Pharmacokinetics of Levodopa and 3-O-Methyldopa in Parkinsonian Patients Treated with Levodopa and Ropinirole and in Patients with Motor Complications.

Parkinson's disease (PD) is a progressive, neurodegenerative disorder primarily affecting dopaminergic neuronal systems, with impaired motor function as a consequence. The most effective treatment for PD remains the administration of oral levodopa (LD). Long-term LD treatment is frequently associated with motor fluctuations and dyskinesias, which exert a serious impact on a patient's quality of life. The aim of our study was to determine the pharmacokinetics of LD: used as monotherapy or in combination with ropinirole, in patients with advanced PD. Furthermore, an effect of ropinirole on the pharmacokinetics of 3-OMD (a major LD metabolite) was assessed. We also investigated the correlation between the pharmacokinetic parameters of LD and 3-OMD and the occurrence of motor complications. Twenty-seven patients with idiopathic PD participated in the study. Thirteen patients received both LD and ropinirole, and fourteen administered LD monotherapy. Among 27 patients, twelve experienced fluctuations and/or dyskinesias, whereas fifteen were free of motor complications. Inter- and intra-individual variation in the LD and 3-OMD concentrations were observed. There were no significant differences in the LD and 3-OMD concentrations between the patients treated with a combined therapy of LD and ropinirole, and LD monotherapy. There were no significant differences in the LD concentrations in patients with and without motor complications; however, plasma 3-OMD levels were significantly higher in patients with motor complications. A linear one-compartment pharmacokinetic model with the first-order absorption was adopted for LD and 3-OMD. Only mean exit (residence) time for 3-OMD was significantly shorter in patients treated with ropinirole. Lag time, V/F, CL/F and tmax of LD had significantly lower values in patients with motor complications. On the other hand, AUC were significantly higher in these patients, both for LD and 3-OMD. 3-OMD Cmax was significantly higher in patients with motor complications as well. Our results showed that ropinirole does not influence LD or 3-OMD concentrations. Higher 3-OMD levels play a role in inducing motor complications during long-term levodopa therapy.

Genetic polymorphisms in the renin-angiotensin system and cognitive decline in Parkinson's disease.

BACKGROUND: Renin-angiotensin system (RAS) influences the central nervous system not only through its peripheral impact-the brain possesses its own local RAS. Studies showed altered RAS components in Parkinson's disease (PD) and their association with oxidative stress which may be linked to neurodegeneration and dementia. Moreover, the protective functions of RAS blockade antagonists against cognitive decline and dementia have been suggested. This study aimed to examine whether genetic variability in RAS genes correlates with cognitive decline in PD. METHODS AND RESULTS: We genotyped single nucleotide polymorphisms (SNPs) in angiotensinogen (AGT: rs699, rs4762), angiotensin II receptors (AGTR1: rs5186 and AGTR2: rs5194, rs1403543) genes, as well as insertion/deletion polymorphism in the angiotensin-converting enzyme (ACE I/D) gene in 256 PD patients, divided into three groups: without cognitive decline, with mild cognitive impairment and with PD dementia. We did not find any significant differences in the frequencies of the analysed polymorphisms in any of the groups. CONCLUSIONS: Despite no direct correlation between the investigated polymorphisms in RAS genes and cognitive decline in PD, we believe the impact of those genotypes may be indirect, affecting RAS blockade treatment.

