The influence of polypharmacy on grade III/IV toxicity, prior discontinuation of chemotherapy and overall survival in ovarian cancer.

BACKGROUND: Ovarian cancer is mostly diagnosed in the elderly woman who is likely to have comorbid disease and to take several comedications on a regular basis. Aim of this study was to evaluate the influence of polypharmacy on grade III/IV toxicity, prior discontinuation of chemotherapy and survival. PATIENTS AND METHODS: In this individual participant data meta-analysis the original data of three phase II/III studies of the North-Eastern German Society of Gynecological Oncology (NOGGO) were analyzed using multivariate logistic and Cox regression. RESULTS: Overall, 1213 patients with recurrent ovarian cancer were included in these analyses. An increasing amount of medication was associated with overall grade III/IV toxicity (p<0.001; OR 1.120), and hematological (p<0.001; OR 1.056) and non-hematological (p<0.001; OR 1.134) toxicities. Prior discontinuation of chemotherapy was not influenced by an increasing amount of medication (p=0.196). There was no association of polypharmacy with overall survival (p=0.068). CONCLUSION: As polypharmacy does not influence survival ovarian cancer patients taking several comedications may be included in clinical trials and should not be deprived of adequate cancer treatment. However, a thorough monitoring is mandatory due to the increased risk of toxicities.

Genetic variants of the insulin receptor substrate-1 are influencing the therapeutic efficacy of oral antidiabetics.

AIM: The therapeutic efficacy of oral hypoglycaemic drugs varies between individuals, and pharmacogenetic factors contribute to this variability. The Gly972Arg polymorphism in the insulin receptor substrate-1 (IRS-1) has been shown to play a role in insulin signal transduction and therapeutic failure to sulphonylurea drugs. METHODS: We studied the association between the IRS-1 polymorphism and the haemoglobin A1c (HbA1c) level in diabetic patients treated with insulinotropic versus non-insulinotropic hypoglycaemic drugs as a marker for the efficacy of an antidiabetic treatment. Genotyping of the IRS-1 Arg(972) variant was performed in type 2 diabetes patients treated with either sulphonylurea drugs, glinides or insulin or with metformin, acarbose or glitazones using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. RESULTS: Significantly higher HbA1c levels were observed in carriers of the Arg(972) variant after treatment with insulinotropic drugs compared to wild-type carriers (8.3 vs. 7.6%, p = 0.005, independent t-test). Furthermore, patients with secondary failure to insulinotropic hypoglycaemic drugs switching finally to insulin showed even higher HbA1c levels in carriers of Arg(972) compared to wild-type (8.7 vs. 7.6%, p = 0.005, independent t-test). CONCLUSIONS: Thus, we were able to replicate the earlier findings of an association between the IRS-1 Arg(972) variant and secondary failure to sulphonylurea drugs, and further observed a general association between HbA1c and this polymorphism in type 2 diabetes patients treated with insulinotropic hypoglycaemic drugs but not with metformin.

Relative impact of genotype and enzyme induction on the metabolic capacity of CYP2C9 in healthy volunteers.

Pharmacokinetics in individual subjects is determined by genes and environment. The relative contributions of enzyme induction and inherited genomic variation to cytochrome P450 enzyme 2C9 (CYP2C9) activity are unknown. In 130 volunteers, CYP2C9 activity was measured in vivo using tolbutamide as a probe drug. Tolbutamide was administered orally, and the pharmacokinetics of the drug was analyzed twice--before and after four doses of 450 mg rifampin. Mean total apparent clearances (Cl/F) in the genotype groups CYP2C9*1/*1, *1/*2, *1/*3, *2/*3, and *3/*3 before rifampin were 0.78, 0.74, 0.52, 0.40, and 0.13 l/h, respectively. After rifampin administration, these clearances increased in all genotype groups by a median factor of 1.9 (range 1.1-4.8). The combined effects of genes and environment could be predicted by a simple additive model. Thus, enzyme induction resulted in an approximately twofold difference in CYP2C9 activity, irrespective of the CYP2C9 genotypes. But the difference in activity levels between the CYP2C9*1/*1 and *3/*3 genotypes before the administration of rifampin was sixfold.

