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The polycyclic aromatic hydrocarbons present in tobacco smoke bind to a nuclear receptor called the aryl hydrocarbon receptor which induces CYP1A2 expression. Geriatric age, which is associated with decreased renal function, probably decreases the clearance of NCLO and other hydrophilic metabolites (2). Zanger and Schwab also suggested that other unknown genes may control CYP1A2 variability in expression and function (16). [...]it is possible that other genes may explain the differences in CYP1A2 activity between Asians and Caucasians (5). Total CLO PMs previously described in the literature Allorge France ND 71yo ♀ nonsmoker 6.85 4.32 81 CYP1A2*7 (18) Shad USA Caucasian 41yo ♂ nonsmoker 5.95 3.56 98 Not genotyped† (20) Italian Caucasians described by us as having CLO C/D ratio > mean+2SD of their group stratified by sex and smoking Ruan Italy Caucasians 5 cases 5.38-8.06 3.60-6.08 59-100 Possible confounders‡ (5) Asians described by us as having CLO C/D ratio > mean+2SD of their group stratified by sex and smoking Ruan China Chinese Han 5 cases 4.30-6.22 3.04-4.31 81-115 CYP1A2 mutation?§ (5) Ruan China Chinese Han 14 cases 4.22-13.70 2.74-10.31 34-128 Possible confounders‡ (13) Ruan Taiwan Chinese 8 cases 3.93-11.90 2.18-8.49 41-161 Possible confounder¶ (13) Ruan Korea Koreans 9 cases 4.71-6.52 2.95-3.84 91-119 Possible confounder¶ (13) Ruan South India South Indians 2 cases 5.09-8.29 42-69 Possible confounder¶ (13) UMs previously described in the literature: non-Asians needing >900mg/day to reach 350ng/ml Bender Germany ND 21yo ♂ smoker <0.17# 2059 Genetic UM†† (21) Eap Switzerland ND 21yo ♂ smoker 0.53 0.28‡‡ 1250 Genetic UM†† (22) Eap Germany ND 71yo ♀ nonsmoker <0.018 <0.009 >3955 Genetic UM†† (22) Ozdemir Canada ND 31yo ♂ smoker 0.34 0.17 2059 Genetic UM†† (23) Riesselman USA AA 38yo ♂ smoker 0.27-0.36 0.09-0.24 1458-3889 Induced§§ (24) Maccall UK ND 26yo ♂ smoker <0.37 >946 (25) Maccall UK ND 23yo ♂ <0.36 >972 (25) Alfaro Ethiopia ND 25yo ♂ smoker¶¶ 0.25 1400 (26) Alfaro USA Caucasian 30yo ♂ smoker¶¶ 0.22-0.27 1296-1591 (26) Bersani Italy Caucasian 23yo ♂ smoker## 0.21 1667 (27) Asians described by us as having CLO C/D ratio < mean−2SD of their group stratified by sex and smoking Ruan South India South Indians 31yo ♀ nonsmoker 0.34 >1016 Induced††† (13) Ruan Several‡‡‡ Asians§§§ 6 more cases 0.47-0.97 0.26-0.52 653-1036 Lack of adherence§§§ (13) † The patient was followed for 23months with 6 Cs and stabilized with a CLO D of 75mg/day.

Clinicians need to remember that (1) systemic inflammations can increase clozapine level; (2) clozapine, by itself, can cause inflammation, particularly during titration that is too rapid for that patient; (3) clozapine may increase the risk of infection; and (4) more specifically, clozapine may be particularly strongly associated with the risk of pneumonia. Pneumonia appears to be associated with high mortality in clozapine patients around the world. Clinicians who are alert to the risk of pneumonia in clozapine patients may significantly decrease mortality in clozapine patients. There is no data on COVID-19 infections in clozapine patients, but based on what we know about clozapine pharmacology, we can hypothesise that clozapine, possibly by impairing immunological mechanisms, may increase the risk of pneumonia in infected patients. More importantly, once fever and/or pneumonia develops, the clozapine dose should be cut in half to decrease the risk of clozapine intoxication. If there is any doubt that in spite of halving the dose there are still signs of clozapine intoxication, completely stopping clozapine may be indicated. Once the signs of inflammation and fever have disappeared, the clozapine dose can be increased to the prior dosage level.