Kidney damage from nonsteroidal anti-inflammatory drugs-Myth or truth? Review of selected literature.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely available drugs with anti-inflammatory and analgesic properties. Their mechanism of action is associated with the enzymes of the arachidonic acid cycle (cyclooxygenases: COX-1 and COX-2). The cyclooxygenase pathway results in the formation of prostanoids (prostaglandins [PGs], prostacyclins, and thromboxanes). It affects various structures of the human body, including the kidneys. Medical literature associates the usage of NSAIDs with acute kidney injury (AKI), tubulointerstitial nephritis (TIN), as well as nephrotic syndrome and chronic kidney disease (CKD). AKI associated with the chronic consumption of NSAIDs is mainly attributed to pharmacological polytherapy and the presence of cardiovascular or hepatic comorbidities. The pathomechanism of AKI and CKD is associated with inhibition of the biosynthesis of prostanoids involved in the maintenance of renal blood flow, especially PGE2 and PGI2. It is suggested that both COX isoforms play opposing roles in renal function, with natriuresis increased by COX-1 inhibition followed by a drop in a blood pressure, whereas COX-2 inhibition increases blood pressure and promotes sodium retention. TIN after NSAID use is potentially associated with glomerular basement membrane damage, reduction in pore size, and podocyte density. Therefore, nephrotic proteinuria and impairment of renal function may occur. The following article analyzes the association of NSAIDs with kidney disease based on available medical literature.

The Effect of Hypoxia on the Expression of CXC Chemokines and CXC Chemokine Receptors-A Review of Literature.

Hypoxia is an integral component of the tumor microenvironment. Either as chronic or cycling hypoxia, it exerts a similar effect on cancer processes by activating hypoxia-inducible factor-1 (HIF-1) and nuclear factor (NF-κB), with cycling hypoxia showing a stronger proinflammatory influence. One of the systems affected by hypoxia is the CXC chemokine system. This paper reviews all available information on hypoxia-induced changes in the expression of all CXC chemokines (CXCL1, CXCL2, CXCL3, CXCL4, CXCL5, CXCL6, CXCL7, CXCL8 (IL-8), CXCL9, CXCL10, CXCL11, CXCL12 (SDF-1), CXCL13, CXCL14, CXCL15, CXCL16, CXCL17) as well as CXC chemokine receptors-CXCR1, CXCR2, CXCR3, CXCR4, CXCR5, CXCR6, CXCR7 and CXCR8. First, we present basic information on the effect of these chemoattractant cytokines on cancer processes. We then discuss the effect of hypoxia-induced changes on CXC chemokine expression on the angiogenesis, lymphangiogenesis and recruitment of various cells to the tumor niche, including myeloid-derived suppressor cells (MDSCs), tumor-associated macrophages (TAMs), tumor-associated neutrophils (TANs), regulatory T cells (Tregs) and tumor-infiltrating lymphocytes (TILs). Finally, the review summarizes data on the use of drugs targeting the CXC chemokine system in cancer therapies.

Impact of selected genetic factors on clopidogrel inactive metabolite level and antiplatelet response in patients after percutaneous coronary intervention.

BACKGROUND AND OBJECTIVE: Clopidogrel is frequently used as part of optimal dual antiplatelet therapy in high-bleeding risk patients with the acute coronary syndrome. The concentration of the inactive carboxylic acid metabolite of clopidogrel might be useful to evaluate the response to clopidogrel therapy. Therefore, we sought to correlate the inhibition of platelet aggregation with the plasma level of the inactive metabolite of clopidogrel in patients after percutaneous coronary interventions (PCI) and their associations with the most frequently studied genetic polymorphisms. For this purpose, the fast and simple HPLC method for determining the concentration of the inactive metabolite was developed. METHODS: The effect of CYP2C19, CYP3A4/5, ABCB1 and PON1 genes on the plasma inactive metabolite concentration of clopidogrel and the platelet aggregation was investigated in 155 patients before and after PCI. RESULTS: The concentration of the inactive metabolite of clopidogrel was not significantly different in the intermediate metabolizers (IM) of CYP2C19 compared with extensive metabolizers (EM) both before and after PCI, while inhibition of platelet aggregation was found to be significantly better in EM than in IM. The presence of the A allele at position 2677 in the ABCB1 gene was associated with a significantly lower concentration of inactive metabolite of clopidogrel before PCI. CONCLUSION: The CYP2C19*2 allele was associated with decreased platelet reactivity during clopidogrel therapy before and after PCI. Simultaneous determination of platelet aggregation and concentration of the inactive clopidogrel metabolite may be useful in clinical practice to find the cause of adverse effects or insufficient treatment effect in patients chronically treated with clopidogrel.

