Characteristics of the anti-dementia drug system of Zisu Fang preparations based on pharmacokinetic and pharmacodynamic analysis

Objectives:To investigate the pharmacokinetics (PK) and pharmacodynamics (PD)of index components of Zisu Fang preparations and additionally analysis the anti-dementia drug system characteristics.Methods:A PK-PD-drug interaction (DI) method was applied to determine the characteristics of index components of Zisu Fong preparations in vivo.Results:In the PK study,maximum plasma concentration,area under the plasma concentration-time curve,and mean residence time of index components of Zisu Fang preparations were higher in the memory-deficit model group than in the control group.This suggested that the index components of Zisu Fang preparations had an affinity for the state of dementia in this model.In the PD study,at the peak time points of anti-dementia efficacy (0.17 h and 1 h),the plasma concentrations of index components of Zisu Fang preparations reached the first or second largest plasma concentration peak or were close to the plasma concentration peak,and showed positive correlation between these two peaks,indicating that the index components of Zisu Fang synergistically exerted an anti-dementia effect.According to the association analysis of PK-PD-DI,baicalin,rosmarinic acid,salvianolic acid B,matrine,and tanshinone ⅡA were the main active ingredients of the anti-dementia drug system of Zisu Fang preparations in vivo,but were only efficacious against dementia when all five components were present at a specific concentration and proportion.Conclusions:Based on the PK and PD correlation analysis,baicalin,rosmarinic acid,salvianolic acid B,matrine,and tanshinone ⅡA are the main active ingredients of Zisu Fang preparations with regard to its anti-dementia effects,and represent the basic characteristics of drug system:natures,synergy,and affinity.

Ultrasound deep brain stimulation decelerates telomere shortening in Alzheimer’s disease and aging mice

Telomere length is a reliable biomarker for health and longevity prediction in both humans and animals.The common neuromodulation techniques,including deep brain stimulation(DBS)and optogenetics,have excellent spatial resolution and depth penetration but require implementation of electrodes or optical fibers.Therefore,it is important to develop methods for noninvasive modulation of telomere length.Herein,we reported on a new method for decelerating telomere shortening using noninvasive ultrasound deep brain stimulation(UDBS).Firstly,we found that UDBS could activate the telomerase-associated proteins in normal mice.Then,in the Alzheimer’s disease mice,UDBS was observed to decelerate telomere shortening of the cortex and myocardial tissue and to effectively improve spatial learning and memory abilities.Similarly,UDBS was found to significantly slow down telomere shortening of the cortex and peripheral blood,and improve motor and cognitive functions in aging mice.Finally,transcriptome analysis revealed that UDBS upregulated the neuroactive ligand-receptor interaction pathway.Overall,the present findings established the critical role of UDBS in delaying telomere shortening and indicated that ultrasound modulation of telomere length may constitute an effective therapeutic strategy for aging and aging-related diseases.

Postmarketing safety evaluation: depside salt injection made from Danshen(Radix Salviae Miltiorrhizae)

OBJECTIVE: To systematically examine the postmarketing safety of depside salt injection made from Danshen(Radix Salviae Miltiorrhizae),identifythe potential risk factors, and ensure its clinical safety.METHODS: We examined a comprehensive series of studies on the production process, quality standards, pharmacology, population pharmacokinetics, and safety evaluation of depside salt injection made from Danshen(Radix Salviae Miltiorrhizae). Data from Ⅰ-Ⅳ clinical drug trials, hospital information systems(HIS), and spontaneous reporting systems(SRS) were also analyzed.RESULTS: The effective components of salvianolic acid salt content reached almost 100%, and the magnesium lithospermate B content reached morethan 80%. The median lethal dose(LD50) calculated by the Bliss method was 1.49 g/kg, with 95%confidence intervals of 1.29-1.72 g/kg. Long-term tests on Beagle dogs indicated that doses of less than 80 mg/kg were safe and doses of 320 mg/kg were toxic. Adverse drug reactions(ADRs) included digestive disorders; drug-induced erythrocyte deformation in lung, liver, spleen, kidney, bone marrow, intestinal mucosa, lymph nodes, and other tissues; megakaryocytes in lung, liver, and spleen resulting from mild hemolysis; and mild hyperplasia in bone marrow hematopoietic tissue. Other studies indicated no irritative effect of the injection on local tissues and blood vessels, and no allergic reactions, erythrocyte coagulation, or hemolysis. SRS data showed that the most common ADRs were headache, head distention, dizziness, facial flushing, skin itching, thrombocytopenia, and the reversibility of elevated Aspartate transaminase. HIS data indicated no damage to renal function from using depside salt injection made from Danshen(Radix Salviae Miltiorrhizae) at a dosage higher than the recommended dose.CONCLUSION: This study analyzes the clinical characteristics of ADRs from depside salt injection made from Danshen(Radix Salviae Miltiorrhizae),and discusses the factors influencing such reactions. It provides scientific reference and recommendations for clinically safe medication of the Danshen injection.

