Identification of chemical constituents in vitro and in vivo of Er Shen Zhenwu Decoction by utilizing ultra-high-performance liquid chromatography with quadrupole time-of-flight mass spectrometry.

Er Shen Zhenwu Decoction is a prescription for treating chronic heart failure of heart and kidney yang deficiency, while its active ingredients remain unclear and difficult to identify. This paper aims to apply a rapid assay strategy of ultra-high-performance liquid chromatography-quadrupole time-of-flight mass spectrometry to collect the mass spectrometry data of Er Shen Zhenwu Decoction and its decomposed recipes (monarch, minister, and assist). By comparing with retention time and MSE fragmentation patterns, 67 and 34 components in vitro and in vivo were identified, respectively, the main ingredients include saponins, terpenes, alkaloids, phenolic acids, tanshinone, urea, steroids, aromatics, organic acids, carbohydrates, and so forth, of which the monarch medicine > minister medicine > assist medicine. By comparison with reference standards, paeoniflorin, rosmarinic acid, ginsenoside Rg1, ginsenoside Re, ginsenoside Rb1 and atractylenolide III were identified in vitro and paeoniflorin, ginsenoside Rg1, ginsenoside Re and ginsenoside Rb1 were identified in vivo. In this study, the chemical ingredients of Er Shen Zhenwu Decoction were analyzed by ultra-high-performance liquid chromatography-quadrupole time-of-flight mass spectrometry technology and each compound was grouped into the decomposed recipes. The identified substances can be used as references for Er Shen Zhenwu Decoction quality control and potential medicinal substances in chronic heart failure of heart and kidney yang deficiency treatment.

[Progress in pharmacodynamic basis, mechanism, and prediction of Q-markers of Zhenwu Decoction in treatment of chronic heart failure].

Zhenwu Decoction(ZWD) has a history of more than 1 800 years in traditional Chinese medicine(TCM), which is used to treat various diseases characterized by Yangqi deficiency and exuberant water and dampness. It is currently the classic prescription for the treatment of chronic heart failure(CHF). This study provides a basis for the treatment of CHF with ZWD by elaborating the traditional efficacy, theoretical basis, and underlying mechanism of the prescription. Based on the research methods and judgment basis of quality markers(Q-markers) of Chinese medicine, the Q-markers of ZWD in the treatment of CHF were predicted from the aspects of transfer and traceability, specificity, effectiveness, compatibility environment, measurability, and processing. Demethyl-coclaurine,benzoylaconine, atractylenolide Ⅲ, paeoniflorin, 6-gingerol, 8-gingerol, pachymic acid, and dehydrotumulosic acid can be used as Q-markers of ZWD for treating CHF. The result provides a reference for exploring the pharmacodynamic substances of ZWD in the treatment of CHF.

RISK OF NEW ONSET TYPE II DM IN MDD PATIENTS RECEIVING SECOND-GENERATION ANTIPSYCHOTICS TREATMENT: A NATIONWIDE COHORT STUDY.

BACKGROUND: Second-generation antipsychotics (SGA) augmentation treatment has showed better efficacy in patients with major depressive disorder (MDD). However, the association between SGA and diabetes mellitus (DM) in MDD patients deserves further investigation. The study aimed to examine the risk of new onset type II DM in MDD patients receiving SGA treatment. METHODS: From the Psychiatric Inpatient Medical Claim Dataset, MDD patients treated with SGA continuously for more than 8 weeks were analyzed in a 1:1 propensity score matched pair sample to 1,049 patients that had never been treated with SGA. Patients were followed up to 5 years based on ICD-9 CM codes indicating incident type II DM. Cumulative incidences of type II DM were calculated and the Cox proportional hazards model with competing risk was applied to determine the risk factors for type II DM onset. RESULTS: Cumulative incidences of new-onset type II DM between the two groups were similar. Use of SGA showed no significant increase in risk for new-onset type II DM (hazard ratio [HR] = 0.898; 95% confidence interval [CI], 0.605-1.334; P-value = 0.596). Increased risk for type II DM was shown to be associated with aging (per year) (HR = 1.039; 95% CI, 1.026-1.053; P-value < 0.001) and history of hyperlipidemia (HR = 2.323; 95% CI, 1.469-3.675; P-value < 0.001). CONCLUSIONS: This study indicated that there is no significant difference in the risk of developing type II DM between MDD patients with and without SGA exposure. More studies focused on the benefit-risk assessment of SGA treatment in patients with MDD are warranted.

