CYP2D6 basic genotyping as a potential tool to improve the antiemetic efficacy of ondansetron in prophylaxis of postoperative nausea and vomiting.

BACKGROUND: Postoperative nausea and vomiting (PONV) is a common complication after anesthesia and surgery. Ondansetron is one of the most widely used drugs in the prophylaxis of PONV and is extensively metabolized in humans. In vitro metabolism studies have shown that ondansetron is a substrate for human hepatic cytochrome P450 enzymes. The cytochrome P450 (human hepatic cytochrome [CYP]) 2D6 inhibitor quinidine reduced in vitro hydroxylation of ondansetron, which indicates the important role of CYP2D6 in ondansetron metabolism. Genotyping these alleles allows the prediction of the extensive metabolizer (EM) and poor metabolizer (PM) phenotypes with approx. 90-96% accuracy. OBJECTIVES: The aim of our study was to evaluate whether the pharmacological prevention of PONV with ondansetron depends on the most common CYP2D6 alleles (CYP2D6*1, *3, *4, *5, and NxN [multiplication gene]). MATERIAL AND METHODS: Genotyping for the defective CYP2D6*3, CYP2D6*4 and CYP2D6*5 alleles among 93 surgical female patients was performed by polymerase chain reaction amplification and restriction fragment length polymorphism (PCR-RFLP). RESULTS: The genetically defined EMs and ultrarapid metabolizers (UMs) of CYP2D6 had a statistically significant (p < 0.02) higher frequency of nausea and vomiting after strumectomy (33.3%) than intermediate metabolizers (IMs) (10.3%) and PMs (0%). The relative risk (odds ratio [OR]) of PONV occurrence was 5 times higher for EMs/UMs than IMs/PMs. CONCLUSIONS: Our results suggest that PONV treatment with ondansetron could be improved by basic, widely available and inexpensive PCR-RFLP genetic tests.

[Clinical drug trials in elderly persons]. / Kliniczne badania leków u osób w starszym wieku.

Older people belong to the social group who is the largest consumer of drugs. But despite this commonly known statement, the evidence base for the pharmacotherapy of older patients is small and insufficient. Elderly persons are often excluded from many clinical drug trials, which are used to determine the effectiveness and safety of drugs. The reasons to exclude the elderly patients from randomised controlled drug trials are: the age-related changes in different body functions, coexisting morbidities, drug complications connected with polypharmacotherapy, poor cognitive functions, inability to consent or even death. Mentioned reasons make more likely that included old frail patients will be unable to complete the trial. However in the context of growing old the population of many countries, it is imperative to find new ways in order to enhance participation of older people in clinical drug trials which allow to avoid dangerous risk of pharmacotherapy. The examples of recommended ways are: minimalization or avoidance of traditional exclusion criteria; inclusion larger sample sizes of the elderly into the population trials, the usage of short, simple, understandable and adaptable for this special group of persons, information and consent forms; using a measure, such as CGA-comprehensive geriatric assessment, for multidimensional evaluation of old patient status. Mentioned recommendations may enhance the objectivization of clinical research outcomes in the old age persons.

Influence of anticancer therapy on oxidation phenotype and acetylation phenotype in patients with acute myeloblastic leukemia.

The aim of this study was to determine whether antineoplastic cytostatic therapy induces changes in the oxidation or acetylation phenotypes in patients with acute myeloblastic leukemia (AML). The investigations involved 22 patients with AML undergoing chemotherapy with daunorubicin, cytosine arabinoside, etoposide and mitoxantrone. The oxidation phenotype prior to therapy and after termination of induction was examined in all 22 patients and was examined in 10 patients after termination of the first consolidation cycle. The acetylation phenotype was examined prior to therapy and after termination of induction in 21 patients and after termination of the first remission consolidation cycle in 9 patients. The oxidation phenotype was determined by means of the method by Eichelbaum and Gross. The acetylation phenotype was determined using Varley's modification of the Bratton-Marshall method. Anticancer therapy affected the oxidation phenotype, causing decreased activity of the cytochrome P450 isoenzyme CYP2D6. This decrease suggests that daunorubicin, cytosine arabinoside, etoposide and mitoxantrone may impair the metabolism of other active substances metabolized by this isoenzyme, which should be taken into consideration in planning the dosage scheme in individual patients and considering interactions between drugs. Evaluation of the effect of administered cytostatic drugs on acetylation phenotype revealed no statistically significant decrease in the rate of sulfadimidine acetylation.