Using Richardson and Davidson’s model and the sciences of pharmacokinetics and clinical pharmacopsychology, this article reviewed the: (1) poor life expectancy associated with treatment-resistant schizophrenia (TRS), which may be improved in patients who adhere to clozapine; (2) findings that clozapine is the best treatment for TRS (according to efficacy, effectiveness and well-being); and (3) potential for clozapine to cause vulnerabilities, including potentially lethal adverse drug reactions such as agranulocytosis, pneumonia, and myocarditis. Rational use requires: (1) modification of the clozapine package insert worldwide to include lower doses for Asians and to avoid the lethality associated with pneumonia, (2) the use of clozapine levels for personalizing dosing, and (3) the use of slow and personalized titration. This may make clozapine as safe as possible and contribute to increased life expectancy and well-being. In the absence of data on COVID-19 in clozapine patients, clozapine possibly impairs immunological mechanisms and may increase pneumonia risk in infected patients. Psychiatrists should call their clozapine patients and families and explain to them that if the patient develops fever or flu-like symptoms, the psychiatrist should be called and should consider halving the clozapine dose. If the patient is hospitalized with pneumonia, the treating physician needs to assess for symptoms of clozapine intoxication since halving the dose may not be enough for all patients; consider decreasing it to one-third or even stopping it. Once the signs of inflammation and fever have disappeared, the clozapine dose can be slowly increased to the prior dosage level.

PurposeTo develop and validate a population pharmacokinetic (PPK) model of valproic acid (VPA) in adult Chinese patients with bipolar disorder, and provide guidance for individualized therapy in this population.MethodsA total of 1104 serum concentrations from 272 patients were collected in this study. The data analysis was performed using a nonlinear mixed-effects modeling approach. Covariates included demographic parameters, biological characteristics, and concomitant medications. Bootstrap validation (1000 runs), normalized prediction distribution error (NPDE), and external validation of 50 patients were employed to evaluate the final model.ResultsA one-compartment model with first-order absorption and elimination was developed for VPA extended-release tablets. VPA clearance was significantly influenced by three variables: sex (12% higher in male patients), daily dose (increasing with the 0.13 exponent), and body weight (increasing with the 0.56 exponent). Typical values for the absorption rate constant (Ka), apparent clearance (CL/F), and apparent distribution volume (V/F) for a female patient weighing 70 kg administered VPA 1000 mg/day were 0.18 h−1, 0.46 L/h, and 12.84 L, respectively. The results of model evaluation indicated a good stable and precise performance of the final model.ConclusionsA qualified PPK model of VPA was developed in Chinese patients with bipolar disorder. This model could be used as a suitable tool for the personalization of VPA dosing for bipolar patients.

White blood cell (WBC) monitoring has reduced clozapine-treated patient deaths associated with agranulocytosis to a rarity. However, clozapine protocols and package inserts worldwide provide no instructions for preventing myocarditis or pneumonia during clozapine titrations. Prescribers worldwide are largely unaware of that. Meanwhile, as they worry about agranulocytosis, their clozapine-treated patients are at risk of dying from pneumonia or myocarditis. Consequently, an international guideline with 104 authors from 50 countries/regions was recently published to provide personalised clozapine titration schedules for adult inpatients. This forum article reviews pneumonia and myocarditis occurring during clozapine titration, as well as the three most innovative aspects of this new guideline: (1) personalised titration, (2) C reactive protein (CRP) measures, and (3) dose predictions based on blood levels. Clozapine metabolism is influenced by 3 levels of complexity: (1) ancestry groups, (2) sex-smoking subgroups, and (3) presence/absence of poor metabolizer status. These 3 groups of variables should determine the maintenance dose and speed of clozapine titration; they are summarised in a table in the full-text. The international clozapine titration guideline recommends measuring CRP levels simultaneously with WBC, at baseline and weekly at least for the first 4 weeks of titration, the highest risk period for clozapine-induced myocarditis.