Tentative exploration of pharmacodynamic substances: Pharmacological effects, chemical compositions, and multi-components pharmacokinetic characteristics of ESZWD in CHF-HKYd rats.

The chemical components of Xin'an famous prescription Ershen Zhenwu Decoction (ESZWD) are still unclear. The results showed that ESZWD could significantly reduce left ventricular end diastolic diameter, decrease N-terminal pro-brain natriuretic peptide (NT-proBNP), angiotensinII, aldosterone, reactive oxygen species, and malondialdehyde, increase serum superoxide dismutase, while had no significant effect on inflammatory factors. Ultra-performance liquid chromatography/quadrupole-time-of-flight mass spectrometry (UPLC/Q-TOF-MS) analysis detected 30 prototype components in model rats' serum, mainly including alkaloids, saponins, terpenoids, tanshinones, phenols. UPLC-MS/MS successfully detected the pharmacokinetic parameters of four components, and correlation analysis shows that there are negative correlations between four compounds and serum NT-proBNP. Thirty components of ESZWD may play a therapeutic role in chronic heart failure with heart-kidney Yang deficiency (CHF-HKYd) by improving myocardial injury, reducing oxidative stress levels, and inhibiting activation of the RAAS system in rats. Salsolinol, aconitine, paeoniflorin, and miltrione are equipped with potential characteristics as pharmacodynamic substances for ESZWD in treating CHF-HKYd. Additionally, the constituents of ESZWD in CHF-HKYd rats are different from normal rats, which provided a reference for the selection of subjects for further study.

Evaluation and Clinical Implication of Zhenwu Decoction on Seven Cytochrome P450 Enzyme in Chronic Heart Failure Rats.

BACKGROUND: Recently, the combination of Traditional Chinese Medicine (TCM) formulae and other drugs has been used frequently in clinical practice, while the possibility of herb-drug interaction (HDI) risk remains a challenge. Since metabolic enzymes mediate the majority of drug interactions, evaluating the effects of formulae on metabolic enzymes is therefore instructive for the rational formulation of drug delivery plans. OBJECTIVE: Herein, we are devoted to estimating the effects of Zhenwu detection (ZWD) on activities and mRNA expression of 7 cytochrome P450 (CYP450) isoenzymes in chronic heart failure (CHF) rats. METHODS: The CHF rats were replicated by coronary artery ligation and were randomly divided into sham operation group, model group, ZWD low- (2.188 g/kg), middle- (4.375 g/kg), and high- (8.750 g/kg) dose groups, n=6. After 8 weeks, rats were administrated with ZWD and normal saline (NS) for four weeks, and the mixed solution of 7 probe drugs (1 mL/kg) was subsequently injected into 30 rats through the caudal vein after the last administration. Pharmacokinetic parameters and mRNA expression of 7 probe drugs were measured by using UPLC-MS/MS and RT-qPCR, respectively. RESULTS: Activities and mRNA expression of CYP1A2, CYP2B1, CYP2C6, CYP2C11, CYP3A1 were inhibited in CHF rats, and ZWD could reverse this effect except for CYP2B1. CONCLUSION: Overall, these findings underscore that for CHF patients, the HDI should be taken into consideration when ZWD is used on its own or combined with drugs meditated by CYP1A2 (CYP1A2 in rats), CYP2C9 (CYP2C6 in rats), CYP2C19 (CYP2C11 in rats) and CYP3A4 (CYP3A1 in rats). Furthermore, since the apparent volume of distribution (Vd) of amodiaquine, dextromethorphan and bupropion has been proved to be far greater than the total volume of body fluids, we speculate that the dose adjustment and potential organotoxicity of these substrates may need further consideration.

