Uloga genskog polimorfizma metaboličkih enzima P450(CYP) kao čimbenika osjetljivosti na učinkovitost i toksičnost lijeka te nastanak karcinoma

The polymorphic P450 (CYP) enzyme superfamily is the most important system involved in the biotransformation of many endogenous and exogenous substances including drugs, toxins, and carcinogens. Genotyping for CYP polymorphisms provides important genetic information that help to understand the effects of xenobiotics on human body. For drug metabolism, the most important polymorphisms are those of the genes coding for CYP2C9, CYP2C19, CYP2D6, and CYP3A4/5, which can result in therapeutic failure or severe adverse reactions. Genes coding for CYP1A1, CYP1A2, CYP1B1, and CYP2E1 are among the most responsible for the biotransformation of chemicals, especially for the metabolic activation of pre-carcinogens. There is evidence of association between gene polymorphism and cancer susceptibility. Pathways of carcinogen metabolism are complex, and are mediated by activities of multiple genes, while single genes have a limited impact on cancer risk. Multigenic approach in addition to environmental determinants in large sample studies is crucial for a reliable evaluation of any moderate gene effect. This article brings a review of current knowledge on the relations between the polymorphisms of some CYPs and drug activity/toxicity and cancer risk.Među enzimima I. faze biotransformacije sustav citokroma P450 (CYP) prednjači po katalitičkoj svestranosti i pokazuje vrlo visok stupanj polimorfnosti. Istraživanja polimorfizama gena CYP rezultirala su brojnim genetičkim informacijama koje nam pomažu u razumijevanju učinaka ksenobiotika na ljudski organizam. Ova superporodica enzima najvažniji je enzimski sustav uključen u biotransformaciju mnogih endogenih i egzogenih spojeva uključujući lijekove. Za metabolizam lijekova važan je polimorfizam CYP2C9, CYP2C19, CYP2D6 i CYP3A4/5 enzima. Među najvažnije izoforme odgovorne za biotransformaciju različitih kemijskih spojeva a posebno metaboličku aktivaciju prokarcinogena pripadaju CYP1A1, CYP1A2, CYP1B1, CYP2E1. Genska analiza ključnih enzima metabolizma lijekova pomaže u predviđanju terapijskog učinka ili razvoja štetnih nuspojava lijekova. Stoga primjena genotipizacije u kliničkoj praksi pomaže u optimizaciji i individualizaciji terapije i smanjenju medicinskih troškova. Polimorfizam metaboličkih enzima može imati važan učinak na terapiju antidepresivima, antipsihoticima, antikoagulantima, antidijabeticima, antitumorskim lijekovima te lijekovima za liječenje ulkusa i HIV-a. Podaci koje donosi toksikogenomika istražujući individualne predispozicije za karcinogene, teratogene i druge toksičke učinke ksenobiotika, pridonose rasvjetljavanju molekularnih mehanizama kojima kemijski spojevi iz okoliša ili na radnome mjestu utječu na nastanak bolesti u ljudi. Postoje značajni dokazi o povezanosti genskih polimorfizama i osjetljivosti za razvoj karcinoma. Metabolički putovi karcinogenih supstancija su kompleksni, posredovani aktivnošću različitih gena, dok pojedinačni geni najčešće imaju ograničen učinak. Stoga je multigenski pristup, uz uključivanje važnih čimbenika iz okoliša u studijama s velikim brojem ispitanika bitan za pouzdanu procjenu rizika od razvoja karcinoma

Klinička primjena i značaj praćenja vrijednosti vitamina A i E u serumu

Vitamini su važni za razvoj i održavanje zdravlja ljudi. Dijele se s obzirom na njihove strukturne i funkcionalne sličnosti te prema njihovoj topivosti. Vitamini A, D, E i K bolje su topivi u mastima, dok su vitamini B-kompleksa i vitamin C topivi u vodi. Praćenje vrijednosti vitamina bitno je kod pojedinih bolesti, osobito kada je to važno za prognozu bolesti. Cilj ovog rada bio je analizirati vrijednosti vitamina A i E u uzorcima seruma u periodu od dvije godine. Dokazane su značajne razlike u vrijednostima vitamina A između muškaraca i žena. Vitamini A i E ovise o dobi ispitanika pa su i referentni intervali podijeljeni prema dobi. Vrijednosti vitamina A i E znatno se razlikuju prema dijagnozama, a nakon podjele prema dobi vrijednosti se znatno razlikuju u skupini odraslih ispitanika. Status vitamina u organizmu koristan je liječniku za praćenje bolesti i terapije vitaminskim pripravcima, ali i pacijentu jer mu omogućuje uvid u uspješnost uzimanja terapije

