scholarly journals Allele-Specific Change of Concentration and Functional Gene Dose for the Prediction of Steady-State Serum Concentrations of Amitriptyline and Nortriptyline in CYP2C19 and CYP2D6 Extensive and Intermediate Metabolizers

2004 ◽  
Vol 50 (9) ◽  
pp. 1623-1633 ◽  
Author(s):  
Werner Steimer ◽  
Konstanze Zöpf ◽  
Silvia von Amelunxen ◽  
Herbert Pfeiffer ◽  
Julia Bachofer ◽  
...  
Keyword(s):  
Functional Gene ◽  
Extensive Metabolizers ◽  
Specific Change ◽  
Gene Dose ◽  
Drug Concentrations ◽  
Steady State Serum ◽  
Ultrarapid Metabolizer ◽  
Allele Specific ◽  
Few Data ◽  
Intermediate Metabolizers

Abstract Background: Recently, new polymorphisms were described in connection with intermediate and ultrarapid CYP2D6 metabolism. These may allow a much desired prediction of metabolic activity within the extensive metabolizer group. The functional consequences are still being discussed with few data available for clinical patients. Methods: We conducted a prospective, blinded two-center study seeking correlations between CYP2C19 (*2,*3, and *4; conventional PCR) and CYP2D6 genotypes (*1 to *10, *35, and *41; real-time and multiplex PCR) and drug concentrations (Emit® and HPLC) in 50 Caucasians receiving amitriptyline (AT; 75 mg twice a day). Results: Eighteen CYP2C19 heterozygotes (*1/*2) had higher AT (P = 0.033) and lower nortriptyline (NT; P = 0.059) concentrations than 30 homozygotes (*1/*1). For CYP2D6, we calculated two new indices, i.e., the allele-specific change of concentration on identical background (ASCOC) and a quantitative functional gene dose. The ASCOC describes the change in NT concentration attributable to a mutant allele compared with the wild type. We found significantly higher concentrations for alleles *4 (95.6%; P <0.0001), *10 (63.3%; P <0.001), and *41 (39.8%; P <0.0001) but not for *2 and *35. Assigning of semiquantitative gene doses of 0, 0.5, or 1 to each allele instead of applying the current classification system (predicted phenotypes: 3 intermediate metabolizers, 46 extensive metabolizers, and 1 ultrarapid metabolizer) produced significant NT concentration differences: gene doses of 0.5 (n =3), 1 (n = 14), 1.5 (n = 11), 2 (n = 21) and 3 (n = 1; P <0.00001). Conclusions: AT and NT concentrations can be predicted within the group of CYP2D6 extensive metabolizers. The ASCOC provides substantial advantages compared with current methods of analysis. CYP2D6 but not CYP2C19 correlates with the sum of both concentrations used to guide AT therapy.

Effect of PK-guided tamoxifen dose escalation on endoxifen serum concentrations in CYP2D6 intermediate and poor metabolizers.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 595-595
Author(s):  
Frans Opdam ◽  
Vincent O. Dezentje ◽  
Jan den Hartigh ◽  
Henk-jan Guchelaar ◽  
Trees Hessing ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Side Effects ◽  
Cancer Patients ◽  
Dose Escalation ◽  
Poor Metabolizers ◽  
Tamoxifen Treatment ◽  
Extensive Metabolizers ◽  
Breast Cancer Patients ◽  
One Step ◽  
Intermediate Metabolizers