Clinical Correlates of the NR3C1 Gene Methylation at Various Stages of Psychosis.

BACKGROUND: Dysregulation of epigenetic processes might account for alterations of the hypothalamic-pituitary-adrenal axis observed in patients with schizophrenia. Therefore, in this study, we aimed to investigate methylation of the glucocorticoid receptor (NR3C1) gene in patients with schizophrenia-spectrum disorders, individuals at familial high risk of schizophrenia (FHR-P), and healthy controls with respect to clinical manifestation and a history of psychosocial stressors. METHODS: We recruited 40 first-episode psychosis patients, 45 acutely relapsed schizophrenia (SCZ-AR) patients, 39 FHR-P individuals, and 56 healthy controls. The level of methylation at 9 CpG sites of the NR3C1 gene was determined using pyrosequencing. RESULTS: The level of NR3C1 methylation was significantly lower in first-episode psychosis patients and significantly higher in SCZ-AR patients compared with other subgroups of participants. Individuals with FHR-P and healthy controls had similar levels of NR3C1 methylation. A history of adverse childhood experiences was associated with significantly lower NR3C1 methylation in all subgroups of participants. Higher methylation of the NR3C1 gene was related to worse performance of attention and immediate memory as well as lower level of general functioning in patients with psychosis. CONCLUSIONS: Patients with schizophrenia-spectrum disorders show altered levels of NR3C1 methylation that are significantly lower in first-episode psychosis patients and significantly higher in SCZ-AR patients. Higher methylation of the NR3C1 gene might be related to cognitive impairment observed in this clinical population. The association between a history of adverse childhood experiences and lower NR3C1 methylation is not specific to patients with psychosis. Longitudinal studies are needed to establish causal mechanisms underlying these observations.

Variability of platelet response to clopidogrel is not related to adverse cardiovascular events in patients with stable coronary artery disease undergoing percutaneous coronary intervention.

BACKGROUND: Antiplatelet response to clopidogrel and its influence upon the risk of cardiovascular adverse events among patients with stable coronary artery disease undergoing percutaneous coronary intervention (PCI) has not been investigated fully. METHODS: Two hundred eleven patients treated with aspirin and clopidogrel were included in the study. Immediately before PCI, residual platelet reactivity testing with impedance aggregometry assay and a single-nucleotide polymorphism genotyping analysis targeting variants of CYP2C19, ABCB1, and PON1 genes was performed. After the index PCI, the patients were screened for cardiovascular events 6 months following bare-metal stent implantation or 12 months following drug-eluting stent implantation. RESULTS: High on-treatment platelet reactivity (HTPR) was observed in 19.43% individuals and low-TPR (LTPR) in 26.54%. In multivariate analysis, HTPR was significantly (p < 0.05) associated with a history of diabetes, higher systolic blood pressure, and platelet count comparing to that of other patients. LTPR was significantly associated with no history of hypertension, younger age, lower platelet count, absence of the CYP2C19*2 variant, and lower CRP plasma level. Overall, cardiac adverse events were noted in 14.23% patients. Survival analysis with the Cox proportional hazard model showed no influence of residual platelet reactivity during clopidogrel therapy upon both ischemic and hemorrhagic events. However, significant predictors for composite of major adverse cardiac events and hospitalization for cardiovascular causes were identified (the higher CCS class prior to coronary intervention and the higher creatinine serum concentration). CONCLUSIONS: The platelet response to clopidogrel has no impact upon post-procedural adverse events at mid-term follow-up in patients with stable CAD undergoing PCI. This finding suggests that routine platelet reactivity testing is not beneficial in this group of patients.

Pharmacokinetics of levodopa in patients with Parkinson disease and motor fluctuations depending on the presence of Helicobacter pylori infection.

