NUDT15 polymorphism influences the metabolism and therapeutic effects of acyclovir and ganciclovir.

Nucleobase and nucleoside analogs (NNA) are widely used as anti-viral and anti-cancer agents, and NNA phosphorylation is essential for the activity of this class of drugs. Recently, diphosphatase NUDT15 was linked to thiopurine metabolism with NUDT15 polymorphism associated with drug toxicity in patients. Profiling NNA drugs, we identify acyclovir (ACV) and ganciclovir (GCV) as two new NNAs metabolized by NUDT15. NUDT15 hydrolyzes ACV and GCV triphosphate metabolites, reducing their effects against cytomegalovirus (CMV) in vitro. Loss of NUDT15 potentiates cytotoxicity of ACV and GCV in host cells. In hematopoietic stem cell transplant patients, the risk of CMV viremia following ACV prophylaxis is associated with NUDT15 genotype (P = 0.015). Donor NUDT15 deficiency is linked to graft failure in patients receiving CMV-seropositive stem cells (P = 0.047). In conclusion, NUDT15 is an important metabolizing enzyme for ACV and GCV, and NUDT15 variation contributes to inter-patient variability in their therapeutic effects.

The Effect of Xinmailong Infusion on Sepsis-Induced Myocardial Dysfunction: a Pragmatic Randomized Controlled Trial.

ABSTRACT: Sepsis-induced myocardial dysfunction (SIMD) contributes significantly to cardiovascular dysfunction during septic shock. We aimed to evaluate the potential role of Xinmailong injection (XMLI), a polypeptide medicine extracted from Periplaneta americana, in reversing the progression of myocardial damage to SIMD in sepsis patients. This was a multicenter, randomized, double-blind, parallel-group trial. We recruited all patients consecutively admitted to intensive care units (ICUs) who were aged 18 to 85 years old and met the sepsis 3.0 criteria. The primary outcome measure was the incidence of sepsis-induced myocardial dysfunction while in the ICU. Of the 192 patients, 96 were assigned to the treatment group, and 96 to the control group. Subsequently, 41 patients [41/96 (42.7%)] in the XMLI group and 61 patients in the placebo group [61/96 (63.5%)] were confirmed to have diastolic dysfunction on the fifth day (D5). The incidence of diastolic SIMD was significantly different between the two groups (P = 0.004). There were 36 deaths in the two groups during the 28-day follow-up, with a general mortality rate of 18.8% (36/192). The 28-day mortality rates were not significantly different between the groups (P = 0.45). However, the brain natriuretic peptide (BNP) plasma concentration trends on D0, D2, and D5 significantly differed between the two groups (P = 0.049). In septic patients, XMLI decreased the occurrence rate of diastolic SIMD more effectively than the placebo. The improvement in serum BNP concentration was also greater in the XMLI group. XMLI may, therefore, effectively and safely improve cardiac function in patients with sepsis.

Addition of Chinese herbal remedy, Tongguan Capsules, to the standard treatment in patients with myocardial infarction improve the ventricular reperfusion and remodeling: Proteomic analysis of possible signaling pathways.

ETHNOPHARMACOLOGICAL RELEVANCE: Tongguan Capsules (TGC), a patented Chinese herbal remedy containing Salvia miltiorrhiza, Astragalus membranaceus, Borneolum syntheticum and Grasshopper, has been previously tested in the experimental model of animal hearts subjected to ischemia/reperfusion injury and its cardioprotective effect has been described. AIM OF THE STUDY: This clinical trial was aimed at investigation whether the administration of TGC to patients suffered myocardial infarction (MI), would diminish dilation of the left ventricular (LV) and reduce development of the adverse clinical consequences. METHODS: Eligible patients were enrolled and randomized 1:1 to TGC (4.5 g/d for 6 months) superimposed on standard treatment for MI, or the control group receiving the standard protocol alone. The outcomes of this trial were valued after 6 months and reported as a mean change from the baseline in LV end-systolic volume index (LVESVI) and as a frequency of MI recurrence, target-vessel revascularization, severity of heart failure or significant arrhythmia that required the additional therapy within 6 months. In addition, arrays with a panel of specific antibodies were used to assess levels of major cytokines and other pathophysiologic markers, that prompted conclusions about the mechanisms of the ultimate clinical outcomes in both patient's subgroups. RESULTS: Meaningfully, obtained results indicated that MI patients randomly assigned to the TGC treatment, demonstrated a significant reduction of LVESVI (-4.03 ± 0.73 vs. 1.59 ± 0.43 mL/m2, P < 0.001) and a lower incidence of the major adverse cardiovascular events (5.45% vs. 11.44%, P = 0.033). Meaningfully, those patients consistently demonstrated lower serum levels of major inflammatory cytokines, as well as reduced levels of markers of myocardial apoptosis and fibrosis. CONCLUSION: Addition of TGC to the current conventional treatment of MI patients, significantly reduced their adverse LV remodeling and contributed to the more positive clinical outcome. TRIAL REGISTRATION: ChiCTR-IPR-17011618.

Danqi soft capsule prevents infarct border zone remodelling and reduces susceptibility to ventricular arrhythmias in post-myocardial infarction rats.