Purpose Icotinib hydrochloride {4-[(3-ethynylphenyl)amino]-6,7-benzo-12-crown-4-quinazoline hydrochloride}, a novel epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI), was designed for the treatment of non-small cell lung cancer (NSCLC). In the present study, we investigated the influence of the CYP2C19*2 and CYP2C19*3 alleles on the pharmacokinetics of icotinib in healthy Chinese volunteers. Methods In a single-dose pharmacokinetic study, 12 healthy Chinese volunteers received an oral dose of 600 mg of icotinib. Plasma was sampled for up to 72 h post-dose, followed by quantification of icotinib by liquid chromatography-mass spectrometry/mass spectrometry (LC-MS-MS). Results Five subjects genotyped as homozygous extensive metabolizers (CYP2C19*1/*1), 6 subjects genotyped as heterozygous extensive metabolizers (CYP2C19*1/*2 or CYP2C19*1/*3), and 1 subject genotyped as a poor metabolizer (CYP2C19*2/*3) and was withdrawn from the research because of urticaria. The mean icotinib AUC 0-∞ and C max (14.56 ±5.31 h mg/L and 2.32 ± 0.49 μg/mL) in homozygous EMs was 1.56 and 1.41-fold lower than that in heterozygous EMs (22.7 ± 6.11 and 3.28 ± 0.48, P  = 0.046 and 0.047). The mean CL/F (44.18 ± 12.17 L/h) in homozygous EMs was 1.55-fold higher than that in heterozygous EMs (28.42 ± 9.23 L/h, P  = 0.013). Conclusions The data showed that the pharmacokinetics of icotinib differ significantly between homozygous EMs and heterozygous EMs in CYP2C19.

Background The pharmacokinetics of milnacipran have been studied in Caucasian subjects but not in Chinese subjects. Methods This single-center, open-label study evaluated the pharmacokinetics and safety of oral milnacipran administered as a randomized, three-way crossover, single-dose (25, 50 and 100 mg) and in multiple doses for 8 days (up to 100 mg/day administered as 50 mg twice daily) in Han Chinese healthy volunteers. Both the single- and multiple-dose studies included 12 different adults (six males and six females), respectively. Pharmacokinetic parameters for milnacipran were determined using WinNonlin version 6.3. The safety evaluation included adverse events (AEs) assessed by monitoring, physical examinations, vital signs, and clinical laboratory tests. Results Plasma concentrations of milnacipran reached a time to maximum concentration ( t max ) of 1.2–4.3 h after each single dose, and then declined, with a mean half-life ( t ½ ) of 7.0–7.3 h over the dose range of 25–100 mg; the area under the curve (AUC) and maximum concentration ( C max ) values increased in a dose-proportional manner. After multiple doses, steady state was reached by day 4 and the accumulation was low, with an accumulation index <1.65. No significant sex differences were observed in milnacipran pharmacokinetic parameters and, additionally, no severe AEs were observed in the single- or multiple-dose studies. The most common reported AEs were nausea, vomiting, dizziness and water brash, which appears to be dose-related. Conclusion Milnacipran was safe and well-tolerated in healthy volunteers and displayed linear increase in the C max and AUC values at doses ranging from 25 to 100 mg once daily.

Introduction: The aim of this study was to investigate the potential role of a microRNA panel as early diagnostic markers for Alzheimer's disease (AD). Methods: The differentially expressed serum microRNAs were screened with microarray among cognitively normal controls (CNC), mild cognitive impairment (MCI), and AD. QRT-PCR assay was applied to evaluate differentially expressed microRNAs with two independent cohorts including 202 participants. Logistic regression model based on microRNA panel was constructed using a training cohort and then validated using an independent cohort. Results: First, four differentially expressed serum microRNAs (let-7g, miR-197, miR-126 and miR-29a) were found, which expressions were positively correlated with mini mental state examination (MMSE) score. Second, a microRNA panel with the four microRNAs demonstrated good diagnostic performance for MCI and AD with 84% and 92% accuracy. Third, when combined with MMSE score, the diagnostic performance of the microRNA panel was further improved. Discussion: Blood microRNAs are potential AD biomarkers that may lead to new diagnostic strategies. Keywords: Alzheimer's disease/ microRNA/ early diagnosis