scholarly journals Audit on clozapine dose and plasma level correlation for patients with chronic treatment-resistant psychosis

BJPsych Open ◽  
2021 ◽  
Vol 7 (S1) ◽  
pp. S90-S90
Author(s):  
Olivia Macnamara ◽  
John Lawton ◽  
Sudheer Lankappa
Keyword(s):  
Plasma Level ◽  
Plasma Levels ◽  
Small Sample ◽  
Positive Trend ◽  
Average Interval ◽  
Clozapine Dose ◽  
Wide Range ◽  
Toxicity Risk ◽  
Trough Levels ◽  
Level Monitoring

AimsClozapine is associated with a risk of severe adverse events for which there are current monitoring systems are in place; however, there are no established regimens for monitoring of clozapine plasma levels. Recent Medicines and Healthcare products Regulatory Agency (MHRA) guidance advises clozapine levels should be monitored in certain clinical situations where toxicity may be suspected. This audit aimed to evaluate current practice of clozapine level monitoring within one Local Mental Health Team (LMHT).MethodElectronic (RiO) records of 41 patients (33 male, 8 female; aged from 27 to 76 years; mean age 45 years) registered to the ZTAS system within the Nottingham City Central LMHT were reviewed. 46% had been on clozapine for over 16 years. 73.3% of patients were within clusters 12 and 13; 25.4% of patients were in cluster 11, with one patient in cluster 8. Dates of clozapine plasma level tests for each patient between 2006 and 2020 were found on the electronic NoTIS system, along with clozapine, norclozapine and total clozapine levels. Concurrent clozapine dose and regimens were obtained from pharmacy records from 2018 onwards.Result273 clozapine plasma levels were conducted between 2006 and 2020. The average interval between levels taken was 10 months, 2 weeks but had a wide range, the shortest interval being 2 days, the longest being 13 years. 88 levels taken were >600 ug/L, suggesting increased toxicity risk. 108 levels were <350 ug/L, suggesting possible sub-optimal dosing or non-compliance. Statistical tests on correlation coefficient, although statistically non-significant (R = 0.37), showed a positive trend between total clozapine dose and the plasma level between all 3 parameters (i.e. clozapine, norclozapine and total clozapine).ConclusionThere does not appear to be any routine plasma clozapine level monitoring throughout the LMHT with an average interval between tests of 10 months. There was a non-significant but positive trend between total daily dose of clozapine and clozapine level. 32% of clozapine levels returned were higher than the recommended level. We would recommend as suggested in the guidelines from MHRA, clozapine plasma levels should be monitored in certain clinical situations with increased toxicity risk. Trough levels should be taken with records of time of previous dose taken. Limitations of this study included a small sample size (41 patients) with data collection reliant on electronic systems. It was unclear if these results represent trough levels, making values difficult to interpret. Multifactorial impact on clozapine metabolism causes wide patient variability in plasma levels.

Does a plasma level of chlorpromazine help?

1981 ◽  
Vol 11 (4) ◽  
pp. 729-734 ◽  
Author(s):  
Theodore van Putten ◽  
Philip R. A. May ◽  
Donald J. Jenden
Keyword(s):  
Plasma Level ◽  
Plasma Levels ◽  
Internal Standard ◽  
Gas Chromatography Mass Spectrometry ◽  
Therapeutic Window ◽  
Fixed Dose ◽  
Speed Of Response ◽  
Wide Range ◽  
Dose Period ◽  
Schizophrenic Patients

SynopsisForty-eight newly admitted schizophrenic patients were treated with a fixed, conservative (6·6 mg/kg) dose of chlorpromazine (CPZ) for 28 days. CPZ plasma levels were measured by a gas chromatography mass spectrometry method (GCMS) using 2H6-chlorpromazine as an internal standard. At the end of the fixed-dose period, ‘responders’ had the same plasma levels as ‘non-responders’, suggesting that lack of response is primarily a matter of the illness' sensitivity to CPZ, not to a plasma level below some therapeutic window. After the fixed-dose period, the dosage of CPZ was increased in the ‘non-responders’ by physician's choice. Improvement occurred over a wide range of 10–225 picomoles (3–72 ng)/ml. Above 300 picomoles (95 ng/ml) 4 inaccessible patients eventually became much worse, suggesting psychotoxicity. It is in the inaccessible patient whose illness is only minimally, or not at all, sensitive to CPZ that a plasma level might be especially useful.Interpretation of plasma levels is complicated by the speed of response: some initial non-responders improved by the 56th day of treatment on very conservative plasma levels.

