was carried out to determine the ocular pharmacokinetics, efficacy and potential endothelial toxicity of moxifloxacin (MF) after a single intracameral bolus injection of 500 µg/0.1 ml in a rabbit model. MATERIALS AND METHODS: Forty-eight eyes of 24 New Zealand White Rabbits were separated into six groups, each including four rabbits. 0.1 ml of 0.5% intracameral moxifloxacin (500 µg) injection was injected to the right eyes and 0.1 ml of balanced salt solution to the left eyes (control). Aqueous humor (AH) and vitreous samples were collected at the 0.5th, 1st, 3rd, 6th, 12th and 24th hours from both eyes of group 1, 2, 3, 4, 5 and 6, respectively. MF concentrations were determined by high performance liquid chromatography. These were compared with the minimum inhibitory concentrations (MIC) and mutant prevention concentrations (MPC) for frequent endophthalmitis pathogens. Electron and light microscopical evaluation of the corneas were performed. RESULTS: Moxifloxacin reaches higher concentration than the MIC of all common endophthalmitis pathogens in the AH and exceeds the mutant prevention concentration levels for Streptococcus pneumonia, Streptococcus viridans, flouroquinolone susceptible Coagulase-negative staphylococcus and flouroquinolone susceptible Staphylococcus aureus for 6 h. The half-life of moxifloxacin in the AH was 2.2 h. Electron and light microscopic evaluation revealed no noticeable sign of toxicity. CONCLUSIONS: Peroperative intracameral moxifloxacin injection for endophthalmitis prophylaxis is a safe and effective method in uncomplicated phacoemulsification surgery.

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.

Effect of atorvastatin on CYP2C9 metabolic activity as measured by the formation rate of losartan metabolite in hypercholesterolaemic patients.

HMG-CoA reductase inhibitors (statins) have a potential to interact with substrates of the drug-metabolizing enzyme cytochrome P450 2C9 (CYP2C9). This may lead to concentration-dependent toxicity such as skeletal muscle side effects. Atorvastatin, a widely used statin, is presently inadequately investigated in vivo with regard to effects on CYP2C9 activity in human beings. The aim of this study was to determine the effect of atorvastatin on the activity of CYP2C9 in a group of Turkish hypercholesterolaemic patients. We prospectively investigated the atorvastatin effect on CYP2C9 activity in a sample of Turkish hypercholesterolaemia patients (11 women, 7 men) who commenced atorvastatin (10 mg/day). Losartan was used as a probe drug to determine CYP2C9 metabolic activity. A single 25-mg oral dose of losartan was given to the patients before, on the first day and after the fourth week of the atorvastatin treatment. Urinary concentrations of losartan and its metabolite, E3174, were measured by high-pressure liquid chromatography (HPLC). Urinary losartan/E3174 ratios were used as an index of CYP2C9 activity. As the baseline enzyme activity may influence the extent of drug-drug interactions, the CYP2C9*2 and 2C9*3 alleles were identified by using PCR-RFLP. In the patients with the CYP2C9*1*1 genotype (n = 12), atorvastatin treatment did not cause a significant change in losartan/E3174 ratios (medians; 95% CI) neither after the first day (0.73; 0.34-1.61) nor at the fourth week (0.71; 0.36-1.77) of the treatment as compared with the baseline activity (0.92; 0.57-1.74, p = 0.38). Similarly, no significant change in the baseline CYP2C9 activity (0.91; 0.30-1.60) was observed in patients with the CYP2C9*1*2 genotype as compared with those of the first day (1.08; 0.08-2.72) and fourth week (0.64; 0.0-3.82) of the atorvastatin treatment (n = 4, p = 0.86). These observations in a hypercholesterolaemic patient sample suggest that atorvastatin does not have a significant effect on enzymes encoded by the CYP2C9*1*1 and CYP2C9*1*2 genotypes when co-administered with a CYP2C9 substrate, losartan.

Functional effects of endothelial nitric oxide synthase genetic polymorphisms on haemorheological parameters in healthy human individuals.

