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PubMed2006

The AmpliChip CYP450 genotyping test: Integrating a new clinical tool.

The AmpliChip CYP450 Test, which analyzes patient genotypes for cytochrome P450 (CYP) genes CYP2D6 and CYP2C19, is a major step toward introducing personalized prescribing into the clinical environment. Interest in adverse drug reactions (ADRs), the genetic revolution, and pharmacogenetics have converged with the introduction of this tool, which is anticipated to be the first of a new wave of such tools to follow over the next 5-10 years. The AmpliChip CYP450 Test is based on microarray technology, which combines hybridization in precise locations on a glass microarray and a fluorescent labeling system. It classifies individuals into two CYP2C19 phenotypes (extensive metabolizers [EMs] and poor metabolizers [PMs]) by testing three alleles, and into four CYP2D6 phenotypes (ultrarapid metabolizers [UMs], EMs, intermediate metabolizers [IMs], and PMs) by testing 27 alleles, including seven duplications. CYP2D6 is a metabolic enzyme with four activity levels (or phenotypes): UMs with unusually high activity; normal subjects, known as EMs; IMs with low activity; and PMs with no CYP2D6 activity (7% of Caucasians and 1-3% in other ethnic groups). Levels of evidence for the association between CYP2D6 PMs and ADRs are relatively reasonable and include systematic reviews of case-control studies of some typical antipsychotics and tricyclic antidepressants (TCAs). Evidence for other phenotypes is considerably more limited. The CYP2D6 PM phenotype may be associated with risperidone ADRs and discontinuation due to ADRs. Venlafaxine, aripiprazole, duloxetine, and atomoxetine are newer drugs metabolized by CYP2D6 but studies of the clinical relevance of CYP2D6 genotypes are needed. Non-psychiatric drugs metabolized by CYP2D6 include metoprolol, tamoxifen, and codeine-like drugs. CYP2C19 PMs (3-4% of Caucasians and African Americans, and 14-21% of Asians) may require dose adjustment for some TCAs, moclobemide, and citalopram. Other drugs metabolized by CYP2C19 are diazepam and omeprazole. The future of pharmacogenetics depends on the ability to overcome serious obstacles, including the difficulties of conducting and publishing studies in light of resistance from grant agencies, pharmaceutical companies, and some scientific reviewers. Assuming more studies are published, pharmacogenetic clinical applications may be compromised by economic factors and the lack of physician education. The combination of a US FDA-approved test, such as the AmpliChip CYP450 Test, and an FDA definition of CYP2D6 as a 'valid biomarker' makes CYP2D6 genotyping a prime candidate to be the first successful pharmacogenetic test in the clinical environment. One can use microarray technology to test for hundreds of single nucleotide polymorphisms (SNPs) but, taking into account the difficulties for single gene approaches such as CYP2D6, it is unlikely that very complex pharmacogenetic approaches will reach the clinical market in the next 5-10 years.

Alleles↗

PubMed2002

[Diagnosis of thrombophilia based on coagulation and genetic studies].

Venous thromboembolism and associated complications often leading to permanent disability or death are an important problem in modern medicine. Congenital or acquired disorders of the hemostatic system, such as hypercoagulation or thrombophilia, predispose to thrombosis. The aims of the study were as follows: 1. To assess the prevalence of thrombophilia in venous thromboembolism and in healthy subjects by testing resistance to activated protein C and other markers of hemostasis; 2. To screen for factor V Leiden with a PCR-based assay; 3. To evaluate the usefulness of the adopted analytical approach for the detection of thrombophilia in clinical practice. 29 patients (17 females and 12 males) with venous thromboembolism and a history of thrombotic episodes before the age of 40, either idiopathic or associated with protracted immobilization, pregnancy or puerperium, were enrolled in the study. The control group consisted of 25 age-matched healthy subjects (14 females and 11 males) without any history of thrombosis. The following hemostatic parameters were measured: 1. Activated protein C resistance (APC-R); 2. Protein C (PC) and antithrombin III (AT III) activities; 3. Protein S (PS) activity; 4. Fibrinogen (FB) concentration; 5. Euglobin lysis time (ELT); 6. Prothrombin time (PT); 7. Activated partial thromboplastin time (APTT). The presence of Leiden mutation was detected by PCR amplification and digestion of products with Mnl 1 restrictase. The results were tested statistically using: 1. Kolmogorov-Smirnov D test; 2. Student's t-test; 3. linear regression analysis; 4. chi 2 test. The following conclusions were drawn: 1. Prevalence of thrombophilia in patients with venous thromboembolism is 31%, a figure consistent with literature data (no signs of thrombophilia were found in the control group); 2. Resistance to activated protein C is sufficient proof of Leiden mutation provided that APCR index (r) is less than 0.9 (borderline r values (0.9-1.1) require further genetic testing). 3. Methods of diagnosis of thrombophilia used in this study could be applied in routine clinical practice, the most useful ones being resistance to activated protein C, fibrinogen concentration and protein S activity. With this approach the detection of higher risk of thrombotic-embolic episodes, either acquired or inborn, is possible in most cases.