Monitoring of tricyclic antidepressant plasma levels and clinical response: a review of the literature. Part I.

1989 ◽  
Vol 4 (1) ◽  
pp. 43-60 ◽  
Author(s):  
I.R. De Oliveira ◽  
P.A.S. Do Prado-Lima ◽  
B. Samuel-Lajeunesse
Keyword(s):  
Plasma Concentration ◽  
Plasma Level ◽  
Clinical Response ◽  
Plasma Levels ◽  
Tricyclic Antidepressants ◽  
Tricyclic Antidepressant ◽  
Review Of The Literature ◽  
Comprehensive Review ◽  
Plasma Level Monitoring ◽  
Level Monitoring

SummaryPart I of this paper presents a comprehensive review of plasma level monitoring of tricyclic antidepressants (TCAs) and their relationship to clinical response to antidepressant therapy. Imipramine, nortriptyline, amitriptyline, clomipramine and desipramine are the most widely studied TCAs in this regard. Typical therapeutic plasma concentration ranges are suggested for some of these agents, although a consensus is lacking.

scholarly journals Plasma levels of tricyclics and related antidepressants: are they necessary or useful?

1995 ◽  
Vol 19 (9) ◽  
pp. 548-550 ◽  
Author(s):  
David Taylor ◽  
Denise Duncan
Keyword(s):  
United States ◽  
Plasma Level ◽  
Plasma Levels ◽  
Dose Adjustment ◽  
The United States ◽  
Plasma Level Monitoring ◽  
The Uk ◽  
Level Monitoring

Opinions on the value of measuring tricyclic plasma levels vary substantially. In the United States, plasma levels of several tricyclics are frequently used to ‘optimise’ therapy. In the UK, plasma level monitoring is less often undertaken and measured levels are more usually used simply to assure compliance rather than as a guide to dose adjustment.

scholarly journals Short-term variation in plasma mitotane levels confirms the importance of trough level monitoring

2014 ◽  
Vol 171 (6) ◽  
pp. 677-683 ◽  
Author(s):  
T M A Kerkhofs ◽  
L J J Derijks ◽  
M H T Ettaieb ◽  
E M W Eekhoff ◽  
C Neef ◽  
...  
Keyword(s):  
Plasma Level ◽  
Plasma Levels ◽  
Early Morning ◽  
Morning Dose ◽  
Drug Of Choice ◽  
Standard Management ◽  
Median Plasma ◽  
Therapeutic Plasma Level ◽  
Level Monitoring ◽  
Control Study

ObjectiveMitotane is the drug of choice in patients with adrenocortical carcinoma. The anti-neoplastic effect is correlated with mitotane plasma levels, which render it crucial to reach and maintain the concentration above 14 mg/l. However, mitotane pharmacokinetics is poorly understood. The aim of this study was to investigate the variation in plasma mitotane levels during the day and the influence of a single morning dose.DesignA prospective case–control study was conducted to investigate the variation in plasma mitotane levels.MethodsPatients who had been treated for at least 24 weeks and had reached the therapeutic plasma level (14 mg/l) at least once were eligible. In the first group, mitotane levels were determined hourly for the duration of 8 h after administration of a single morning dose. In the second group, mitotane levels were assessed similarly without administration of a morning dose.ResultsTen patients were included in this study, and three patients participated in both groups. Median plasma level at baseline was 16.2 mg/l (range 11.3–23.3 mg/l) in the first group (n=7) and 17.0 mg/l (13.7–23.8) in the second group (n=6). Plasma levels displayed a median increase compared with baseline of 24% (range 6–42%) at t=4 after morning dose and a change of 13% (range −14 to 33%) at t=4 without morning dose (P=0.02).ConclusionA substantial increase in mitotane plasma levels was observed in steady-state patients within a period of 8 h after morning dosing. Without morning dose, mitotane curves showed a variable profile throughout the day. This implies that random sampling could yield incidentally high levels. For this reason, we recommend early-morning trough sampling as standard management in monitoring mitotane treatment.

