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Biomedical subjects

E Rapaport

Publications and source records attributed to E Rapaport.

At least 19 recordsLinked to original sources
PubMed1992

Antimalarial activities of oligodeoxynucleotide phosphorothioates in chloroquine-resistant Plasmodium falciparum.

Synthetic oligonucleotides and their chemical modifications have been shown to inhibit viral and cellular gene expression by sequence-specific antisense hybridization to target mRNAs. We now report that oligodeoxynucleotide phosphorothioates and their nuclease-resistant modifications are effective in micromolar and submicromolar concentrations against the growth of both chloroquine-resistant and chloroquine-sensitive strains of Plasmodium falciparum in vitro. Parasitized human erythrocytes were found to be accessible to radioactively labeled oligodeoxynucleotides, whereas the uninfected erythrocytes did not permit any cellular entry of the same compounds. The dihydrofolate reductase-thymidylate synthase gene of P. falciparum was demonstrated to be a good target for sequence-dependent inhibition of plasmodial growth by exogenously administered modified oligonucleotides. The antimalarial activities observed in vitro were identical for chloroquine-sensitive and chloroquine-resistant strains of P. falciparum. The antimalarial activity of oligodeoxynucleotide phosphorothioates is related to sequence complementarity to certain regions of the plasmodial genome as well as to non-sequence-defined activities.

Animals↗
PubMed1992

Thrombolytic therapy for myocardial ischemia and infarction.

Thrombolysis during the early hours of a myocardial infarction significantly improves patient survival in a hospital. Beyond 6 hours, up to 24 hours, thrombolysis may still contribute to a reduction in mortality. However, further confirmation is desirable before such therapy late in the course of an evolving infarct can be routinely recommended. Although clot-specific agents such as recombinant tissue-type plasminogen activator (rt-PA) produce a higher initial patency rate, reocclusion rates are higher in the absence of the profound systemic fibrinolysis produced by agents such as streptokinase. This may explain the GISSI-2 results where 15-day survival was no different between the streptokinase- and rt-PA-treated subjects. Although the manner of heparin administration may have clouded these results, current research is directed toward looking at combinations of thrombolytic agents that would combine drugs efficient in producing early patency with those that produce a more pronounced fibrinolytic state. More effective adjunctive therapy is also under intense investigation, particularly specific antithrombin agents that would produce more effective anticoagulation following thrombolysis, and more effective antiplatelet agents that would help prevent reocclusion.

Heparin↗
PubMed1991

Thrombolysis, anticoagulation, and reocclusion.

Based on apparent higher recanalization rates of the infarct-related artery, preferential use of thrombolytic agents with high clot specificity has been proposed for treating patients with acute myocardial infarction. In the Thrombolysis in Myocardial infarction (TIMI-I) and European Cooperative Group studies, higher reperfusion rates were observed with alteplase compared with streptokinase, causing many to assume that the former would achieve a greater reduction in early hospital mortality. However, the Gruppo Italiano per lo Studio della Streptochinasi nell'Infarto Miocardico (GISSI-2) and its associated International Study Group failed to show any differences in 15-day mortality between these agents in more than 20,000 patients. This apparent lack of correlation between reperfusion rates and early mortality may be explained in part when one considers that recanalization or patency rates measured at a given point in time, such as 90 minutes after onset of therapy, fail to define the subsequent vessel status. Early reocclusion is the major reason for this and is a major limitation to the clinical efficacy of thrombolytic drugs. Following recanalization, residual fibrin-bound thrombin adherent to the site of arterial injury from plaque rupture strongly promotes rethrombosis. Although antiplatelet and antithrombin agents such as aspirin and heparin help to decrease rethrombosis, these agents are far from ideal. Thrombolytic agents that produce a significantly prolonged systemic thrombolytic state, such as streptokinase and anistreplase, are likely to result in less rethrombosis. Therefore, a systemic fibrinolytic state would appear to be an advantage rather than a disadvantage, particularly because the incidence of intracerebral hemorrhage does not appear to be greater with their use compared with agents producing less systemic fibrinolysis.(ABSTRACT TRUNCATED AT 250 WORDS)

Anticoagulants↗
PubMed1991

Overview: rationale of thrombolysis in treating acute myocardial infarction.