Activated Protein C Resistance↗

PubMed1994

Use of breath hydrogen and methane as markers of colonic fermentation in epidemiological studies: variability in excretion.

Breath hydrogen and methane are specific end products of colonic fermentation, a process which may play a protective role against colon cancer. To assess the possibility of using these markers in epidemiological studies, we characterized the intra- and intersubject variability of breath hydrogen and methane excretion over 15 consecutive days among 32 men and women of various ethnic backgrounds (16 Asians, 8 Caucasians, 8 Hawaiians). Participants were asked to collect four end-expiratory samples each day, which we had shown previously would optimally characterize daily hydrogen excretion. There was substantial within-subject variation in breath hydrogen over the study, although breath methane levels were more constant over time. We found that about 4 days of measurement of breath hydrogen and 1 day of measurement for breath methane are required to correctly characterize individuals according to their long-term excretion of these gases. This was true for Asians and non-Asians. Although breath methane appears to be more practical to measure, it is a less sensitive marker of colonic fermentation than breath hydrogen. Whereas all subjects excreted hydrogen, only 28% of the subjects excreted methane, and methane excretor status of a few participants varied during the study. Because the breath test is noninvasive and reliable, we tested the multiple day collection protocol among colon cancer patients and controls and found it to be well accepted. We conclude that it is practical to measure breath hydrogen and methane in large epidemiological studies conducted at the individual level. The potential use for these markers is discussed.

Aged↗

PubMed2005

Influence of condensation temperature on selected exhaled breath parameters.

BACKGROUND: The effects of changes in cooling temperature on biomarker levels in exhaled breath condensate have been little investigated. The aim of the study was to test the effect of condensation temperature on the parameters of exhaled breath condensate and the levels of selected biomarkers. METHODS: Exhaled breath condensate was collected from 24 healthy subjects at temperatures of -10, -5, 0 and +5 C degrees. Selected parameters (condensed volume and conductivity) and biomarkers (hydrogen peroxide, malondialdehyde) were measured. RESULTS: There was a progressive increase in hydrogen peroxide and malondialdehyde concentrations, and condensate conductivity as the cooling temperature increased; total condensate volume increased as the cooling temperature decreased. CONCLUSION: The cooling temperature of exhaled breath condensate collection influenced selected biomarkers and potential normalizing factors (particularly conductivity) in different ways ex vivo. The temperature of exhaled breath condensate collection should be controlled and reported.

Adult↗

PubMed2002

Plasma markers of hypercoagulability in patients with serious infections and risk of septic shock.

Hyperthrombinogenesis due to bacterial septicemia may aggravate the risk of irreversible septic shock. In 22 patients with septicemia complicating urinary or alimentary infections, daily assessment of hemostasis was performed throughout 1 week. Standard screening of hemostasis revealed significantly increased mean values of prothrombin time, fibrinogen, and fibrinogen degradation product (FDP) concentration. However, platelet counts, activated partial thromboplastin times (APTT), thrombin times, ethanol gelation tests, and antithrombin activity remained within the normal range. By contrast, except for insignificant changes in protein C activity and activated factor VII content, specific markers of plasma hypercoagulability, that is, thrombin-antithrombin (TAT) complexes, prothrombin activating factor F 1+2, activated factor XII (XIIa), and dimer D were all markedly increased. Pathologic levels of TAT and Xlla were found in 82% and 73% of all plasma samples, respectively. The augmentation of TAT correlated with prolongation of thrombin time and increases in F 1+2 levels. The increase in XIIa correlated with thrombocytopenia, prolongation of APTT, exhaustion of antithrombin, and accumulation of F 1+2 and FDP in the plasma. Moreover, a significant increase in XIIa, stronger positivity of the ethanol gelation test, a greater increase in FDP, and a more pronounced decrease in protein C activity were observed in 8 patients with fatal septic shock. This study suggests the usefulness of TAT and XIIa measurements in the early recognition of plasma hypercoagulation in serious infections.

Adult↗

PubMed1998

Biomarker strategies to evaluate the environmental effects of chemicals.

