Epidural analgesia with sufentanil in relation to OPRM1 and ABCB1 polymorphisms.

The aim of this study was to evaluate the association between OPRM1 and ABCB1 polymorphisms on pain relief with epidural sufentanil in 69 patients after rectosigma resection for cancer. The median number of injections (SD) 2.31 (1.36), IQR=1, required by 118AA subjects was significantly lower in comparison with 118AG group 5.25 (3.13), IQR=6.5, (chi(2)=9.75, p=0.001); correspondingly median drug consumption of 1.16 (0.79), IQR=1.083, defined daily doses (DDD) was significantly less in the 118AA group in comparison with 2.14 (1.17), IQR=2.23, DDD in 118AG subjects, (chi(2)=7.00, p=0.008). Opioid-induced adverse effects were observed in 15 % and 33 % of patients in 118AA and 118AG groups, respectively (chi(2)=8.16, p=0.004). The median number of injections (SD) required by women and men was 3.30 (2.16), IQR=2, and 2.80 (1.59), IQR=1, respectively (chi(2)=6.25, p=0.012). Opioid-induced adverse effects were observed in 26 % and 12 % of women and men, respectively (chi(2)=5.49, p=0.011). Heterozygotes of OPRM1 polymorphism and women were more difficult to treat subpopulations that required higher doses of rescue analgesic medication and suffered more adverse effects.

Correction to: Pupillometry as an indicator of L-DOPA dosages in Parkinson's disease patients.

Unfortunately, original article has been published without acknowledgement section.

Pupillometry as an indicator of L-DOPA dosages in Parkinson's disease patients.

Dopamine was shown to induce mydriasis by excitation of alpha-adrenergic receptors at the dilator pupillae muscle. Pupilla diameter may thus serve as an indirect measure of peripheral pharmacokinetics of L-DOPA and dopamine. The aim of this study is to evaluate the effect of L-DOPA dosage on pupillometric parameters in Parkinson's disease (PD) patients. Sixteen PD patients and 14 healthy control subjects (CS) were studied. The statistical analysis revealed significant differences between CS and PD patients for the mean maximum and minimum pupil diameters (p = 0.017, p = 0.028, respectively), with higher values found in PD. Moreover, a significant dose-response relationship was found between the maximum pupil diameter and both the morning L-DOPA dose (R 2 = 0.78) and the total daily L-DOPA dose (R 2 = 0.93). A sigmoid-shaped curve best describes the dose-response relationship, with a ceiling effect at about 400 mg L-DOPA daily dose. In conclusion, measuring pupillometric parameters represents a sensitive tool for non-invasive evaluation of the peripheral effect of L-DOPA, especially with daily doses below 400 mg L-DOPA.

OPRM1 and ABCB1 polymorphisms and their effect on postoperative pain relief with piritramide.

Genetic factors may contribute to the differential response to opioids. The aim of this study was to evaluate the association between polymorphisms of µ1-opioid receptor gene OPRM1 (rs1799971), and P-glycoprotein transporter gene ABCB1 (rs1045642, rs2032582), and piritramide efficacy under postoperative patient-controlled analgesia (PCA). In 51 patients, OPRM1 variant was associated with decreased efficacy in early postoperative period evidenced by sum of pain intensity difference in the 0-6 h postoperative period (SPID(0-6)), (F=3.27, p=0.029). Mean (SD) SPID(0-6) was observed in the 118AA genotype 22.9 (6.1) mm, which was significantly higher from the 118GG genotype 10.0 (4.4) mm, p=0.006. The lowest cumulative dose was recorded in 118AA genotype 19.1 (9.8) mg, which was significantly less than in the 118GG genotype group 36.6 (6.1) mg, p=0.017. Opioid-induced adverse effects were observed in 11, 30, and 100 % of patients in 118AA, 118AG, and 118GG genotype groups, respectively (p<0.05). Piritramide efficacy and safety was not significantly affected by ABCB1 (rs1045642, rs2032582) polymorphisms. Variant OPRM1 118G allele is associated with decreased acute postoperative pain relief after piritramide. Decreased efficacy leads to higher drug consumption under PCA settings, which however, does not fully compensate insufficient pain relief, but increases incidence of adverse effects.