CYP2D6 ultrarapid metabolism and morphine/codeine ratios in blood: was it codeine or heroin?

The concentration ratio of morphine (Mor) over codeine (Cod) in opiate positive blood samples is used to discriminate between the use of illegal heroin (high ratios) and therapeutic codeine (low ratios). However, genetically caused CYP2D6 ultra-rapid metabolism might lead to Mor/Cod comparable to heroin intake. A single oral dose of 30 mg codeine was administered to 11 CYP2D6 ultrarapid metabolizers (UMs) and 12 extensive metabolizers (EMs). Codeine and its morphine metabolites and Mor/Cod were quantified in plasma and urine by liquid chromatography with tandem mass spectrometry within 24 h after codeine intake. The Mor/Cod in plasma were below 1 for both UMs and EMs during the first 12 h. After 12 h, 9% of the 11 UM and none of the 12 EM had ratios > 1. In urine, Mor/Cod ratios were below one for all EMs and UMs during the first 12 h. Thus, CYP2D6 genotyping in general will not explain Mor/Cod ratios > 1 in plasma or urine, unless the time of drug intake is more than 24 h previous.

Possible role of MDR1 two-locus genotypes for young-age onset ulcerative colitis but not Crohn's disease.

BACKGROUND: The role of the single nucleotide polymorphisms (SNPs) on positions 2677G>T/A and 3435C>T of the multi-drug-resistance gene 1 (MDR1) in inflammatory bowel disease (IBD) remains unclear. AIMS: To further elucidate the potential impact of MDR1 two-locus genotypes on susceptibility to IBD and disease behaviour. PATIENTS AND METHODS: Three hundred eighty-eight German IBD patients [244 with Crohn's disease (CD), 144 with ulcerative colitis (UC)] and 1,005 German healthy controls were genotyped for the two MDR1 SNPs on positions 2677G>T/A and 3435C>T. Genotype-phenotype analysis was performed with respect to disease susceptibility stratified by age at diagnosis as well as disease localisation and behaviour. RESULTS: Genotype distribution did not differ between all UC or CD patients and controls. Between UC and CD patients, however, we observed a trend of different distribution of the combined genotypes derived from SNPs 2677 and 3435 (chi(2) = 15.997, df = 8, p = 0.054). In subgroup analysis, genotype frequencies between UC patients with early onset of disease and controls showed significant difference for combined positions 2677 and 3435 (chi(2) = 16.054, df = 8, p = 0.034 for age at diagnosis >or=25, lower quartile). Herein the rare genotype 2677GG/3435TT was more frequently observed (odds ratio = 7.0, 95% confidence interval 2.5 - 19.7). In this group severe course of disease behaviour depended on the combined MDR1 SNPs (chi(2) = 16.101, df = 6, p = 0.017 for age at diagnosis >or=25). No association of MDR1 genotypes with disease subgroups in CD was observed. CONCLUSIONS: While overall genotype distribution did not differ, combined MDR1 genotypes derived from positions 2677 and 3435 are possibly associated with young age onset of UC and severe course of disease in this patient group.

Genotype and phenotype relationship in drug metabolism.

Pharmacogenetics, one of the fields of clinical pharmacology, studies how genetic factors influence drug response. If hereditary traits are taken into account appropriately before starting drug treatment, the type of drug and its dosage can be tailored to the individual patient's needs. Today, the relationships between dosage requirements and genetic variations in drug-metabolizing enzymes such as cytochrome P450 (CYP) 2D6, CYP2C9, and CYP2C19 or in drug transporters such as p-glycoprotein (ABCB1) and OATP-C (SLC21A6) are substantiated best. A standard dose will bring about more adverse effects than usual if enzymatic activity is lacking or feeble. Sometimes, however, therapeutic response might be better because of higher concentrations: proton pump inhibitors for eradication of Helicobacter pylori are more efficacious in carriers of a deficient CYP2C19 variant. In some cases, genetic tests can help distinguish between responders and nonresponders of a specific drug treatment, and genotype-based dosage is possible.