595 Background: Breast cancer patients with absent or reduced CYP2D6 activity may benefit less from tamoxifen treatment because of impaired biotransformation to the active metabolite endoxifen. We investigated whether a temporary one-step dose escalation of tamoxifen in CYP2D6 poor (PM) and intermediate metabolizers (IM) could increase endoxifen serum concentration to a similar level observed in CYP2D6 extensive metabolizers (EM) without increasing toxicity. Methods: From a prospective study population of early breast cancer patients using tamoxifen, 12 CYP2D6 poor and 12 intermediate metabolizers were selected and included in a one-step tamoxifen dose escalation study during two months. The escalation dose (120 mg maximum) was calculated by multiplying the individual’s endoxifen level divided by the median endoxifen concentration (33.7 nM) observed in CYP2D6 extensive metabolizers by 20 mg. Toxicity was assessed and all patients returned to the standard dose of 20 mg after two months. Results: Tamoxifen dose escalation in CYP2D6 poor and intermediate metabolizers significantly increased endoxifen concentrations (PMs: from 8.0 nM to 27.3 nM, p<0.001; IMs: from 17.8 nM to 30.3 nM, p=0.002) without increasing side effects. In intermediate but not in poor metabolizers dose escalation increased endoxifen to levels comparable with those observed in extensive metabolizers using tamoxifen 20 mg once daily (33.7 nM). Conclusions: CYP2D6 genotype and endoxifen guided tamoxifen dose escalation increased endoxifen concentrations without increasing short term side effects. Whether such tamoxifen dose escalation is effective and safe in view of long term toxic effects is uncertain and needs to be explored. Clinical trial information: NTR1509.

Rapid Elimination of Quinidine in Pediatric Patients

PEDIATRICS ◽  
1982 ◽  
Vol 70 (3) ◽  
pp. 370-375
Author(s):  
Stanley J. Szefler ◽  
Daniel R. Pieroni ◽  
Robert L. Gingell ◽  
Danny D. Shen
Keyword(s):  
Oral Dose ◽  
Drug Concentration ◽  
Pediatric Patients ◽  
Oral Absorption ◽  
Serum Drug Concentration ◽  
Older Children ◽  
Time Curve ◽  
Drug Concentrations ◽  
Steady State Serum ◽  
Adult Volunteers

The oral absorption and elimination of quinidine in pediatric patients was studied. Single oral doses of quinidine sulfate were administered to 13 patients ranging in age from 4 to 22 years of age. Serum quinidine concentration reached a peak within 30 minutes to two hours after drug administration. The serum half-life of quinidine varied from 2.5 to 6.7 hours and was, on the average, shorter than the reported estimates for adult volunteers and cardiac patients (means ranging from 4.9 to 7.3 hours). Hence, more frequent dosing or the use of slow-release preparations may be necessary in some pediatric patients in order to avoid excessive fluctuation in serum drug concentrations over a dosage interval. The oral dose clearance of quinidine (ie, oral dose divided by the area under the serum concentration time curve) varied over a threefold range, from 0.151 to 0.570 liter/hr/kg, and was found to correlate inversely with age (r = .80). In comparison with mean clearance estimates that have been reported for normal adult volunteers (0.293 ± 0.078 liter/hr/kg), children less than 12 years of age (0.461 ± 0.117 liter/hr/kg) were found to have significantly higher clearances, whereas no difference was observed between older children (0.287 ± 0.101 liter/hr/kg) and adults. Inasmuch as the average steady-state serum drug concentration for a given daily maintenance dose is directly related to clearance rate, children less than 12 years of age may require a higher dosage of quinidine on a per kilogram of body weight basis. Proper selection of quinidine dosage, careful adjustment of dosage according to age, and regular monitoring of drug response and serum drug concentration are essential steps to a rational management of quinidine therapy in children.

scholarly journals Tissue Pharmacokinetics of Cefazolin in Patients with Lower Limb Infections

2013 ◽  
Vol 57 (11) ◽  
pp. 5679-5683 ◽  
Author(s):  
Amira A. Bhalodi ◽  
Seth T. Housman ◽  
Ashley Shepard ◽  
James Nugent ◽  
David P. Nicolau
Keyword(s):  
Lower Limb ◽  
Area Under The Curve ◽  
Kidney Injury ◽  
Generation Cephalosporin ◽  
Tissue Samples ◽  
Content Type ◽  
Drug Concentrations ◽  
Steady State Serum ◽  
Exposure Profile

