Plasma Clozapine and N -Desmethylclozapine (Norclozapine) Concentrations and the Clozapine/Norclozapine Ratio : Effect of Dose, Sex, and Cigarette Smoking.

Background: Smoking enhances plasma clozapine clearance, but the magnitude of the effect across the dose and age ranges is unclear.

Methods: We audited clozapine dose and predose plasma clozapine and N -desmethylclozapine (norclozapine) concentrations by sex and smoking habit in samples submitted for clozapine TDM, 1996-2017.

Results: There were 105,316/60,792 and 34,288/31,309 samples from male/female smokers/nonsmokers, respectively.

Effect of Coffee and Chocolate Ingestion on Clozapine Dose and on Plasma Clozapine and Norclozapine Concentrations in Clinical Practice.

Background: Some reports point to dietary caffeine intake as a cause of increased plasma clozapine concentrations in certain patients.

Methods: We compared clozapine dose and plasma clozapine and N-desmethylclozapine (norclozapine) concentrations in male and female smokers and nonsmokers in relation to reported (i) coffee (caffeine) and (ii) chocolate (caffeine and theobromine) intake in samples submitted for clozapine therapeutic drug monitoring, 1993-2017.

Results: There was information on coffee ingestion for 16,558 samples (8833 patients) from males and 5886 samples (3433 patients) from females and on chocolate ingestion for 12,616 samples (7568 patients) from males and 4677 samples (2939 patients) from females.

Effect of Cigarette Smoking on Clozapine Dose and on Plasma Clozapine and N-Desmethylclozapine (Norclozapine) Concentrations in Clinical Practice.

Background: Cigarette smoking enhances plasma clozapine clearance and thus affects the clozapine dose requirement.

Methods: We compared clozapine daily dose and plasma clozapine and N-desmethylclozapine (norclozapine) concentrations in male and female smokers and nonsmokers in samples submitted for clozapine therapeutic drug monitoring (1996-2017).

Results: There were 105,316/60,792 and 34,290/31,309 samples with dose information from male and female smokers/nonsmokers, respectively.

Assessing Adherence to Clozapine: Practical Considerations.

Background: The clinical assessment of adherence to clozapine may prove difficult.

Method: We studied the incidence of nonadherence (plasma clozapine <0.01 mg L -1 ) in samples submitted to a clozapine therapeutic drug monitoring (TDM) service, 1993-2017.

A population pharmacokinetic model to guide clozapine dose selection, based on age, sex, ethnicity, body weight and smoking status.

Aims: Guidance on clozapine dosing in treatment-resistant schizophrenia is based largely on data from White young adult males. This study aimed to investigate the pharmacokinetic profiles of clozapine and N-desmethylclozapine (norclozapine) across the age range, accounting for sex, ethnicity, smoking status and body weight.

Methods: A population pharmacokinetic model, implemented in Monolix, that linked plasma clozapine and norclozapine via a metabolic rate constant, was used to analyse data from a clozapine therapeutic drug monitoring service, 1993-2017.

Clozapine: Dose, Sex, Ethnicity, Smoking Habit, Age, Body Weight, and Plasma Clozapine and N -Desmethylclozapine (Norclozapine) Concentrations in Clinical Practice.

Background: Guidance on clozapine dosing in treatment refractory schizophrenia is based largely on data from young adult male White patients.

Aim: This study aimed to audit the plasma clozapine and N -desmethylclozapine (norclozapine) concentrations attained in male and female patients of different ethnicity and smoking habit.

Method: The effect of dose, sex, ethnicity, age, body weight, and smoking habit on plasma clozapine and norclozapine concentrations were studied using data from a therapeutic drug monitoring service, 1993 to 2017.

Plasma Clozapine and Norclozapine After Use of Either Crushed Tablets or Suspension Compared With Tablets.

Background: With clozapine, either crushed tablets suspended in an aqueous medium or proprietary suspension is sometimes prescribed as an alternative to tablets, but bioequivalence data are scant.

Methods: We compared clozapine dose, and plasma clozapine and N -desmethylclozapine (norclozapine) concentrations after use of either tablets or crushed tablets/suspension in samples submitted for clozapine therapeutic drug monitoring, 1993 to 2017.

Results: There were 846 patients (1646 samples) given crushed tablets/suspension and 6065 patients (10,779 samples) given tablets.

Fatal Unintentional Non-Fire Related Carbon Monoxide Poisoning: Data from Narrative Verdicts in England and Wales, 1998-2019.

Unintentional non-fire related (UNFR) carbon monoxide (CO) poisoning continues to cause fatalities. The narrative verdicts from coroners concerning fatal UNFR CO poisoning in England and Wales, 1998-2019, were collated by the Office for National Statistics. Search terms related to CO exposure were used to obtain information regarding the circumstances of death.

Antipsychotic-Related Fatal Poisoning, England and Wales, 1993-2019: The Impact of Second-Generation Antipsychotics.

Background: Deaths from antipsychotic (AP) poisoning have increased in England and Wales despite restriction of the use of thioridazine in 2000.

Methods: We analyzed data from the Office for National Statistics drug-related death database, England and Wales, 1993-2019, to investigate fatal AP poisoning.

Results: There were 2286 deaths (62% male patients).

Analytical Detection of Novel Stimulants by Immunoassay and Liquid Chromatography-High Resolution Mass Spectrometry: Case Studies on Ethylphenidate and Mephedrone.