BACKGROUND: According to recent investigations, the eradication of Helicobacter pylori (H. pylori) may influence levodopa (LD) pharmacokinetics (PK) and improve the motor function of infected patients with Parkinson disease (PD). The aim of this study was to compare PK of LD and its metabolite 3-O-methyldopa (3-OMD), between H. pylori-positive (HP+) and -negative (HP-) patients with PD and motor fluctuations. MATERIALS AND METHODS: Patients with the clinical diagnosis of PD, under stable LD therapy, reporting daily motor fluctuations and who had no history of previous eradication treatment were screened for the H. pylori infection with an antigen stool test. Two groups of patients-bacteria-infected and noninfected-matched demographically and clinically, were selected for the examination of PK values. Blood samples were collected after morning oral LD dose. Noncompartmental PK parameters were computed from the LD and 3-OMD plasma concentration-time data. RESULTS: Interindividual variability was seen in LD absorption curve in both groups. There were no clinically significant differences in PK parameters of LD and 3-OMD. Changes of small magnitude but with possible clinical impact were found according to tmax and Cmax that tended to be lower in HP- patients and AUC0-t that was larger in the HP+ group. The Cmax value of 3-OMD was almost identical in both groups. The HP- group had smaller AUC0-∞t of 3-OMD. CONCLUSIONS: The H. pylori infection in PD patients with motor fluctuations, despite not significantly influencing PK parameters of LD and 3-OMD, may still have important clinical implications.

Effect of allograft inflammatory factor-1 gene polymorphisms on rheumatoid arthritis treatment with methotrexate.

OBJECTIVE: Methotrexate (MTX) in low doses is used in the therapy of rheumatoid arthritis (RA). The aim of many studies is to identify factors predicting the outcome of treatment with methotrexate in rheumatoid arthritis. The action of MTX in RA is associated with the inhibition of inflammatory mediators synthesis. AIF-1 is a cytokine playing a role in chronic inflammatory processes. The levels of AIF-1 were significantly increased in synovial fluid from patients with RA. The aim of this study was to investigate the association between AIF1 gene polymorphisms (rs2269475:C>T, rs2736182:G>A, rs2259571:A>C) and response to treatment of RA patients with MTX. MATERIAL AND METHODS: The study was carried out on 221 patients diagnosed with active rheumatoid arthritis, treated with MTX. Good responders were defined as patients who were receiving MTX and had a DAS28 of ≤2.4 at 6 months. RESULTS: With regard to the AIF1 rs2259571 polymorphism the remission of RA symptoms was observed in 52.99% of AA genotype carriers, in 45.25% of subjects with AC genotype, and in 32.84% with CC. The differences were statistically significant. CC vs AA p=0.03, OR 0.41, 95%CI (0.18-0.92). CONCLUSION: The results of this study suggest that the patients with the rs2259571 CC AIF1 genotype have a poorer response to therapy with MTX.

CYP2C19 polymorphism affects single-dose pharmacokinetics of oral pantoprazole in healthy volunteers.