[Effect of liver cirrhosis on pharmacokinetics and pharmacodynamics of drugs]. / Vliv jaterní cirhózy na farmakokinetiku a farmakodynamiku léciv.

Metabolic liver functions are significantly involved in the total clearance of a number of drugs. In liver cirrhosis the reduced drug elimination is a result of the blood flow through the liver, hepatocytes function and volume of hepatic tissue. Pharmacokinetic and pharmacodynamic changes depend on the nature and degree of hepatic impairment and on the characteristics of the dosed drug. Hepatocytes have a different extraction ability with respect to the individual drugs. The following are examples of drugs with high hepatic extraction: anodyne, propranolol, metoprolol, verapamil and lidocaine. These drugs are significantly dependent on the first passage through the liver. Intrahepatic and extrahepatic collateral blood flows significantly increase their bio-logical availability and reduce the clearance. The reduction in hepatic clearance of drugs with low extraction coefficient, such as chlordiazepoxide, diazepam or furosemide, is a result of its own limited functional capacity to eliminate the drug. Predicting a hepatic metabolic disorder based on a common bio-chemical assessment of enzyme activities is not sufficient. In advanced liver cirrhosis a higher risk is demonstrated for drugs with a narrow therapeutic width. It is always necessary to take into account whether the pharmacotherapy is necessary, use small doses and cautiously monitor the patient.

Impact of MDR1 genetic polymorphisms on postoperative piritramide analgesia.

OBJECTIVES: The aim of prospective study was to evaluate the therapeutic efficacy of piritramide in patients after removal of parathyroid glands in relation to MDR1 genotype. In the treatment of moderate acute postoperative pain, piritramide plays a major role. It is difficult to predict its optimal therapeutic efficacy and tolerability in individual patients. METHODS: We compared the effect of piritramide in 56 patients after surgical removal of parathyroid glands in a prospective study. We evaluated pain intensity, pain difference and sum of pain difference (SPID) using visual analogue scale (VAS in mm) and adverse effects in the relationship with the MDR1 - polymorphism of G2677T/A. RESULTS: In the wild-type group (2677GG), there was maximal pain difference of 30.6 ± 24.9 and SPID of 209.33 ± 95.80 while in genotype 2677TT and 2677GT, the corresponding values were 19.5 ± 25.5 and 147.07 ± 91.38, respectively. In group of patients with wild type of 2677GG genotype, there was 80 % of responders with more than 50 % reduction in VAS as compared to baseline while in group with carriers of 2677T allele, there are only 39 % of responders present (χ² = 5. 83; p = 0.016). Furthermore, the total consumption of piritramide was lower in comparison with the variant-allele carrying group (p = 0.008). The total incidence of adverse drug reactions was observed in 40 % of patients with wild type of 2677GG genotype when compared to 83% in the group carrying the variant allele (χ² = 7.92; p = 0.005). Significantly more patients in the wild-type group were satisfied with postoperative pain treatment in comparison to the variant allele group (χ² = 6. 49; p = 0.0109). CONCLUSION: We observed a better analgesic effect of piritramide and a decreased incidence of side effects in the wild-type genotype (2677GG) group, when compared with variant-allele carrying patients (Tab. 2, Fig. 1, Ref. 7).

Tramadol efficacy in patients with postoperative pain in relation to CYP2D6 and MDR1 polymorphisms.