scholarly journals P520 Association between ustekinumab trough levels and biomarkers in patients with Crohn’s disease

2020 ◽  
Vol 14 (Supplement_1) ◽  
pp. S449-S450
Author(s):  
M I Nicolás de Prado ◽  
C Iniesta Navalón ◽  
R Gomez Espin ◽  
M Gil Candel ◽  
L Serrano Díaz ◽  
...  
Keyword(s):  
Crohn’S Disease ◽  
Crohn's Disease ◽  
Small Sample ◽  
Biochemical Response ◽  
Enzyme Linked Immunosorbent Assay ◽  
Positive Trend ◽  
Biochemical Remission ◽  
The Relationship ◽  
Trough Levels ◽  
Statistic Result

Abstract Background Ustekinumab (UTK) is a human immunoglobulin (Ig) G1 kappa monoclonal antibody approved in 2017 for the treatment of Crohn’s Disease (CD). Up until now, there has not been enough evidence of the relationship between ustekinumab trough levels (UTL) and the clinical evolution and biological markers of the disease. Our study aimed to investigate the relationship between UTL and different biomarkers in a real-world setting. Methods We performed a retrospective observational study including patients up to 18 years with CD receiving subcutaneous maintenance regimen of 90 mg UTK every 8 weeks and available UTL. Biochemical response and remission were evaluated with faecal calprotectin (FC) and C-Reactive Protein (CRP) levels. The biochemical response was defined as a decrease of 50% or more of FC and/or CRP baseline levels, and biochemical remission as FC level &lt;150µg/ml and/or PCR&lt;0.4 mg/dl. UTL was determined from serum samples collected prior to the injection using a commercially available validated enzyme-linked immunosorbent assay (ELISA). Continuous variables were tested using the Mann–Whitney U-test. Receiver operating characteristic (ROC) curves were used to estimate the cut-off of the UTK trough level; for scoring purposes, we chose a cut-off that would maximise the sum of sensitivity and specificity. A value of p &lt; 0.05 was considered statistically significant. Statistical analysis was performed using SPSS for Windows. Results Forty-two patients were included (27 men and 15 female), with an average age of 47.7 years. The average FC levels were 1358,5μg/ml at the beginning of the treatment. In the maintenance period, we observed a biochemical response in 69% of patients, whose UTL were significantly higher than in non-responders (2.25 µg/ml [IQR: 3.08] vs. 0..65 µg/ml [IQR: 1.95]. respectively; p = 0.037). Likewise. 38% of patients achieved biochemical remission (responders 2.125 µg/ml [IQR: 2.25] vs. non-responders 1.5 µg/ml [IQR: 3.26]; p = 0.476). The AUC for predicting biochemical response by means of UTL was 0.703 [CI 95%: 0.529–0.877] (p = 0.037), with sensitivity of 51%, specificity of 76% and a cut-off of 2.20 μg/ml. Conclusion There is limited data on the association between UTL and patient outcome. Our study demonstrates the association between improvement of different biomarkers and higher levels of UTL, with a significant statistic result for biochemical response and non-significant statistic result for biochemical remission, maybe due to a small sample, but with a positive trend. Further studies are necessary in order to conclude that UTL is significant in the management and evolution of the disease and to determinate the optimal cut-off.