OBJECTIVES: Pantoprazole is metabolized by cytochrome P450 2 C19, which shows genetic polymorphism. The effect of CYP2C19 polymorphism on single-dose pharmacokinetics of oral pantoprazole in healthy volunteers was evaluated. METHODS: Pantoprazole pharmacokinetics was determined in 32 healthy volunteers after a 40-mg single oral dose of the drug. RESULTS: Carriers of CYP2C19*2/*2 (n = 2) were characterized by higher, starting from 3.5 h post dose, plasma concentrations of pantoprazole in comparison to wild-type (CYP2C19*1/*1, n = 6) volunteers. In subjects with CYP2C19*17/*17 genotype (n = 6) significantly lower plasma concentrations of the drug vs CYP2C19*1/*1 carriers, were observed from 3.0 h after oral pantoprazole administration. Carriers of CYP2C19*1/*17 (n = 6) and CYP2C19*2/*17 (n = 6) displayed concentration-time profiles comparable to wild-type subjects. CYP2C19*2/*2 volunteers showed a decrease in terminal elimination rate constant (λ(z)) by 83.3%, prolongation of terminal half-life (t(½)) by 572%, a rise in area under the concentration-time curve (AUC) and mean residence time (MRT) by 506% and 259% respectively. Heterozygotes, i.e.. CYP2C19*1/*2 vs CYP2C19*1/*1 were characterized by higher AUC (4.38 ± 1.00 mg·h/L vs 3.00 ± 1.02 mg·h/L, p < 0.05) and C(max) (2.13 ± 0.42 mg/L vs 1.61 ± 0.35 mg/L, p < 0.05) respectively. A significant reduction in MRT (3.83 ± 0.82 h vs 2.73 ± 0.23 h, p < 0.05) in carriers of CYP2C19*17/*17 vs CYP2C19*1/*1 genotypes was observed. Population modeling confirmed the influence of *1/*2, *2/*2, and *17/*17 genotypes on the pharmacokinetics of pantoprazole. The lowest population oral clearance was assessed in the carriers of genotype *2/*2 (3.68 L/h) and the highest value in subjects with genotype *17/*17 (31.13 L/h). CONCLUSION: These data suggest that CYP2C19 polymorphism is an important determinant of pantoprazole pharmacokinetics.

Allograft inflammatory factor-1 gene polymorphisms in patients with rheumatoid arthritis.

AIM: Allograft inflammatory factor-1 (AIF-1) is a cytoplasmic, inflammation-responsive protein. The increased expression of AIF-1 in synovial tissues and fluid from rheumatoid arthritis (RA) patients has been detected. Several single-nucleotide polymorphisms have been identified in the AIF1 gene, among them three leading to changes in amino acid sequence. The aim of this study was to examine the association between AIF1 rs2259571:A>C, rs2736182:G>A, and rs13195276:C>T polymorphisms and RA. We examined 380 patients with RA and 376 control subjects. RESULTS: There were no statistically significant differences in distribution of rs2736182 and rs2259571 genotypes and alleles between RA patients and control group. Moreover, there were no significant associations with the age of disease diagnosis, rheumatoid factor, extra-articular manifestation, and anti-cyclic citrullinated peptide (CCP) antibodies, whereas the active form of RA (patients with disease activity score (DAS28)>2.4) was more frequently diagnosed in patients with rs2259571 CC genotypes compared with patients with AA genotype (p=0.007, odds ratio=2.30, 95% confidence interval=1.25-4.25). CONCLUSION: Our results suggest that the AIF1 rs2259571 CC genotype is associated with the active form of RA.

Effects of CYP2C19, MDR1, and interleukin 1-B gene variants on the eradication rate of Helicobacter pylori infection by triple therapy with pantoprazole, amoxicillin, and metronidazole.

OBJECTIVE: Eradication of H. pylori is an important treatment strategy in peptic ulcer patients. Current regimens of eradication consist of proton pump inhibitor (PPI) and two antibiotics. Effects of PPI may depend on their metabolism, and other factors important for the pathophysiology of peptic ulcer disease. Aim of the present study was to evaluate an association of CYP2C19, MDR1, and IL-1B polymorphisms with the eradication rate of H. pylori in Polish Caucasian patients treated with a triple therapy of pantoprazole, amoxicillin, and metronidazole. METHODS: A total of 139 peptic ulcer patients, positive for H. pylori infection, were treated with triple therapy (pantoprazole + amoxicillin + metronidazole). Subsequently, the patients were divided into two groups (group 1, success, and group 2, failure of eradication after therapy) and genotyped by the PCR-RFLP method for the presence of CYP2C19 variant alleles (*2, *3, and *17), and MDR1 3435C>T and IL-1B +3954C>T polymorphisms. Pantoprazole serum concentrations were measured using the HPLC method. RESULTS: No significant differences in frequency or distribution of CYP2C19 genotypes were found between the two groups of patients (i.e., with successful H. pylori eradication and treatment failure). However, any carrier of defective CYP2C19*2/*2 genotype was found among patients with treatment failure. Similarly, MDR1 and IL-1B genotypes were found to be significantly associated with the success or failure of H. pylori eradication. Univariate and multivariate analysis of the genotypes did not reveal any significant association between the genotypes and H. pylori eradication. Pantoprazole concentrations differed significantly, and were the highest in patients with defective allele CYP2C19*2 carriers and lowest in hyperactive genotype homozygotes CYP2C19*17/*17. CONCLUSION: The results suggest that the CYP2C19 genotype contrary to MDR1 and IL-1B genotypes may have an impact on the efficacy of H. pylori eradication in peptic ulcer patients treated with pantoprazole in Polish Caucasian peptic ulcer patients administered pantoprazole, amoxicillin, and metronidazole.