The constitutive endothelial nitric oxide synthase (eNOS) plays a major role in circulatory homoeostasis and shows genetic polymorphism. eNOS is expressed and functional in blood cells, including erythrocytes. There is limited knowledge about the consequences of eNOS genetic variability in haemorheological parameters and erythrocyte functioning. The purpose of this study was to investigate the effects of three eNOS genetic polymorphisms, namely exonic G894T (Glu298Asp), intronic VNTR (27-bp repeat) and 5'-flanking T(-786)C polymorphisms on haemorheological variables, such as erythrocyte deformability and erythrocyte aggregation (rouleaux formation) in healthy non-smoking volunteers. Sixty subjects (19 women, 41 men) were examined for genotypes and haemorheological variables. Genotypes were determined by polymerase chain reaction and restriction analysis. Haemorheological variables were measured by means of a laser-assisted optical rotational cell analyser (LORCA). Erythrocyte aggregation was significantly decreased in individuals with 894TT genotype when compared to subjects with the (G) allele. Aggregation indices (AI) were 54.7±3.2% versus 61.0±0.9% (p=0.026), and the half-lives (t(1/2) ) for aggregation formation were 3.43±0.43 versus 2.55±0.12 sec. (p=0.024), respectively. Similarly, VNTR-bb genotype significantly altered erythrocyte aggregability. AI values were 58.7±1.1% in subjects with VNTR-a allele versus 63.7±1.2% in subjects with bb genotype (p=0.011); t(1/2) values were 2.86±0.16 versus 2.20±0.13 sec., respectively (p=0.016). T(-786)C polymorphism did not change any haemorheological parameters. These findings suggest that eNOS 894TT genotype is associated with decreased erythrocyte aggregation, while VNTR-bb genotype increases aggregability in healthy human individuals. eNOS genetic variants may contribute in the pathogenesis of microvascular disorders by altering erythrocyte functions in human beings.

Effect of ocular compression on intraocular penetration of systemic ofloxacin.

Intraocular levels of ofloxacin are documented after topical and systemic administration, but systemic administration of ofloxacin in ocular compression has not yet been studied. This study was undertaken to determine the intraocular penetration of systemic ofloxacin into aqueous and vitreous humor after the application of ocular compression in rabbit eyes. Ocular compression with the Honan balloon was applied for 30 min to the right eyes of 11 albino New Zealand white rabbits. After the application of ocular compression, 2 mg/mL of ofloxacin was administered intravenously. Samples from aqueous and vitreous humor were collected 30 min after infusion. Ofloxacin concentrations were determined through high-performance liquid chromatography. The mean aqueous level of ofloxacin was significantly higher in the compression group (2.40+/-1.00 microg/mL) than in the no-compression group (1.61+/-1.06 microg/mL) (P<.05). The mean vitreous concentrations of ofloxacin were 0.70+/-0.33 microg/mL and 0.50+/-0.18 microg/mL in the compression and no-compression groups, respectively. A significant difference was observed between vitreous levels of ofloxacin in the compression and no compression groups (P<.05). Ocular compression enhanced the penetration of ofloxacin in both aqueous and vitreous humor. The drug level in the aqueous humor was sufficient for the minimum inhibitory concentration for 90% of isolates (MIC90) to inhibit most microorganisms. Although the mean vitreous ofloxacin concentration was increased by previous ocular compression, it was not sufficiently above the MIC90 for most ocular pathogens that caused endophthalmitis.

Lens concentration of ofloxacin and lomefloxacin in an experimental endophthalmitis model.