ABSTRACTCefazolin, a first-generation cephalosporin with activity against methicillin-susceptibleStaphylococcus aureusand streptococci, is often used to treat lower limb infections caused by these pathogens. Antimicrobial penetration is often limited in these patients due to compromised vasculature. Therefore, we sought to evaluate the exposure profile of cefazolin in serum and tissue in patients with lower limb infections. Anin vivomicrodialysis catheter was inserted into the tissue near the margin of the wound and constantly perfused with lactated Ringer's solution. Steady-state serum and tissue samples were simultaneously collected over a dosing interval. Serum protein binding was also assessed. Serum concentrations were analyzed by noncompartmental analysis. Tissue concentrations were corrected for percentin vivorecovery by using the retrodialysis technique. Seven patients with a mean weight of 95.45 ± 18.51 kg and a mean age of 54 ± 19 years were enrolled. Six patients received 1 g every 8 h, and one patient received 2 g every 24 h due to acute kidney injury. The free area under the curve from 0 to 8 h (fAUC0–8) values for serum and wound were 48.0 ± 18.66 and 56.35 ± 41.17 μg · h/ml, respectively, for the patients receiving 1 g every 8 h. ThefAUC0–24values for serum and wound were 1,326.1 and 253.9 μg · h/ml, respectively, for the single patient receiving 2 g every 24 h. The mean tissue penetration ratio (tissue/serumfAUC ratio) was 1.06. These data suggest that the amount of time that free-drug concentrations remain above the MIC (fT>MIC) for cefazolin in wound tissue is adequate to treat patients with lower limb infections.

Predictive Techniques Applied to Imipramine Therapeutic Drug Monitoring

DICP ◽  
1989 ◽  
Vol 23 (5) ◽  
pp. 389-394
Author(s):  
M. Mar Fernandez de Gatta ◽  
Milagros Tamayo ◽  
Maria José Garcia ◽  
Cristobal Montojo ◽  
J. Ramón Gutierrez ◽  
...  
Keyword(s):  
Steady State ◽  
Therapeutic Drug Monitoring ◽  
Drug Monitoring ◽  
Prediction Error ◽  
Pharmacokinetic Parameters ◽  
Therapeutic Drug ◽  
Population Pharmacokinetic ◽  
Serum Concentrations ◽  
Drug Concentrations ◽  
Steady State Serum

The aim of this study was to establish the performance of pharmacokinetic methods employing little data on serum drug concentrations obtained in routine therapeutic drug monitoring of imipramine. Forty-three and 123 serum levels were obtained in 8 adult depressive patients (aged 57–80 y) and 34 enuretic children (aged 5–13 y), respectively. Forecasting of the serum concentrations was performed based on mean population pharmacokinetic parameters (method A), with knowledge of one steady-state serum concentration (method B), and from two or more steady-state serum concentrations (method C). The accuracy and precision of each method were evaluated from the mean prediction error (ME) and from the root mean squared prediction error (RMSE), respectively. The values of ME and RMSE of methods B and C proved to be significantly lower than those found using method A. Method C was the most precise and accurate in both populations. Method A underestimates the serum concentrations observed in adults (ME >0) but overestimates them in children (ME <0), although to a lesser extent. The study shows that it is possible to obtain a good estimation of individual dosage needs from one or more serum concentrations obtained at steady state. Clinical application of these methods (B and C) yields an increase in the efficiency and safety of the treatment, particularly in special populations such as geriatric and pediatric patients.

Pharmacogenomic Association with Neurotoxicity in Hispanic Children with Acute Lymphoblastic Leukemia (ALL)

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3962-3962 ◽  
Author(s):  
Claire A McClain ◽  
M Brooke Bernhardt ◽  
Amanda Berger ◽  
Ryan Winslow ◽  
Michael E Scheurer ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Conflicts Of Interest ◽  
Lymphoblastic Leukemia ◽  
Poor Metabolizers ◽  
Extensive Metabolizers ◽  
Hispanic Children ◽  
Significant Difference ◽  
Hispanic Patients ◽  
Grade 3 ◽  
Intermediate Metabolizers