Evaluation of Zhenwu Decoction Effects on CYP450 Enzymes in Rats Using a Cocktail Method by UPLC-MS/MS.

This thesis is aimed at shedding light on the effects of the Zhenwu decoction (ZWD) on the activities and mRNA expressions of seven CYP450 isoenzymes. In the first step, we determined the main chemical compounds of ZWD by high-performance liquid chromatography (HPLC). Next, 48 male (SD) rats were randomly divided into the normal saline (NS) group and the ZWD low- (2.1875 g/kg), medium- (4.375 g/kg), and high- (8.75 g/kg) dose groups (12 per group). All rats were gavaged once daily for 28 consecutive days. A mixed solution of seven probe drugs was injected into 24 rats through the caudal vein after the last intragastric administration. Lastly, a validated cocktail method and real-time quantitative reverse-transcription polymerase chain reaction (RT-qPCR) were used to detect pharmacokinetic parameters and mRNA expressions, respectively. Compared with the NS group, ZWD at medium- and high-dose groups could significantly induce CYP2C6 (P < 0.05) activity, while the mRNA expression (P < 0.05) increased only in the high-dose group. Additionally, CYP2C11 activity was induced and consistent with mRNA expression (P < 0.05). Moreover, ZWD could induce the activity of CYP3A1 (P < 0.05), but the mRNA expression showed no significant differences except in high-dose groups. Additionally, ZWD has no effects on CYP1A2, CYP2B1, CYP2C7, and CYP2D2. In conclusion, the significant inductive effects of ZWD on three CYP450 isoenzymes indicated that when ZWD was coadministrated with drugs mediated by these enzymes, not only should the potential herb-drug interactions (HDIs) be observed, but the dosage adjustment and tissue drug concentration should also be considered. Furthermore, the approach described in this article can be applied to study the importance of gender, age, and disease factors to HDI prediction.

Long-term Use of Clozapine is Protective for Bone Density in Patients with Schizophrenia.

Low bone mineral density (BMD) prevails among patients with schizophrenia. Antipsychotics use plays an important role in BMD. Previous cross-section study suggests that clozapine treatment may benefit BMD of women with schizophrenia. However, the effect of long-term clozapine therapy on BMD remains unknown. This prospective study compared clozapine and non-clozapine antipsychotics in long-term effects on BMD among both men and women with schizophrenia. Patients with schizophrenia and age-matched healthy individuals were enrolled from two centers. All patients, including clozapine receivers and non-clozapine antipsychotics recipients, kept clinically stable with unchanged antipsychotics and doses for at least 6 months at enrollment and during the follow-up period. BMD was examined by dual-energy X-ray absorptiometer upon enrollment and at 1- or 3-year follow-up. Thorough clinical and laboratory variables were measured too. The mean BMD of patients receiving clozapine was higher than that of the non-clozapine patients at both enrollment and follow-up. Overall, the patients in the clozapine group gained BMD, while those in the non-clozapine group lost BMD after 1-3 years (p = 0.015). There was no significant difference of BMD change between clozapine-treated patients and healthy controls. Factors associated with BMD change in the clozapine group included calcium level (B = -0.607, p = 0.021) and T3 level (B = -0.077, p = 0.007). This longitudinal study suggests that long-term clozapine treatment may protect BMD compared to prolactin-raising and non-clozapine prolactin-sparing antipsychotics among patients with schizophrenia. Future prospective studies are warranted to testify whether switching from non-clozapine antipsychotics to clozapine can rescue BMD.

Sex-specific factors for bone density in patients with schizophrenia.