Early PK-Analysis Predicts Molecular Response In Patients With Early Chronic Phase Chronic Myelogenous Leukemia (CML-CP) Treated With Frontline Nilotinib

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1485-1485
Author(s):  
Dominik Wolf ◽  
Jorn Skavland ◽  
Christoph Seger ◽  
Sieghart Sopper ◽  
Wiktor-Wieslaw Jedrzejczak ◽  
...  
Keyword(s):  
Steady State ◽  
Plasma Level ◽  
Single Cell ◽  
Plasma Levels ◽  
Research Funding ◽  
Trough Level ◽  
Drug Intake ◽  
Molecular Response ◽  
Drug Levels ◽  
Trough Levels

Abstract Introduction Tyrosine kinase inhibitor (TKI) trough plasma level testing and pharmacodynamic evaluation (i.e. quantification of phosphorylated BCR-ABL downstream targets) may help to optimize patient-tailored dosing in CML-CP. For 2nd generation TKIs the clinical value of TKI plasma level and protein phosphorylation quantification remains unclear. The ENEST1st study (NCT01061177) is focused on examining the role of first-line nilotinib therapy in CML-CP. This ENEST1st substudy addresses the value of plasma-level testing and protein single cell phosphorylation pharmacodynamics as predictors of response and long-term outcomes. Methods Nilotinib levels were centrally quantified by means of mass spectrometry (HPLC-MS/MS) in 54 patients at 3 hours after first drug intake at day (d) 1 (Cmax) and at d7, d28 as well as at months (mo) 3, 6, 12 prior to morning drug intake (Cmin=trough level). Single cell quantification of intracellular protein phosphorylation was performed by flow cytometry (phosphoflow) in the myelocyte cell population after full blood fixation/cell permeabilization/erythrocyte lysis and analyzed 3 hours after first drug intake at d1 and on d7 and d28. Primary endpoint of the study was MR4 (BCR-ABL <0.01% IS) at 18 months. Results Our initial analysis focuses on correlation of drug levels with molecular response by correlating PK data to early molecular response, i.e. ≤10% BCR-ABL (IS) reduction at 3 mo as well as 0.1% IS (MMR), MR4 and MR5. At 3, 6, 12 and 18 mo, 24%, 56%, 74% and 77 % of the here investigated patients achieved MMR; 2%, 22%, 34% and 44% achieved MR4 and MR5 was detected in 0%, 5%, 15% and 14% of patients at the respective time points. Only 1 patient at 3mo had >IS 10% BCR-ABL. On d1 at 3 hours after intake of the first tablet the median peak plasma levels reached 408 ng/ml increasing to a median trough level of 834 ng/ml at d7, 888 ng/ml at d28, 919 ng/ml at 3mo, 1122 ng/ml at 6m and 1003 ng/ml at 12mo. Initial Cmax-levels at d1 significantly correlated with steady state levels thereafter (e.g. with trough levels at 12mo: r=0.56, p=0.004). Three mo drug levels were significantly negatively associated with lower BCR-ABL mRNA burden at 12m and 24m (r=-0.44, p=0.011 for m12 and r=-0.35, p=0.014 for m24). When median steady state drug levels were compared in different response categories (yes/no: MR4, MR5, MMR, >IS 10% at 3mo), significantly higher nilotinib trough levels at day 90 and mean trough level (day 28-180) were seen in patients achieving the primary endpoint of the study (MR4 at 18mo). Similarly, 3mo and mean through levels were also significantly higher in patients achieving MR5 at 12 or 18mo. As only one patient did not reach <10% at 3mo, we cannot evaluate if early PK data are able to predict this endpoint. The probability of achieving MR5 at 12mo and 24mo was significantly higher in the top third of the day 90 PK level (cumulative incidence of MR5 in the respective PK groups at 12mo: 5.6% vs. 5.6% vs. 44.4% and at 24mo: 5.6% vs. 22% vs. 44.4%). Cumulative incidence of MR4 was faster in the higher PK group (6mo: 6% vs. 18% vs. 42%; 12mo: 22% vs. 29% vs. 57% and at 24mo: 46% vs. 67% vs. 58%), which however did not reach statistical significance. Phosphoflow of myelocytes revealed that compared to baseline, phosphorylation of almost all investigated proteins decreases over time, including significant reduction of phospho-Gab2(Y452), Abl(Y245), STAT5(Y694), Erk1/2(T202/Y204), and p38(T108/Y182) at d28. Correlation of plasma levels with changes in phosphorylation status revealed a negative correlation of increasing drug levels with decreasing phospho-p38 and phospho-STAT5 status. A more detailed signaling analysis of cellular subsets related to molecular response criteria are in progress. Conclusions Single cell myelocyte phosphoprotein detection allowed monitoring of the BCR-ABL signalling network. Inter-individual plasma levels show a relatively wide variability and Cmax levels upon first drug exposure correlate with later trough levels pointing out to a potential individual pharmacogenetic background regulating drug availability. PK-based optimizing of nilotinib-dosing may help to further improve response depth (i.e. reaching MR4 or MR5), which is assumed to be a prerequisite for treatment discontinuation. Disclosures: Wolf: Novartis: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding. Mustjoki:Novartis: Honoraria, Research Funding. Greil:Novartis: Honoraria, Research Funding. Hjorth-Hansen:Pfizer, BMS: Honoraria, Travel expenses Other. Verhoef:Novartis: Research Funding. Mark:Novartis: Employment. Haenig:Novartis: Employment. Jurjonas:Novartis: Employment. Giles:Novartis: Consultancy, Research Funding. Hochhaus:Novartis: Research Funding. Porkka:Novartis: Honoraria, Research Funding. Ossenkoppele:Novartis: Consultancy, Research Funding; BMS: Consultancy. Gjertsen:Novartis: Honoraria, Research Funding.