Treatment of coronary thrombosis with thrombolytic agents was first introduced in the 1950s. Clinical trials, primarily with streptokinase during the 1960s and 1970s, addressed the effects of thrombolysis on mortality rates after acute myocardial infarction, but were inconclusive and largely ignored. In 1976, Chazov et al. from the Soviet Union demonstrated that intracoronary streptokinase could produce prompt recanalization of a totally occluded infarct-related artery. In 1980, DeWood et al. demonstrated that 87% of patients with classic Q-wave myocardial infarction had total occlusion from coronary thrombosis of the infarct-related artery when studied during the first 4 hours of their infarction and that 65% of these arteries were still occluded when patients were studied between 12 and 24 hours after infarction. These observations stimulated renewed interest in thrombolytic therapy for acute myocardial infarction. Mortality trials have subsequently demonstrated that agents such as recombinant tissue plasminogen activator, streptokinase, and anisoylated plasminogen streptokinase activator complex remarkably reduce early mortality rates among patients with acute myocardial infarction when treatment is instituted within the first 6 hours of infarction. Benefit has yet to be demonstrated, however, in patients with acute myocardial infarction characterized by ST-segment depression. This whole area is currently under study by the TIMI investigators. TIMI-3B is a mortality study in which patients with either non-Q-wave myocardial infarction or unstable angina with rest pain are randomly assigned to receive either tissue plasminogen activator or placebo. Results of this trial will help us in the future to determine the appropriate role of thrombolytic therapy in treating acute ischemic syndromes other than transmural myocardial infarction.

Humans↗
PubMed1990

The role of perfusion data.

The use of a thrombolytic agent, whether streptokinase, t-PA, or APSAC, clearly has a profound benefit in reducing mortality when used in the early hours following an acute myocardial infarction. The reasons for this benefit in mortality are unexplained by early patency rates alone. The choice of one thrombolytic agent over another ultimately must rest on the results of randomized studies directly comparing them, with mortality as the end-point. Hopefully, GISSI-II and ISIS-III will give us these answers.

Anistreplase↗
PubMed1990

Protein phosphorylation in response to stress in Clostridium acetobutylicum.

The possible involvement of protein phosphorylation in the clostridial stress response was investigated by radioactively labeling growing cells of Clostridium acetobutylicum with 32Pi or cell extracts with [gamma-32P]ATP. Several phosphoproteins were identified; these were not affected by the growth stage of the culture. Although the extent of protein phosphorylation was increased by heat stress, the phosphoproteins did not correspond to known stress proteins seen in one-dimensional sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Purified clostridial DnaK, a stress protein, acted as a kinase catalyzing the phosphorylation of a 50-kilodalton protein. The phosphorylation of this protein was enhanced in extracts prepared from heat-stressed cells. Diadenosine-5',5"'-P1,P4-tetraphosphate had no influence on protein phosphorylation.

1-Butanol↗
PubMed1990

Early versus late opening of coronary arteries: the effect of timing.

Intuitively, one would assume that the benefit from the use of thrombolytic therapy in reducing mortality in acute myocardial infarction (AMI) is directly related to early recanalization of the thrombosed infarct-related artery. However, a meta-analysis of early clinical trials and the ISIS-II trial results suggests that thrombolysis initiated between 6 and 24 h after the onset of infarction still reduces mortality. Verification of this observation is currently being sought in three ongoing trials of late reperfusion. These are the EMERA trial in South America, using streptokinase; the LATE study involving several European countries, the United States, Canada, and Australia, using tissue plasminogen activator (tPA); and the TAMI-6 trial, in which either tPA or placebo is given 6 to 24 h postinfarction, and patients with closed infarct-related arteries are randomized further to either angioplasty or no angioplasty. There are theoretical reasons that late reperfusion may be beneficial. These reasons include the prevention of infarct expansion and ventricular remodeling leading to ventricular dilatation, the provision of electrophysiologic stability lessening the likelihood of malignant ventricular arrhythmias, and the ability of collaterals emanating from the recanalized artery to perfuse ischemic but still viable myocardium. There are also reasons that late reperfusion might be harmful, including myocardial stunning, microvascular damage, and intramyocardial hemorrhage leading to an increased likelihood of myocardial rupture. It does appear, however, that once recanalization occurs, maintenance of patency improves late outcome, as shown in the Western Washington Intracoronary Streptokinase Trial, the TAMI trial, the TIMI trial, and the Duke study.(ABSTRACT TRUNCATED AT 250 WORDS)

Humans↗
PubMed1989

Generation of extracellular ATP in blood and its mediated inhibition of host weight loss in tumor-bearing mice.