Pharmacokinetics of codeine and its metabolite morphine in ultra-rapid metabolizers due to CYP2D6 duplication.

Codeine is an analgesic drug acting on mu-opiate receptors predominantly via its metabolite morphine, which is formed almost exclusively by the genetically polymorphic enzyme cytochrome P450 2D6 (CYP2D6). Whereas it is known that individuals lacking CYP2D6 activity (poor metabolizers, PM) suffer from poor analgesia from codeine, ultra-fast metabolizers (UM) due to the CYP2D6 gene duplication may experience exaggerated and even potentially dangerous opioidergic effects and no systematical study has been performed so far on this question. A single dose of 30 mg codeine was administered to 12 UM of CYP2D6 substrates carrying a CYP2D6 gene duplication, 11 extensive metabolizers (EM) and three PM. Genotyping was performed using polymerase chain reaction-restriction fragment length polymorphism methods and a single-base primer extension method for characterization of the gene-duplication alleles. Pharmacokinetics was measured over 24 h after drug intake and codeine and its metabolites in plasma and urine were analyzed by liquid chromatography with tandem mass spectrometry. Significant differences between the EM and UM groups were detected in areas under the plasma concentration versus time curves (AUCs) of morphine with a median (range) AUC of 11 (5-17) microg h l(-1) in EMs and 16 (10-24) microg h l(-1) in UM (P=0.02). In urine collected over 12 h, the metabolic ratios of the codeine+codeine-6-glucuronide divided by the sum of morphine+its glucuronides metabolites were 11 (6-17) in EMs and 9 (6-16) in UM (P=0.05). Ten of the 11 CYP2D6 UMs felt sedation (91%) compared to six (50%) of the 12 EMs (P=0.03). CYP2D6 genotypes predicting ultrarapid metabolism resulted in about 50% higher plasma concentrations of morphine and its glucuronides compared with the EM. No severe adverse effects were seen in the UMs in our study most likely because we used for safety reasons a low dose of only 30 mg. It might be good if physicians would know about the CYP2D6 duplication genotype of their patients before administering codeine.

A 40-basepair VNTR polymorphism in the dopamine transporter (DAT1) gene and the rapid response to antidepressant treatment.

Finding predictors of the response to antidepressant therapy is a major goal of molecular psychiatry. The genes encoding the serotonin (SERT) and dopamine (DAT1) transporters are among the possible candidate genes modulating an individual's antidepressant response. In a naturalistic prospective cohort study with a total of 190 fully assessed patients, improvement of depression symptoms during the 3 weeks following initiation of antidepressant therapy was recorded using the 21-item Hamilton Depression Rating Scale (HDRS). The SLC6A3 3' UTR 40-bp variable number of tandem repeats (VNTR) and the SLC6A4 5' 44-bp insertion/deletion polymorphism were analyzed by polymerase chain reaction. There was a significantly smaller number of rapid responders among homozygous carriers of the DAT1 9-repeat allele (9/9) than among heterozygous (9/10) and homozygous (10/10) carriers of the 10-repeat allele (19 versus 37 versus 52%, respectively, P=0.0037). Median decline in HDRS score was 35, 40, and 52% in patients with the 9/9, 9/10, and 10/10 genotypes, respectively (P=0.013). The effect was found in all classes of medications (selective serotonin reuptake inhibitors (SSRIs), tricyclics, mirtazapine, venlafaxine) and statistically significant also within the subgroup of patients having received SSRIs. The serotonin promoter insertion/deletion genotype had no effect in the entire study group, but there was an insignificant trend of better response in the l/l and l/s carriers who received SSRIs or mirtazapine. In conclusion, the dopamine transporter VNTR polymorphism influenced rapid response to antidepressant therapy. Compared with homozygous carriers of the 10-repeat allele, carriers of the 9/10 genotype had an odds ratio (OR) calculated by logistic regression analysis of 1.6 (95% CI 0.8-3.2) and carriers of the 9/9 genotype had an OR of 6.0 (1.5-24.4) for no or poor response. Further studies are required to confirm this clinical association and to elucidate the underlying mechanisms.