Klinička primjena i značaj praćenja vrijednosti vitamina A i E u serumu

Vitamini su važni za razvoj i održavanje zdravlja ljudi. Dijele se s obzirom na njihove strukturne i funkcionalne sličnosti te prema njihovoj topivosti. Vitamini A, D, E i K bolje su topivi u mastima, dok su vitamini B-kompleksa i vitamin C topivi u vodi. Praćenje vrijednosti vitamina bitno je kod pojedinih bolesti, osobito kada je to važno za prognozu bolesti. Cilj ovog rada bio je analizirati vrijednosti vitamina A i E u uzorcima seruma u periodu od dvije godine. Dokazane su značajne razlike u vrijednostima vitamina A između muškaraca i žena. Vitamini A i E ovise o dobi ispitanika pa su i referentni intervali podijeljeni prema dobi. Vrijednosti vitamina A i E znatno se razlikuju prema dijagnozama, a nakon podjele prema dobi vrijednosti se znatno razlikuju u skupini odraslih ispitanika. Status vitamina u organizmu koristan je liječniku za praćenje bolesti i terapije vitaminskim pripravcima, ali i pacijentu jer mu omogućuje uvid u uspješnost uzimanja terapije

How to conquer tardive dyskinesia: could pharmacogenetics and therapy drug monitoring be useful tools?

Tardive dyskinesia is a neurological disorder characterized by involuntary, repetitive mo-vements of the face, tongue, and limbs, which may result from a long-term use of antip-sychotics

Effect of antiepileptic drug comedication on lamotrigine concentrations

Aim To estimate the effect size of concomitant antiepileptic therapy on the concentrations of lamotrigine, a drug often prescribed in combination with other antiepileptic drugs (AED), which can act as enzyme inducers or inhibitors. Methods A total of 304 patients with epilepsy, aged 18- 70 years, were divided into a lamotrigine monotherapy group and groups receiving lamotrigine with AEDs that act as enzyme inducers, enzyme inhibitors, or both. We compared lamotrigine monotherapy serum concentrations with those where lamotrigine was administered with a metabolic inhibitor valproate, metabolic inducers carbamazepine, oxcarbazepine, phenobarbital, phenytoin, or topiramate, and both an inducer and an inhibitor. Results Comparison of trough lamotrigine monotherapy concentrations and lamotrigine polytherapy concentrations showed an almost similar median concentration in case of drug-inducers, and higher lamotrigine concentration in case of comedication with valproate as an inhibitor. A significant difference was confirmed after dose correction (P < 0.001). Significant positive correlations of lamotrigine trough serum concentrations with valproate were observed before and after the dose correction (r = 0.480, P < 0.001 and r = 0.561, P < 0.001, respectively). Positive correlations between the dose-corrected lamotrigine trough concentration and carbamazepine (r = 0.439; P < 0.001) or monohydroxy metabolite of oxcarbazepine (MHD) (r = 0.675; P < 0.001) were also significant. Conclusion Higher valproate levels resulted in higher inhibition potency and higher lamotrigine levels. Increased dose-corrected concentrations of inducers carbamazepine and MHD, after the process of induction was finished, did not lower lamotrigine concentrations. These findings can be of clinical significance for optimal AED dosing

Association of smoking cigarettes, age, and sex with serum concentrations of olanzapine in patients with schizophrenia

