[Effect of Moxibustion Stimulation of "Feishu" (BL 13) and "Xinshu" (BL 15) on Expression of Myocardial MyD 88 Protein and Caspase 3 mRNA in Chronic Heart Failure Rats].

OBJECTIVE: To observe the effect of moxibustion stimulation of "Feishu" (BL 13) and "Xinshu" (BL 15) on pathological changes of myocardium and the expression of myocardial myeloid differentiation factor 88 (MyD 88) protein and Caspase 3 mRNA in chronic heart failure (CHF) rats, so as to explore its mechanism underlying improvement of CHF. METHODS: SD male rats were randomly divided into normal (n=9), model (n=8), moxibustion (n=8), medication (n=8) and moxibustion + medication (n=8) groups. In addition, the other 6 rats (3/normal and 3/model groups) were used for measuring cardiac ventricle weight and H.E. stain. The CHF model was made by intraperitoneal injection of Adriamycin (ADR, from 1 to 4 mg/kg, once every other day for 15 days). Mild moxibustion was applied to bilateral BL13 and BL15 for 15 min, once daily for 3 weeks. Rats of the medication group were treated by Captopril (gavage) for 3 weeks. The expression of myocardial Caspase 3 mRNA and MyD 88 protein of the left ventricle was determined by quantitative real time-PCR and Western blot, respectively. RESULTS: In comparison with the normal group, the myocardial damage (cell swelling, cytoplasma vaculation, and disordered arrangement, rupture and lysis of some cardiac muscle fibers), and the expression levels of myocardial MyD 88 protein and Caspase 3 mRNA were obviously increased in the model group(P<0.01). After the interventions, the myocardial damage was relatively milder, and the expression of myocardial MyD 88 protein and Caspase 3 mRNA were significantly down-regulated in the moxibustion, me-dication and moxibustion+medication groups in comparison with the model group(P<0.05). No significant differences were found among the 3 treatment groups in the expression levels of MyD 88 protein and Caspase 3 mRNA(P>0.05). CONCLUSIONS: Moxibustion intervention can suppress CHF induced up-regulation of expression of myocardial MyD 88 protein and Caspase 3 mRNA in rats, which may contribute to its effect in relieving myocardial injury.

Pharmacodynamic and pharmacokinetic study of pegylated liposomal doxorubicin combination (CCOP) chemotherapy in patients with peripheral T-cell lymphomas.

AIM: To investigate the pharmacodynamic and pharmacokinetic parameters of pegylated liposomal doxorubicin (PLD) combined with cyclophosphamide, vincristine, and prednisolone in patients with peripheral T-cell lymphomas (PTCL). METHODS: Seven chemonaive patients and four patients with relapsed peripheral T-cell lymphomas were treated with a CCOP regimen consisting of an intravenous administration of cyclophosphamide (750 mg/m(2)), vincristine (1.4 mg/m(2)), and PLD (30 mg/m(2)) on d 1, as well as an oral administration of prednisolone (60 mg/m(2)) on d 1-5. This regimen was repeated every 3 weeks for six cycles, and the clinical response and toxicity of the regimen were monitored. In addition, the plasma concentration of PLD at different time points was determined before and after treatment. The pharmacokinetics (PKs) software was used to estimate the pharmacokinetic parameters of PLD. RESULTS: The 11 PTCL patients received 35 treatment cycles. Three of them achieved complete response (CR), two partial response (PR), four stable disease (SD), and two progressive disease (PD). The overall response rate (ORR) was 45.5%, and the CR rate was 27.3%. In the 7 chemonaive patients, three achieved CR, two PR, one SD, and one PD. The ORR was 71.4%, and CR rate was 42.9%. The median follow-up time was 15 months, but 6 out of 11 patients were dead at the time of data analysis. The 1-year overall survival rate was 45.5%, and the median progression-free survival (PFS) rate was 6.5 [95% confidence interval (95% CI) 3.17-19.02] with a survival rate of 11.5 months (95% CI 6.65-16.36). The main toxicity was myelosuppression. Oral mucositis and hand-foot syndrome seldom occurred. The PLD plasma concentration from nine patients ranged from 1.7036 to 9.2207 mg·L(-1) after administration of the CCOP regimen (0-168 h). The pharmacokinetic parameters AUC(0-∞), CL, t(1/2), and V(d) were 910.76 mg/L·h, 0.043 L·h(-1)·m(-2), 68.40 h, and 3.56 L/m(2), respectively. CONCLUSION: The CCOP regimen was effective and well tolerated in patients with peripheral T-cell lymphomas. The results of the pharmacokinetic parameters showed that PLD had long retention time in blood circulation.

Phase II trial of gemcitabine plus cisplatin in patients with advanced non-small cell lung cancer.

