Određivanje donepezil hidroklorida u humanoj plazmi i ljekovitim oblicima pomoću HPLC s detekcijom fluorescencije

A sensitive, isocratic reversed-phase high performance liquid chromatographic method involving fluorescence detection was developed for the determination of donepezil hydrochloride in tablets and in human plasma. Pindolol was successfully used as an internal standard. Good chromatographic separation was achieved by using analytical column C18. The system operated at room temperature using a mobile phase consisting of methanol, phosphate buffer (0.02 mol L1) and triethyl amine (pH 3.5) (55: 45: 0.5 V/V/V) at a flow rate 0.9 mL min1. The analyte and internal standard were extracted from human plasma via liquid-liquid extraction. The proposed method was validated for selectivity, linearity, accuracy and precision. The calibration curve was linear over the range of 5-2000 ng mL1 of donepezil with detection limit of 1.5 ng mL1. Intra- and inter-day relative standard deviations were less than 2.5 %. The method was found to be suitable for the quality control of donepezil hydrochloride in bulk drug as well as in human plasma.Ovaj rad opisuje HPLC metodu određivanja donepezil hidroklorida (DP) u tabletama i u ljudskoj plazmi u nano području. Postavljena je osjetljiva metoda izokratične HPLC s fluorescencijskom detekcijom. Kao unutarnji standard upotrebljen je pindolol. Dobro kromatografsko odjeljivanje postignuto je primjenom analitičke kolone C18. Radna temperatura bila je sobna, a kao mobilna faza upotrebljena je smjesa metanola, fosfatnog pufera (0,02 mol L1) i trietilamina (pH 3,5) (55:45:0.5 V/V/V). Analit i unutarnji standard su ekstrahirani iz ljudske plazme ekstrakcijom tekuće-tekuće. Predložena metoda je validirana s obzirom na selektivnost, područje linearnosti, ispravnost i preciznost. Kalibracijska funkcija bila je linearna u području od 5-2000 ng mL1 donepezila, a granica detekcije iznosila je 2 ng mL1. Relativna standardna devijacija za repetabilnost i intermedijarnu preciznost bila je manja od 2,5 %. Metoda je primjenljliva u kontroli kvalitete ljekovitih formulacija s DP-om i u praćenju DP-a u ljudskoj plazmi

Hyperprolactinemia during antipsychotics treatment increases the level of coagulation markers

Masamichi Ishioka, Norio Yasui-Furukori, Norio Sugawara, Hanako Furukori, Shuhei Kudo, Kazuhiko Nakamura Department of Neuropsychiatry, Graduate School of Medicine, Hirosaki University, Hirosaki, Japan Objective: The strong association between psychiatric patients who receive antipsychotics and the incidence of venous thromboembolism (VTE) is known. Although previous reports suggest that hyperprolactinemia often increases markers of activated coagulation, few studies have examined the direct relationship between the prolactin level elevated by antipsychotics and activated markers of activated coagulation.Method: The participants included 182 patients with schizophrenia (male =89, female =93) who received antipsychotic treatments for at least 3 months. Markers of VTE (D-dimer, fibrin/fibrinogen degradation products, and thrombin–antithrombin complex) and serum prolactin concentrations were measured.Results: Prolactin levels were significantly correlated with the logarithmic transformation of the D-dimer (r=0.320, P=0.002) and fibrin/fibrinogen degradation product levels (r=0.236, P=0.026) but not of the thrombin–antithrombin complex level (r=0.117, ns) among men. However, no correlations were found between the VTE markers and prolactin levels among women. These results were confirmed using multiple regression analyses that included demographic factors and antipsychotic dosages. Conclusion: The current study indicates that hyperprolactinemia is associated with an increase in markers of activated coagulation among men receiving antipsychotics. This finding clinically implies that monitoring and modulating prolactin levels among men are important to decrease the risk of VTE. Keywords: prolactin, antipsychotics, venous thromboembolis

Differences in etiological beliefs about schizophrenia among patients, family, and medical staff

Natsumi Tarakita,1,2 Kazutaka Yoshida,1 Norio Sugawara,3 Kazutoshi Kubo,1,4 Hanako Furukori,5 Akira Fujii,2 Kazuhiko Nakamura,1 Norio Yasui-Furukori1 1Department of Neuropsychiatry, Graduate School of Medicine, Hirosaki University, Hirosaki, Japan; 2Department of Mental Health, Mutsu City Hospital, Mutsu, Japan; 3Department of Clinical Epidemiology, Translational Medical Center, National Center of Neurology and Psychiatry, Kodaira, Tokyo, Japan; 4Department of Neuropsychiatry, Hirosaki-Aiseikai Hospital, Hirosaki, Japan; 5Department of Neuropsychiatry, Kuroishi-Akebono Hospital, Kuroishi, Japan Objectives: To determine whether etiological beliefs are different among schizophrenia patients, their family, and medical staff. Patients and methods: A cross-sectional study was performed at five hospitals and one mental clinic and included 212 patients, 144 family members, and 347 medical staff other than psychiatrists. A questionnaire about the possible etiological causes of schizophrenia was used. Results: There were significant differences in response scores among the three groups on using Angermeyer’s and Goulding’s classifications. Factor analyses revealed the following four subscales: Psychosocial, Biological, Environmental, and Cultural connotations. The structure varied among patients, family, and medical staff. Conclusion: The perspectives of schizophrenia etiology were different among patients, family, and medical staff. Keywords: schizophrenia, etiology, perception, family, caregivers, beliefs, etiological causes, patients, medical staf

