Abstract 15241: Proteinase-activated Receptor 1 Antagonist Inhibited the Progression of Monocrotaline Induced Pulmonary Hypertension in Rats

Circulation ◽  
2015 ◽  
Vol 132 (suppl_3) ◽  
Author(s):  
Yukimitsu Kuwabara ◽  
Kohtaro Abe ◽  
Mayumi Hirano ◽  
Yoshitaka Hirooka ◽  
Kenji Sunagawa ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Pulmonary Hypertension ◽  
Survival Time ◽  
Median Survival ◽  
Median Survival Time ◽  
Systolic Pressure ◽  
Treatment Protocol ◽  
Systemic Blood Pressure ◽  
Therapeutic Effects ◽  
Systemic Blood

Introduction: Pulmonary hypertension (PH) is characterized by thrombus formation, vasoconstriction and vascular remodeling. The normal pulmonary artery, in contrast to the systemic artery, has a unique property to contract in response to thrombin via thrombin receptor Proteinase-activated receptor 1 (PAR1). Hypothesis: We hypothesized that PAR1 plays a key role in the pathogenesis and pathophysiology in PH and examined the therapeutic effects of PAR1 antagonist on PH. Methods and Results: Adult male SD rats developed PH after a single subcutaneous injection of 60 mg/kg monocrotaline (MCT) on day 0. The indexes of pulmonary vascular resistance (PVR: RV systolic pressure/cardiac output) and RV hypertrophy (RVH: RV/LV+septum) increased from 0.33±0.03 (normal, n=5) to 1.3±0.1 mmHg•min/mL (MCT, n=10, p<0.01) and from 0.28±0.01 (n=6) to 0.49±0.02 (n=15, p<0.01), respectively, on day 21. We administered PAR1 antagonist (atopaxar: 30mg/kg/day, p.o.) on day 0 (preventive protocol) or day 14 (treatment protocol) of MCT injection. In comparison with MCT rats, the preventive and treatment protocols significantly reduced PVR (0.68±0.09 and 0.89±0.11 mmHg•min/mL, n=8 and 10, p<0.01 and p<0.05) and RVH (0.37±0.02 and 0.40±0.03, n=10 and 12, p<0.01 and p<0.05). Atopaxar had no effect on systemic blood pressure. In the isolated perfused lung preparations, a bolus infusion of 300 nmol PAR1-activating peptide elevated pulmonary arterial pressure by 0.33±0.08 mmHg in the normal (n=6) and 11.8±2.4 mmHg in MCT (n=9; p<0.01 vs. normal), while attenuated in the preventive protocol (1.99±0.96 mmHg, n=6). Atopaxar significantly prolonged the survival periods of MCT rat (median survival time: 26 days, n=17) in both preventive (median survival time: more than 56 days, n=14, p<0.01) and treatment (median survival time: 30 days, n=17, p<0.05) protocols. Conclusion: The PAR1 activity increased in MCT rats. Inhibiting the increased activity of PAR1 was effective in preventing the progression of PH without decreasing systemic blood pressure. PAR1 is thus a potentially novel therapeutic target for the treatment of PH.

scholarly journals CTNI-30. THERAPEUTIC EFFECTS OF RADIOTHERAPY WITH CONCOMITANT AND ADJUVANT TEMOZOLOMIDE VERSUS RADIOTHERAPY WITH CONCOMITANT TEMOZOLOMIDE ALONE IN CHILDREN WITH DIPG: A SINGLE-CENTER EXPERIENCE WITH 82 CASES

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii49-ii49
Author(s):  
Mingyao Lai ◽  
Juan Li ◽  
Qingjun Hu ◽  
Jiangfen Zhou ◽  
Shaoqun Li ◽  
...  
Keyword(s):  
Survival Time ◽  
Median Survival ◽  
Median Survival Time ◽  
Disease Recurrence ◽  
Diffuse Intrinsic Pontine Glioma ◽  
Hematological Toxicity ◽  
Therapeutic Effects ◽  
Single Center Experience ◽  
Adjuvant Temozolomide ◽  
Temozolomide Chemotherapy

