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.

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.

Inhibition of 17β-estradiol activation by CYP1A1: genotype- and regioselective inhibition by St. John's Wort and several natural polyphenols.

Several epidemiological studies associate certain CYP1A1 genotypes, alone or in combination, with an increased risk of estrogen-related cancers. Previously we demonstrated that metabolic activation of estrogens by CYP1A1 is a genotype-dependent reaction with the CYP1A1.2 (Ile462Val) variant being the most efficient catalyst (Kisselev et al.

Moxifloxacin does not alter ciclosporin pharmacokinetics in transplant patients: a multiple-dose, uncontrolled, single-centre study.

Background: Moxifloxacin has a broad antibacterial spectrum and rapid bactericidal activity, and is thus a good option for the treatment of bacterial infections in patients who have undergone organ or bone marrow transplantation. Transplant patients also receive immunosuppressant therapy such as ciclosporin.

Objective: The primary objective of this study was to assess the steady-state pharmacokinetics of ciclosporin with and without concomitant treatment with moxifloxacin in transplant recipients.

Genetic polymorphisms in endothelin-receptor-subtype-a-gene as susceptibility factor for obstructive sleep apnea syndrome.

Introduction: Traits of obstructive sleep apnea syndrome (OSAS) such as impaired ventilatory control, craniofacial abnormalities, and concomitant cardiovascular diseases are associated with modified endothelin-1 gene (EDN-1) or endothelin-receptor-subtype-a (EDNRA) gene. The endothelin system regulates the cardiovascular homeostasis. EDN-1 interacts mainly with EDNRA for signal transduction.

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.

Vitamin D receptor poly(A) microsatellite and colorectal cancer risk in Caucasians.

Background: Colorectal cancer incidence and prognosis are influenced by vitamin D intake and expression of the vitamin D receptor (VDR). Polymorphisms of the VDR are linked to several diseases. This study was aimed to investigate whether variants of the VDR poly(A) microsatellite are associated with colorectal cancer incidence.

St John's wort extract (Ze 117) does not alter the pharmacokinetics of a low-dose oral contraceptive.

Purpose: St John's wort (Hypericum perforatum) is an herbal remedy that is widely used in the treatment of depression. Recent clinical data have demonstrated that St John's wort extracts interfere with the action of various drugs and possibly also with combined oral contraceptives. Therefore, we investigated the effects of a St John's wort extract (Ze 117) with low hyperforin content on the pharmacokinetics of ethinylestradiol and 3-ketodesogestrel.

Below median birth weight in appropriate-for-gestational-age preterm infants as a risk factor for bronchopulmonary dysplasia.

Aims: To assess the presence of chorioamnionitis and intrauterine growth as prenatal risk factors for broncho pulmonary dysplasia (BPD) in appropriate-for-gestational-age (AGA) infants of <28 weeks' gestation.

Methods: Gender, race, birth weight, gestational age, histology of the placenta, diagnosis of BPD at 36 weeks' gestation, postnatal dexamethasone treatment, and death were recorded in 150 preterm infants born at <28 weeks' gestation, and admitted between 1996 and 2001.

Results: In 122 AGA infants (mean gestational age: 26.

Genetic variants in FKBP5 affecting response to antidepressant drug treatment.

Introduction: Hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis is a pathogenic mechanism of depression, and genetic polymorphisms in HPA axis genes have been described to influence response to antidepressant drugs. In particular, two polymorphisms in FKBP5, a co-chaperone of the glucocorticoid receptor, were strongly associated with response to therapy. We aimed to analyze whether these findings could be reproduced in a different sample of otherwise comparable inpatients with major depression.

Endothelin-1 gene variant Lys198Asn and plasma endothelin level in obstructive sleep apnea.

Obstructive sleep apnea (OSA) is a recognized risk factor for cardiovascular disorders. Thus, an association between endothelin-1 (EDN1) and OSA can be assumed. We investigated a cohort of 364 consecutive patients (age 57 +/- 10 years) with mild to severe OSA for the EDN1 variant Lys198Asn (G/T) and endothelin plasma levels and compared them with 57 controls.

Common genetic variations in human brain-specific tryptophan hydroxylase-2 and response to antidepressant treatment.

Objective: Genetic variability within the serotoninergic system may predict the response to antidepressant drugs. Several polymorphisms in the gene coding for the brain-specific tryptophan hydroxylase (TPH2) have been associated with susceptibility to psychiatric diseases. In this study, we analyzed the correlation between TPH2 polymorphisms and response to antidepressant drugs.

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).

An anomalous haplotype distribution of the arrestin domain-containing 4 gene (ARRDC4) haplotypes in Caucasians.

Little was known about the sequence variability of the human Arrestin domain-containing 4 gene (ARRDC4). We sequenced its DNA from exon 2 to exon 8 in a sample of 92 Russians. Seven variants were identified; one of them has not been described yet.