Measurements method of the audio recordings acoustic quality indicator prepared for registration and processing in the Unified Biometric System

2019 ◽  
pp. 40-46 ◽  
Author(s):  
V.V. Savchenko ◽  
A.V. Savchenko
Keyword(s):  
Quality Control ◽  
Small Sample Size ◽  
Personal Data ◽  
Digital Processing ◽  
Small Sample ◽  
Practical Implementation ◽  
Acoustic Measurements ◽  
Pitch Frequency ◽  
Wide Range ◽  
Automated Quality Control

We consider the task of automated quality control of sound recordings containing voice samples of individuals. It is shown that in this task the most acute is the small sample size. In order to overcome this problem, we propose the novel method of acoustic measurements based on relative stability of the pitch frequency within a voice sample of short duration. An example of its practical implementation using aninter-periodic accumulation of a speech signal is considered. An experimental study with specially developed software provides statistical estimates of the effectiveness of the proposed method in noisy environments. It is shown that this method rejects the audio recording as unsuitable for a voice biometric identification with a probability of 0,95 or more for a signal to noise ratio below 15 dB. The obtained results are intended for use in the development of new and modifying existing systems of collecting and automated quality control of biometric personal data. The article is intended for a wide range of specialists in the field of acoustic measurements and digital processing of speech signals, as well as for practitioners who organize the work of authorized organizations in preparing for registration samples of biometric personal data.

scholarly journals Are high NT-proBNP levels more related to inflammation than to left ventricular systolic dysfunction in acute myocarditis?

2021 ◽  
Vol 10 (Supplement_1) ◽  
Author(s):  
B Sara ◽  
JJ Monteiro ◽  
P Carvalho ◽  
C Ribeiro Carvalho ◽  
J Chemba ◽  
...  
Keyword(s):  
Ejection Fraction ◽  
Plasma Levels ◽  
Left Ventricular Systolic Dysfunction ◽  
Small Sample Size ◽  
Acute Myocarditis ◽  
Systolic Dysfunction ◽  
Left Ventricular ◽  
Small Sample ◽  
Left Ventricular Ejection ◽  
Ventricular Ejection Fraction

