Angiotensin II receptor antagonists: an emerging new class of cardiovascular therapeutics.
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Acceptance of the notion that physiologically specific interruption of the renin-angiotensin-aldosterone system (RAAS) is of considerable therapeutic benefit in the treatment of hypertension and congestive heart failure has generated great interest in the search for novel pharmacological inhibitors. The RAAS is expressed at the whole body, organ/tissue and cellular level through the action of the octapeptide angiotensin II (Ang II), the primary effector molecule of the RAAS. The availability of selective, potent, orally active and long-acting nonpeptide Ang II type 1 (AT1) receptor antagonists provided the opportunity to obtain the benefits of selectively blocking the RAAS at the level of the AT1 receptor that mediates most, if not all, of the important actions of Ang II, and avoid the nonspecificity of the Ang I converting enzyme (ACE) inhibitors. Losartan was the first, but by no means remained the only nonpeptide AT1 receptor antagonist. Numerous other "sartans" have emerged in the past several years and successfully completed clinical development. With the exception of Eprosartan, all others, i.e. Candesartan, Irbesartan, Saprisartan, Tasosartan, Telmisartan, Valsartan and Zolasartan, are based on modifications of Losartan's prototypic chemical structure. AT1 receptor antagonists represent the newest addition to the arsenal of cardiovascular therapeutics. The predominant role of the AT1 receptor in mediating the pathophysiological role of Ang II underlies the effectiveness of this novel class of agents to lower arterial blood pressure, reduce pre- and afterload, inhibit sympathetic nervous system activity and prevent cardiovascular hypertrophy and cardiac failure induced by inappropriate control of the RAAS. (+info)
Treatment with l-cis diltiazem before reperfusion reduces infarct size in the ischemic rabbit heart in vivo.
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l-cis Diltiazem, an optical isomer of diltiazem, protects against myocardial dysfunction in vitro, whereas its Ca2+ channel blocking activity is about 100 times less potent than that of diltiazem. However, there is no evidence that l-cis diltiazem actually protects against ischemia/reperfusion injury in vivo. To assess this, we employed an anesthetized rabbit model, where the left circumflex artery was occluded for 15 min and reperfused for 360 min. Treatment with diltiazem before and during ischemia (bolus 200 microg/kg and 15 microg/kg per minute for 25 min, i.v.; 575 microg/kg total) showed slightly depressed hemodynamic parameters, while l-cis diltiazem (1150 microg/kg) had no effect. Treatment with l-cis diltiazem produced a high recovery of the thickening fraction and limited the infarct size in a dose-dependent manner. Furthermore, the treatment with l-cis diltiazem (1150 microg/kg) or diltiazem (575 microg/kg) 5 min before reperfusion also limited the infarct size, but not after reperfusion. These results suggest that l-cis diltiazem affects some events in the onset of reperfusion, independently of Ca2+-channel-blocking action. Our observations are the first to show that l-cis diltiazem demonstrated its cardioprotective action in the ischemic rabbit heart in vivo. (+info)
Comparison of transmyocardial revascularization with medical therapy in patients with refractory angina.