Abstract Introduction Vincristine is vital in the treatment of acute lymphoblastic leukemia (ALL), but is dose-limited by the development of disabling neuropathies. Vincristine is metabolized extensively by polymorphically expressed CYP3A4/5, which contributes to its 10-fold inter-patient pharmacokinetic variability. Further, there is more recent evidence that an inherited polymorphism in the CEP72 rs924607 gene contributes to vincristine sensitivity. Hispanic children have among the lowest rates of ALL survival when compared to other ethnicities, and pharmacogenomic variability among races is postulated to contribute. This is the first study to examine specifically both CYP3A5 polymorphisms and CEP72 gene expression in correlation with vincristine neurotoxicity in a large cohort of Hispanic ALL patients. Methods Banked germline blood samples from 300 self-identified Hispanic patients with ALL treated at Texas Children's Hospital between 1990 and 2015 were interrogated for allelic discrimination of CEP72 and at the CYP3A5*3, *6, and *7 polymorphic loci using TaqMan assays. Patient medical records were electronically searched for evidence of neuropathic events. Neuropathies were categorized as motor or sensory and graded using the Modified ("Balis") Pediatric Scale of Peripheral Neuropathies. Missing administered vincristine data was imputed using the patient's known treatment protocol and date of event coupled with protocol specifics retrieved from the literature. Multivariate analysis was run modeling the influences of CYP3A5 and CEP72 genotypes on the development and time to development of greater than or equal to Grade 3 neuropathies. Descriptive statistics were used to identify the prevalence of CYP3A5 and CEP72 genotypes and the associated phenotypes in this patient population. Time to neuropathy analysis was performed using the Kaplan-Meier failure estimates and log-rank test in Stata V.12.1 (College Station, TX). Results Based on CYP3A5 polymorphisms, overall, we found that 5% of our patients were extensive metabolizers of vincristine, 33% were intermediate metabolizers, and 62% were poor metabolizers. Additionally, we found that the TT risk CEP72 genotype is a rare finding in our cohort (9.3%). Clinically, we found that 18.4% of our patients experienced greater than or equal to Grade 3 neurotoxicity. Assessing the influence of being both a CYP3A5 intermediate or poor metabolizer and having the TT risk CEP72 genotype was limited by the paucity of patients with both genotypes (n=25). However, CYP3A5 poor metabolizers experienced neurotoxicity more often than intermediate or extensive metabolizers, although we did not find a statistically significant correlation between phenotype and incidence of neurotoxicity. Additionally, we found that there was a statistically significant difference in time to development of neurotoxicity within the first 100 days of treatment between intermediate and poor CYP3A5 metabolizers (P=0.036), with poor metabolizers experiencing greater than or equal to Grade 3 neurotoxicity sooner (Figure 1). Conclusions For the first time, we show that CYP3A5 poor metabolizers experienced greater than or equal to Grade 3 neurotoxicity significantly sooner than intermediate metabolizers within the first 100 days of treatment. We found a low prevalence of the minor allele of CEP72 rs924607TT in our Hispanic cohort. However, classification of CYP3A5 metabolizers and genotypes within our Hispanic population as well as our incidence of neurotoxicity are consistent with current literature. Further testing in a larger cohort should be performed but this study reinforces the significance of CYP3A5 metabolism of vincristine in leading to significant neurotoxicity and suggests that, at least in Hispanic patients, vigilance to early development of neurotoxicity should be performed by practitioners. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Intermediate Metabolizers And Increased Risk Of Adverse Events in Psychiatric In-patients. an Update Including All Relevant Alleles With Reduced Function and Applying Gene-dose for Analysis

2005 ◽  
Vol 27 (2) ◽  
pp. 254-255
Author(s):  
Werner Steimer ◽  
Julia Bachofer ◽  
Johannes Popp ◽  
Stephan Heres ◽  
Werner Kissling ◽  
...  
Keyword(s):  
Adverse Events ◽  
Gene Dose ◽  
Increased Risk ◽  
Intermediate Metabolizers

scholarly journals Gihp-Naco Prospective Registry: Characterization and Care of Major Bleeding in Patients Treated By Direct Oral Anticoagulants