Environmental risk assessment of chemicals depends on the production of toxicity data for surrogate species of mammals, birds, and fish and on making comparisons between these and estimated or predicted environmental concentrations of the chemicals. This paper gives an overview of biomarker assays and strategies that might be used as alternatives, that is, to replace, reduce, or refine currently used ecotoxicity tests that cause suffering to vertebrates. In the present context a biomarker is a biologic response to an environmental chemical at the individual level or below which demonstrates a departure from normal status. Of immediate interest and relevance are nondestructive assays that provide a measure of toxic effect in vertebrate species and that can be used in both laboratory and parallel field studies. A major shortcoming of this approach is that such assays are currently only available for a limited number of chemicals, primarily when the mode of action is known. Nondestructive assays can be performed on blood, skin, excreta, and eggs of birds, fish, reptiles, and amphibians. An interesting recent development is the use of vertebrate cell cultures, including transgenic cell lines that have been developed specifically for toxicity testing. The ultimate concern in ecotoxicology is the effects of chemicals at the level of populations and above. Current risk assessment practices do not address this problem. The development of biomarker strategies could be part of a movement toward more ecologic end points in the safety evaluation of chemicals, which would effect a reduction in animal tests that cause suffering.

Animal Testing Alternatives↗

PubMed2003

Detection of lung cancer with volatile markers in the breath.

STUDY OBJECTIVES: To evaluate volatile organic compounds (VOCs) in the breath as tumor markers in lung cancer. Alkanes and monomethylated alkanes are oxidative stress products that are excreted in the breath, the catabolism of which may be accelerated by polymorphic cytochrome p450-mixed oxidase enzymes that are induced in patients with lung cancer. DESIGN: Combined case-control and cross-sectional study. SETTING: Five academic pulmonary medicine services in the United States and the United Kingdom. PATIENTS AND PARTICIPANTS: One hundred seventy-eight bronchoscopy patients and 41 healthy volunteers. INTERVENTION: Breath samples were analyzed by gas chromatography and mass spectroscopy to determine alveolar gradients (ie, the abundance in breath minus the abundance in room air) of C4-C20 alkanes and monomethylated alkanes. MEASUREMENTS: Patients with primary lung cancer (PLC) were compared to healthy volunteers, and a predictive model was constructed using forward stepwise discriminant analysis of the alveolar gradients. This model was cross-validated with a leave-one-out jackknife technique and was tested in two additional groups of patients who had not been used to develop the model (ie, bronchoscopy patients in whom cancer was not detected, and patients with metastatic lung cancer [MLC]). RESULTS: Eighty-seven of 178 patients had lung cancer (PLC, 67 patients; MLC, 15 patients; undetermined, 5 patients). A predictive model employing nine VOCs identified PLC with a sensitivity of 89.6% (60 of 67 patients) and a specificity of 82.9% (34 of 41 patients). On cross-validation, the sensitivity was 85.1% (57 of 67 patients) and the specificity was 80.5% (33 of 41 patients). The stratification of patients by tobacco smoking status, histologic type of cancer, and TNM stage of cancer revealed no marked effects. In the two additional tests, the model predicted MLC with a sensitivity of 66.7% (10 of 15 patients), and it classified the cancer-negative bronchoscopy patients with a specificity of 37.4% (34 of 91 patients). CONCLUSIONS: Compared to healthy volunteers, patients with PLC had abnormal breath test findings that were consistent with the accelerated catabolism of alkanes and monomethylated alkanes. A predictive model employing nine of these VOCs exhibited sufficient sensitivity and specificity to be considered as a screen for lung cancer in a high-risk population such as adult smokers.

Alkanes↗

PubMed2005

N-terminal pro-B-type natriuretic Peptide predicts significant coronary artery lesion in the unstable angina patients with normal electrocardiogram, echocardiogram, and cardiac enzymes.

BACKGROUND: Brain natriuretic peptide (BNP) and N-terminal pro-brain natriuretic peptide (NT-proBNP) are not specific for ventricular dysfunction and other cardiac processes, such as myocardial ischemia, may also cause elevation of these markers. METHODS AND RESULTS: To determine whether elevation of NT-proBNP without elevation of cardiac specific markers can predict coronary artery disease (CAD), the serum level of NT-proBNP was measured in 161 patients with unstable angina (61.0+/-8.1 years, male 54.0%) with normal ventricular function (left ventricular ejection fraction >55% and no regional wall motion abnormality by echocardiography) and normal troponin I level (<0.05 ng/ml). In these patients, levels of C-reactive protein and myoglobin were normal and none had Q wave on electrocardiographic (ECG). The NT-proBNP level was higher in patients with CAD (n=74) than in patients without CAD (n=87) (173.1+/-231.6 vs 68.1+/-62.5 pg/ml, p<0.001). At the standard cut-off point of >200 pg/ml, elevated NT-proBNP level shows high probability of CAD (odds ratio, 10.1; 95% confidence interval, 2.6-38.7, p=0.001). The NT-proBNP level positively correlated with the extent of CAD (r=0.329, p=0.001). In multivariate analysis, the NT-proBNP was an independent predictor of CAD. CONCLUSION: These results suggested that NT-proBNP is a useful screening test for CAD in the unstable angina patients with normal ECG, echocardiogram and cardiac enzyme levels.

Adult↗

PubMed2002