Studies on antiplatelet effect of OP-41483, a prostaglandin I2 analog, in experimental animals. I. Effect on platelet function and thrombosis

Antiplatelet and antithrombotic effects of OP-41483, a PGl2 analog, were studied in experimental animals, and the following results were obtained: 1) With 10 min-intravenous infusion to guinea pigs, OP-41483 inhibited platelet adhesiveness and platelet aggregation at 300-1000 ng/kg/min and 1000 ng/kg/min, respectively. In these effects, OP-41483 was 1-3 times more potent than carbacyclin and 3 times less potent than PGl2. 2) With oral administration to guinea pigs, OP-41483 given as its alpha-cyclodextrin clathrate (OP-41483 alpha-CD) inhibited platelet adhesiveness at doses higher than 1.0 mg/kg (expressed in terms of OP-41483), whereas PGl2 and carbacyclin did not at 10 mg/kg. OP-41483 alpha-CD also inhibited platelet aggregation after a single dose of 3 mg/kg and repeated doses of 3 mg/kg/day for 7 days. 3) In the electrically induced thrombosis model of guinea pig mesenteric artery, OP-41483 (300-1000 ng/kg/min, i.v.-infusion) and OP-41483 alpha-CD (1.0-3.0 mg/kg, p.o.) inhibited thrombus formation, but heparin (1.0-10 U/kg/min, i.v.-infusion) did not. 4) In the rabbit extracorporeal circulation thrombosis model, OP-41483 (100 and 300 ng/kg/min, i.v.-infusion) inhibited thrombus formation in the extracorporeal shunt and prevented the decrease in platelet count, hematocrit and fibrinogen level in circulating blood. Heparin (1.0-3.0 U/kg/min, i.v.-infusion) also inhibited the thrombus formation and the decrease in fibrinogen level, but did not inhibit the decrease in hematocrit and platelet count.     

Acute myocardial infarction: comparison of results of Tl-201, Tc-99m pyrophosphate and In-111 antimyosin Fab imagings]

To evaluate the extent and characteristics of infarct areas, we performed indium-111 monoclonal antimyosin Fab (InAM), thallium-201 (TL) and Tc-99m pyrophosphate (PYP) imagings in 17 patients with acute myocardial infarction, and tried to find out the mechanism that causes difference of these imagings. In each study, the extent scores as an index of the infarct area were obtained by single photon emission computed tomography (SPECT), and comparisons were made between the results obtained. The overlap between InAM and TL imagings obtained by SPECT was evaluated. Location, severity, extent and patterns of accumulation were compared between InAM and PYP with both planar image and SPECT. The extent scores of InAM correlated well with those of TL (r = 0.73, p < 0.01). However, the overlap of both methods was recognized in 8 of 17 patients, in whom wall thickness of the infarct area as obtained by echocardiography was well preserved. The left ventricular regional asynergy was mild in 6 of these 8 patients. Coronary angiography showed poor or no collateral circulation in these cases. Although there were generally close correlations of the extent scores between InAM and PYP, discrepancy was noted in 2 cases for location; 2 for severity, 5 for extent, and 3 for patterns of accumulation. These differences may be attributed to the timings of imaging, coronary reperfusion and different mechanisms of accumulation. In conclusion, the extent of acute myocardial infarction obtained by InAM correlates well with those obtained by TL and PYP, with some exceptions.     

Inhibitory effect of OP-41483.alpha-CD, a prostacyclin analog, on peripheral vascular lesion models in rats.

The effect of a chemically stable prostacyclin analog, OP-41483 alpha-cyclodextrin clathrate (OP-41483.alpha-CD), on vascular lesions, platelet aggregation and blood pressure were examined and compared with those of prostaglandin E1 alpha-cyclodextrin clathrate (PGE1.CD) in in vivo rat models. 1) In the laurate (1 mg/leg, i.a.)-induced arterial thrombotic model, OP-41483.alpha-CD (1 microgram/kg/min, i.v.) prevented the progression of femoral arterial vascular lesions and enhanced the development of collaterals in the femoral artery. PGE1.CD did not inhibit the progression of vascular damages. 2) In the model of vasoconstriction induced by epinephrine (0.05 mg/tail, s.c.) and ergotamine (2 mg/kg, s.c.), OP-41483.alpha-CD and PGE1.CD, at 1 microgram/kg/min, inhibited the progress of of tail gangrene and lessened the decrease in tail cutaneous blood flow. 3) OP-41483.alpha-CD (1 microgram/kg/min) suppressed the ADP (0.1 mg/kg/min, i.v.)-induced decrease in the number of circulating platelets without affecting the change in blood pressure. In contrast, PGE1.CD (3 micrograms/kg/min) inhibited ADP-induced thrombocytopenia with a decrease in blood pressure. These results indicate that OP-41483.alpha-CD has antiplatelet and cutaneous blood flow improving activities that are greater than its hypotensive effect and may be of therapeutic potential in peripheral vascular diseases.     