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BACKGROUND: Transmyocardial revascularization involves the creation of channels in the myocardium with a laser to relieve angina. We compared the safety and efficacy of transmyocardial revascularization performed with a holmium laser with those of medical therapy in patients with refractory class IV angina (according to the criteria of the Canadian Cardiovascular Society). METHODS: In a prospective study conducted between March 1996 and July 1998 at 18 centers, 275 patients with medically refractory class IV angina and coronary disease that could not be treated with percutaneous or surgical revascularization were randomly assigned to receive transmyocardial revascularization followed by continued medical therapy (132 patients) or medical therapy alone (143 patients). RESULTS: After one year of follow-up, 76 percent of the patients who had undergone transmyocardial revascularization had improvement in angina (a reduction of two or more classes), as compared with 32 percent of the patients who received medical therapy alone (P<0.001). Kaplan-Meier survival estimates at one year (based on an intention-to-treat analysis) were similar for the patients assigned to undergo transmyocardial revascularization and those assigned to receive medical therapy alone (84 percent and 89 percent, respectively; P=0.23). At one year, the patients in the transmyocardial-revascularization group had a significantly higher rate of survival free of cardiac events (54 percent, vs. 31 percent in the medical-therapy group; P<0.001), a significantly higher rate of freedom from treatment failure (73 percent vs. 47 percent, P<0.001), and a significantly higher rate of freedom from cardiac-related rehospitalization (61 percent vs. 33 percent, P<0.001). Exercise tolerance and quality-of-life scores were also significantly higher in the transmyocardial-revascularization group than in the medical-therapy group (exercise tolerance, 5.0 MET [metabolic equivalent] vs. 3.9 MET; P=0.05); quality-of-life score, 21 vs. 12; P=0.003). However, there were no differences in myocardial perfusion between the two groups, as assessed by thallium scanning. CONCLUSIONS: Patients with refractory angina who underwent transmyocardial revascularization and received continued medical therapy, as compared with similar patients who received medical therapy alone, had a significantly better outcome with respect to improvement in angina, survival free of cardiac events, freedom from treatment failure, and freedom from cardiac-related rehospitalization. (+info)
American Society of Clinical Oncology clinical practice guidelines for the use of chemotherapy and radiotherapy protectants.
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PURPOSE: Because toxicities associated with chemotherapy and radiotherapy can adversely affect short- and long-term patient quality of life, can limit the dose and duration of treatment, and may be life-threatening, specific agents designed to ameliorate or eliminate certain chemotherapy and radiotherapy toxicities have been developed. Variability in interpretation of the available data pertaining to the efficacy of the three United States Food and Drug Administration-approved agents that have potential chemotherapy- and radiotherapy-protectant activity-dexrazoxane, mesna, and amifostine-and questions about the role of these protectant agents in cancer care led to concern about the appropriate use of these agents. The American Society of Clinical Oncology sought to establish evidence-based, clinical practice guidelines for the use of dexrazoxane, mesna, and amifostine in patients who are not enrolled on clinical treatment trials. METHODS: A multidisciplinary Expert Panel reviewed the clinical data regarding the activity of dexrazoxane, mesna, and amifostine. A computerized literature search was performed using MEDLINE. In addition to reports collected by individual Panel members, all articles published in the English-speaking literature from June 1997 through December 1998 were collected for review by the Panel chairpersons, and appropriate articles were distributed to the entire Panel for review. Guidelines for use, levels of evidence, and grades of recommendation were reviewed and approved by the Panel. Outcomes considered in evaluating the benefit of a chemotherapy- or radiotherapy-protectant agent included amelioration of short- and long-term chemotherapy- or radiotherapy-related toxicities, risk of tumor protection by the agent, toxicity of the protectant agent itself, quality of life, and economic impact. To the extent that these data were available, the Panel placed the greatest value on lesser toxicity that did not carry a concomitant risk of tumor protection. RESULTS AND CONCLUSION: Mesna: (1) Mesna, dosed as detailed in these guidelines, is recommended to decrease the incidence of standard-dose ifosfamide-associated urothelial toxicity. (2) There is insufficient evidence on which to base a guideline for the use of mesna to prevent urothelial toxicity with ifosfamide doses that exceed 2.5 g/m(2)/d. (3) Either mesna or forced saline diuresis is recommended to decrease the incidence of urothelial toxicity associated with high-dose cyclophosphamide use in the stem-cell transplantation setting. Dexrazoxane: (1) The use of dexrazoxane is not routinely recommended for patients with metastatic breast cancer who receive initial doxorubicin-based chemotherapy. (2) The use of dexrazoxane may be considered for patients with metastatic breast cancer who have received a cumulative dosage of 300 mg/m(2) or greater of doxorubicin in the metastatic setting and who may benefit from continued doxorubicin-containing therapy. (3) The use of dexrazoxane in the adjuvant setting is not recommended outside of a clinical trial. (4) The use of dexrazoxane can be considered in adult patients who have received more than 300 mg/m(2) of doxorubicin-based therapy for tumors other than breast cancer, although caution should be used in settings in which doxorubicin-based therapy has been shown to improve survival because of concerns of tumor protection by dexrazoxane. (5) There is insufficient evidence to make a guideline for the use of dexrazoxane in the treatment of pediatric malignancies, with epirubicin-based regimens, or with high-dose anthracycline-containing regimens. Similarly, there is insufficient evidence on which to base a guideline for the use of dexrazoxane in patients with cardiac risk factors or underlying cardiac disease. (6) Patients receiving dexrazoxane should continue to be monitored for cardiac toxicity. Amifostine: (1) Amifostine may be considered for the reduction of nephrotoxicity in patients receiving cisplatin-based chemoth (+info)
Reduction of myocardial infarct size with sCR1sLe(x), an alternatively glycosylated form of human soluble complement receptor type 1 (sCR1), possessing sialyl Lewis x.