Optimization of lidocaine application in tumescent local anesthesia.

Tumescent local anesthesia is based upon the infusion of large volumes of neutralized anesthetic solutions, mainly lidocaine, at very low concentrations. This results in the paralysis of sensory nerve endings and minute nerve twigs, leading to a reduction in pain. The aim of this study was to assess the safety of lidocaine application in tumescent local anesthesia on different regions of patient's bodies. Measures of safety included the analysis of lidocaine concentrations and its pharmacokinetic parameters. In total, 48 patients were infused with tumescent anesthesia in the hypogastrium, buttocks and thighs, axillae, breasts, trunk, and face and neck areas. Lidocaine was infused in doses ranging from 5.2-40 mg/kg b.w., and in concentrations of 0.05% (hypogastrium, buttocks, thighs) or 0.1-0.15% (axillae, breasts, trunk, face, neck), using a total amount of 300-3200 mg. As the peak lidocaine concentration did not exceed 5 microg/ml (commonly known as the toxic threshold), the results of our study indicate that the doses used (not exceeding 40 mg/kg b.w.) are completely safe for patients undergoing tumescent anesthesia in different body areas. The observation of statistically significant correlations between both the dose and the total amount of lidocaine administered and its peak plasma concentration, together with the lack of correlations between the dose and the amount and the time taken to reach peak concentration, allows the safety of each anesthetic dose to be predicted. An analysis of the heterogeneous dynamics of lidocaine plasma concentration changes in tumescent anesthesia in different body areas indicates that both the rates and the degrees of absorption and elimination depend on the area of infiltration; this is in turn related to the vascularization of any given area. The study of lidocaine concentration and pharmacokinetic parameters also showed that there may potentially be a higher risk of a large anesthetic concentration developing within a short period of time during anesthesia of the upper parts of the body. During tumescent anesthesia, significantly higher plasma concentrations of lidocaine were observed in the face and neck than in the hypogastrium, buttocks and thighs, axillae, breast and trunk 0.5 to 4 h after its infusion. This indicates the need for carefully conducted patient observations immediately after infiltration into the aforementioned areas.

[Phenotypes of oxidation and acetylation in Alzheimer's disease--preliminary report]. / Fenotyp oksydacji i fenotyp acetylacji w chorobie Alzheimera--doniesienie wstepne.

AIM: The relationship between genetically determined polymorphic oxidation and acetylation and susceptibility to some disease has aroused much interest. The aim of our study was to evaluate whether patients with Alzheimer's disease differ from healthy persons in their ability to oxidize sparteine and acetylate sulphadimidine as model substance. METHOD: Oxidation and acetylation phenotype were estimated in 20 patients with Alzheimer's disease. The control group consisted of 160 healthy volunteers for comparison of oxidation phenotype and 45 healthy subjects for comparison of acetylation phenotype. RESULTS: The phenotyping of oxidation revealed two distinct populations among 20 patients with Alzheimer's disease: 19 persons (95%) were extensive metabolizers (EMs) of sparteine and 1 person (5%) was a poor metabolizer (PMs). In 160 healthy persons, 146 persons (91.2%) were extensive metabolizers of sparteine and 14 persons (8.8%) were poor metabolizers. The difference between the frequency distribution of PMs and EMs in healthy persons and in patients with Alzheimer's disease was not statistically significant. The phenotyping of acetylation showed that among 20 patients with Alzheimer's disease 10 persons (50%) were rapid acetylators and 10 persons (50%) were slow acetylators. In 45 healthy subjects the phenotype of rapid acetylation was observed in 23 persons (5 1%) and slow acetylation in 22 persons (49%). Our study showed a lack of statistically significant differences between the percentage of rapid acetylators (51%) and of slow acetylators (49%) in the control group of healthy volunteers and in the group ofAlzheimer's disease. CONCLUSION: The results of our study may suggest that phenotypes of oxidation and acetylation are not associated with risk of the development of Alzheimer's disease.

