Analgesic effects of piritramide in acute postoperative pain - comparison of intramuscular administration with patient-controlled intravenous analgesia and impact of OPRM1 and ABCB1 polymorphisms.

AIMS: The aim of this study was to compare the efficacy, consumption and safety after piritramide administered either intramuscularly (IM) on demand or via patient-controlled intravenous analgesia (PCA) and to examine the impact of OPRM1 and ABCB1 gene polymorphisms on the drug efficacy/safety in both regimens. METHODS: One hundred and four patients scheduled for elective inguinal hernioplasty received piritramide with PCA or IM for postoperative pain management. We evaluated piritramide consumption, pain intensity using visual analogue scale (VAS) and adverse effects. RESULTS: Median (IQR) piritramide consumption was 18.5 (13.5-31.2) and 15.0 (15.0-15.0) mg in the PCA and IM groups, respectively (P=0.0092). The respective values of area under the VAS2-16-time curve were 40 and 280 mm.h (P=0.0027). Opioid-induced adverse effects were more frequent in the PCA than in the IM group. Variant OPRM1 allele was associated with decreased pain relief, increased opioid consumption and increased incidence of adverse effects, while ABCB1 polymorphisms showed no impact on the observed parameters. CONCLUSIONS: We observed higher piritramide consumption, better pain relief and slightly worse safety profile in the PCA group compared with IM administration. Variant OPRM1 118G allele carriers required higher opioid dosing and suffered from more adverse effects, however, the differences between genotypes have been less pronounced in the PCA patients likely due to improved pain management via PCA.

Impact of smoking on metabolic changes and effectiveness of drugs used for lung cancer.

OBJECTIVE: This article reviews the published studies dealing with the influence of cigarette smoking on metabolic changes and effectiveness of drugs used in the systemic chemotherapy of the lung cancer. METHODS: The literature search of interactions between cigarette smoking and drugs used for lung cancer was carried out. The abstracted data mostly involved some induction of key drug-metabolizing enzymes of cytochrome CYP1A1/2, CYP2D6, CYP3A4 and isoforms of UDP-glucuronosyltransferase. RESULTS: Metabolic changes are important both in the non-chemotherapy and for the drugs used in the chemotherapy. They can change pharmacokinetic and pharmacodynamic effects of drugs. Primarily, we addressed potential differences in drug effects on smokers and non-smokers. The increased clearance of erlotinib and irinotecan may have impact on effectiveness of the lung cancer therapy. The effects of taxanes and gemcitabine are more complex. CONCLUSION: The evaluated studies show that continued smoking after lung cancer diagnosis is related to poor prognosis, reduced survival, risk of second primary malignancies, and increased cancer recurrence. Of particular importance is the deterioration in the quality of life and an increased incidence of the adverse drug reactions in smokers. The patient's cigarette smoking history should be considered carefully and smoking cessation must be taken into account.

Treatment of tobacco dependence as a standard part of oncology care.

After the oncological diagnosis, smoking has a major impact on survival, course and effectiveness of oncology treatment, and quality of the further life. Smoking worsens surgery outcomes, reduces the effectiveness of radiation therapy and chemotherapy, increases the risk of side effects of oncology treatment, and increases the incidence of tumor duplication or other comorbidities like venous thrombosis, cardiovascular diseases or infections. The article contains a summary of practical recommendations for oncology patients, including smoke-free environments, the importance of zero exposure to tobacco smoke, clear advice to stop smoking to smokers and offer of tobacco dependence treatment. Except of brief intervention within few tens of seconds up to 10 minutes, intensive treatment should be available, for example in special tobacco-dependence centers. In the documentation smoking status should be recorded including exposure to passive smoking, interventions to smokers (both active and passive) should be empathically repeated. The motivation to treat tobacco dependence should be mainly related to their specific oncological diagnosis, prognosis, course and effectiveness of its treatment. Treatment of tobacco dependence should be an obvious part of quality oncological care by doctors and nurses in intensity according to their time availability. Keywords: tobacco smoking, smoking cessation, nicotine dependence, chemotherapy, pharmacological interactions, adverse effects, cancer.