OBJECTIVES: The aim of our study was to evaluate impact of CYP2D6 and MDR1 polymorphisms on the analgesic efficacy of tramadol in patients after a knee arthroscopy. BACKGROUND: Pharmacokinetics of tramadol and its metabolites is stereoselective and displays high interindividual variability correlating with polymorphic CYP2D6 in the population. Available data provide controversial results regarding the analgesic efficacy of tramadol in subjects with different CYP2D6 genotypes. METHODS: Pain intensity was assessed using visual analogue scale at 2 and 24 hours after the knee arthroscopy in 156 patients. Polymorphisms CYP2D6*3,*4,*5,*6, and gene duplication and C3435T in MDR1 gene were analyzed by PCR - RFLP. RESULTS: Mean VAS2h value in the whole study group was 44.0 ± 16.5 mm. Mean pain difference, was lowest in the UM group and highest in the PM group. The pain difference varied significantly among the CYP2D6 subgroups (F = 4.29; p = 0.006) with significant differences between homEM vs hetEM, homEM vs PM, and UM vs PM subgroups. There were no significant differences among MDR1 subgroups with regards of pain difference. Mean tramadol consumption was 2.47 ± 1.17 mg/kg during the 24 h period. There were no significant differences in the drug consumption, reporting of adverse reactions, need for rescue analgesic medication or verbal description of pain among the CYP2D6 or MDR1 genotype subgroups. CONCLUSION: CYP2D6 plays a significant role in tramadol analgesic efficacy. The non-opioid analgesia in PMs was associated with better subjective pain relief in patients after a knee arthroscopy (Tab. 3, Ref. 18).

Pupillometry in healthy volunteers as a biomarker of tramadol efficacy.

WHAT IS KNOWN AND OBJECTIVE: The opioid effect of tramadol, which can be detected by pupillary response, is predominantly mediated by the O-demethylated metabolite, formed via CYP2D6. This study was designed to evaluate the effects of tramadol using different parameters of pupillometry as biomarkers. METHODS: Sixty-nine healthy volunteers received tramadol hydrochloride drops orally at a dose of 0·7 mg/kg. Pre-dose and 2-h post-dose pupillometric measurements were performed. The polymorphism of CYP2D6 was analysed. RESULTS AND DISCUSSION: Large interindividual variability was observed in the tramadol-induced pupillary reaction. Miosis was induced in 69·6% and mydriasis in 30·4% of the subjects. The pupillary response differed in relation to the CYP2D6 genotype. A maximal difference in initial pupil diameter of 0·81 mm was found in extensive metabolizers. There were significant effects observed on the pupillary light reflex parameters with tramadol administration (P < 0·05) except for the reflex amplitude and constriction velocity. WHAT IS NEW AND CONCLUSION: The pharmacodynamic effects of tramadol were easily detected using both static and dynamic pupil parameters. The pharmacodynamic profiles were markedly influenced by the CYP2D6 phenotype.

The role of diclofenac and piritramide in the management of acute postoperative pain in hernioplasty.

OBJECTIVES: The aim of the study was to compare the effects of diclofenac and piritramide in acute postoperative pain after hernioplasty. BACKGROUND: In the treatment of moderate acute postoperative pain, non-steroidal anti-inflammatory drugs and opioids play the major role. The data on safety and effect of analgesia based on opioid and non-opioid drugs are still a controversial topic. METHODS: We compared the first-line treatment effects of diclofenac and piritramide in 105 patients after hernioplasty in a retrospective manner. The subsequent therapy combined piritramide with diclofenac. We evaluated the intensity of pain and its relief using a visual analogue scale (VAS). We also evaluated the necessity of application of other analgesics. RESULTS: One hour after the application of the first analgesic dose, we observed complete pain relief in 39.5% of patients treated with piritramide and in 19.4% of patients treated with diclofenac (chi2=5.17; p=0.02). After the use of piritramide, the pain relief (3.84 +/- 1.27 mm) was significantly higher than after diclofenac (3.34 +/- 0.77 mm). Another injection was needed in 76% and 54% of patients subjected to first-line treatment based on diclofenac and piritramide, respectively. CONCLUSION: We observed that the first-line analgesic treatment based on piritramide was more effective when compared to that based on diclofenac (Tab. 3, Ref. 3). Full Text in free PDF www.bmj.sk.

[Genotyping of CYP2D6 and CYP2C19]. / Genotypizace cytochromu P450 2D6 a 2C19.