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 2877-2877
Author(s):  
Gilles Pernod ◽  
Pierre Albaladejo ◽  
Charles-Marc Samama ◽  
Pierre-Marie Sie ◽  
jean Luc Bosson
Keyword(s):  
Atrial Fibrillation ◽  
Major Bleeding ◽  
Research Funding ◽  
Oral Anticoagulants ◽  
Direct Oral Anticoagulants ◽  
Phase Iii ◽  
Trauma Patients ◽  
Clotting Factors ◽  
Drug Concentrations ◽  
Few Data

Abstract Introduction: Direct oral anticoagulants, previously new oral anticoagulants (NOACs) had a favorable risk–benefit profile, both for stroke prevention or systemic embolic events in patients with atrial fibrillation (AF), or for venous thromboembolism (VTE) treatment. Although the rate of intracranial hemorrhage is lower, the risk for major bleeding is similar as for warfarin. Only few data are available for the management of major bleeding in clinical practice. The aim of this study is to present preliminary results regarding characterization and care of major bleeding through a French prospective registry. Methods: The GIHP (French Working group on Perioperative hemostasis) – NACO registry is a prospective observatory started in June 2013 in 32 emergency centers in France and Belgium. Only patients treated by NOACs and hospitalized for major bleeding or urgent surgery were registered. Results: In a midterm analysis in June 2014, 339 patients were included, among which 219 for major bleeding. 75 patients were treated by dabigatran (150 mg bid: 81%), and 142 by rivaroxaban (20 mg od: 54%) (2 patients were treated by Apixaban). The mean age was 76.4 +/- 11y, and mean BMI 26.3. Creatinine clearance was lower than 60 ml/min in 65%. Patients were treated for atrial fibrillation (80%) or VTE (20%). Among patients with AF, 67.2% had CHADS2 at 2 or less. 61.6% of patients received concomitantly at least one drug interfering with CYP or Pgp, and 26.9% received another antithrombotic drug at the time of bleeding. Major hemorrhagic sites were gastrointestinal (25%) and intracranial, either spontaneous (20%) or post-trauma (15%). AOD concentrations were determined in 46% of patients. 20% of the patients with major bleeding had a plasma concentration less than 50 ng/ml. As expected, there is no relationship between drug concentrations and standard hemostatic tests such as PT and aPTT. 38.4% of patients received PCC or aPCC, and 25.7% benefited for any additional procedures (surgery, endoscopy, embolization…). 42.2% of bleeding completely stopped after the administration of clotting factors. At 30d of follow up, 9.1% of patients presented a cardiovascular event, and all-cause mortality was 14.2%. Conclusion: This midterm analysis of the GIHP NACO registry shows consistent results with phase III studies, with some particularities compared to clinical trials, especially in the use of PCC. The registry allows the analysis of specific population such as trauma patients and highlights the care of such major hemorrhages. Disclosures Pernod: LFB: Research Funding; CSL: Research Funding; Octapharma: Research Funding. Off Label Use: PCC and aPCC ro reverse effect of antithrombotic drugs. Albaladejo:LFB: Research Funding; CSL: Research Funding; Octapharma: Research Funding. Samama:LFB: Research Funding; CSL: Research Funding; Octapharma: Research Funding. Sie:LFB: Research Funding; CSL: Research Funding; Octapharma: Research Funding. Bosson:LFB: Research Funding; CSL: Research Funding; Octapharma: Research Funding.

scholarly journals CYP2D6 Reduced Function Variants and Genotype/Phenotype Translations of CYP2D6 Intermediate Metabolizers: Implications for Personalized Drug Dosing in Psychiatry

2021 ◽  
Vol 12 ◽  
Author(s):  
Espen Molden ◽  
Marin M. Jukić
Keyword(s):  
Functional Score ◽  
Individual Dose ◽  
Dose Individualization ◽  
Drug Dosing ◽  
Long Time ◽  
Ultrarapid Metabolizer ◽  
Variant Alleles ◽  
International Experts ◽  
Current Guidelines ◽  
Intermediate Metabolizers