[The influence of clomipramine on CYP2D6 activity]. / Wplyw klomipraminy na aktywnosc CYP2D6--doniesienie wstepne.

AIM: Genetically determined activity ofCYP2D6 may be modified by some drugs through inhibition processes. Inhibition properties of TCA's were confirmed mainly in in vitro studies. The aim of the study was to assess the influence of clomipramine on CYP2D6 activity in vivo. METHOD: 11 patients diagnosed with depression according to ICD-10 and DSM-IV (major depression) criteria were included in the study. In all the cases clomipramine therapy was indicated. CYP2D6 activity was assessed by the phenotyping method. All patients were treated simultaneously. Each of the patients ingested one tablet containing 100 mg of sparteine sulfate. Urine excreted during the following 6 h was collected. Based on sparteine metabolic ratio (MR) the phenotype status was estimated twice: after the wash-out period, before clomipramine treatment, sparteine metabolic ratio (MRI), and after 2-weeks of clomipramine treatment (MR2). RESULTS: During clomipramine treatment MR2 values were statistically significantly higher than MRI. In 3 patients (27.3%) treated with clomipramine the changes of phenotype status were observed. CONCLUSIONS: Clomipramine is a CYP2D6 inhibitor and may change the CYP2D6 phenotype status (EM into PM).

[Contemporary concept of placebo usage in clinical trials of new drugs]. / Wspólczesne koncepcje stosowania placebo w klinicznych badaniach nowych leków.

The placebo-controlled trials have been almost always controversial since the beginning of introduction of this method into new pharmacotherapy investigations. From the legal and ethical point of view the usage of placebo is more and more frequently criticized because it devoids the patients of standard therapy advantages. Therefore, contemporary tendency to solve of ethical placebo problem connected with clinical trials of new drugs is often--application of more safe methods of results objectifying in new therapy by comparison of the results of clinical trials in the group taking a new drug to be tested to the one treated by conventional, standard, established the best so far known, pharmacotherapy.

[Clinical significance of oxidation and acetylation genetic polymorphism in patients with hyperthyreosis]. / Kliniczne znaczenie fenotypu oksydacji i fenotypu acetylacji u chorych na nadczynnosc tarczycy.

INTRODUCTION: The relationship between genetically determined polymorphic oxidation and acetylation and susceptibility to some disease was aroused much interest. The aim of our study was to evaluate whether patients with hyperthyreosis differ from healthy persons in their ability to oxidize sparteine and acetylate sulphadimidine as model drugs. Oxidation and acetylation were estimated in 48 patients with hiperthyreosis. MATERIAL AND METHODS: The control group consisted of 160 healthy volunteers for comparison of oxidation phenotype and 60 healthy volunteers for comparison of acetylation phenotype. The phenotyping of oxidation revealed two distinct populations among 40 patients with hyperthyreosis: 38 persons (95%) were extensive metabolizers (EM) of sparteine and 2 persons (5%) was poor metabolizers (PM). In 160 healthy persons (91.2%) were EM and 14 persons (8.8%) were PM. The difference between frequency distribution of PM and EM in healthy persons and in patients with hyperthyreosis was not statistically significant. RESULTS: The phenotyping of acetylation showed among 48 patients with hyperthyreosis 8 persons (13%) were rapid acetylators (RA) and 40 persons (87%) were slow acetylators (SA). In 60 healthy volunteers the phenotype of rapid acetylation was observed in 31 persons (51%) and slow acetylation in 29 persons (49%). Relative risk (odds ratio) of development of thyroid diseases was 5.34 times higher for SA in comparison to RA. The prevalence of SA among patients with hyperthyreosis in comparison to healthy volunteers was statistically significant (p < 0.0002). CONCLUSIONS: The results of our study may suggest that slow acetylation phenotype is associated with increased risk of the development of hyperthyreosis.