BACKGROUND: Polymorphisms in drug metabolizing enzymes are considered as a major factor influencing the incidence of adverse drug reactions or failure of pharmacotherapy. Our aim was to compare the distribution of functional polymorphisms in the genes CYP2D6 and CYP2C19 between healthy control group and of patients reffered to our department due to adverse drug reactions or insufficient efficacy of a treatment. METHODS AND RESULTS: The group of patients comprised of 60 subjects, 218 healthy unrelated subjects were included in the cotrol group. In both groups genotypes of CYP2D6 and CYP2C19 were analyzed. There were significantly fewer extensive metabolizers of CYP2D6 in the patient group comparison with healthy control subjects (25.0% vs. 49.8%) while the proportion of intermediate metabolizers was significantly higher than in helthy population (58.3% vs. 38.5%). We also observed more poor metabolizers than in control group (13.3% vs. 6.8%), but the difference did not reach level of statistical significance probably due to low number of subjects. The distribution of either ultrarapid metabolizers of CYP2D6 or deficient alleles of CYP2C19 was similar in both groups. CONCLUSIONS: Clinically apparent alteration of drug effects are often caused by partial or complete deficit of CYP2D6 activity. Our results confirm the importance of CYP2D6 polymorphisms on the efficycy and safety of pharmacotherapy.

Miotic action of tramadol is determined by CYP2D6 genotype.

Polymorphic CYP2D6 is the enzyme that activates the opioid analgesic tramadol by O-demethylation to its active metabolite O-demethyltramadol (M1). Our objective was to determine the opioid effects measured by pupillary response to tramadol of CYP2D6 genotyped volunteers in relation to the disposition of tramadol and M1 in plasma. Tramadol displayed phenotypic pharmacokinetics and it was possible to identify poor metabolizers (PM) with >99% confidence from the metabolic ratio (MR) in a single blood sample taken between 2.5 and 24 h post-dose. Homozygous extensive metabolizers (EM) differed from PM subjects by an almost threefold greater (P=0.0014) maximal pupillary constriction (Emax). Significant correlations between the AUC and Cmax values of M1 versus pupillary constriction were found. The corresponding correlations of pharmacokinetic parameters for tramadol itself were weaker and negative. The strongest correlations were for the single-point metabolic ratios at all sampling intervals versus the effects, with rs ranging from 0.85 to 0.89 (p<0.01). It is concluded that the concept of dual opioid/non-opioid action of the drug, though considerably stronger in EMs, is valid for both EM and PM subjects. This is the theoretical basis for the frequent use and satisfactory efficacy of tramadol in clinical practice when given to genetically non-selected population.

Polymorphisms of the MDR1 gene in the Czech population.

There exists a marked inter-individual variability of P-glycoprotein expression and activity, which can be of clinical importance due to the large number of drugs that are substrates for the transporter. Previously identified polymorphisms in the MDR1 gene belong to important factors causing this phenomenon. Our aim was to investigate the frequency of major functional SNPs of the MDR1 gene coding for P-glycoprotein in the Czech population. DNA was isolated from whole blood of 189 healthy, young and unrelated subjects (99 females and 90 males, aged from 23 to 28 years). The genotypes of polymorphic positions C3435T, G2677T/A, C1236T and T-76A were determined by PCR-RFLP. Observed allelic frequencies were 56.5%, 46.0%, 0.53%, 44.5% and 37.6% for the alleles 3435T, 2677T, 2677A, 1236T and -76A, respectively. We have found 64 subjects homozygous for 3435T, 42 for 2677T, 40 for 1236T and 31 for -76A alleles. The allelic distribution complies well with Hardy-Weinberg equilibrium. Allelic frequencies of functionally important MDR1 variants are in the Czech population similar to that of other Caucasian populations.

Time trend analysis and variations in statins prescribing in the Czech Republic.