Abstract Funding Acknowledgements Type of funding sources: None. Background Plasma levels and N-terminal pro B-type natriuretic peptide (NT- proBNP), a cardiac neurohormone released in response to increased ventricular stress, represent an important predictor of clinical outcomes and left ventricular (LV) dysfunction; Although, its diagnostic and prognostic role in patients with acute myocarditis is not completely established; Our aim was to evaluate the relationship of BNP levels and LV ejection fraction (LVEF) in patients with myocarditis; Methods Data from patients (pts) discharged with the diagnosis of myocarditis, from 2008 and 2018 were retrospectively analysed. Results 62 pts were included. Mean age was 39.7 17 years and 89% (58 patients) were men. Plasma levels of NT-proBNP measured at admission ranged from 24 to 3110 pg/mL (median 514, IQR 947), and exceeded upper normal levels in 51 pts (82%). This values positively correlated with C- reactive protein (CRP) (p= 0.005, r = 0.36), leucocytes (p = 0.03, r= 0.37) and neutrophil-to-lymphocyte ratio (p= 0.05, r= 0.35), but not with left ventricular ejection fraction (LVEF) (p= 0.829). Higher levels of BNP were associated with higher troponin peak levels but not with increased mortality (p = 0.811), need of inotropic support (p= 0.059) or arrhythmic events (p= 0.130). Inflammatory parameters were significantly increased when BNP&gt; 514 pg/mL vs BNP &lt;514 pg/mL (CRP 7.2 vs 4 mg/dL, p= 0.008). This relationship was maintained at BNP &gt; 900. LVEF was comparable in both groups (p = 0.938); In this population, the magnitude of recovery of the NT- proBNP values (variation between NT-proBNP at admission and discharge) strongly correlated with the magnitude of the inflammatory markers at admission (all p &lt; 0,005) Conclusion In patients with acute myocarditis, there is a significant relationship between NT-proBNP levels and inflammation (as measured by leucocytes, NLR or CRP), but not with LVEF; Despite the limitation of a small sample size, we could hypothesize that NTproBNP in this subset of patients appears to be regulated not only by hemodynamic changes but also by the underlying systemic inflammatory process and, therefore, it interpretation should take that into account;

Side Effects of Clozapine and Their Relationship with Clinical Variables in Patients with Schizophrenia

2017 ◽  
Vol 41 (S1) ◽  
pp. S197-S197
Author(s):  
G. Gürcan ◽  
Ş. Hun Şenol ◽  
A.E. Anıl Yağcıoğlu ◽  
A. Ertuğrul
Keyword(s):  
Metabolic Syndrome ◽  
Side Effects ◽  
Plasma Levels ◽  
Rating Scale ◽  
Clinical Status ◽  
Clinical Variables ◽  
Clozapine Treatment ◽  
Clozapine Dose ◽  
Severity Of Disability ◽  
Competing Interest

IntroductionThe side effects of clozapine may affect the treatment process negatively, and increase the disability.AimsWe aimed to assess the side effects of clozapine, and their relationship with the clinical variables in schizophrenia patients, and study the predictors of disability.MethodsConsecutive 122 outpatients who met DSM-IV criteria for schizophrenia, and were on clozapine treatment were included in the study. Information about sociodemographic characteristics, past and current clinical status were gathered through a clinical interview and review of the medical records, and physical measures and laboratory tests, including clozapine plasma levels, were recorded. The patients were assessed with SCID-I, Positive and Negative Syndrome Scale, UKU-Side Effect Rating Scale, WHO-Disability Assessment Schedule-II.ResultsHypersalivation, weight gain, sedation and constipation were the most common side effects of clozapine. Although the mean plasma clozapine levels were high (828.11 ± 445.5 ng/mL), no significant effect of clozapine dose and plasma levels were detected on the severity of side effects, except for constipation. Metabolic syndrome prevalence was found to be 50% according to ATP IIIA criteria. Duration of clozapine treatment, clozapine dose and plasma levels were not significantly different between patients with and without metabolic syndrome. Regression analysis showed that the severity of schizophrenia psychopathology and the number of side effects predicted the severity of disability.ConclusionsSide effects of clozapine increase the disability of patients with schizophrenia and should be monitored regularly. On the other hand, clozapine dose and plasma levels do not determine the severity of most of the common side effects.Disclosure of interestThe authors have not supplied their declaration of competing interest.

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