Font Size: a A A

New Drug Sgl-2 Treatment Of Viral Myocarditis Pharmacological Mechanisms And Treatment Of Heart Failure The Role Of New Drugs Sgl-3 Study

Posted on:2008-09-07Degree:DoctorType:Dissertation
Country:ChinaCandidate:X D SongFull Text:PDF
GTID:1114360218956011Subject:Genetics
Abstract/Summary:PDF Full Text Request
Part 1:SGL-2Background:Viral myocarditis is an important human disease that affects about 5% to 20% of the population. Coxsackieviruses B3 (CVB3) is one of the major cause for viral myocarditis. So far, not many effective treatments are available for the disease. The main components of SGL-2 have been traditionally used to control common cold and other virus-induced disorders in China. Thus, the aim of this study was to investigate the antiviral effects of SGL-2 on CVB3 in vivo and in vitro.Methods and Results:The effect of SGL-2 in vitro was evaluated in HeLa cells or in cultured rat neonatal cardiac myocytes infected by CVB3, Ribavirin was chosen as positive control. Our results showed that SGL-2 possesses potent antiviral effects on CVB3 in vitro by XTT and plaque forming assay (IC50 was 7.16±0.8 and 2.63±0.5μg/ml, respectively). CC50 was 16-fold higher in SGL-2 treated cells than in Ribavirin treated cells (SGL-2:1648±219μg/ml vs. Ribavirin: 103±14μg/ml). Time course studies demonstrated that antiviral effect of SGL-2 was mainly found during 0-4 h of the infection. We further explored the mechanism of SGL-2 in CVB3 and found that SGL-2 effectively blocked the attachment and penetration of CVB3 into cells. To confirm the antiviral effect of SGL-2 in vivo, 4- week- old male Balb/C mice (n=125) were used and inoculated intraperitoneally with 0.1 ml of CVB3 suspension (10 PFU) or saline as control (n=25). At 48h postinoculation, the infected mice were administered intragastrically with SGL-2 either 200 mg.kg-1.d-1, 600 mg.kg-1.d-1 or 1800 mg.kg-1.d-1, with Ribavirin (90 mg.kg-1.d-1, PO) as positive control and saline as sham treatment group (n=25 in each above group). After 28 days, SGL-2 treatment increased the survival rate from 16% (vehicle) to 64% (SGL-2:1800 mg.kg-1.d-1) by the Kaplan-Meier method. In addition, SGL-2 protected the cardiac pathological changes induced by CVB3, and decreased myocardial virus titer significantly (vehicle: 3.6±1.7 vs. SGL-2: 1.9±0.9,p<0.05).Conclusions:The results showed that SGL-2 is a very promising potent antiviral agent with a highly significant effect on survival and pathological changes in CVB3-induced myocarditis.Part 2:SGL-3Background:With significant improvements in the treatment of congestive heart failure (CHF), the morbidity and mortality of patients with CHF remain unacceptably high. The main component of SGL-3 has been traditionally used to treat heart failure symptoms for thousand years in China, thus, we proposed that SGL-3 may inhibit myocardial hypertrophy and prevent heart failure.Methods and results:To investigate effect of SGL-3 on myocardial remodeling and cardiac function, we established models of cardiac hypertrophy in vivo and in vitro. In cultured rat neonatal cardiac myocytes, SGL-3 inhibited cardiac myocyte hypertrophy (10μg/ml) which was induced by angiotensin-Ⅱ(1μtmol/L), reduced [3H] leucine incorporation by 74%±26% and cell surface area by 104%±31%. In vivo, twenty- week- old male Wistar rats were used and subjected to suprarenal abdominal aorta constriction (AAC) operation (n=48) or sham operation (n=12). Twenty weeks after surgery, heart failure was detected in AAC rats by using echocardiography, then the AAC rats were treated with either SGL-3 (150 mg.kg-1.d-1, 500 mg.kg-1.d-1 and 1500 mg.kg-1.d-1, PO, n=12 in each group) or Captopril (270 mg.kg-1.d-1, PO) plus Metoprolol (1,800 mg.kg-1.d-1, PO) (n=12) for 18 weeks respectively. Cardiac hemodynamic and morphological parameters were obtained by using multi-functional physiology recorder and echocardiography. The result revealed that SGL-3 can improve cardiac systolic function more effectively (EF: 51.8%±8.42% for AAC group, 75.6%±7.65% for sham operation group, 69.3%±7.73% for SGL-3 treated group) than Captopril plus Metoprolol (EF: 56.3%±8.41%). Histological examination of cardiac structure showed that the extent of cardiac myocyte hypertrophy was restrained and myocardial fibrosis, circulating renin-aldosterone system and ANP were inhibited in AAC rats treated with SGL-3, compared with vehicle (p<0.05).Conclusion:These fmdings indicated that XL attenuates cardiac myocyte hypertrophy both in vitro and in vivo and halts the process from hypertrophy to heart failure.
Keywords/Search Tags:Cardiovascular, Viral Myocarditis, Cardiac Remodeling, Heart Failure, Pharmacology
PDF Full Text Request
Related items