[Smoking and pharmacological interactions]. / Kourení a lékové interakce.

Cigarette smoking can affect drug metabolism via pharmacokinetic and pharmacodynamic mechanisms, and a sudden change in smoking status can render patients at risk of serious adverse reactions, eg. after clozapine. Patients should be regularly monitored with regard to their smoking status and extent of cigarette consumption and doses of relevant medications adjusted accordingly.

Pleiotropic effects of niacin: Current possibilities for its clinical use.

Niacin was the first hypolipidemic drug to significantly reduce both major cardiovascular events and mortality in patients with cardiovascular disease. Niacin favorably influences all lipoprotein classes, including lipoprotein[a],and belongs to the most potent hypolipidemic drugs for increasing HDL-C. Moreover, niacin causes favorable changes to the qualitative composition of lipoprotein HDL. In addition to its pronounced hypolipidemic action, niacin exerts many other, non-hypolipidemic effects (e.g., antioxidative, anti-inflammatory, antithrombotic), which favorably influence the development and progression of atherosclerosis. These effects are dependent on activation of the specific receptor HCA2. Recent results published by the two large clinical studies, AIM-HIGH and HPS2-THRIVE, have led to the impugnation of niacin's role in future clinical practice. However, due to several methodological flaws in the AIM-HIGH and HPS2-THRIVE studies, the pleiotropic effects of niacin now deserve thorough evaluation. This review summarizes the present and possible future use of niacin in clinical practice in light of its newly recognized pleiotropic effects.

Nabumetone and 6-MNA Pharmacokinetics, Assessment of Intrasubject Variability and Gender Effect.

In this open-label, laboratory-blinded, 2-way single dose study in 24 volunteers of both sexes we found that (1) nabumetone reaches mean Cmax ± SD of 0.56 ± 0.20 mg·L at mean tmax of 8.63 ± 7.05 hours, and mean area under the curve (AUC)last of 18.07 ± 7.19 h·mg·L; (2) there are no statistically significant differences between both sexes in pharmacokinetics of nabumetone; (3) 6-methoxy-2-naphthylacetic acid (6-MNA) reaches higher AUClast in men compared with women (mean ± SD, 721.23 ± 185.53 h·mg·L and 545.27 ± 97.69 h·mg·L, respectively; P = 0.013); (4) there is lower 6-MNA clearance in men (0.65 ± 0.22 L·h) in comparison with women (0.88 ± 0.18 L·h, P = 0.019), (5) intersubject variability of nabumetone and 6-MNA is between 35%-45% and 10%-30% for all assessed pharmacokinetics parameters (AUClast, Cmax, partial AUC values); (6) intrasubject variability (ISCV) for AUClast is low, 15.59% and 6.40% for nabumetone and 6-MNA, respectively, (7) ISCV for Cmax is 13.66% and 5.42% for nabumetone and 6-MNA, respectively. Nabumetone thus belongs to compounds with low to moderate ISCV and therefore this product is expected to produce consistent effects in clinical practice.

Niacin in the Treatment of Hyperlipidemias in Light of New Clinical Trials: Has Niacin Lost its Place?

Niacin is considered to be a powerful drug for the treatment of lipid and lipoprotein abnormalities connected with "residual cardiovascular risk", which persist in high-risk patients even when the target goals of LDL-C are achieved with statin therapy. Recent large randomized clinical studies - AIM-HIGH (Atherothrombosis Intervention in Metabolic Syndrome With Low HDL/High Triglycerides) and HPS2-THRIVE (Heart Protection Study 2-Treatment of HDL to Reduce the Incidence of Vascular Events) - delivered some disappointing results, leading to the conclusion that no further benefit (decreased parameters of cardiovascular risk) is achieved by adding niacin to existing statin therapy in patients with high cardiovascular risk. Moreover, in these studies, several adverse effects of the treatment were observed; therefore, niacin treatment for hypolipidemias is not recommended. In this paper, we analyze the mechanisms underlying the hypolipidemic and antiatherogenic effects of niacin as well as some limitations of the designs of the AIM HIGH and HP2-THRIVE studies. We also provide the possibilities of rational usage of niacin for specific types of dyslipidemias.