AIM: To investigate the pharmacodynamics and pharmacokinetics of gemcitabine (dFdC) administered on d 1 and 5 plus cisplatin administered on d 1 in chemonaive patients with stage IIIB or IV non-small cell lung cancer (NSCLC). METHODS: In each combination cycle, gemcitabine was administered at a dose of 1250 mg/m(2) as a 30 min intravenous (iv) infusion on d 1 and 5 followed by cisplatin at a dose of 75 mg/m(2) as a 3 h iv infusion on d 1 every 3 weeks. There was an interval of 1 h between the two infusions. Clinical response and toxicity of the regimen were observed. Furthermore, the plasma concentrations of gemcitabine (dFdC) and its metabolite (dFdU) at different time points were detected during the first cycle of infusion. Pharmacokinetic software (PKS) was used to estimate the pharmacokinetic parameters of gemcitabine and its metabolite dFdU. RESULTS: A total of 28 patients was enrolled in the study. The median age was 54 years (range 27-75 years), and most patients were in good clinical condition. Twenty-seven patients received two or more treatment cycles. The overall clinical response rate was 33.3%. The median overall survival time was 13 months. The estimated median time to tumor progression (TTP) was 6.2 months, and the 1-year survival rate was 55.6%. Toxicities were tolerated. The main toxicity was myelosuppression; 35.7% of patients had grade 3/4 hematologic toxicities and 28.6% had grade 3/4 non-hematologic toxicities, which were commonly gastrointestinal responses. The pharmacokinetic parameters of dFdC and dFdU were not different between pre- and post-administration of gemcitabine on d 1 and 5. dFdU was minimal (0.729+/-0.637 microg/mL) before gemcitabine was infused on d 5, and gemcitabine was not present. CONCLUSION: The regimen is active and well tolerated in chemonaive patients with advanced NSCLC. After gemcitabine was administered on d 1 and 5, the pharmacokinetic parameters of dFdC and dFdU showed no difference from those before the infusion, and dFdU was minimal before gemcitabine was administered on d 5.

[Effects of fasudil on the expression of Rho kinase-1 and airway inflammation in a mouse model of asthma.].

OBJECTIVE: To explore the role of Rho kinase-1 (ROCK-1) in airway inflammation of asthma by observing the effects of fasudil, a specific inhibitor of ROCK-1, on the expression of Rho kinase-1 and airway inflammation in a mouse model of asthma. METHODS: Twenty-four female BALB/c mice were randomly divided into 3 groups (n = 8 each): a control group, an asthmatic group and a treatment group. Mice in the asthmatic and the treatment groups were sensitized by intraperitoneal injection of OVA (25 microg) precipitated with 1 mg of alum in 200 microl of saline on days 1 and 15, and subsequently challenged by nebulization of 2% OVA on days 22-26. Mice in the control group were sensitized with Al(OH)3 saline and challenged with saline instead of OVA. Mice of the treatment group were injected intraperitoneally with fasudil (10 mg/kg) 1 h before each OVA challenge. All the mice were killed 24 h after the final challenge, and bronchoalveolar lavage fluid (BALF) was collected for counting total inflammatory cells and eosinophils (EOS). Cytokines and chemokines in BALF were measured by ELISA. The lung tissue slides were examined histologically. The protein and mRNA expression of ROCK-1 were measured by immunohistochemistry and RT-PCR respectively. RESULTS: (1) OVA challenge in mice of the asthmatic group caused a marked increase in the number of the total cells and eosinophils in BALF (q = 25.909, 35.002, respectively, all P < 0.01). When fasudil was applied, both the total cell counts and the eosinophil numbers were significantly decreased. The total cell number was decreased from (1.45 +/- 0.12) x 10(9)/L to (0.89 +/- 0.09) x 10(9)/L (q = 16.676, P < 0.01), and the number of eosinophils was decreased from (0.52 +/- 0.06) x 10(9)/L to (0.20 +/- 0.04) x 10(9)/L (q = 21.537, P < 0.01). (2) Compared with the control group, OVA challenge in mice of the asthmatic group induced eotaxin, IL-5 and IL-13 release into BALF (q = 18.246, 23.009, 25.826, respectively, all P < 0.01). The eotaxin, IL-5 and IL-13 levels in BALF after OVA challenge were (45 +/- 8) ng/L, (157 +/- 23) ng/L and (429 +/- 46) ng/L, respectively. Application of fasudil resulted in inhibition of the augmented levels of eotaxin, IL-5 and IL-13 in BALF, decreased to (20 +/- 5) ng/L, (57 +/- 14) ng/L and (254 +/- 28) ng/L, respectively (q = 13.119, 17.503, 8.449, respectively, all P < 0.01). (3) Mice in the control group showed no detectable inflammatory response in the lung, whereas OVA-challenged mice induced infiltration of inflammatory cells around airways and blood vessels. The majority of the infiltrated inflammatory cells were eosinophils. Application of fasudil significantly reduced the infiltration of inflammatory cells in the peribronchial areas compared with the asthmatic mice. (4) The expression levels of ROCK-1 mRNA and protein in mice of the asthmatic group (0.67 +/- 0.05 and 1.09 +/- 0.06) were much higher than those of the control group (0.26 +/- 0.05 and 0.87 +/- 0.09) (q = 25.614, 8.156, all P < 0.01). When fasudil was administered, the expression levels of ROCK-1 mRNA and protein were significantly attenuated to 0.35 +/- 0.04 and 0.98 +/- 0.08, compared with those of the asthmatic group (q = 20.379, 4.135, all P < 0.01). (5) The expression level of ROCK-1 mRNA was positively correlated with the number of eosinophils and the levels of eotaxin, IL-5 and IL-13 in BALF (r = 0.709, 0.600, 0.613, 0.650, all P < 0.01). CONCLUSION: Airway inflammation of bronchial asthma was improved by inhibiting expression and activity of ROCK-1 by fasudil, suggesting that ROCK-1 may be involved in asthmatic airway inflammation induced by OVA challenge.