[Implications of pharmacogenetics in every-day practice]. / Bedeutung der Pharmakogenetik für die tägliche Praxis.

Pharmacogenetics as one of the areas of clinical pharmacology addresses hereditary factors involved in individually different responses to drugs. Clinical trials combined with molecular genetics seek for underlying reasons influencing efficacy and toxicity of drugs. The declared goal of pharmacogenetics is to provide physicians with knowledge and tools to allow an individualized patient-directed pharmacotherapy. This concept is best evolved for clinical practice in the field of drug-metabolizing enzymes, especially for the cytochromes P450 (CYP) 2D6, CYP2C19 and thiopurine S-methyltransferase (TPMT). Patients with inherited enzyme deficiencies are at risk to accumulate excessive drug concentrations when treated with standard doses which may lead to adverse drug reactions or even to life-threatening conditions. Genetic factors are also involved in drug-target interactions (e. g. receptors). Prospective controlled clinical trials are needed to evaluate the benefit of pharmacogenetics for therapy outcome and to define its role in clinical practice.

Acute myopathy in a type 2 diabetic patient on combination therapy with metformin, fenofibrate and rosiglitazone.

AIMS/HYPOTHESIS: This report describes the case of a 75-year-old male type 2 diabetic Caucasian who was admitted to the clinical ward because of acute pain and cramps in both calf muscles. MATERIALS AND METHODS: Neuromuscular function was assessed by electromyography and electroneurography of the right leg. An open biopsy was taken from the left vastus lateralis muscle for histological and histochemical analyses. Southern blotting was performed to detect defects in mitochondrial DNA and tRNA. Cytochrome P450 (CYP-P450) polymorphisms were analysed in blood cells. RESULTS: Fifteen weeks before admission, the patient's lipid-lowering medication was switched from simvastatin to fenofibrate because of predominant hypertriglyceridaemia; this did not affect creatine kinase levels. Three weeks before admission, rosiglitazone was added to his existing metformin therapy because of worsening metabolic control. Upon admission, serum enzymes indicating myopathy were elevated (creatine kinase 6897 U/l, myoglobin 902 ng/ml) and kidney function was impaired (creatinine 0.116 mmol/l, blood urea nitrogen 2.3 mmol/l). Electrophysiology revealed myopathy and sensory polyneuropathy. Histology showed multiple damage of the myofibrillar architecture. There was no evidence of defects in mitochondrial DNA or tRNA. Furthermore, no functional limitations in CYP2C9, CYP2C19 and CYP2D6 were detected. Following withdrawal of the oral medication and intravenous hydration, clinical symptoms and laboratory parameters gradually decreased. CONCLUSIONS/INTERPRETATION: Until more data from controlled trials are available, we recommend that combination therapy with fibrates and thiazolidinediones should be monitored frequently by measurements of serum creatine kinase and creatinine, specifically in patients with pre-existing nephropathy and polyneuropathy.

Association of cyclophosphamide pharmacokinetics to polymorphic cytochrome P450 2C19.

Cyclophosphamide (CP), a widely used cytostatic, is metabolized by polymorphic drug metabolizing enzymes particularly cytochrome P450 (CYP) enzymes. Its side effects and clinical efficacy exhibit a broad interindividual variability, which might be due to differences in pharmacokinetics. CP-kinetics were determined in 60 patients using a global and a population pharmacokinetic model considering functionally relevant polymorphisms of CYP2B6, CYP2C9, CYP2C19, CYP3A5, and GSTA1. Moreover, metabolic ratios were calculated for selected CP metabolites, analyzed by (31)P-NMR-spectroscopy. Analysis of variance revealed that the CYP2C19*2 genotype influenced significantly pharmacokinetics of CP at doses

[The value of pharmacogenetic tests in antidepressive medication therapy]. / Pharmakogenomik in der klinischen Praxis. Der Stellenwert pharmakogenetischer Tests in der antidepressiven Arzneitherapie.