Patients with schizophrenia are susceptible to low bone mineral density (BMD). Many risk factors have been suggested. However, it remains uncertain whether the risk factors differ between men and women. In addition, the study of bone density in men is neglected more often than that in women. This study aims to examine specific risk factors of low BMD in different sexes. Men (n=80) and women (n=115) with schizophrenia, similar in demographic and clinical characteristics, were enrolled in three centers. Clinical and laboratory variables (including blood levels of prolactin, sex and thyroid hormones, cortisol, calcium, and alkaline phosphatase) were collected. BMD was measured using a dual-energy X-ray absorptiometer. Men had lower BMD than women. Predictors for BMD in men included hyperprolactinemia (B=-0.821, P=0.009), body weight (B=0.024, P=0.046), and Global Assessment of Functioning score (B=0.027, P=0.043); in women, BMD was associated with menopause (B=-1.070, P<0.001), body weight (B=0.027, P=0.003), and positive symptoms (B=0.094, P<0.001). In terms of the effect of psychotic symptoms, positive symptoms were related positively to BMD in women, but not in men. The findings suggest that sex-specific risk factors should be considered for an individualized intervention of bone loss in patients with schizophrenia. Physicians should pay particular attention to bone density in men with hyperprolactinemia and postmenopausal women. Further prospective studies in other populations are warranted to confirm these findings.

Effectiveness of aripiprazole, olanzapine, quetiapine, and risperidone augmentation treatment for major depressive disorder: a nationwide population-based study.

OBJECTIVE: Previous studies suggested that antidepressants augmented with second-generation antipsychotics (SGAs), including aripiprazole, olanzapine, quetiapine, and risperidone, resulted in better treatment response or higher rates of remission in patients with major depressive disorder (MDD). However, population-based study on SGA augmentation for patients with MDD remains limited. The purpose of this study was to investigate the effectiveness of SGA augmentation for treatment of MDD using the National Health Insurance Research Database in Taiwan. METHOD: The subjects were patients with MDD (ICD-9-CM code: 296.2 and 296.3) who were initially admitted to psychiatric inpatient settings for the first time between January 1, 1996, and December 31, 2007, and could be tracked until December 31, 2011. To assess the treatment effect of SGA augmentation, 993 MDD patients who received aripiprazole, olanzapine, quetiapine, or risperidone augmentation treatment for 8 weeks or more were included in this 1-year mirror-image study. Outcome measures included length of psychiatric hospitalization and number of psychiatric admissions and emergency room (ER) visits. RESULTS: After patients received SGA augmentation treatment, key psychiatric service use (including length of psychiatric hospitalization [P < .0001], number of psychiatric admissions [P < .0001], and ER visits [P = .0006]) due to MDD diagnosis was significantly reduced. Subgrouping analysis for each SGA drug also showed significant reduction in number of psychiatric admissions for MDD patients who received aripiprazole (P < .0001), olanzapine (P = .003), quetiapine (P < .0001), and risperidone (P < .0001). CONCLUSIONS: The study provides support that aripiprazole, olanzapine, quetiapine, and risperidone augmentation therapy could be effective in reducing psychiatric service utilization among MDD patients.

A pilot study of an illness management and recovery program in discharged patients with schizophrenia.

BACKGROUND: Accumulated evidence supports the effectiveness of equipping chronically ill patients with illness management knowledge and skills. The Illness Management and Recovery (IMR) program developed by the United States government has been widely adopted for persons with mental illness. However, few studies support its effectiveness in patients with schizophrenia. PURPOSE: This pilot study developed a culturally adapted and abbreviated version of the IMR for Taiwanese patients with schizophrenia who were ready for discharge from the hospital. Furthermore, we investigated the impact of the program in terms of illness knowledge, drug attitude, insight, and psychopathology. METHODS: The original IMR was condensed and modified for implementation during participants' preparation for hospital discharge. Using a preexperimental design, pretest and posttest assessments for a single group of 26 participants received the new IMR twice a week for 3 weeks on the four outcome indicators of illness knowledge, drug attitude, insight, and psychopathology. RESULTS: Participants improved in terms of treatment-related illness knowledge, insight, and affective-domain psychopathology (p < .01) after intervention completion. Average participant attendance was 5.45 sessions out of 6 total sessions. CONCLUSIONS/IMPLICATIONS FOR PRACTICE: The intensive symptom and medication-focused IMR model for soon-to-be-discharged patients with schizophrenia had positive impacts on illness management. In the future, studies using a two-group randomized controlled design and extended follow-up should be conducted to determine the long-term effects of IMR.