Abstract OBJECTIVE To retrospectively analyze the therapeutic effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy with concomitant temozolomide alone for pediatric diffuse intrinsic pontine glioma (DIPG), and to evaluate the value of temozolomide in the treatment of pediatric DIPG. METHODS The clinical data of children with confirmed DIPG in Guangdong Sanjiu Brain Hospital between January 1, 2010 and December 30, 2019 were collected. The inclusive criteria included (1) receiving a total radiotherapy dose of 54 Gy in 27 fractions, (2) treated with concomitant temozolomide chemotherapy, and (3) with or without adjuvant temozolomide chemotherapy. RESULTS A total of 82 pediatric patients were eligible for the study, with a median age of 7 years (range 2–16 years). The median follow-up was 8.6 months (range 2–28 months) and the median survival time was 9.4 months. The median survival time of 66 patients treated with radiotherapy with concomitant and adjuvant temozolomide was 9.8 months, longer than 7.5 months of the other 16 patients treated with radiotherapy with concomitant temozolomide alone, with statistical differences (P=0.010). Moreover, bevacizumab and nimotuzumab didn’t bring survival benefits to patients with disease recurrence or progression. Hematological toxicity (Grade IV) was not found. CONCLUSION Radiotherapy with concomitant and adjuvant temozolomide prolongs the survival time of children with DIPG.

Prevalence of Pulmonary Hypertension and Renal Dysfunction by Systemic Blood Pressure Categories in Sickle Cell Disease.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 3169-3169 ◽  
Author(s):  
Victor R. Gordeuk ◽  
Mark T. Gladwin ◽  
Gregory Kato ◽  
Oswaldo Castro
Keyword(s):  
Blood Pressure ◽  
Pulmonary Hypertension ◽  
Renal Dysfunction ◽  
Sickle Cell ◽  
Systemic Blood Pressure ◽  
Systemic Hypertension ◽  
Cell Disease ◽  
Systemic Blood ◽  
Creatinine Concentration ◽  
Increased Risk

Abstract In an emerging paradigm of sickle cell disease (SCD) vasculopathy, the risk for pulmonary and systemic hypertension, renal dysfunction, proteinuria, stroke and early death may be related to the degree of hemolysis, nitric oxide scavenging and resultant damage to the vasculature (JAMA2005;293:1653). The systemic blood pressure (BP) in sickle cell anemia (SS) is lower than in normal subjects. Yet, the concept of relative systemic hypertension has been proposed because SS pts. Have higher BP than subjects with other forms of congenital anemias (Am J Med Sci 1993). Furthermore, apparently minor BP increases in SS are associated with stroke risk (Am J Med Sci1993;305:150, Am J Med1997;102:171). We hypothesized that in contrast to otherwise healthy individuals without SCD, systolic blood pressures (sBP) of 120 to 139 mm Hg define relative hypertension in SCD and identify patients at increased risk for vasculopathy and its complications. We analyzed entry data from 195 adult patients enrolled in the prospective Sickle Cell Pulmonary Hypertension Screening Study (NEJM2004;350:886), and stratified their ECHO-determined tricuspid regurgitant jet velocity (TRV) and serum creatinine concentration according to sBP categories. As shown in Figure 1, among Hb SS and S beta thal patients, the prevalence of pulmonary hypertension (PHTN, TRV 2.5 m/sec or greater) was 26% with sBP &lt;120 mm Hg, 36% with sBP 120–139 mm Hg and 89% with sBP 140 mm Hg or higher (P &lt;0.0005 for trend). Similarly, the prevalence of a serum creatinine concentration of 1.0 mg/dL or higher was 7% with sBP &lt;120 mm Hg, 13% with sBP 120–139 mm Hg and 30% with sBP 140 mm Hg or higher (P = 0.002 for trend, Figure 2). The increasing prevalences of PHTN and renal dysfunction with the three progressively higher sBP categories are consistent with our hypothesis that sBP 120–139 represents relative hypertension and increased risk for vascular complications in patients with SCD. Whether treatment of relative hypertension in sickle patients would improve vasculopathy and lower their risk for PHTN, renal impairment or other complications such as stroke, is unknown. Consideration should be given to clinical trials to answer this important question. Figure Figure Figure Figure