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1 This study investigated the effects of soluble complement receptor type 1 (sCR1) or sCR1sLex, agents which function as a complement inhibitor or as a combined complement inhibitor and selectin adhesion molecule antagonist, respectively, on the infarct size and cardiac troponin T (cTnT) release caused by regional myocardial ischaemia and reperfusion in the rat. 2 Eighty-two, male Wistar rats were subjected to 30 min occlusion of the left anterior descending coronary artery (LAD) followed by 2 h of reperfusion. Haemodynamic parameters were continuously recorded and at the end of the experiments infarct size (with p-nitro-blue tetrazolium) and cTnT release were determined. 3 Infusion of sCR1 (1, 5 or 15 mg kg-1, each n=7) or sCR1sLe(x) (1, 5 or 15 mg kg-1, n=7, 13 or 13, respectively) 5 min prior to LAD-reperfusion caused a reduction in infarct size from 59+/-2% (PBS - control, n=12) to 46+/-6%, 25+/-9% and 37+/-6% or 42+/-6%, 35+/-6% and 35+/-4%, respectively. 4 Infusion of sCR1 (15 mg kg-1, n=5) or sCR1sLe(x) (15 mg kg-1, n=5) also reduces the myocardial TnT release from 80+/-20 ng ml-1 (control) to 13+/-7 or 4+/-1 ng ml-1, respectively. 5 Thus, sCR1 or sCRsLe(x) significantly reduce infarct size and cardiac TnT release caused by 30 min of regional myocardial ischaemia and 2 h of reperfusion in the rat. The mechanisms of the cardioprotective effects of sCR1 or sCR1sLe(x) are not entirely clear, but may be due complement inhibition and/or prevention of the adhesion and activation of neutrophils. (+info)
Cardioprotective effects of N-hydroxyguanidine PR5 in myocardial ischaemia and reperfusion in rats.
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1. The potential for the N-hydroxyguanidine compound PR5 (N-(3, 4-dimethoxy-2-chlorobenzylideneamino)-N'-hydroxyguanidine) as a cardioprotective agent in heart ischaemia and reperfusion injury was investigated using rat models. 2. Administration of 1-10 mg kg-1 of PR5 5 min before 10 min of left coronary artery occlusion, followed by 20 min reperfusion, strongly inhibited reperfusion burst of arrhythmias and markedly improved the survival of the animals (e.g. ventricular fibrillation incidence 93 vs 43% (P<0.05); mortality 47 vs 0% (P<0.05), for controls and for 3 mg kg-1 of PR5, respectively). 3. Administration of 3 mg kg-1 of PR5 1 min before reperfusion to rats subjected to 10 min occlusion, 20 min reperfusion was most effective in reducing arrhythmias and decreasing mortality (43 vs 0%, P<0.05), but effects were also seen when PR5 was administered 0, 1 and 5 min after start of reperfusion. 4. Coronary occlusion/reperfusion (10 - 20 min) increased malondialdehyde (MDA) of rat hearts (0.88+/-0.13 for sham vs 1.45+/-0.12 nmol mg-1 protein for ischaemic; P<0.05). In rats where 3 mg kg-1 PR5 were administered 1 min before reperfusion the increase was attenuated (MDA being 1.04+/-0.12; P<0.05 vs ischaemic). 5. PR5 caused a substantial reduction of the infarction size in rats subjected to 180 min left coronary artery occlusion, followed by 120 min of reperfusion; the necrotic zone being 326+/-32 mg for controls vs 137+/-21 mg for animals treated with 3x3 mg kg-1 of PR5 (P<0.01). 6. PR5 reduced the elevation of the ST-segment of the ECGs, as well as caused pronounced attenuation of the rapid blood pressure drop seen at the start of reperfusion following coronary artery occlusion. 7 We conclude that the N-hydroxyguanidine PR5 provides remarkable protection against ischaemia and reperfusion induced myocardial necrosis and life-threatening arrhythmias. These effects of PR5 are discussed in relation to a recently discovered ability of N-hydroxyguanidines to function as electron acceptors at the xanthine oxidase enzyme. (+info)
Reflex cardiovascular response to brief abdominal visceral ischemia is mediated in part by prostaglandins.