A randomized controlled trial of an adapted Illness Management and Recovery program for people with schizophrenia awaiting discharge from a psychiatric hospital.

OBJECTIVE: Most research on the Illness Management and Recovery (IMR) program for people with severe mental illnesses has focused on individuals with stable symptoms living in the community, with less attention to persons being treated in an inpatient setting. We evaluated the feasibility and effects of an IMR program adapted for individuals with schizophrenia who were awaiting discharge into the community. METHOD: A randomized controlled trial was conducted at 2 hospitals in Taiwan to compare the adapted IMR program with treatment as usual (TAU). Ninety-seven individuals with schizophrenia were randomized to the adapted IMR program or TAU. Four outcome indicators including illness-management knowledge, attitudes toward medication, insight, and symptoms were assessed at baseline, posttreatment, and at a 1-month follow-up following discharge from the hospital. RESULTS: Participants in the adapted IMR group showed significantly greater improvements at posttreatment and 1-month follow-up in illness-management knowledge, attitudes toward medication, insight, and negative symptoms on the Brief Psychiatric Rating Scale (BPRS) than individuals in the TAU group. There were no significant differences between the 2 groups on other subscales of the BPRS. CONCLUSIONS AND IMPLICATIONS FOR PRACTICE: This is the first controlled evaluation of a version of the IMR program in an East Asian culture, and the first to evaluate it in an acute care inpatient setting. Our findings support the feasibility and potential benefits of implementing an adapted IMR program, focused on the prevention of relapses and rehospitalizations, during the discharge period of an inpatient treatment stay to prepare individuals to reenter the community.

Pulse analysis in bipolar disordered and nonpsychotic human subjects.

The research literature indicates that patients with bipolar disorder (BPD) differ from healthy individuals in various ways that are also recognized in traditional Chinese medicine. The purpose of the current study was to analyze the pulse spectra in BPD patients to determine any differences from nonpsychotic healthy individuals. Sphygmography was used to measure the radial arterial pulse waves in all subjects. We analyzed the original waveforms and then transformed them into frequency spectra via Fourier transformation. The relative strength of each harmonic, believed to be connected to meridians in Chinese medicine, was identified from the frequency, and we compared the differences among the harmonics. A total of sixty individuals, thirty with BPD and thirty nonpsychotic healthy controls, participated in the study. The harmonic values of C4 (Lung Meridian) on the right hand, 401.33 ± 50.10 vs. 762.44 ± 125.17, were significantly different (p < 0.05) between the BPD group and the nonpsychotic healthy group. The harmonic percentage of C3 (Spleen Meridian) on the right hand, 7.85 ± 0.59% vs. 10.79 ± 1.01%, and C4 (Lung Meridian), 1.80 ± 0.15 vs. 3.24 ± 0.43, was significantly different (p < 0.05) between the two groups. The results were similar for the right and left hands. In this study, we objectively detected constitutional differences between BPD patients and healthy controls through arterial pulse analysis. The pulse spectrum analyzer is a non-invasive diagnostic tool that can be used to integrate scientific technology with traditional Chinese medicine. We plan further study in this field to improve the accuracy of diagnosis in Chinese medicine.

The pulse spectrum analysis at three stages of pregnancy.