The pharmacokinetics and effect of antidepressants are influenced by genetic factors. Modern methods of genotyping allow fast and inexpensive identification of genetic variants and thus can be used in clinical diagnostics to improve the tolerance to drug therapy. Numerous studies have investigated the significance of genetic variants in drug-metabolizing enzymes, drug and natural substrate transporters, neurotransmitter receptors, and molecules involved in signal transduction. While the interindividual differences in oral clearance, half-life, and bioavailability caused by genetic variants in the cytochrome P450 liver enzymes can be overcome by individual adjustment of dosage according to certain genotypes, the effects of genetic variants in antidepressive target structures are more difficult to translate into clinical recommendations. This article gives an overview of the currently available literature and points to situations in which the determination of pharmacogenetic variants might change drug therapy or therapeutic strategies for the individual patient. Dose adjustments for common antidepressant drugs based upon differences in pharmacokinetic parameters caused by genetic variability will be given.

CYP1A1 alleles in women with focal nodular hyperplasia of the liver (FNH).

OBJECTIVE: Disorders of steroid hormone metabolism might be related to the etiology of focal nodular hyperplasia of the liver (FNH), a benign tumor, especially prevalent in women. The cytochrome P450 1A1 (CYP1A1) enzyme is implicated in the bioactivation of multiple precarcinogens as well as in the metabolism of steroids. Genetic polymorphisms of CYP1A1 have been associated with altered catalytic activity in the hydroxylation of sex hormones and this may account for interindividual variability in exposure to hormone-mediated cell proliferation signals and reactive steroid metabolites. In the study at hand, we aimed to evaluate a possible association between CYP1A1*1, *2A, *2B, and *4 alleles and FNH. METHOD: Genotyping of 26 affected female patients of Caucasian origin was carried out using PCR/RFLP. RESULTS: Allele frequencies for the CYP1A1 variants *2A, *2B and *4 in 26 female patients with FNH were 0.058, 0.019 and 0.058, respectively. Crude odds ratios for the individual alleles were 0.75 (95% CI 0.23-2.44), 0.72 (95% CI 0.10-5.34) and 1.96 (95% CI 0.59-6.50), respectively. There were no significant differences between these values and corresponding allele frequencies obtained in a large German sample of unaffected Caucasian women. CONCLUSION: The present data do not suggest a relevant association between CYP1A1 polymorphisms and focal nodular hyperplasia of the liver in female Caucasians.

[The Estonian Genome Project in the context of European genome research]. / Das estnische Genomprojekt im Kontext der europäischen Genomforschung.

It is the aim of the Estonian Genome Project to establish a database which compiles phenotype and genotype data of a large part of the Estonian population. The Gene Bank will only be used for scientific and public health research. Researchers hope that it will help identify disease genes and prepare the ground for the personalized medicine of the future. Additionally, the project will improve Estonian's international competitiveness in high technology and have a strong educational effect on the population. The legal framework, the Human Genes Research Act, was passed by the Estonian parliament in December 2000. It had been drafted by a group of experts who took into account all available international guidance documents on genetic research. With the pilot project involving three selected regions successfully finished, the main project has now started.

[History of German-Baltic relations in medicine]. / Geschichte der deutsch-baltischen Beziehungen in der Medizin.