The advent of hundreds of new compounds aimed at the substance misuse market has posed new analytical challenges. A semi-quantitative liquid chromatography-high-resolution mass spectrometry (LC-HRMS) method has been developed to detect exposure to two novel stimulants, mephedrone and ethylphenidate, and selected metabolites. Centrifuged urine (50 µL) was diluted with LC eluent containing internal standards (mephedrone-d3, methylphenidate-d9 and ritalinic acid-d10; all 0.

Detection of fentanyl and fentanyl analogues in biological samples using liquid chromatography-high resolution mass spectrometry.

Background: Fentanyl and analogues such as butyrylfentanyl, carfentanil, 4-fluorobutyrylfentanyl, and furanylfentanyl may be either added to, or sold as, heroin. Fentanyl and carfentanil have approximately 100 and 10,000 times the potency of morphine, respectively, and there is thus a high risk of death with the use of these drugs.

Methods: We looked for fentanyl/fentanyl analogues using liquid chromatography-high resolution mass spectrometry (LC-HRMS) in selected biological samples obtained post-mortem February 2017-end January 2018.

The interpretation of hair analysis for drugs and drug metabolites.

Introduction: Head hair analysis for drugs and drug metabolites has been used widely with the aim of detecting exposure in the weeks or months prior to sample collection. However, inappropriate interpretation of results has likely led to serious miscarriages of justice, especially in child custody cases.

Objective: The aim of this review is to assess critically what can, and perhaps more importantly, what cannot be claimed as regards the interpretation of hair test results in a given set of circumstances in order to inform future testing.

Sodium valproate and clozapine induced neutropenia: A case control study using register data.

Background: The use of clozapine is limited due to the occurrence of neutropenia, and the rare but life threatening adverse event of agranulocytosis. There is little epidemiological research into clinical factors that may impact on this risk. We conducted a case control study examining the clinical risk factors for neutropenia patients treated with clozapine.

The Use of Granulocyte Colony-Stimulating Factor in Clozapine Rechallenge: A Systematic Review.

Purpose/background: Clozapine is associated with hematological abnormalities, with neutropenia and agranulocytosis of most concern. Granulocyte colony-stimulating factor (G-CSF) has been used to support clozapine rechallenge after neutropenia with the aim of maintaining the neutrophil count. This study aims to explore the practice, use, safety, and efficacy of G-CSF in this context.

Women Administered Standard Dose Imatinib for Chronic Myeloid Leukemia Have Higher Dose-Adjusted Plasma Imatinib and Norimatinib Concentrations Than Men.

Background: The standard dose of imatinib for the treatment of chronic-phase chronic myeloid leukemia (CML) is 400 mg·d. A predose plasma imatinib concentration of >1 mg·L is associated with improved clinical response. This study aimed to assess the plasma imatinib and norimatinib concentrations attained in patients with chronic myeloid leukemia administered standard doses of imatinib adjusted for dose, age, sex, body weight, and response.

Ultra-fast LC-MS/MS in therapeutic drug monitoring: Quantification of clozapine and norclozapine in human plasma.

A novel approach to high-throughput, targeted liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis has been developed. A single chromatographic system can be used for the analysis of a range of 20 drugs and metabolites with a total analysis time of 36 s (one 96-well plate of prepared samples per hour). To demonstrate the applicability of this approach to quantitative analysis, a method has been validated for the therapeutic drug monitoring of clozapine and norclozapine following automated extraction from human plasma.

Clozapine-Associated Agranulocytosis Treatment With Granulocyte Colony-Stimulating Factor/Granulocyte-Macrophage Colony-Stimulating Factor: A Systematic Review.

Purpose/background: Clozapine is associated with hematological abnormalities, notably neutropenia, which may progress to agranulocytosis. Granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF) have been used to reduce the frequency and duration of clozapine-associated neutropenia. This review aims to explore the use, efficacy, and tolerability of these cytokines in the treatment of clozapine-associated agranulocytosis.

Measurement of Clozapine, Norclozapine, and Amisulpride in Plasma and in Oral Fluid Obtained Using 2 Different Sampling Systems.

Background: There is a poor correlation between total concentrations of proton-accepting compounds (most basic drugs) in unstimulated oral fluid and in plasma. The aim of this study was to compare clozapine, norclozapine, and amisulpride concentrations in plasma and in oral fluid collected using commercially available collection devices [Thermo Fisher Scientific Oral-Eze and Greiner Bio-One (GBO)].

Methods: Oral-Eze and GBO samples and plasma were collected in that order from patients prescribed clozapine.

An assessment of the variation in the concentration of acetylcysteine in infusions for the treatment of paracetamol overdose.

Background: Intravenous acetylcysteine is the treatment of choice for paracetamol poisoning. A previous UK study in 2001 found that 39% of measured acetylcysteine infusion concentrations differed by >20% from anticipated concentrations. In 2012, the UK Commission on Human Medicines made recommendations for the management of paracetamol overdose, including provision of weight-based acetylcysteine dosing tables.

Prevalence and Predictors of Clozapine-Associated Constipation: A Systematic Review and Meta-Analysis.

Constipation is a frequently overlooked side effect of clozapine treatment that can prove fatal. We conducted a systematic review and meta-analysis to estimate the prevalence and risk factors for clozapine-associated constipation. Two authors performed a systematic search of major electronic databases from January 1990 to March 2016 for articles reporting the prevalence of constipation in adults treated with clozapine.