OBJECTIVES: This study is the first to detect the radial pulses of the three diagnosis positions (inch, bar, and cubit) in both wrists (six positions) by pulse spectrum analysis. The purpose of this study was to identify the difference among pulses of the six positions at three stages of pregnancy and to examine whether the results of this study agree with the theory of Traditional Chinese Medicine (TCM), which states that the cubit pulse shows unique changes for an expectant woman and that the pulse changes coincide with the progression of gestation. SUBJECTS AND METHODS: One hundred and fifty (150) healthy pregnant women were divided into three groups according to gestational age (9-14 weeks, 20-28 weeks, and 32-37 weeks of gestation) and 50 healthy nonpregnant women were used as controls. A pulse analyzer was used to detect the six positions of the radial pulses and to calculate the 10 relative energy values of the spectrum's harmonics of the six positions. RESULTS: Results show that most of the 10 relative spectral energy values of the right and left cubits are statistically (p<0.01) higher than those of the inch for the pregnant women as compared with the nonpregnant women. In addition, the 10 relative spectral energy values of the six positions are not identical at the three stages of pregnancy. CONCLUSIONS: The cubit pulse is unique for pregnant women, which is consistent with the theory of TCM. In addition, the pulse conditions at the three stages of pregnancy are dissimilar.

Differences in pulse spectrum analysis between atopic dermatitis and nonatopic healthy children.

OBJECTIVES: Atopic dermatitis (AD) is a common allergy that causes the skin to be dry and itchy. It appears at an early age, and is closely associated with asthma and allergic rhinitis. Thus, AD is an indicator that other allergies may occur later. Literatures indicate that the molecular basis of patients with AD is different from that of healthy individuals. According to the classics of Traditional Chinese Medicine, the body constitution of patients with AD is also different. The purpose of this study is to determine the differences in pulse spectrum analysis between patients with AD and nonatopic healthy individuals. METHODS: A total of 60 children (30 AD and 30 non-AD) were recruited for this study. A pulse spectrum analyzer (SKYLARK PDS-2000 Pulse Analysis System) was used to measure radial arterial pulse waves of subjects. Original data were then transformed to frequency spectrum by Fourier transformation. The relative strength of each harmonic wave was calculated. Moreover, the differences of harmonic values between patients with AD and non-atopic healthy individuals were compared and contrasted. RESULTS: This study showed that harmonic values and harmonic percentage of C3 (Spleen Meridian, according to Wang's hypothesis) were significantly different. CONCLUSIONS: These results demonstrate that C3 (Spleen Meridian) is a good index for the determination of atopic dermatitis. Furthermore, this study demonstrates that the pulse spectrum analyzer is a valuable auxiliary tool to distinguish a patient who has probable tendency to have AD and/or other allergic diseases.

Intraocular pressure-lowering effect of auricular acupressure in patients with glaucoma: a prospective, single-blinded, randomized controlled trial.

OBJECTIVE: The objective of the study was to evaluate the effect of auricular acupressure in controlling intraocular pressure (IOP) in patients with glaucoma. DESIGN: Thirty-three (33) patients were recruited through advertisement at the clinic for glaucoma. These patients were divided into the auricular acupressure group (16 patients, 28 glaucoma eyes) and the sham group (17 patients, 32 glaucoma eyes). Patients in the acupressure group received auricular acupoint (kidney, liver, and eye) stimulator tapping and regular massage twice a day for 4 weeks. Patients in the sham group received tapping at sham auricular acupoints (wrist, shoulder, and jaw) without massage stimulation. The IOP and visual acuity (VA) were assessed before and after the treatment in the first 4 weeks and followed up, up to 8 weeks. RESULTS: After the treatment and at the 8-week follow-up, IOP and VA improved significantly in the acupressure group when compared with pretreatment (p < 0.05). The most significant IOP-lowering effect was seen at about 3-4 weeks after auricular acupressure. IOP returned to the initial level after acupressure had been discontinued for 4 weeks. Significant improvement of the uncorrected VA (UCVA) was noted at about 2-4 weeks in the acupressure group. UCVA improvement was also noted in the sham group. The difference was only significant in week 3. Improvement of the best-corrected VA was noted in both groups, but was only significant in week 2. CONCLUSIONS: Our data suggest that auricular acupressure can be used as a complementary treatment to ameliorate IOP and VA for patients with glaucoma.