Ethnic and cultural perspectives in psychopharmacology

Culture and ethnicity represent indispensable dimensions in patient care. Reflecting their cultural and personal backgrounds, patients’ concepts on the cause and course of illnesses and treatment expectations often diverge substantially from their physicians deeply immersed in biomedical traditions directing their attention, assessment, and treatment goals. Such discrepancies, pervasive in most clinical encounters, further aggravated where patients and physicians come from distinct cultural systems, contribute to clinically significant nonadherence and placebo response. Efforts in exploring and bridging such gaps are crucial in enhancing therapeutic alliance, treatment engagement, optimization of placebo response, and thus better outcome. At the same time, cross-ethnic variations in pharmacological responses, caused by both genetic and epigenetic factors, are also ubiquitous and clinically significant. Genes controlling both pharmacokinetics and pharmacodynamics are highly polymorphic, whose patterns vary across ethnicity. Superimposed on such genetic variations, exposure to various xenobiotics including herbs, as well as psychosocial stresses, also affect drug responses through pharmacokinetic and pharmacodynamic mechanisms. The rapidly developing fields of pharmacogenetics and pharmacogenomics hold promise for clinicians to take both genetic and epigenetic factors into consideration at the same time, in order to predict the dosing, side-effect profiles, and efficacy of psychiatric medications. Ethnicity is an important dimension in the construction of such pharmacogenomic panels and in interpreting testing results. Finally, while striving to be cognizant of the importance of culture and ethnicity in clinical care, clinicians should also be mindful of the fact that cross-ethnic variations are embedded in interindividual variations and guard against the pitfalls of stereotyping

Possible impact of the CYP2D6*10 polymorphism on the nonlinear pharmacokinetic parameter estimates of paroxetine in Japanese patients with major depressive disorders

Junji Saruwatari,1 Hiroo Nakashima,1 Shoko Tsuchimine,2 Miki Nishimura,1 Naoki Ogusu,1 Norio Yasui-Furukori21Division of Pharmacology and Therapeutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan; 2Department of Neuropsychiatry, Graduate School of Medicine, Hirosaki University, Hirosaki, JapanAbstract: It has been suggested that the reduced function allele with reduced cytochrome P450 (CYP) 2D6 activity, CYP2D6*10, is associated with the interindividual differences in the plasma paroxetine concentrations, but there is no data presently available regarding the influence of the CYP2D6*10 polymorphism on the pharmacokinetic parameters, eg, Michaelis–Menten constant (Km) and maximum velocity (Vmax), in Asian populations. The present study investigated the effects of the CYP2D6 polymorphisms, including CYP2D6*10, on the pharmacokinetic parameters of paroxetine in Japanese patients with major depressive disorders. This retrospective study included 15 Japanese patients with major depressive disorders (four males and eleven females) who were treated with paroxetine. The CYP2D6*2, CYP2D6*4, CYP2D6*5, CYP2D6*10, CYP2D6*18, CYP2D6*39, and CYP2D6*41 polymorphisms were evaluated. A total of 56 blood samples were collected from the patients. The Km and Vmax values of paroxetine were estimated for each patient. The allele frequencies of CYP2D6*2, CYP2D6*4, CYP2D6*5, CYP2D6*10, CYP2D6*18, CYP2D6*39, and CYP2D6*41 were 6.7%, 0%, 10.0%, 56.7%, 0%, 26.7%, and 0%, respectively. The mean values of Km and Vmax were 50.5±68.4 ng/mL and 50.6±18.8 mg/day, respectively. Both the Km and Vmax values were significantly smaller in CYP2D6*10 allele carriers than in the noncarriers (24.2±18.3 ng/mL versus 122.5±106.3 ng/mL, P=0.008; 44.2±16.1 mg/day versus 68.3±15.0 mg/day, P=0.022, respectively). This is the first study to demonstrate that the CYP2D6*10 polymorphism could affect the nonlinear pharmacokinetic parameter estimates of paroxetine in Asian populations. The findings of this study suggest that the CYP2D6*10 polymorphism may be associated with the smaller values of both the Km and Vmax in Japanese patients with major depressive disorders, and these results need to be confirmed in further investigations with a larger number of patients.Keywords: pharmacokinetics, dose requirement, Michaelis–Menten constant, maximum velocit