Lipid-lowering effect of fluvastatin in relation to cytochrome P450 2C9 variant alleles frequently distributed in the Czech population.

BACKGROUND: CYP2C9*3 allele has been reported to correlate with increased plasma concentration of fluvastatin active form in healthy volunteers. We analyzed the correlation between the CYP2C9 genotype and cholesterol-lowering effect of fluvastatin in human hypercholesterolemic patients. MATERIAL/METHODS: The study was prospective, without any interventions to standard procedures of hypolipidemic treatment. CYP2C9 genotype was determined by PCR-RFLP assay in 87 patients on concomitant fluvastatin therapy, in 48 patients on monotherapy, and in a control group of 254 healthy volunteers of Czech nationality. Biochemical and clinical data were collected before the initiation of fluvastatin treatment and 12 weeks later. RESULTS: The frequency of CYP2C9 alleles did not differ significantly among groups of patients and volunteers. The most frequently observed allele was CYP2C9*2. Treatment with 80 mg of fluvastatin daily of 48 patients on monotherapy for 12 weeks resulted in mean low-density lipoprotein cholesterol (LDL-C) reduction by 25%, mean serum total cholesterol (TC) reduction by 21%, and mean triglyceride (TG) reduction by 28%. The CYP2C9*1/*3 genotype was associated with a decrease in LDL-C levels (by 40.0% for CYP2C9*1/*3, but only by 22.4% for CYP2C9*1/*1), and with the reduction of TC (by 28.6% in CYP2C9*1/*3 versus 20.2% in CYP2C9*1/*1). CONCLUSIONS: In hypercholesterolemic patients, LDL-C serum concentration was decreased more significantly in fluvastatin-treated subjects bearing the CYP2C9*1/*3 genotype compared to CYP2C9*1/*1 genotype. However, due to rare occurrence of some CYP genotypes, it was impossible to report a definitive positive genotype-fluvastatin effect association.

Genetic polymorphisms of CYP2C8 in the Czech Republic.

AIM: CYP2C8 represents 7% of the hepatic cytochrome system and metabolizes around 5% of drugs in phase I processes. It also plays a significant role in metabolism of endogenous compounds. More than 20 single-nucleotide polymorphisms (SNPs) have been noted, mainly in exons 3, 5, and 8. The most studied SNPs may lead to decreased enzyme activity and may have impact on drug metabolism. Variant alleles are called CYP2C8*2 (I269F), CYP2C8*3 (R139K, K399R), and CYP2C8*4(I264M). Our aim was to investigate the frequency of major functional SNPs among the Czech population. MATERIAL AND METHODS: DNA was isolated from whole blood of 161 healthy, young, and unrelated subjects (94 men and 67 women, aged from 23 to 28 years). The genotypes of polymorphic positions CYP2C8*2, CYP2C8*3 (G416A, A1196G), and CYP2C8*4 were determined by polymerase chain reaction-restriction fragment length polymorphism. RESULTS AND CONCLUSION: Observed allele frequencies were 10.9%, 5.9%, and 0.3% for the alleles CYP2C8*3, CYP2C8*4, and CYP2C8*2, respectively. Both CYP2C8*3 (G416A, A1196G) alleles have been found in complete linkage disequilibrium. The allele distribution complies well with Hardy-Weinberg equilibrium. Allele frequencies of functionally important CYP2C8 variants in the Czech population are similar to that of other Caucasian populations.

[Our experience with maraviroc treatment in HIV positive patients]. / Nase zkusenosti s maravirocem u HIV pozitivních pacientu.