Doxepin inhibits CYP2D6 activity in vivo.

OBJECTIVE: Doxepin is a tricyclic antidepressant formulated as a mixture of E-(trans) and Z-(cis) stereoisomers. Cytochrome P450 2D6 (CYP2D6) catalyzes the hydroxylation of E-doxepin and E-N-desmethyldoxepin stereospecically. There is evidence that tricyclic antidepressants might inhibit CYP2D6 activity but there is no data about the influence of doxepin on CYP2D6. MATERIALS AND METHODS: Eleven patients diagnosed with depression according to ICD-10 criteria were included in the study. After wash-out period, before doxepin treatment, sparteine metabolic ratio (MR1) was assessed. After 2-weeks of doxepin treatment, MR2 was estimated. Sparteine and its metabolites were determined in urine by gas chromatographic method of Eichelbaum et al. RESULTS: Based on MR1 values, 10 patients were classified as EM (extensive metabolizers) and 1 patient as PM (poor metabolizer). During the study, after doxepin treatment, none of patients has changed phenotype status. However, MR2 values were statistically significantly higher than MR1. CONCLUSION: These results show the inhibitory effect of doxepin on CYP2D6 activity and may be of clinical value, especially in polymedicated patients treated with other CYP2D6 substrates or inhibitors.

[Renal tubular dysfunction in patients with rheumatoid arthritis starting with low dose of methotrexate]. / Ocena czynnosci kanalika proksymalnego u chorych na reumatoidalne zapalenie stawów, rozpoczynajacych leczenie metotreksatem.

BACKGROUND: The elevation of N-acetyl-beta-D-glucosaminidase (NAG) in urine has been shown to be associated with reversible renal tubular damage. OBJECTIVES: The aim of the study was to examine the effect of first oral low dose methotrexate (MTX) on urinary excretion of NAG comparing with MTX concentration in serum and urine in a cohort of patients with rheumatoid arthritis (RA). METHODS: Urinary NAG to urinary creatinine ratio (NAG index) determined in 43 patients (5 males, 38 females) with RA who started taking the first oral dose of 10 mg of MTX. Urinary NAG index was observed at 24 h and 48 h after the first MTX dose. MTX concentration was measured in blood at 90 minutes and in blood and urine at 24 h after the drug administration. RESULTS: NAG-enzymuria was increased in 72.1% of the patients before administration of MTX therapy (10.8 UI/g creatinine). There was no change in NAG index at 24 and 48 h after first dose of MTX (9.1 and 10.7 UI/g of creatinine). No differences of NAG-enzymuria in non-steroidal anti-inflammatory drug (NSAID)-treated patients and NSAID-free patients before and after MTX administration were revealed. The patients with decreased creatinine clearance had before treatment higher NAG index than those with normal creatinine clearance but there was not any significant increase of NAG activity after first dose of MTX in the patients with decreased creatinine clearance. Continued treatment with MTX resulted in a decrease in NAG activity accompanied by serum C-reactive protein concentration. CONCLUSION: The use of low dose MTX with or without NSAIDs does not influence the renal tubular function in patients with RA.

[Significance of CYP2D6 oxidation genotype as a risk factor in development of allergic diseases]. / Znaczenie genotypu oksydacji CYP2D6 jako czynnika zwiekszajacego ryzyko wystapienia chorób alergicznych.