IntroductionOlanzapine is an atypical antipsychotic drug which is effective in the treatment of schizophrenia. Cigarette smoking, age, and sex could be related to the pharmacokinetics and serum concentrations of olanzapine in patients with schizophrenia. The aim of the study was to examine whether there was a significant difference in the serum olanzapine concentrations with regard to the mentioned factors. Materials and methodsA total of 58 outpatients with schizophrenia (37 smokers, 42 men, 35 older than 40 years) participated in the study. Blood was sampled in serum tubes just before taking the next dose of olanzapine. Olanzapine was extracted by liquid-liquid extraction and was measured by an in-house high-performance liquid chromatography method on Shimadzu Prominence HPLC System with diode array detector SPD-M20A (Shimadzu, Kyoto, Japan). The results were expressed as the ratio of concentration to the daily dose of olanzapine (C/D). Non-parametric statistical tests were used to analyse differences between variables. ResultsThe median C/D of olanzapine (interquartile range) in smokers was 6.0 (3.4-10.2) nmol/L/mg and in non-smokers 10.1 (5.9-17.6) nmol/L/mg; P = 0.007. The median C/D of olanzapine in patients younger than 40 years was 5.6 (4.5-10.2) nmol/L/mg and in patients older than 40 years 8.4 (5.6-13.0) nmol/L/mg; P = 0.105. The median C/D of olanzapine in male patients was 6.6 (4.6-10.4) nmol/L/mg and in female patients 9.0 (5.9-15.3) nmol/L/mg; P = 0.064. ConclusionsThe serum olanzapine concentration was significantly lower in smoking than in non-smoking patients with schizophrenia. No significant difference was demonstrated with regard to age and sex

Autonomic dysfunction in clinically isolated syndrome suggestive of multiple sclerosis

OBJECTIVES: The aim of this study was to determine the extent of autonomic dysfunction in patients with clinically isolated syndrome (CIS) by using a standardized battery of autonomic tests in the form of the Composite Autonomic Scoring Scale (CASS). ----- METHODS: This was a prospective, cross sectional study which included 24 consecutive patients who were diagnosed with CIS and 17 healthy controls. In all participants, heart rate and blood pressure responses to the Valsalva maneuver, heart rate response to deep breathing and blood pressure response to passive tilt were performed. In 16 patients, Quantitative Sudomotor Axon Reflex Test (QSART) and catecholamine measurement was performed. ----- RESULTS: The proportion of CIS patients with pathological adrenergic index was statistically significantly higher compared to healthy controls (12 vs 2, p=0.018), while there was no difference in cardiovagal index between groups. Five patients had a sudomotor index of 1 (in 4 there was hypohydrosis <50% and in 1 persistent foot hyperhidrosis). When combining adrenergic, cardiovagal and sudomotor index into CASS, 8 patients (50%) had evidence of autonomic dysfunction, 7 mild and one moderate. ----- CONCLUSION: Sympathetic nervous system is frequently affected in CIS patients. ----- SIGNIFICANCE: CASS is able to detect autonomic nervous system dysfunction in CIS patients

Verification policies in Croatian medical biochemistry laboratories: a survey of the practice

The aim of this study was to screen practices used in verification procedures for methods/analysers among medical biochemistry laboratories (MBLs) in Croatia. We hypothesized that these procedures differ widely from laboratory to laboratory and wanted to gather specific data on steps used in the verification workflow. In order to obtain data, an online survey was conducted. The survey, divided in two sections, contained 29 questions and statements addressing general characteristics and specific steps of the verification workflow of each individual MBL. The survey was disseminated among managers of all MBLs in Croatia. A total of 108/196 (55%) laboratories participated in the survey. Forty nine MBLs were excluded from the second part of the survey: 14 have not implemented verification procedures, and 35 MBLs due to the absence of answers. The most relevant results of the second part of the survey showed that: 18/59 (0.31) of the responding MBLs have difficulties when defining acceptance criteria, 27/59 (0.46) used the Clinical and Laboratory Standards Institute protocol for precision estimation; the majority of MBLs used a median of 20 samples for method/analyser comparisons and estimated bias using internal quality control samples; reference intervals provided by external sources are mainly adopted; 60% of MBLs do not include linearity verification in their protocol and do not use the national document for the estimation of measurement uncertainty. Heterogeneous verification protocols are routinely utilized across Croatian MBLs which clearly confirms that a national document might help in the harmonization of verification procedures