UNLABELLED: BACKGROUND; Although antiretroviral therapy has changed the clinical course of HIV infection, AIDS remains an incurable disease. Virus entry inhibitors, including maraviroc as the only registered representative of the class, represent a newly emerged group of anti-retrovirals with novel mechanism of action. The primary endpoint is to evaluate the clinical efficacy parameter of maraviroc by measuring viral load at the end of the 4 week treatment period. The secondary endpoint is to evaluate the effectiveness of the drug by monitoring the changes of the viral load values and CD4+ cell counts during the period of 125 weeks. Drug safety was also assessed. METHODS AND RESULTS: Data of 23 subjects were collected, 21 patients were from the Czech Republic and 2 patients from France. Decrease in viral load in the 4th, 24th and 48th week was more than two orders of magnitude (-2.136; -2.448; -2.452 log10 copies/ml). The CD4+ cell count increased (71.71, 143.00, 196.43 cells/mm3). Drug safety was assessed by monitoring the frequency of adverse effects. The data obtained were compared with the III. phase of clinical trials. CONCLUSIONS: Our experience with maraviroc was positive. Maraviroc proved to be an effective antiretroviral agent for a combination therapy of HIV infection.

[Determination of nabumetone and 6-methoxy-2-naphthylacetic acid in plasma using HPLC with UV and MS detection]. / Stanovení nabumetonu a kyseliny 6-methoxy-2-naftyloctové v plazme pomocí HPLC s UV a MS detekcí.

The study aimed to establish and validate an analytical method for the determination of nabumetone and 6-methoxy-2-naphthylacetic acid (6-MNA) in human plasma after a single therapeutic dose of the drug. Two methods based on HPLC with UV and MS detection were compared. Optimal results in sample preparation were achieved using solid phase extraction. The recovery reached approximately 84% and 86-90% for nabumetone and 6-MNA, respectively. A reverse C18 column was used for HPLC separation of the analytes. The limit of UV detection was 50 nM and 0.1 microM for 6-MNA and nabumetone, respectively. The limit of MS detection was 1 microM and 0.5 microM for 6-MNA and nabumetone, respectively. Precision ranged between 4.2-14.4% and 4.6-8.5% using UV and MS detection for nabumetone, respectively. The respective values for 6-MNA were 2.4-12.5% and 2.1-9.4%. Accuracy ranged between 93.4-109.6% in UV detection and 86.2-107.9% using UV and MS detection for nabumetone, respectively. The respective values for 6-MNA were 87.8-107.4% and 86.3-106.4%. The method was subsequently applied to determine the pharmacokinetic parameters of nabumetone and 6-MNA in a group of 24 healthy volunteers.

[Infrared pupilometry as a biomarker of drug effects]. / Pupilometrie jako bioindikátor úcinku léciv.

BACKGROUND: Measurement of the size of the pupil is used as a biomarker of drug efficacy, assessing mainly their effect on the central nervous system. The aim of our study was to evaluate sensitivity of various pupilometric parameters as biomarkers of widely used opioid analgesic drug tramadol. METHODS AND RESULTS: Pharmacodynamic action of tramadol drops given orally in standardized dose of 0.7 mg/kg was studied in 60 healthy volunteers. Commercially available infrared pupilometer Pupilscan II was used for the measurements of static and dynamic pupilometric parameters prior the dosing and 2.5 hours afterwards. Drug-induced decreases of the initial diameter (0.49 mm) and final diameter (0.38 mm) were significant in the right eye, as well as in the left eye. Minimal parameters (0.35 mm) and time to minimum (0.03 mm) were significantly lower after tramadol administration in the left and right eye only. CONCLUSIONS: Our results confirm the use of pupilometry as an objective, non-invasive tool for evaluation of pharmacodynamic activity of drugs.

Cytochrome P450 2D6 polymorphism and drug utilization in patients with oral lichen planus.