Impact of Induction Chemotherapy and Preoperative Chemoradiotherapy on Operative Morbidity and Mortality in Patients with Locoregional Adenocarcinoma of the Stomach or Gastroesophageal Junction

Background Significant tumor downstaging has been achieved in patients with localized gastric or gastroesophageal adenocarcinoma by induction chemotherapy and preoperative chemoradiotherapy (CTX–CTXRT). However, the influence of CTX–CTXRT on operative morbidity and mortality has not yet been clarified. The aim of the present study was to document the frequency and nature of morbidity and mortality after surgery combined with CTX–CTXRT, and identify factors predictive of postoperative complications in patients with localized gastric or gastroesophageal adenocarcinoma. Methods A prospectively collected database on 71 consecutive patients who underwent CTX–CTXRT at M.D. Anderson Cancer Center between January 1997 and August 2004 was reviewed. Postoperative morbidity and mortality were investigated, and risk factors for overall complications were identified by multivariate logistic regression analysis. Results Overall morbidity and mortality rates were 38.0% (27 patients) and 2.8% (2 patients), respectively. Age greater than 60 years [relative risk 11.3 (95% confidence interval 2.50–50.6)] and body mass index (BMI) of 26 kg/m² or above [relative risk 4.08 (95% confidence interval 1.08–15.4)] were significant risk factors for overall complications. Conclusions CTX–CTXRT can be performed safely with an acceptable operative morbidity and a low operative mortality rate in patients with gastric or gastroesophageal cancer, with careful consideration of added risk associated with age and obesity.     

Diverse functions of the p75 neurotrophin receptor

The pan-neurotrophin receptor p75NTR belongs to a large family of receptors, which includes tumor necrosis factor receptors, Fas and approximately 25 other members. The p75NTR is the first receptor to be cloned molecularly. Recent years have seen the emergence of a consensus regarding the signaling pathways activated by p75NTR and its potential biological function, although receptor characterization had not been targeted for some years. We now know that p75NTR has surprisingly diverse effects, ranging from cell death to regulation of axon elongation. This diversity can be explained by the complex formation of p75NTR with other receptors and multiple signaling molecules that interact with the intracellular domain of p75NTR.     

Myocardial "elektive disseminierte Parenchymnekrose" revisited

A 43-year-old man was found to show cardiac arrest during overnight detention in a police station. The autopsy revealed no abnormality other than a fatty liver on gross examination. Microscopic examination of the heart showed typical disseminated hypoxemic foci of necrosis with hemorrhaging but without infiltration of inflammatory cells, which Büchner, about 60 years ago, proposed as a sign of acute coronary insufficiency without acute coronary occlusion due to massive hemorrhage. However, the disseminated focal hemorrhagic necrosis of microscopic size found in the present study appears to be one of early signs of ischemia in the heart muscle and to occur frequently at silent ischemic heart attacks during daily life.     

The effect of unilateral internal carotid arterial occlusion upon contralateral duplex study: criteria for accurate interpretation.

To determine the influence of unilateral internal carotid arterial occlusion (ICO) on Doppler frequency spectral analysis (DFSA) of the patent contralateral carotid artery, a retrospective review of 154 patients between July 1987 and December 1991 with angiographically confirmed ICO was performed, correlating duplex and arteriographic findings in a blinded fashion. Biplane arteriograms and bilateral carotid artery duplex studies that used a 5.0 MHz Doppler probe with a 1.5 mm3 sample volume at a 60 degree angle of insonation were performed on all patients. Each carotid artery was categorized by the severity of stenosis as quantified by arteriography: 1% to 15% (n = 41); 16% to 49% (n = 48), 50% to 79% (n = 21), 80% to 99% (n = 34), and bilateral occlusion (n = 10). DFSA peak systolic frequencies were commonly exaggerated in the presence of contralateral ICO and use of standard criteria for DFSA interpretation overestimated bifurcation stenoses in 43 of 89 lesions (48.3%) when determining nonhemodynamically significant lesions (less than 50% diameter reduction) with a sensitivity of only 57.3% and specificity of 96.9%. Conversely, prediction of hemodynamically significant lesions (greater than 50% diameter reduction) with standard criteria had 96.9% sensitivity but only 57.3% specificity. Modification of these criteria to account for the velocity increase or "jet effect" in the ipsilateral carotid artery system increased the sensitivity and specificity to 97.8% in predicting nonhemodynamically and hemodynamically significant stenoses respectively. A Doppler frequency spectrum with a peak systolic frequency (PSF) greater than 4.0 kHz and end-diastolic frequency (EDF) less than 5 kHz with an "open window" distinguished lesions with less than 50% diameter reduction.(ABSTRACT TRUNCATED AT 250 WORDS)     

Chlorpropham-induced splenotoxicity and its recovery in rats.