Pharmacokinetic-pharmacodynamic modeling of levodopa in patients with advanced Parkinson disease.

OBJECTIVES: The aims of the present study were to investigate the pharmacokinetic and pharmacodynamic (pk/pd) relationship of levodopa (l-dopa) in patients with advanced Parkinson disease (PD) and also to evaluate the effect of tolcapone on the pk/pd analysis of l-dopa in 1 patient with severe dyskinesias and fluctuations. METHODS: The pharmacokinetics (plasma concentrations of l-dopa and 3-O-methyldopa [3-OMD]) and motor effects (global score of the Unified Parkinson's Disease Rating Scale-III) of a single dose of l-dopa (plus the peripheral decarboxylase inhibitor 1:4) were determined in 14 patients with advanced PD. Patients were classified into 2 groups according to Hoehn and Yahr scale (stages 2 and 3). In 1 patient with severe dyskinesias and fluctuations, pk/pd of l-dopa were evaluated before and after coadministration of tolcapone at 100 mg 2 times daily for 1 month. The pk/pd analysis was based on an estimate of the maximal response model with a semiparametric approach to effect site equilibrium. RESULTS: The highest levels of l-dopa and 3-OMD were observed in patients with stage 3 of Hoehn and Yahr scale. We showed differences in the pk/pd parameters after coadministration of tolcapone in 1 patient as well as the clinical improvement.Univariate analysis showed some significant correlations (P < 0.05) between l-dopa pk/pd parameters and patients' age, duration of l-dopa treatment, and duration of the disease. Multivariate analysis adjusted for patients' age, sex, duration of the disease, and Hoehn and Yahr stage showed that presence of diphasic (dyskinesia-improvement-dyskinesia [DID]) dyskinesias was the only independent predictor of larger threshold level - EC50 (mean concentration at half maximal effect) of l-dopa (P = 0.034). CONCLUSIONS: The motor complications during long treatment therapy in patients with advanced PD especially with stage 3 Hoehn and Yahr scale were correlated to the higher plasma concentrations of l-dopa. In the presented study, patients with motor complications, especially with DID dyskinesias, exhibited a larger threshold level (EC50). The clinical improvement of a patient who received l-dopa and tolcapone can be explained by tolcapone-induced changes of peripheral and central l-dopa pharmacokinetics, which led to a decrease of l-dopa EC50 and 3-OMD concentrations. Our data indicate that pk/pd analysis may be helpful for monitoring the efficiency of therapeutic strategy applied in PD patients.

N-acetyltransferase 2 (NAT2) polymorphism in patients with atopic asthma.