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Prostaglandin concentrations are elevated in intestinal lymph during brief abdominal visceral ischemia, and exogenously applied prostaglandins can directly stimulate or sensitize ischemically sensitive visceral sympathetic nerve fibers. However, it is not known if prostaglandin production during abdominal ischemia is sufficient to contribute to the reflex cardiovascular response (e.g., hypertension). Accordingly, in anesthetized cats, the femoral artery was cannulated for measurement of arterial blood pressure, and the superior mesenteric and celiac arteries were isolated and fitted with snare occluders. After dual occlusion of these arteries ( 0.05). In group 2, acetylsalicylic acid significantly (P < 0.05) reduced the reflex rise in blood pressure by 46% (28 +/- 3 to 15 +/- 4 mmHg). A second, more invasive preparation (group 3) was utilized to 1) minimize the confounding, transient, nonreflex rise in blood pressure associated with arterial ligation, and 2) further assess the inhibitory effect of indomethacin. In group 3, the ischemia-induced blood pressure rise of 28 +/- 6 mmHg was reduced by 43% to 16 +/- 4 mmHg after indomethacin (n = 4, P < 0.05). Thus blockade of the cyclooxygenase pathway by two structurally dissimilar inhibitors attenuated the visceral-cardiovascular reflex response to brief ischemia, suggesting that prostaglandins released during visceral ischemia contribute significantly to the activation of the reflex cardiovascular response. (+info)
Effect of potential confounding factors on the thrombolysis in myocardial infarction (TIMI) trial frame count and its reproducibility.
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BACKGROUND: The potential factors that introduce variability into TIMI frame count (TFC) have not been systematically investigated. The goal of this study was to determine if nitrate use, dye injection rate, catheter size, the phase of the cardiac cycle in which dye is injected, or heart rate affect the TFC and to investigate the reproducibility of the TFC. METHODS AND RESULTS: The dye injection rate was increased 1 mL/s, and angiography was repeated. A coronary angiogram was taken first with an 8F catheter and then with a 6F catheter. After taking angiograms, intracoronary nitrate was given to the patient, and the second angiography was performed. Basal heart rate was increased 20 beats/min, and angiography was repeated. Dye injection was performed at the beginning of systole and diastole. The TFC was not significantly changed by increasing the dye injection rate (P=0.467) or by changing catheter size (P=0.693). Nitrate administration significantly increased the TFC from 26.4+/-11.9 to 32.8+/-13.3 frames (P<0.001). Dye injection at the beginning of diastole significantly decreased the TFC from 30.1+/-8.8 to 24.4+/-7.9 frames (P<0.001) for the left coronary artery and from 24.16+/-4.49 to 21. 24+/-4.45 frames (P<0.001) for the right coronary artery. Increasing heart rate significantly decreased the TFC from 30.4+/-6.1 to 25. 3+/-7.2 frames (P<0.001). Intraobserver and interobserver reproducibility of the TFC was good (mean difference, 1.33+/-1.24 and 2.57+/-1.72 frames, respectively). CONCLUSIONS: Nitrate use, heart rate, and the phase of the cardiac cycle in which dye is injected had significant effects on the TFC. Therefore, studies comparing TFC need to consider these factors, and the use of nitrates should be either standardized or randomized. (+info)