To determine the reversibility of hematological and pathological changes in spleen induced by sub-chronic administration of chlorpropham (CIPC), male F344 rats were given CIPC in the diet at 0, 600, 3000 or 15,000 ppm for 13 weeks (administration period) and then were given standard (0 ppm) diet for 10 weeks (recovery period). At 0, 1, 2, 4 or 10 weeks in the recovery period, 5 rats in each groups were examined for hematology and pathology. At the end of CIPC administration, dose-dependent and significant methemoglobinemia, anemia, splenomegaly and pathological lesions indicating hemolytic anemia were observed in all the treated groups. The hematological changes, congestion of red pulp, lymphoid atrophy, increased extramedullary hematopoiesis in spleen and hematopoietic cell hyperplasia in bone marrow were diminished during the 10 weeks recovery period. However, increased hemosiderin deposition and capsular fibrosis in spleen of the treated groups remained at the end of recovery period. The results indicated that hematological changes induced by sub-chronic administration of CIPC were reversible but hemosiderin deposition and fibrosis in spleen were not reversible in the recovery period examined, suggesting the significance of splenic lesion in CIPC-toxicity.     

Hemodynamic effects of digoxin on congestive heart failure in old myocardial infarction, dilated cardiomyopathy, acute myocardial infarction and mitral stenosis

The hemodynamic effects of digoxin (0.01 mg/Kg) on congestive heart failure were compared in 32 patients with old myocardial infarction (OMI) (n = 9), dilated cardiomyopathy (DCM) (n = 10), acute myocardial infarction (AMI) (n = 5) and mitral stenosis (MS) (n = 8). The responses of heart rate (HR) and pulmonary capillary pressure (PCP) to digoxin in OMI, DCM and MS were marked but different in each of these groups and no significant changes were found in patients with AMI. The responses of cardiac index (CI) to digoxin in patients with OMI and DCM in whom left ventricular myocardial contractile force was impaired were divided into 2 groups (Group 1: CI increased more than 15% and Group 2: less than 15%). In Group 1, both CI and percent fractional shortening (%FS) before digoxin administration were lower than in Group 2, i.e., 1.97 +/- 0.27 vs 2.80 +/- 0.48 L/min/m2 (p less than 0.001) and 10.9 +/- 8.0 vs 19.5 +/- 11.9% (p less than 0.05), respectively. In MS, CI increased after digoxin administration only in the 2 patients with low CI and rapid HR in the control state. These results indicate that the mode of hemodynamic response to digoxin is considerably different in various diseases. They further suggest that digoxin should not be used in the early phase of AMI, although digoxin was of great clinical benefit in patients with OMI and DCM through such mechanisms as its positive inotropic and negative chronotropic effects and lowering of PCP.     

An epidemiologic and histopathological study of sudden cardiac death in Osaka Medical Examiner's Office

From 1982 to 1986, 1230 sudden death cases were autopsied in Osaka Medical Examiner's Office. Among them, 810 cases were sudden cardiac deaths (SCD) including coronary heart disease (77%), cardiomyopathy (7%), valvular disease (3%). All SCD cases were dead within 24 hours of the appearance of the fatal symptoms, and most of them (72%) were considered instantaneous death. Many of the fatal symptoms began in bed (31%), at bath (17%), at toilet (8%), or at work (8%). Thirty-four percent of them were thought by themselves or by their families to be healthy before the death. Hypertension (38%), coronary heart disease (13%) and diabetes mellitus (11%) were the major past history recorded. Microscopic observation of the hearts of 200 cases autopsied in 1986 showed various cardiac lesions: hypertrophy, atrophy, degenerations of myocytes, cellular and fatty infiltrations of the interstitium. According to their cardiac lesions and degrees of severity of coronary sclerosis, patients who died suddenly were divided into 8 groups as follows: 1. myocardial infarction (41) 2. myocarditis (6) 3. hypertrophic cardiomyopathy (19) 4. chronic ischemia with severe coronary sclerosis (65) 5. chronic ischemia with moderate coronary sclerosis (27) 6. small vessel disease (18) 7. amyloidosis (1) 8. unknown (23). These results suggest that coronary heart disease and hypertension play an important role in SCD.