BACKGROUND AND AIMS: Allergic asthma is a chronic inflammatory disorder of the airways where, on exposure to allergens, the body mounts an immune response. The etiology of asthma is complex and multifactorial. Rapid and slow acetylators reflect the genetically determined variation in the elimination of xenobiotics. Recent advances have demonstrated the importance of genetic and environmental factors in the development of atopic asthma. Hepatic arylamine N-acetyltransferase 2 (NAT2) takes part in the detoxification of some drugs and arylamine xenobiotics. The aim of the present study was to determine the NAT2 polymorphism in patients with atopic asthma. METHODS: In the study, 184 unrelated asthmatic patients and 181 healthy controls were included. The mutations at positions 481T, 803G, 590A and 857A of the NAT2 gene were determined by a polymerase chain reaction-restriction fragment length polymorphism assay (PCR-RFLP). RESULTS: The frequency of homozygous fast acetylators did not differ significantly between patients and controls. Compared with the control population, the significant prevalence of slow acetylators in the group of patients with atopic asthma was observed. There was a statistically significant prevalence of subjects with NAT2*5/NAT2*5 and NAT2*5/NAT2*6 genotypes. The risk of an atopic asthma development was 3.4 times greater in slow than in fast acetylators (OR = 3.3657; p <0.000001, 95% CI = 2.1282-5.3228). CONCLUSIONS: These results suggest that NAT2 polymorphism may be involved in the pathogenesis of atopic asthma.

[Optimisation of treatment of Parkinson's disease with levodopa]. / Optymalizacja leczenia choroby Parkinsona preparatami lewodopy.

This article presents the major strategies for individualisation and optimisation of levodopa therapy. The relationship between pharmacokinetic and pharmacodynamic effects of levodopa is discussed. Pharmacokinetic parameters in different stages of Parkinson's disease are interpreted. Moreover, the main differences in pharmacokinetics of levodopa formulations and routes of administration are presented. The authors also suggest methods to increase efficacy and safety of levodopa therapy in patients with Parkinson's disease.

The role of NAT2 gene polymorphism in aetiology of the most frequent neurodegenerative diseases with dementia.

BACKGROUND AND PURPOSE: The role of N-acetyltransferase gene (NAT2) polymorphism in the aetiology of Alzheimer's disease (AD) and Parkinson's disease (PD) is an interesting issue; it is suggested that the slow acetylator genotype favours the damage of central nervous system cells by environmental toxins. The aims of the study were: 1) to determine the genotype of NAT2 in patients with sporadic PD with dementia and in patients with sporadic AD; 2) to evaluate the relationship between the genotype of NAT2 and the age at the onset of the disease, the extent of dementia, and the dose and side effects of L-dopa (in PD patients only); 3) to evaluate the predispositions to PD and AD. MATERIAL AND METHODS: Fifty two PD patients with dementia aged 51-82 years (mean: 70.35) and 53 AD patients aged 58-84 years (mean: 72.58) were recruited. The control group consisted of 90 healthy subjects aged 65-86 years (mean: 72.11). Four standardized instruments for evaluation of dementia in PD patients were used. Clinical scales for PD evaluation were used. Each AD patient satisfied the National Institute of Neurological and Communicative Disorders and Stroke/Alzheimer's Disease and Related Disorders Association criteria for probable AD. Methods of molecular biology were used for genetic studies. RESULTS: The NAT2*5/NAT2*5 genotype was more frequent in PD patients with dementia; the NAT2*4/NAT2*5 genotype was more frequent and the NAT2*4/NAT2*6 genotype was less frequent in AD patients. No relationship was found between genotypes and NAT2 alleles and the age at onset, severity of dementia or with the dose and side effects of L-dopa (in PD patients). CONCLUSIONS: The analysis of NAT2 polymorphism does not seem to be useful in predicting the risk of PD with dementia or AD.

CYP2D6 gene polymorphism as a probable risk factor for Alzheimer's disease and Parkinson's disease with dementia.