Genetic differences in cytochrome P450 (CYP)-mediated metabolism have been known for several decades. The clinically most important polymorphic CYP enzyme is CYP2D6, which plays a key role in the metabolism of many antidepressants and antipsychotics, along with a range of non-psychiatric medications. Dose individualization based on CYP2D6 genotype to improve the effect and safety of drug treatment has been an ambition for a long time. Clinical use of CYP2D6 genotyping is steadily increasing; however, for pre-emptive genotyping to be successful in predicting individual dose requirements, high precision of genotype-to-phenotype translations are required. Recently, guidelines for assigning CYP2D6 enzyme activity scores of CYP2D6 variant alleles, and subsequent diplotype-to-phenotype translations, were published by the Clinical Pharmacogenetics Implementation Consortium (CPIC) and the Dutch Pharmacogenetics Working Group. Consensus on assigning activity scores of CYP2D6 variant alleles and translating diplotype scores into CYP2D6 poor, intermediate, normal, or ultrarapid metabolizer groups were obtained by consulting 37 international experts. While assigning enzyme activities of non-functional (score 0) and fully functional (score 1) alleles are straightforward, reduced function variant alleles are more complex. In this article, we present data showing that the assigned activity scores of reduced function variant alleles in current guidelines are not of sufficient precision; especially not for CYP2D6*41, where the guideline activity score is 0.5 compared to 0.05–0.15 in pharmacogenetic studies. Due to these discrepancies, CYP2D6 genotypes with similar guidelinediplotype scores exhibit substantial differences in CYP2D6 metabolizer phenotypes. Thus, it is important that the guidelines are updated to be valid in predicting individual dose requirements of psychiatric drugs and others metabolized by CYP2D6.

AEM of reaction-bonded SiC

1992 ◽  
Vol 50 (1) ◽  
pp. 344-345
Author(s):  
K Das Chowdhury ◽  
R. W. Carpenter ◽  
W. Braue
Keyword(s):  
Mechanical Properties ◽  
Phase Transformation ◽  
High Temperature ◽  
Epitaxial Growth ◽  
Liquid Silicon ◽  
Structural Ceramic ◽  
Few Data

Research on reaction-bonded SiC (RBSiC) is aimed at developing a reliable structural ceramic with improved mechanical properties. The starting materials for RBSiC were Si,C and α-SiC powder. The formation of the complex microstructure of RBSiC involves (i) solution of carbon in liquid silicon, (ii) nucleation and epitaxial growth of secondary β-SiC on the original α-SiC grains followed by (iii) β>α-SiC phase transformation of newly formed SiC. Due to their coherent nature, epitaxial SiC/SiC interfaces are considered to be segregation-free and “strong” with respect to their effect on the mechanical properties of RBSiC. But the “weak” Si/SiC interface limits its use in high temperature situations. However, few data exist on the structure and chemistry of these interfaces. Microanalytical results obtained by parallel EELS and HREM imaging are reported here.

Ultrastructural study on the development of rat amygdaloid body

1990 ◽  
Vol 48 (3) ◽  
pp. 432-433
Author(s):  
A. Manolova ◽  
S. Manolov
Keyword(s):  
Nerve Cells ◽  
Amygdaloid Complex ◽  
Amygdaloid Body ◽  
Thin Ring ◽  
Morphological Criteria ◽  
Neural Processes ◽  
Abundant Cytoplasm ◽  
Level 1 ◽  
Few Data ◽  
Oval Shape

Relatively few data on the development of the amygdaloid complex are available only at the light microscopic level (1-3). The existence of just general morphological criteria requires the performance of other investigations in particular ultrastructural in order to obtain new and more detailed information about the changes in the amygdaloid complex during development.The prenatal and postnatal development of rat amygdaloid complex beginning from the 12th embrionic day (ED) till the 33rd postnatal day (PD) has been studied. During the early stages of neurogenesis (12ED), the nerve cells were observed to be closely packed, small-sized, with oval shape. A thin ring of cytoplasm surrounded their large nuclei, their nucleoli being very active with various size and form (Fig.1). Some cells possessed more abundant cytoplasm. The perikarya were extremely rich in free ribosomes. Single sacs of the rough endoplasmic reticulum and mitochondria were observed among them. The mitochondria were with light matrix and possessed few cristae. Neural processes were viewed to sprout from some nerve cells (Fig.2). Later the nuclei were still comparatively large and with various shape.

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