Delirium in hemodialysis predicts mortality: a single-center, long-term observational study

Norio Yasui-Furukori,1 Natsumi Tarakita,1 Waka Uematsu,2 Hisao Saito,2 Kazuhiko Nakamura,1 Chikara Ohyama,3 Norio Sugawara4 1Department of Neuropsychiatry, Graduate School of Medicine, Hirosaki University, Hirosaki, 2Department of Urology, Oyokyo Kidney Research Institute, Hirosaki, 3Department of Urology, Graduate School of Medicine, Hirosaki University, Hirosaki, 4Department of Clinical Epidemiology, Translational Medical Center, National Center of Neurology and Psychiatry, Kodaira, Tokyo, Japan Objectives: Delirium signifies underlying brain dysfunction; however, its clinical significance in hemodialysis remains unclear. In this study, we sought to determine whether the occurrence of delirium during hemodialysis was associated with higher mortality.Patients and methods: This was a retrospective, 10-year cohort study. This study was performed at the urology department located within a hospital in Oyokyo, Hirosaki. We analyzed 338 of 751 patients who underwent hemodialysis. Psychiatrists diagnosed patients with delirium according to the corresponding DSM-IV-TR criteria. Cox proportional hazard regression, which was adjusted for patient age at the time of hemodialysis initiation, sex, and the presence of diabetes mellitus, was performed. Hazard ratios (HRs) and their 95% CIs were also reported.Results: In total, 286 patients without psychiatric diseases and 52 patients with delirium were evaluated. Eighty percent of patients with delirium died within 1 year of hemodialysis initiation, while only 22% of patients without delirium died within the same time period (P<0.01). Kaplan–Meier plots demonstrated the existence of associations between delirium and all-cause mortality (global log-rank P<0.001), cardiovascular disease-related mortality (global log-rank P<0.001), and infection-related mortality (global log-rank P<0.001). Moreover, Cox proportional hazard regression showed that delirium was associated with all-cause mortality (HR=1.96, 95% CI: 1.32–2.90), cardiovascular disease-related mortality (HR=2.65, 95% CI: 1.31–5.35), and infection-related mortality (HR=3.30, 95% CI: 1.34–8.10).Conclusion: Delirium is an independent predictor of death in patients undergoing hemodialysis. Keywords: delirium, hemodialysis, mortality, observational study, disturbance of consciousnes

Insomnia in patients on hemodialysis for a short versus long duration

Tetsu Tomita,1 Norio Yasui-Furukori,1 Masaki Oka,1 Takaaki Shimizu,2 Aya Nagashima,2 Kento Mitsuhashi,2 Hisao Saito,3 Kazuhiko Nakamura1 1Department of Neuropsychiatry, Graduate School of Medicine, 2School of Medicine, Hirosaki University, 3Department of Urology, Oyokyo Kidney Research Institute, Hirosaki, Japan Background: Many studies have investigated insomnia and the factors associated with this condition in hemodialysis (HD) patients, although the influence of HD duration has not been thoroughly investigated. In the present study, we investigated the factors, especially the duration of HD, associated with insomnia in HD patients.Patients and methods: A total of 138 patients undergoing HD were recruited, and the Japanese version of the Pittsburgh Sleep Quality Index (PSQI) was used to assess the quality of sleep. Subjects with a total PSQI score up to 4 and those with a score of at least 5 were identified as normal subjects and subjects with insomnia, respectively. Additionally, we assessed restless legs syndrome, depression using the Center for Epidemiologic Studies Depression Scale, and health-related quality of life (QOL) using the Short Form 8 Health Survey. We divided the subjects into two groups according to the median HD duration.Results: The prevalence rate of insomnia was 54.3% among all the subjects. Twenty-one subjects (15.2%) had depression, 26 (18.8%) had restless legs syndrome, and 75 (54.3%) had insomnia. The median HD duration was 4 years. The scores of components 1 and 4 of the PSQI, subjective sleep quality and habitual sleep efficiency, did not show a significant difference between the normal and insomnia groups. The score of component 7, daytime dysfunction, showed a significant difference between the short and long HD duration groups. In multiple regression analysis, the score of the Short Form 8 Health Survey showed a significant association with the PSQI score in the long HD duration group, but no variable showed a significant association in the short HD duration group.Conclusion: Patients with a longer duration of HD indicated that insomnia has an influence on their daily activities, with a significant association between insomnia and QOL. Greater attention should be paid to poor QOL and troubles in daily activities caused by insomnia in patients with a longer HD duration. Keywords: sleep disorders, kidney, quality of life, duration of hemodialysi