BACKGROUND AND PURPOSE: The theory of multifactorial inheritance is considered in the pathogenesis of sporadic Alzheimer's disease (AD) and Parkinson's disease (PD); therefore, it makes the genes regulating bioactivation or detoxification of exogenous substances candidates of sensitivity to Alzheimer's and Parkinson's diseases. The aims of the study were: 1) to determine the genotypes of CYP2D6 cytochrome (CYP2D6) in patients with AD and sporadic PD with dementia; 2) to evaluate the relationship between the CYP2D6 genotype and the age of onset of the disease, the extent of dementia in AD and PD, the dose and side effects of L-dopa in PD; 3) to evaluate the usefulness of CYP2D6 genotyping in predicting predispositions to PD and AD. MATERIAL AND METHODS: 53 patients with AD aged 58-84 (mean age 72.6) and 52 patients with PD with dementia aged 51-82 (mean age 70.4) were recruited. Each AD patient satisfied criteria for probable AD. Diagnostic and Statistical Manual of Mental Disorders 4th edition, Mini-Mental State Examination, Clinical Dementia Rating Scale and Global Deterioration Scale were used for dementia evaluation in PD patients. Clinical scales for PD evaluation were used. Methods of molecular biology were used for genetic studies. RESULTS: There were no differences in CYP2D6 genotype and allele distribution in AD and PD patients. There was no relationship between CYP2D6 alleles and the age of onset and advancement of dementia in AD and PD. No relationship between CYP2D6 alleles and the dose and side effects of L-dopa in patients with sporadic PD with dementia was observed. CONCLUSION: As there were no differences in CYP2D6 polymorphism in AD and PD, CYP2D6 does not seem to be a factor predisposing to these diseases.

NOD2 allele variants in patients with rheumatoid arthritis.

Recent reports have proven the importance of genetic factors and inflammation in the pathogenesis of rheumatoid arthritis (RA). In the current study, the frequency of NOD2/CARD15 gene variants (R702W, G908R, and L1007fsinsC) was examined in a group of 243 RA patients and 220 healthy controls. There were no statistically significant differences in distribution of NOD2 variant alleles between RA patients and controls. Moreover, there was no significant association between NOD2 variant alleles and joint erosions, extraarticular manifestations, rheumatoid factor, number of swollen and tender joints, and erythrocyte sedimentation rate. The results of the present study suggest that NOD2 allele variants have no significant influence on RA susceptibility, activity, and severity.

Effect of CYP2C19*17 gene variant on Helicobacter pylori eradication in peptic ulcer patients.

OBJECTIVE: Eradication of Helicobacter pylori is an important treatment strategy in peptic ulcer patients. Current regimens of eradication consist of proton pump inhibitor (PPI) and two antibiotics. The principal enzyme involved in PPIs metabolism is CYP2C19, which exhibits an interindividual variability of activity, mainly due to genetic polymorphism. Two alleles (CYP2C19*2 and CYP2C19*3), responsible for slow PPIs metabolism, were previously associated with higher efficacy of eradication. Recently, a novel CYP2C19 gene variant (CYP2C19*17), associated with faster metabolism of CYP2C19 substrates, was described. In the present study, a potential association between CYP2C19*17 allele and lower H. pylori eradication efficacy was tested in a group of peptic ulcer patients. METHODS: A total of 125 peptic ulcer patients, positive for H. pylori infection, were treated with triple therapy (pantoprazole+amoxicillin+metronidazole). Subsequently, the patients were divided into two groups (group 1 - success, and group 2 - failure of eradication after therapy) and genotyped for the presence of CYP2C19 variant alleles (*2, *3, and *17). RESULTS: Frequency of CYP2C19 alleles in two groups of patients were: 56.4 versus 65 (p=0.060) for *1, 15.4 versus 5.3 (p=0.015) for *2, and 28.2 versus 25.5 (p=0.663) for *17 allele, respectively. CYP2C19*3 was not detected in the evaluated population. No significant differences in frequency nor distribution of *17 allele were found between two groups of patients. CYP2C19*2 allele was associated with successful H. pylori eradication (p<0.02), *2 allele carriers were found to be over 4-times more prone to the treatment compared to *1/*1 homozygotes (OR=4.2, p=0.015). CONCLUSION: Our results suggest that, contrary to CYP2C19*2, CYP2C19*17 allele has no impact on efficacy of H. pylori eradication in peptic ulcer patients treated with pantoprazole.