The aim of the study was to describe the effect of regulatory changes on the development of statins prescribing in individual districts of the Czech Republic. Retrospective analysis of reimbursed medical prescriptions for statins was based on the data from the General Health Care Insurance Company. The situation was assessed in 75 districts starting from the last quarter of 2001 and repeatedly every quarter up to the last quarter of the 2003. Anatomical Therapeutic Chemical Classification system (ATC) and Defined Daily Dose (DDD) as a unit of measurement were used. In the followed up time period the average consumption of statins in DDDs increased 2.12 times. Nearly tenfold variation across the regions in the number of DDDs per 1000 insured persons per day was found ranking from 4.53 to 46.48 in the last quarter of 2001, while corresponding values in 2003 were 6.10 and 37.55. The amount of DDDs was correlated with numbers of practising internist, general practitioners in individual districts in the same time periods. In the observed period opposite trend of the correlation coefficients was noted for internists and GPs. While the correlation of DDD/1000 persons/day to the number of internists decreased over time, the relation to the number of GPs gradually increased. Almost linear trend with gradual increase of the correlation coefficients between DDD/1000 persons/day and the number of insured persons was noted (T(t) = 0.659 + 0.009.t). Time trend analysis of statins utilization development could help to follow the effect of regulatory changes on its prescribing.

Genetic polymorphism of cytochrome P450 and methods for its determination.

The majority of human P450 dependent drug metabolism is carried out by polymorphic enzymes which can alter plasma concentration of the pharmacological active substance followed by an enhanced or suppressed pharmacological effect. The response of individual patients to drugs can be affected by variations in DNA sequence mainly by single nucleotide polymorphisms (SNPs). Knowledge of functionally important SNPs prior to the drug administrations may assist in the development of individualized pharmacotherapy avoiding unexpected drug responses, such as harmful adverse drug reactions or treatment failures. This review discusses both the basic characteristics of the major polymorphic cytochrome P450 enzymes and examines the pharmacogenetic methods employed to estimate metabolic status. We will focus mainly on the basic principles of genotyping assays involving molecular biology tools.

Switchability of neoral and equoral according to Food and Drug Administration rules and regulations.

According to the US Food and Drug Administration (FDA), if a drug product contains a drug substance that is chemically identical and is delivered to the site of action at the same rate and extent as another drug product, then it is equivalent and can be substituted (switchable) for that drug product. Methods used to define bioequivalence as stated by the FDA rules (FDA 21 CFR 320, 24) are (1) pharmacokinetic (PK) studies in healthy volunteers, (2) comparative clinical trials, and (3) pharmacodynamic (PD) studies (bioactivity). We evaluated the switchability of Equoral (IVAX-USA) with Neoral (Novartis Switzerland using all FDA rules. In a single oral dose, we undertook a comparative bioavailability study of Equoral (IVAX, USA) Neoral (Novartis, USA), and Neoral (Novartis UK). The pharmacokinetics of Equoral and Neoral were determined with blood levels at 0, 0.25, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 16, 24, 30, 36, 42, and 48 hours. The area under curve (AUC), AUC extrapolated to infinity (AUC0-inf), rate of absorption (Tmax), extent of absorption (Cmax), half time (t1/2) of Equoral and Neoral were all within the 90% confidence interval of 80% to 125% boundaries. A comparative multinational multicenter clinical trial in stable renal transplant patients included 70 patients (22 women and 48 men) of mean age of 33 years (range, 26 to 43) was performed in Turkey, Lebanon, and Pakistan. In this study the ratios of LSM and the 90% confidence intervals for the Nontransformed/Parameters (AUC0-t, AUCinf, Tmax, and Cmax) of Equoral and Neoral SGC were 98% and 95%, respectively, which are within the 80% to 125% FDA acceptance range. For immunosuppressive drugs, the site of action is the lymphocyte and the measurable response is the decrease in lymphocyte count caused by the relative concentration of the drug in the lymphocyte. In a controlled switch, fixed-dose study, both Equoral and Neoral achieved the same concentration in the lymphocytes and caused the same degree of lymphocyte count reduction. The results of the testing (bioavailability-bioequivalence, clinical studies, and pharmacodynamic-bioactivity) required by FDA for interchangeability ("switchability") of immunosuppressive agents suggests that Neoral and Equoral are switchable.

[Infrared pupilometry measured by digital photography]. / Infracervená pupilometrie pomocí digitální fotografie.