UNLABELLED: Abstract. BACKGROUND: Bacterial endophthalmitis is a serious complication of ocular surgery and penetrating trauma. The primary causative organisms are strains of Staphylococcus aureus and Staphylococcus epidermidis. Fluoroquinolones are widely used to treat endophthalmitis. There are a few studies on the penetration of fluoroquinolones into the lens in inflamed eyes. A literature search did not identify any data regarding penetration of topical ofloxacin into the lens in normal and inflamed eyes. OBJECTIVE: The aim of this study was to determine the penetration of topical ofloxacin and lomefloxacin into the lens in a rabbit endophthalmitis model. METHODS: New Zealand white rabbits were randomly divided into 2 groups. The left eyes were infected with an intravitreal inoculation of S aureus. The right eyes were used as a noninoculated control. Groups 1 and 2 received topical ofloxacin and lomefloxacin treatment, respectively, 24 hours after the inoculation. Two drops of the study drugs were instilled in the eyes every 30 minutes for 3 hours and then every 60 minutes for 3 hours. Lens samples were obtained 30 minutes after the last ofloxacin or lomefloxacin drops were administered. High-performance liquid chromatography was used to determine the fluoroquinolone concentration. RESULTS: Ten rabbits were equally divided into the 2 treatment groups. There was no significant difference in mean (SD) lens concentrations between the control and inoculated eyes in either treatment group-ofloxacin (0.26 [0.32] µg/mL vs 0.11 [0.05] µg/mL, respectively) and lomefloxacin (0.50 [0.87] µg/mL vs 0.12 [0.08] µg/mL, respectively). CONCLUSION: The results of this small experimental study found that topical ofloxacin and lomefloxacin can accumulate in the crystalline lens after installation. Inflammation did not affect the penetration of ofloxacin or lomefloxacin into the lens.

Plasma and gingival crevicular fluid phenytoin concentrations as risk factors for gingival overgrowth.

BACKGROUND: Gingival enlargement is one of the side effects associated with the administration of phenytoin. The mechanism by which phenytoin induces gingival enlargement is not well understood. This study was conducted to investigate the relationship between plasma and gingival crevicular fluid (GCF) phenytoin concentrations and the degree of gingival overgrowth in patients with similar gingival and plaque indices and also to determine the risk factors for gingival enlargement. METHODS: Eighteen patients taking phenytoin in regular doses > or =6 months prior to the investigation participated in the study. Gingival enlargement was evaluated with two indices to score vertical and horizontal overgrowth. The gingival index (GI), plaque index (PI), gingival bleeding time index (GBTI), probing depth (PD), and clinical attachment level (CAL) were also evaluated. GCF and plasma phenytoin concentrations were determined by using high-performance liquid chromatography (HPLC). RESULTS: There was no significant difference between responders and non-responders for PD, CAL, PI, GI, and GBTI. Phenytoin was detected in all of the GCF and plasma samples using the HPLC analysis method. The mean concentration of phenytoin in GCF was significantly greater than the concentration of phenytoin in plasma. No significant difference was observed for the concentration of GCF phenytoin between responders and non-responders. However, the concentration of plasma phenytoin was significantly higher in responders than non-responders. CONCLUSION: This study showed that plasma phenytoin level appeared to be a risk factor for phenytoin-induced gingival overgrowth.

Serum and gingival crevicular fluid levels of ciprofloxacin in patients with periodontitis.

BACKGROUND: The use of antibiotics as an adjunctive therapy in the treatment of periodontal diseases is of special interest to dental practitioners. In addition to using an appropriate antibacterial agent, clinicians may find it useful to determine the local and systemic concentrations of antibiotics in infected periodontal sites to reduce the levels of bacteria. The purpose of this study was to determine the serum and gingival crevicular fluid, or GCF, concentrations of systemic ciprofloxacin in patients with periodontitis. METHODS: Ten subjects with chronic periodontitis received ciprofloxacin (500 milligrams) twice daily for five days. The authors collected GCF and serum samples immediately after administering the first dose (baseline = 0 hours) and at consecutive time points. The orifice method was used for GCF sampling, and 5 milliliters of venous blood was drawn for serum analysis. The authors used high-performance liquid chromatography to determine ciprofloxacin concentrations in GCF and serum. RESULTS: The authors found that ciprofloxacin concentrations in GCF were significantly higher than concentrations in serum at two, four, seven, 24 and 120 hours. Ciprofloxacin reached the maximum concentration, or Cmax (3.72 micrograms/ mL), in GCF two hours after the initial dose was administered. The concentration decreased to 2.06 microg/mL 24 hours after the initial administration of the drug. Serum Cmax was 2.58 microg/mL at 1.5 hours, and the concentration decreased to 0.26 microg/mL at 24 hours. CONCLUSION: The results of this clinical study show that ciprofloxacin is found in GCF and its concentration in GCF is significantly higher than that in serum. CLINICAL IMPLICATIONS: Ciprofloxacin may be useful in treating patients with periodontitis because it reaches higher concentrations in GCF than in serum.