OBJECTIVE: Oral lichen planus (OLP) is one of the commonest diseases of the oral mucosa. The etiology of the disease is unknown. Our goal was to determine frequencies of functionally important alleles which determine the metabolic rate (phenotype) of individuals with OLP and to compare drug utilization, with focus on CYP2D6, with that of a control group. MATERIAL AND METHODS: The study population consisted of 46 patients with OLP, 60 sex- and age-matched control subjects for drug utilization evaluation and 223 healthy non-medicated controls for genotype comparison. DNA analysis was done using polymerase chain reaction and restriction fragment length polymorphism. The gene CYP2D6 was analyzed for the alleles CYP2D6*3,*4,*5,*6 and gene duplication. Drug utilization was evaluated according to Anatomical Therapeutic Chemical code, liver drug metabolism pathway and mono- or polytherapy. RESULTS: Intake of drugs was significantly higher in the group of OLP patients in comparison with control subjects. The use of CYP2D6 substrates, inhibitors or inducers did not differ between OLP patients and controls. Predicted phenotype frequencies in OLP patients and healthy controls, respectively were as follows: ultrarapid metabolizers 2% and 5.8%, extensive metabolizers 52% and 49.8%, intermediate metabolizers 39% and 37.7% and poor metabolizers 7% and 6.7%. CONCLUSIONS: We did not find a statistically significant difference in the frequency of CYP2D6 alleles between OLP patients and healthy controls. OLP patients used more medication than age- and sex-matched controls.

Enantiomeric determination of tramadol and O-desmethyltramadol in human plasma by fast liquid chromatographic technique coupled with mass spectrometric detection.

A rapid and sensitive method using liquid chromatography-tandem mass spectrometry (LC-MS/MS) for enantiomeric determination of tramadol and its primary phase metabolite O-desmethyltramadol in human plasma has been developed. Tramadol hydrochloride-(13)C, d(3), was used as an isotopic labeled internal standard for quantification. The method involves a simple solid phase extraction. The analytes and internal standard were separated on Lux Cellulose-2 packed with cellulose tris(3-chloro-4-methylphenylcarbamate) using isocratic elution with hexane/isopropanol/diethylamine (90:10:0.1, v/v/v) at a flow rate of 1.3 mL/min. The APCI positive ionization mass spectrometry was used with multiple reaction monitoring of the transitions at m/z 264.2-->58.2 for tramadol, m/z 250.1-->58.2 for O-desmethyltramadol and m/z 268.2-->58.2 for internal standard. Linearity was achieved between 1-800 ng/mL and 1-400 ng/mL (R(2) > or = 0.999) for each enantiomer of tramadol and O-desmethyltramadol, respectively. Intra-day accuracies ranged among 98.2-102.8%, 97.1-109.1% and 97.4-102.9% at the lower, intermediate, and high concentration for all analytes, respectively. Inter-day accuracies ranged among 95.5-104.1%, 99.2-104.7%, and 94.2-105.6% at the lower, intermediate, and high concentration for all analytes, respectively. This assay was successfully used to determine the concentration of enantiomers of tramadol and O-desmethyltramadol in a pharmacogenetic study.

Human urinary metabolomic profile of PPARalpha induced fatty acid beta-oxidation.

Activation of the peroxisome proliferator-activated receptor alpha (PPARalpha) is associated with increased fatty acid catabolism and is commonly targeted for the treatment of hyperlipidemia. To identify latent, endogenous biomarkers of PPARalpha activation and hence increased fatty acid beta-oxidation, healthy human volunteers were given fenofibrate orally for 2 weeks and their urine was profiled by UPLC-QTOFMS. Biomarkers identified by the machine learning algorithm random forests included significant depletion by day 14 of both pantothenic acid (>5-fold) and acetylcarnitine (>20-fold), observations that are consistent with known targets of PPARalpha including pantothenate kinase and genes encoding proteins involved in the transport and synthesis of acylcarnitines. It was also concluded that serum cholesterol (-12.7%), triglycerides (-25.6%), uric acid (-34.7%), together with urinary propylcarnitine (>10-fold), isobutyrylcarnitine (>2.5-fold), (S)-(+)-2-methylbutyrylcarnitine (5-fold), and isovalerylcarnitine (>5-fold) were all reduced by day 14. Specificity of these biomarkers as indicators of PPARalpha activation was demonstrated using the Ppara-null mouse. Urinary pantothenic acid and acylcarnitines may prove useful indicators of PPARalpha-induced fatty acid beta-oxidation in humans. This study illustrates the utility of a pharmacometabolomic approach to understand drug effects on lipid metabolism in both human populations and in inbred mouse models.