BACKGROUND: Pupil size is mainly controlled by the action of parasympathetic and sympathetic nerves. Measurement of pupil size and reaction to light are important in both experimental and clinical settings. METHODS AND RESULTS: We have established infrared pupilometry using a commercially available digital camera and a calculation with standard computer software. Volunteers were habituated in a dark room for five minutes before pupil evaluation. Pupil measurement was repeated three times and the diameter was calculated according to the following formula: D(mm)=30/S(pix)*D(pix), where D(pix) and D(mm) represent the pupil size in pixels and millimetres, respectively, and S(pix) was the length in pixels of a 30 mm standard. Our method was validated by the measurement of the diameter of calibration circles printed on a white sheet of paper. Deviation from the actual size was less than 3%. We also compared the results of pupil size obtained by our method, with the results of the pupilometer Pupillscan II measurement. The relative difference between the two methods was always less than 5%. The applicability of the method was illustrated by measurement of the pharmacodynamic effect of the single dose of tramadol (100 mg p.o.) in seven volunteers, compared with control placebo-treated volunteers. CONCLUSIONS: The proposed method is precise and sensitive enough to be used for pupil size determination.

[Adverse effects and drug interactions]. / Nezádoucí úcinky a lékové interakce.

Adverse drug reactions represent a common clinical problem. They are partly induced by a large variability in drug response, which results from the complex interplay between pharmacokinetics, pharmacodynamics and other disease-associated factors. The review describes metabolic changes caused by polymorphism in the cytochrome P450 and gives examples of induction and inhibition of this enzyme system in relation to adverse drug interaction. From the clinical point of view, attention should be paid especially to antidiabetics, anticoagulants and phenytoin. Therapeutic drug monitoring and genetic-based individualization of the therapy with polymorphically metabolized drugs with narrow therapeutic range can contribute to the decreased incidence of adverse drug reactions.

Attitude of Czech physicians to adverse drug reaction reporting.

This survey was carried out to test physicians' knowledge of the principles of adverse drug reaction (ADR) reporting. Structured interviews were carried out with 500 physicians in all regions of the Czech Republic. The questions were aimed at observing ADR, the obligation and the means of reporting, and the source of drug information used in practice. Ninety percent (n=448) reported that they faced ADR in their practice, and 92% (n=458) were aware of the obligation to report, but most (180 general practitioners, 138 specialists) were unclear as to what should be reported. Knowledge of the subject of ADR reporting was significantly lower (18.4%) among physicians who used primarily the drug information provided by pharmaceutical companies than among those who used other information sources (38.4%). The low level of knowledge of ADR spontaneous reporting system found in our study is one of the reasons for the substantial underreporting of ADR in the Czech Republic compared to other European countries.

Noninvasive evaluation of portal-systemic shunting by glyceryl trinitrate.

Portal-systemic shunting is an important circulatory abnormality in patients with liver cirrhosis. Glyceryl trinitrate (GTN) that is normally subject to first pass elimination, may exhibit higher bioavailability in these patients. This study compares the pharmacodynamic effects of GTN after peroral and sublingual administration for noninvasive assessment of shunting. Six control subjects and 15 patients with cirrhosis were studied after oral and sublingual application of 0.5 mg of GTN. Liver cirrhosis was complicated by portal hypertension in 7 of the patients and 4 patients had surgically implanted portocaval anastomosis. Digital plethysmography, which is highly sensitive and is essentially noninvasive in nature, was used to assess and compare the pharmacodynamic effects of GTN. The following values of the ratio of areas under the pharmacodynamic effects/time curve were obtained: 0.08 +/- 0.06 in healthy subjects, 0.52 +/- 0.21 in patients with uncomplicated cirrhosis, 0.99 +/- 0.34 in patients with portal hypertension and 1.24 +/- 0.43 in patients with portal-systemic shunts. We conclude that increased bioavailability of GTN reflects portal-systemic shunting and might be used providing that the pharmacodynamic data reflect both pharmacokinetic variability and the pharmacokinetic-pharmacodynamic interrelations.