The relationship between genetically determined polymorphic metabolism and susceptibility to allergic diseases has aroused much interest. The aim of our study was to evaluate whether patients with allergic diseases, like atopic asthma and allergic rhinitis differ from healthy persons in their CYP2D6 genotype. Study completed 400 persons, 100 patients with allergic diseases--62 with atopic asthma and 38 with allergic rhinitis and 300 healthy volunteers as a control group. The results of our study revealed a statistically significant predominance of extensive metabolizers among patients with allergic diseases in comparison to healthy volunteers. Relative risk (odds ratio) of development of allergic diseases was 1.85 times higher (p < 0.05), atopic asthma was 1.97 times higher (p < 0.05), allergic rhinitis 1.68 times higher (p > 0.05; NS) for persons with extensive CYP2D6 genotype. Our results represent some evidence for a possible relationship between extensive CYP2D6 genotype and the higher susceptibility to development of allergic diseases.

[Bioavailability and its significance in pharmacotherapy]. / Dostepnosc biologiczna leku i jej znaczenie w farmakoterapii.

The paper provides an overview of information related to bioavailability, including the fundamental notions and the factors, which can change this parameter described in quantitative way drug absorption--one of the processes involved in fate of drug in the organism. Systemic bioavailability is best described by the measurement of the relative amount of an administered dose that reaches the general circulation (Area Under the Curve, AUC), the maximum concentration achieved (Cmax), and the time (tmax) at which this occurs. Liver diseases may substantially increase the oral bioavailability of drugs that are subject to extensive first-pass metabolism e.g. pro-pranolol, lidocaine, metoprolol, verapamil. To avoid toxicity, oral doses of these drugs need to be reduced in patients with severe liver diseases.

[Evaluation of renal function in children undergoing surgery under general anaesthesia]. / Ocena funkcji nerek u dzieci poddawanych zabiegom chirurgicznym w znieczuleniu ogólnym.

UNLABELLED: 47 children (29 boys and 18 girls) aged from 3 to 13 years were examined. The children were operated under general anaesthesia. All children were in good general condition, belonged to anaesthesia risk groups ASA 1 and ASA 2, had no metabolic, endocrinological, haematological diseases nor had renal or hepatic dysfunction. The examined children were divided into two groups with regard to anaesthesia method. 24 healthy children aged 2-16 years were included into control group. Urinary excretion of N-acetyl-beta-D-glucosaminidase (U-NAG), Tamm-Horsfall protein (U-THP), beta 2-microglobulin (U-beta 2-m) and albumins (U-Alb) as indicators of functions of the following nephron structures: glomerular, proximal and distal tubular were assessed. The studies were carried out directly before and on the first day after surgery. RESULTS: Statistically significant differences between values of examined indicators before and after surgery have not been observed. CONCLUSION: The administered methods of anaesthesia have not negatively influenced renal function in children.

[Anticancer chemotherapy containing cisplatin in patients with lung cancer and kidney function]. / Chemioterapia przeciwnowotworowa zawierajaca cisplatyne u chorych na raka pluca a czynnosc nerek.

To carry out safe anticancer chemotherapy one should consider the kidney function. Insufficiency of that main organ responsible for drugs excretion, caused either by neoplastic disease or by chemotherapy, can diminish the possibility or even make impossible of carrying out a complete treatment cycle. The aim of our work was to evaluate the kidney function in patients with lung cancer during anticancer chemotherapy containing cisplatin. The tubular function was studied by estimation the activity of N-acetyl-beta-D-glucosaminidase in urine and glomerular function was studied by estimation the concentration of creatinine in urine, urea, uric acid and electrolytes in plasma. The observations have recorded that neoplastic process, as well as chemotherapy impaired the tubular function. It has showed that it does exist a necessity of detailed estimation of kidney excretory function before, during and after the end of anticancer therapy. Determination of NAG activity in urine may be helpful for the recognition of the patients at high nephrotoxicity risk, who need special care.