Intraperitoneal injections of adenosine 5'-monophosphate (AMP) or adenosine 5'-triphosphate (ATP), but not of adenosine, inorganic phosphate or pyrophosphate, were shown to inhibit tumor growth and host weight loss in tumor-bearing murine hosts. The inhibition of tumor growth and host weight loss did not exhibit a cause-effect relationship, though both were mediated through expansion of red blood cell (RBC) ATP pools which were promoted by administered adenine nucleotides. We then demonstrated that expansion of RBC ATP pools was preceded by expansion of liver ATP pools and that the adenosine precursor for this type of enhanced RBC ATP synthesis originated in the turnover of expanded liver ATP pools. Although adenosine, which is the primary catabolic product of ATP in the peritoneal cavity or the systemic circulation, was sufficient to yield an expansion of mouse liver ATP pools in vivo, external phosphate was required for the subsequent expansion of RBC ATP pools, which in turn produced elevated extracellular (blood plasma) ATP levels. The anticancer activities which correlate with the elevated blood plasma ATP concentrations are proposed to be the result of direct action of extracellular ATP on the tumor and host tissues.

Adenosine Triphosphate↗
PubMed1989

Anticancer activities of adenine nucleotides in mice are mediated through expansion of erythrocyte ATP pools.

ATP and AMP exhibit significant anticancer activities against established footpad CT26 colon adenocarcinoma in CB6F1 mice. Adenosine, inorganic phosphate, and inorganic pyrophosphate were without such effects under identical conditions. Daily intraperitoneal injections of adenine nucleotides in large volumes of saline, starting after the tumors became palpable, resulted in inhibition of tumor growth and a few "cures." The treatment was not toxic to the host as determined by changes in body weights. Weight loss observed in animals upon progression of the fast-growing CT26 tumors was slowed markedly in adenine nucleotide-treated mice. The inhibition of weight loss in tumor-bearing mice was shown to be neither the cause nor the effect of the inhibition of tumor growth. Intraperitoneal injections of AMP or ATP but not of adenosine yielded expansions of erythrocyte ATP pools in host animals. The expanded erythrocyte ATP pools are stable over a period of hours, while slowly releasing micromolar amounts of ATP into the blood plasma compartment, leading to several-fold increases in plasma (extracellular) ATP levels. Based on previous studies in which 1-5 microM extracellular ATP effectively inhibited the growth of a variety of tumor cells in several in vitro systems, it is suggested that similar levels of ATP in blood plasma account for the anticancer activities observed in a murine host.

Adenocarcinoma↗
PubMed1988

Sudden cardiac death.

Most sudden deaths in industrial nations are the result of underlying coronary artery disease. Longitudinal studies have demonstrated that the percent of all coronary events presenting as sudden death increases with age in both men and women. Relative weight is another important risk factor; the age-adjusted rate of sudden cardiac death for the upper weight tercile in the Framingham study was over 2 times higher for men and 3 times higher for women than the rate for the lower weight tercile. Most patients who die suddenly initially experience ventricular tachycardia that subsequently degenerates into ventricular fibrillation. Patients with a high risk of sudden cardiac death include: survivors of myocardial infarction with left ventricular dysfunction or complex ventricular ectopy, or both; survivors of out-of-hospital cardiac arrest, particularly when the event is not associated with an acute myocardial infarction; patients with recurrent ventricular tachycardia; and patients with dilated congestive cardiomyopathy, particularly when associated with ventricular ectopy. Reducing the risk of sudden death in these patients remains a major challenge.

Arrhythmias, Cardiac↗