Today, the three Baltic countries Estonia, Latvia and Lithuania, have well-known medical faculties with international standing. Their individual histories are briefly outlined. However, relations of the German academic world were closest with the university of Dorpat (today: Tartu). It was re-opened in 1802 by tsar Alexander I in order to keep young Baltic people from studying abroad. The medical faculty was its biggest faculty. The university was Russian, but the official language was German. So many a German professor came to Dorpat and many professors from Dorpat were offered a chair at a German university. The scientific imports connected Dorpat with other centres of West-European science, they brought knowledge and ideas and an exchange of information. The standard was high, and among the teaching staff was a handsome number of medical celebrities, e.g. the anatomist August Rauber and the surgeon Ernst von Bergmann. In Dorpat, Rudolf Buchheim brought a new science, experimental pharmacology, into being, which his pupil and successor, Oswald Schmiedeberg, fully established and propagated all over the world.

[Levosimendan. Clinical indications of a new vasoactive substance]. / Levosimendan. Klinische Indikationen einer neuen vasoaktiven Substanz.

Levosimendan is a recently developed drug which is not yet approved for clinical routine use in Germany. The clinical use is limited to a few selected cases and it has been used as a salvage therapy in patients with severe heart insufficiency. As a potent inodilator it has been given to patients with severe heart failure, when all other therapeutic options have failed. However, in some European countries levosimendan is used in clinical routine situations and the European Society of Cardiologists has included the drug in their guidelines for treatment of acute heart failure. The following article describes the main pharmacological characteristics of levosimendan and summarises the indications for this new drug for physicians working in the field of anaesthesia or intensive care.

Pharmacogenetics of antidepressants and antipsychotics: the contribution of allelic variations to the phenotype of drug response.

Genetic factors contribute to the phenotype of drug response. We systematically analyzed all available pharmacogenetic data from Medline databases (1970-2003) on the impact that genetic polymorphisms have on positive and adverse reactions to antidepressants and antipsychotics. Additionally, dose adjustments that would compensate for genetically caused differences in blood concentrations were calculated. To study pharmacokinetic effects, data for 36 antidepressants were screened. We found that for 20 of those, data on polymorphic CYP2D6 or CYP2C19 were found and that in 14 drugs such genetic variation would require at least doubling of the dose in extensive metabolizers in comparison to poor metabolizers. Data for 38 antipsychotics were examined: for 13 of those CYP2D6 and CYP2C19 genotype was of relevance. To study the effects of genetic variability on pharmacodynamic pathways, we reviewed 80 clinical studies on polymorphisms in candidate genes, but those did not for the most part reveal significant associations between neurotransmitter receptor and transporter genotypes and therapy response or adverse drug reactions. In addition associations found in one study could not be replicated in other studies. For this reason, it is not yet possible to translate pharmacogenetic parameters fully into therapeutic recommendations. At present, antidepressant and antipsychotic drug responses can best be explained as the combinatorial outcome of complex systems that interact at multiple levels. In spite of these limitations, combinations of polymorphisms in pharmacokinetic and pharmacodynamic pathways of relevance might contribute to identify genotypes associated with best and worst responders and they may also identify susceptibility to adverse drug reactions.

Individualized medicine - implementation of pharmacogenetic diagnostics in antidepressant drug treatment of major depressive disorders.

Antidepressant drug therapy is characterized by a high rate of therapeutic failure. There is increasing evidence that genetic factors are contributing to the inter-individual variability in antidepressant drug response. Genetic variability is described in both the pharmacokinetic part of drug action as well as in pharmacodynamic structures mediating drug effects. Genetic polymorphisms in drug metabolizing enzymes are well characterized and have large effects on oral clearances or elimination half-lives of antidepressant drugs. These differences can be compensated by adapting the individual dose to genotype in addition to other factors such as gender, weight, age, liver and kidney function. On the part of drug action, genetic variability is described in molecular structures of antidepressant effects. Several studies on response of antidepressants have revealed influences of polymorphisms in neurotransmitter receptors and transporters changing sensitivity of patients to treatment with antidepressants; however, results were often contradictory. A pharmacogenomic approach to individualize antidepressant drug treatment is recommended to be based on several levels: 1) identifying and validating the candidate genes involved in drug-response; 2) providing therapeutic guidelines; and 3) developing a pharmacogenetic test-system for bedside-genotyping.