RBIO-02. THERAPEUTIC EFFECTS OF RADIOTHERAPY WITH CONCOMITANT IN CHILDREN WITH DIPG

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi191-vi192
Author(s):  
Mingyao Lai ◽  
Shaoqun Li ◽  
Juan Li ◽  
Qingjun Hu ◽  
Junjie Zhen ◽  
...  
Keyword(s):  
Survival Time ◽  
Median Survival ◽  
Median Survival Time ◽  
Proportional Hazards ◽  
Disease Recurrence ◽  
Diffuse Intrinsic Pontine Glioma ◽  
Cox Proportional Hazards ◽  
Hematological Toxicity ◽  
Therapeutic Effects ◽  
Kaplan Meier

Abstract OBJECTIVE To retrospectively analyze the therapeutic effects of radiotherapy with concomitant and adjuvant temozolomide（TMZ） versus radiotherapy with concomitant TMZ alone for pediatric diffuse intrinsic pontine glioma (DIPG), and to evaluate the value of radiotherapy and TMZ in the treatment of pediatric DIPG. METHODS The clinical data of children with confirmed DIPG in Guangdong Sanjiu Brain Hospital between January 1, 2010 and March 31, 2020 were collected. The inclusive criteria included (1) receiving a total radiotherapy dose of 54 Gy in 27 fractions, (2) treated with concomitant TMZ chemotherapy, and (3) with or without adjuvant TMZ chemotherapy. A total of 85 pediatric patients were eligible for the study. The Kaplan-Meier method was used for survival analysis, and a multivariable Cox proportional hazards regression model was used to assess the independent prognostic factors. RESULTS Among 85 cases with a median age of 7 years (range 2-16 years), the median follow-up was 9 months (range 3-28 months) and the median survival time was 9 months. The median survival time of 66 patients treated with radiotherapy with concomitant and adjuvant TMZ was 10 months, longer than 6 months of the other 19 patients treated with radiotherapy with concomitant TMZ alone, with statistical differences (p=0.002). Moreover, bevacizumab and nimotuzumab didn't bring survival benefits to patients with disease recurrence or progression. The prognosis in DIPG patients with H3K27M positive expressed is poor. Hematological toxicity (Grade IV) was not found. CONCLUSION Radiotherapy with concomitant and adjuvant TMZ prolongs the survival time of children with DIPG.

scholarly journals DIPG-26. THERAPEUTIC EFFECTS OF RADIOTHERAPY WITH CONCOMITANT AND ADJUVANT TEMOZOLOMIDE VERSUS RADIOTHERAPY WITH CONCOMITANT TEMOZOLOMIDE ALONE IN CHILDREN WITH DIPG: A SINGLE-CENTER EXPERIENCE WITH 82 CASES

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii292-iii292
Author(s):  
Mingyao Lai ◽  
Juan Li ◽  
Qingjun Hu ◽  
Jiangfen Zhou ◽  
Shaoqun Li ◽  
...  
Keyword(s):  
Survival Time ◽  
Median Survival ◽  
Median Survival Time ◽  
Disease Recurrence ◽  
Diffuse Intrinsic Pontine Glioma ◽  
Hematological Toxicity ◽  
Therapeutic Effects ◽  
Single Center Experience ◽  
Adjuvant Temozolomide ◽  
Temozolomide Chemotherapy

Abstract OBJECTIVE To retrospectively analyze the therapeutic effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy with concomitant temozolomide alone for pediatric diffuse intrinsic pontine glioma (DIPG), and to evaluate the value of temozolomide in the treatment of pediatric DIPG. METHODS The clinical data of children with confirmed DIPG in Guangdong Sanjiu Brain Hospital between January 1, 2010 and December 30, 2019 were collected. The inclusive criteria included (1) receiving a total radiotherapy dose of 54 Gy in 27 fractions, (2) treated with concomitant temozolomide chemotherapy, and (3) with or without adjuvant temozolomide chemotherapy. RESULTS A total of 82 pediatric patients were eligible for the study, with a median age of 7 years (range 2–16 years). The median follow-up was 8.6 months (range 2–28 months) and the median survival time was 9.4 months. The median survival time of 66 patients treated with radiotherapy with concomitant and adjuvant temozolomide was 9.8 months, longer than 7.5 months of the other 16 patients treated with radiotherapy with concomitant temozolomide alone, with statistical differences (P=0.010). Moreover, bevacizumab and nimotuzumab didn’t bring survival benefits to patients with disease recurrence or progression. Hematological toxicity (Grade IV) was not found. CONCLUSION Radiotherapy with concomitant and adjuvant temozolomide prolongs the survival time of children with DIPG.

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