Protective Effects of Salvianolate on Myocardial Injury or MyocardiaMnfarction after Elective Percutaneous Coronary Intervention in NSTE-ACS Patients:A Randomized Placebo-Controlled Trial

Objective:To evaluate the protective effects of salvianolate on percutaneous coronary intervention(PCI)related myocardial injury or myocardial infarction after elective PCI in non-ST-segment elevation acute coronary syndrome(NSTE-ACS)patients.Methods:A total of 149 patients with NSTE-ACS who underwent elective PCI were enrolled.The patients were randomly allocated in a 1:1 ratio to the salvianolate group(74 cases)or the control group(75 cases).After exclusion criteria of coronary angiography,60 patients with PCI therapy remained in the salvianolate group and 68 in the control group.The incidence and the severity of PCI related myocardial injury or myocardial infarction,in addition to major adverse cardiac events(MACEs)during 1 year follow-up after PCI were studied between the two groups.Multivariate logistic regression analysis was used to determine the independent factors for PCI related myocardial injury or myocardial infarction after elective PCI.Results:Compared with the control group,salvianolate treatment reduced the incidence of PCI related severe myocardial injury or myocardial infarction(11.7%vs.26.5%,P=0.035).The rate of MACEs or all-cause death within 1 month or 1 year after the procedure was not significantly different between the two groups.Conclusions:Periprocedural treatment with salvianolate reduces the incidence of PCI related severe myocardial injury or myocardial infarction,although it does not influence clinical prognosis.

A Prospective Randomized Multicenter Controlled Trial on Salvianolate for Treatment of Unstable Angina Pectoris in A Chinese Elderly Population

Objective: To evaluate the efficacy and safety of salvianolate in elderly patients with unstable angina pectoris(UAP). Methods: A prospective double-blind randomized placebo-controlled multicenter trial in elderly patients with UAP from 13 third-grade class-A hospitals in China was performed. A total of 318 patients were randomly allocated in a 1:1 ratio to an experimental group(160 patients) and a control group(158 patients). The experimental group was treated with salvianolate for 14 days on the basis of conventional medicine, and the control group was given a placebo for 14 days with the same criteria. Follow-up was lasted 28 days in both groups. The primary endpoint was biweekly frequency of angina pectoris attacks. The secondary endpoints included biweekly dosage of nitroglycerin, the Seattle Angina Questionnaire, angina pectoris severity and duration, myocardial injury markers, high-sensitivity C-reactive protein(hs-CRP) and N-terminal pro-B-type natriuretic peptide(NT-proBNP), as well as major adverse cardiovascular events(MACEs). Safety was assessed according to adverse events and serious adverse events. Results: Baseline characteristics were similar between treatment groups. Compared with those in the control group, the frequency of biweekly angi na attacks(2.92 vs. 4.08, P =0.025), th e biweekly dosage of nitroglycerin, as well as the severity and duration of angina attacks(P <0.01) were reduced by salvianolate. The Seattle Angina Questionnaire score was also significantly improved in the experimental group than in the control group(P <0.05). No significant differences were observed between the two groups with respect to the incidence of MACEs. Salvianolate was well tolerated. Conclusions: Salvianolate appear to have efficacy and well tolerated for elderly patients with UAP.