Effects of the CYP2D6 gene duplication on the pharmacokinetics and pharmacodynamics of tramadol.

The analgesic drug tramadol is bioactivated by CYP2D6 to the opioid receptor agonist O-desmethyltramadol. Case reports indicated that carriers of the CYP2D6 gene duplication may be at high risk for opioid adverse events. However, the effects of the CYP2D6 duplication on kinetics and dynamics of tramadol have not been systematically studied.

Comparison of SLCO1B1 sequence variability among German, Turkish, and African populations.

Background: OATP1B1 is one of the key hepatocellular uptake transporters providing extraction of diverse compounds, including bile acids, xenobiotics, and a variety of drugs, from portal venous blood into the liver. Polymorphisms of the SLCO1B1 gene have been demonstrated to influence in vitro transport function and the pharmacokinetic profile of compounds.

Objective: The goal of our study was the comparison of SLCO1B1 gene sequence variability in three ethnic groups as a basis for future genetic association studies.

Effect of tolterodine on sleep structure modulated by CYP2D6 genotype.

Objective: Tolterodine, a drug for the treatment of overactive bladder symptoms, has a limited entry into the brain, which makes cognitive side effects seldom. However, some case reports have described central-nervous side effects such as sleepiness. The aim of this retrospective analysis was to investigate whether tolterodine-related effects on sleep stage parameters could be explained by different CYP2D6 metabolizer characteristics of subjects.

Vitamin D receptor haplotypes protect against development of colorectal cancer.

Objective: We investigated the association of vitamin D receptor polymorphisms and colorectal cancer incidence in a Caucasian population.

Methods: Frequencies of the vitamin D receptor gene polymorphisms 23005G>A (CDX-2), 27823C>T (FokI), 60890G>A (BsmI), 61050G>A (Tru9I), 61888G>T (ApaI), and 61968T>C (TaqI) were determined in a series of 256 colorectal cancer patients and 256 patients without malignant disease (case-control study) using polymerase chain reaction and restriction fragment length polymorphism genotyping assays (PCR-RFLP). Haplotype analysis based on the six genetic loci was applied to the received genotypes.

Recalling P446. P4501A1 (CYP1A1) opting for clinical application.

This review goes back to spectral studies [see Hildebrandt et al., 1968]. The findings of apparent absolute spectra of two interconvertible forms of microsomal mixed function oxidases are looked back on to recall whether their impact sustained scrutiny or are rather remembered as of sentimental value only.

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.

Randomised, double-blind study of the effects of oxybutynin, tolterodine, trospium chloride and placebo on sleep in healthy young volunteers.

Objective: Central nervous effects of oral anticholinergics may limit the success of incontinence therapy and patient compliance. Only a few studies investigating this topic are available. This study was conducted to determine whether oral anticholinergics alter sleep and psychometric test parameters.

Risk of coronary artery disease as influenced by variants of the human endothelin and endothelin-converting enzyme genes.

Objective: The potent vasoconstrictor endothelin (ET) is generated by enzymatic cleavage catalyzed by the endothelin-converting enzyme 1 (ECE-1) and plays a crucial role in the regulation of vascular tone and endothelial function. Polymorphisms of the ET and ECE genes may contribute to the development and progression of coronary artery disease. Recently, we have shown the functional relevance of the +138 adenine ins/del polymorphism on ET-1 expression in vitro.

Association of MDR1 genotypes with susceptibility to colorectal cancer in older non-smokers.

Objective: The multidrug resistance gene 1 (MDR1) seems to play a role in the carcinogenesis of colorectal tumors. The importance of MDR1 SNPs 2677G > T/A in exon 21 and 3435C > T in exon 26 for cancer susceptibility, however, has not yet been clearly defined.

Methods: Two hundred and eighty-five colorectal cancer patients and 275 controls from five hospitals in the European part of Russia were genotyped for the polymorphisms -129T > C (rs3213619) in exon 1b, 2677G > T/A (rs2032582), and 3435C > T (rs1045642) in this population-based case-control study.

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.

In-vitro transport characteristics discriminate wild-type ABCB1 (MDR1) from ALA893SER and ALA893THR polymorphisms.

Background: Genetic variation of the human ABCB1 (P-glycoprotein; MDR1 gene product) efflux transporter is strongly suggested as a determinant factor governing the pharmacokinetics of diverse drugs and xenobiotics. Despite various efforts to associate polymorphisms in ABCB1 to actual clinical effect and transport function, information is still inconsistent or even controversial.

Methods And Results: Using membrane vesicle preparation from ABCB1-expressing HighFive insect cells, we report here that saturation kinectic parameters of the frequently occurring ABCB1 triallelic variants 893Ser (exon 21, 2677T) and 893Thr (2677A) were considerably different from wild-type 893Ala (2677G), despite similar protein expression levels.