Danqi soft capsule (DQ) is a traditional Chinese medicine containing Salvia miltiorrhiza and Panax notoginseng; it is safe and efficient in treating ischaemic heart diseases. The purpose of the present study was to assess whether DQ could prevent infarct border zone (IBZ) remodelling and decrease ventricular arrhythmias occurrence in post-myocardial infarction (MI) stage. MI was induced by a ligation of the left anterior descending coronary artery. DQ was administered to the post-MI rats started from 1 week after MI surgery for 4 weeks. The results showed that DQ treatment significantly attenuated tachyarrhythmia induction rates and arrhythmia score in post-MI rats. In echocardiography, DQ improved left ventricular (LV) systolic and diastolic function. Histological assessment revealed that DQ significantly reduced fibrotic areas and myocyte areas, and increased connexin (Cx) 43 positive areas in IBZ. Western blot revealed that DQ treatment significantly reduced the protein expression levels of type I and III collagens, α-smooth muscle actin (α-SMA), transforming growth factor-ß1 (TGF-ß1) and Smad3 phosphorylation, while increasing Cx43 amounts. Overall, these findings mainly indicated that DQ intervention regulates interstitial fibrosis, Cx43 expression and myocyte hypertrophy by TGF-ß1/Smad3 pathway in IBZ, inhibits LV remodelling and reduces vulnerability to tachyarrhythmias after MI. This study presents a proof of concept for novel antiarrhythmic strategies in preventing IBZ remodelling, modifying the healed arrhythmogenic substrate and thus reducing susceptibility to ventricular arrhythmias in the late post-MI period.

The effect of Xinkeshu tablets on depression and anxiety symptoms in patients with coronary artery disease: Results from a double-blind, randomized, placebo-controlled study.

A large proportion of patients with coronary artery disease (CAD) suffer from depression or anxiety symptoms and this is associated with increased mortality [1]. This double-blinded, randomized, placebo-controlled, clinical trial (ChiCTR-IPR-17010940) aimed to explore whether Xinkeshu tablets can reduce anxiety or depressive symptoms in CAD patients and how this is related to the concentration of plasma cytokines. Sixty patients with CAD anda Hospital Anxiety and Depression Scale (HADS-a/HADS-d) score of ≥8 were treated with Xinkeshu tablets or placebo for 12 weeks following percutaneous revascularization. Depressive/anxiety symptoms and the levels of 440 peripheral blood cytokines were evaluated at baseline and after 12 weeks treatment. Results showed significantly lower (P < 0.05) HADS-a/HADS-d and PHQ-9 scores in CAD patients treated with Xinkeshu tablets than in those who received placebo. These improvements were associated with changes in certain peripheral blood cytokines; most notably trappin-2, adiponectin, interleukin 1ß (IL-1ß), thrombopoietin, activated leukocyte cell adhesion molecule (ALCAM), neurotrophin-3 (NT-3), and transferrin. A significant correlation between anxiety/depression symptoms and trappin-2, NT-3, transferrin, and ALCAM (p < 0.05) were observed in an independent cohort of patients with CAD. These findings were in-keeping with the anti-depressive effects of Xinkeshu tablets. This trial demonstrates that Xinkeshu tablets can improve anxiety and depression symtoms effectively address in patients with coronary heart disease possibly through increasing the blood ratio of anti-inflammatory:pro-inflammatory cytokines.

Efficacy of Danlou Tablet in Patients with Non-ST Elevation Acute Coronary Syndrome Undergoing Percutaneous Coronary Intervention: Results from a Multicentre, Placebo-Controlled, Randomized Trial.

This study seeks to investigate potential cardioprotection of Danlou Tablets in patients undergoing PCI with non-ST elevation acute coronary syndrome (NSTE-ACS). 219 patients with NSTE-ACS were randomised to Danlou Tablet pretreatment (n = 109) or placebo (n = 110). No patients received statins prior to PCI and all patients were given atorvastatin (10 mg/day) after procedure. The main endpoint was the composite incidence of major adverse cardiac events (MACEs) within 30 days after PCI. The proportion of patients with elevated levels of cTn I>5 × 99% of upper reference limit was significantly lower in the Danlou Tablet group at 8 h (22.0% versus 34.5%, p = 0.04) and 24 h (23.9% versus 38.2%, p = 0.02) after PCI. The 30-day MACEs occurred in 22.0% of the Danlou Tablet group and 33.6% in the placebo group (p = 0.06). The incidence of MACE at 90-day follow-up was significantly decreased in the Danlou Tablet group compared to the placebo group (23.9% versus 37.3%, p = 0.03). The difference between the groups at 90 days was the incidence of nonfatal myocardial infarction (22% versus 34.5%, p = 0.04). These findings might support that treatment with Danlou Tablet could reduce the incidence of periprocedural myocardial infarction in patients with ACS undergoing PCI.

[A study protocol for clinical pathways based on integrative medicine for patients with acute myocardial infarction].

BACKGROUND: Acute myocardial infarction (AMI) is one of the most common cardiovascular diseases. The clinical pathway is the therapeutic program for disease-specific treatment and its implementation may reduce both the duration and cost of the hospital stay. This study aims to construct and evaluate the efficacy of clinical pathways (CPs) based on integrated traditional Chinese and Western medicine for patients with AMI. METHODS AND DESIGN: The clinical pathway of integrative medicine for AMI was constructed on the basis of syndrome evolvement surveys, literature research and expert consultation. Then, a non-randomized controlled, multicenter trial was designed to evaluate the efficacy and safety of the clinical pathway around the length of hospital stay, hospital expenses and the incidence of major cardiovascular events. This also allowed further exploration into the efficacy and safety of the clinical pathway for AMI based on traditional Chinese and Western medicine. DISCUSSION: The study firstly researched CPs based on the integrative medicine in hospitals of Chinese medicine and set up the key methods and skills for the construction of CPs of integrative medicine. This study will provide a powerful reference and direction for single-disease management reform under the healthcare system and set a good example for the improvement of integrative treatments. TRIAL REGISTRATION NUMBER: ChiCTR-TNRC-10000753.