Enatiomeric determination of tramadol and O-desmethyltramadol in human urine by gas chromatography-mass spectrometry.

A GC-MS assay for stereoselective determination of tramadol and its pharmacologically active phase I metabolite O-desmethyltramadol in human urine was developed. Nefopam was used as internal standard. The method involves a simple solid phase extraction with chiral analysis by gas chromatography-electron ionization mass spectrometry using m/z 263; 58, 249; 58, and 179; 58 for the determination of concentration of tramadol, O-desmethyltramadol and internal standard, respectively. Chromatography was performed on a Rt-betaDEXcst column containing alkylated beta-cyclodextrins as a chiral selector. The calibration curves were linear in the concentration range 0.1-20 microg/mL (R(2) > or =0.998). Intra-day accuracies ranged between 97.2-104.9%, 96.1-103.2%, and 97.3-102.8% at the lower, intermediate, and high concentration for all analytes, respectively. Inter-day accuracies ranged between 95.2-105.7%, 99.1-105.2%, and 96.5-101.2% at the lower, intermediate, and high concentration for all analytes, respectively. This method was successfully used to determine the concentration of enantiomers of T and ODT in a pharmacogenetic study.

Polymorphisms of the TPMT gene in the Czech healthy population and patients with inflammatory bowel disease.

Genetic variation in thiopurine S-methyltransferase (TPMT) is a major factors for wide variation in the metabolism and safety of thiopurine drugs. We investigated the frequency of functional gene polymorphisms in 396 patients with inflammatory bowel disease and 300 healthy subjects. Frequencies of functionally deficient alleles TPMT*2, TPMT*3A, TPMT*3B, and TPMT*3B in the patient group were 0.1%, 4.3%, 0.1%, and 0.4%, respectively, and were similar to those of healthy subjects in the Czech population. Our results provide necessary information for pharmacoeconomic studies in the Czech Republic.

Frequency of single nucleotide polymorphisms of CYP2D6 in the Czech population.

CYP2D6 is a member of cytochrome P450 enzymes that metabolise over 25% of commonly used drugs. Genetic polymorphisms can cause insufficient drug efficacy at usually administered doses or can be the cause of adverse drug reaction. CYP2D6 genotyping can be used to predict CYP2D6 phenotype and thereby explain some abnormalities in drug response and thus optimize pharmacotherapy. The aim of this study was to investigate the frequency of functionally important variant alleles of the CYP2D6 gene throughout the Czech population to predict the prevalence of ultra-rapid and poor metabolizer phenotypes. The DNA of 223 unrelated, healthy volunteers was analysed to detect the presence of CYP2D6*6, *5, *4, *3 and gene duplication. The variant allele frequencies in our population were 0.22%, 3.14%, 22.87%, 1.12% and 3.14% for CYP2D6*6, CYP2D6*5, CYP2D6*4, CYP2D6*3 and CYP2D6*MxN, respectively. Fifteen subjects carried two variant alleles leading to predicted poor type of metabolism, 84 subjects were heterozygous extensive metabolizers (het-EM). The full-text contains detailed comparison with European white populations. The distribution of variant alleles complies with the Hardy-Weinberg equilibrium. The frequencies of functional variant alleles of CYP2D6 in Czech population are in concordance with other Caucasian populations.