[Cold stimulation in exertion angina: clinical and physiopathologic findings].
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Adult↗
Biomedical subjects
C Gridelli
Publications and source records attributed to C Gridelli.
Myocardial ischemia induced by prostacyclin and iloprost.
Vasodilators of resistive vessels may induce ischemia in patients with coronary artery disease. To evaluate this possibility during prostacyclin (PGI2; scalar doses up to 10 ng/kg/min) and prostacyclin analog (iloprost; scalar doses up to 6 ng/kg/min) infusions, we studied 33 patients with angina pectoris and proved coronary artery disease. Patients were also submitted to dipyridamole (0.15 mg/kg/min for 4 minutes) and exercise stress testing (starting at 25 W and increasing 25 W every 2 minutes). In a preliminary study the hemodynamic and side effects of iloprost were studied in seven healthy subjects. At an iloprost dose of 4 to 6 ng/kg/min, these subjects had a significant decrease in mean arterial pressure and total peripheral and pulmonary vascular resistances. Side effects were limited to facial flushing and slight headache and were readily reversible. PGI2 induced typical chest pain and significant ST segment depression in six patients with severe coronary artery disease (three with left main and three with triple vessel disease) and poor exercise tolerance (means +/- SD = 362 +/- 99 seconds). All six patients had had angina during the dipyridamole infusion. Similar findings were observed after iloprost infusion in four of these. Aminophylline (125 mg iv) completely relieved chest pain. Although the rate-pressure products occasionally rose during PGI2 and iloprost infusions, there were no significant changes between ischemic (11.3 +/- 2.3 and 10.6 +/- 1.4 X 10(-3) U) and preischemic (10.8 +/- 1.5 and 10.7 +/- 1.4 X 10(-3) U) rates of infusion. Our data indicate that PGI2 and iloprost may induce ischemia independently of changes in oxygen demand, and suggest that these drugs dilate small coronary vessels. This may result in decreased subendocardial perfusion pressure and/or "coronary steal."
Adult↗
[The relation between myocardial oxygen consumption and ischemia during exertion in patients with angina pectoris: effect of propranolol].
Patients with coronary artery disease exhibit a reduced coronary vasodilator reserve in response to exercise testing. Drugs which block coronary beta adrenergic receptors could exacerbate this abnormality leaving the vasoconstrictor alpha tone unopposed and/or counteracting the beta 2-mediated vasodilation elicited by the increase in myocardial oxygen demand. To test this hypothesis we administered propranolol 40 mg qid and placebo, using a cross over randomized single blind protocol, to 14 patients each with effort angina and critical coronary stenosis (greater than or equal to 75%). We performed computer-assisted multistage bicycle ergometer testings (25 W increments at 2 min intervals) after 2 weeks open label placebo (control) and at 2 week intervals following daily administration of propranolol and placebo. Compared to placebo, propranolol reduced significantly (p less than 0.001) peak heart rate (x +/- SD: 114 +/- 6 vs 150 +/- 11 beats/min) and rate pressure product (20.1 +/- 2.1 vs 28.0 +/- 3.9 X 10(-3)) and increased exercise duration (462 +/- 91 vs 355 +/- 85 sec). Conversely 0.1 mV ST segment depression was observed at lower heart rate (106 +/- 9 vs 127 +/- 8 beats/min, p less than 0.001) and rate pressure product (16.9 +/- 3.6 vs 22.4 +/- 2.4 X 10(-3), p less than 0.001). No significant differences were found between placebo and control. Moreover, we assessed the regression lines of the relationship between ST segment depression (ST) and heart rate (HR) during exercise. These have been shown to be shifted to the right after surgical revascularization and are an indirect measure of coronary reserve.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
[Acute administration of verapamil in stable angina: increase of the coronary reserve during the exertion test].
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Angina Pectoris↗
[Myocardial ischemia induced by the cold pressor test in patients with exertion angina. Case contribution].
The aim of the present study was to assess the incidence of myocardial ischemia during cold pressor test in patients with stable exertional angina pectoris. Thirty-seven patients with proven coronary artery disease were submitted to cold pressor and exercise stress testing; computer assisted electrocardiographic recordings were obtained throughout the examinations. Cold stimulation provoked electrocardiographic signs of subendocardial ischemia only in 3 patients. They had suffered of a previous myocardial infarction and showed low exercise tolerance and severe coronary lesions (one with triple vessel and 2 with left main disease). Interestingly, only one of these patients gave an history of angina during cold exposure. Thus these data indicate that chest pain and electrocardiographic signs of ischemia are an uncommon event during cold pressor stimulation which occurs more likely in patients with fairly severe coronary narrowings. More sensitive markers of ischemia and/or different modalities of cold application are required for studies concerning the relationship between cold exposure and angina pectoris.
Angina Pectoris↗
[Changes in angina threshold induced by administration of ergonovine maleate during pacing in patients with chronic exertional angina].
It is widely accepted that the occurrence of chest pain and/or ST segment elevation during ergonovine testing is a hallmark of abnormal coronary constriction. However, the negativity of this test cannot be considered as an incontrovertible proof of the absence of coronary sensitivity to vasoconstriction. Indeed, it could only indicate that the resulting effect is inadequate to critically reduce coronary blood flow. To test this hypothesis we studied 12 patients with proven coronary artery disease and negative ergonovine test who had complained of chronic exertional angina pectoris and referred variable threshold for the occurrence of pain. They were submitted to atrial pacing (starting from 90 bpm, with 10 bpm increments every 2 min) before (control) and after ergonovine administration (total dose = 0.675 mg). Time, heart rate and rate pressure product were evaluated at the onset of angina and significant ischemia (0.1 mV ST segment depression). After ergonovine, angina was achieved earlier (405 +/- 173 vs 526 +/- 180 sec, p less than 0.005) than during control and at a lower heart rate (116 +/- 15 vs 131 +/- 15 bpm, p less than 0.001) and rate pressure product (15.8 +/- 2.0 vs 18.8 +/- 2.3 X 10(3) U, p less than 0.001). Changes in anginal threshold were widely variable among cases being that the time to onset of pain was dramatically reduced in certain patients but unchanged in one. Similar results were obtained when substituting the ischemic to the anginal threshold. Thus, negativity to ergonovine testing does not imply the absence of coronary constriction which may be revealed when increasing myocardial oxygen demand by atrial pacing.(ABSTRACT TRUNCATED AT 250 WORDS)
Aged↗
[Markers of necrosis and anoxia in the post-infarct heart failure: determination of infarct size (author's transl)].
28 patients with acute myocardial infarct (AMI), 10 of whom presenting left ventricular failure, have been studied. By serial determinations of alpha-hydroxybutyrate dehydrogenase (HBDH) and creatine kinase (CK), the releasing times (RT) and the total releases (TR) of the two enzymes have been calculated, according to the Shell's method modified by Norris. The RT of HBDH have resulted more prolonged in the decompensated patients (48.1 +/- 16.0 vs 37.3 +/- 9.1 h; t = 2.297; p less 0.05). Highly significant correlations have been demonstrated between the total releases of the two enzymes; r = 0.816, p less than 0.01 (with failure); r = 0.766, p less than 0.001 (without failure). For neither enzyme, instead, significant differences have been shown between the TR of the two patient groups. The following conclusions can be drawn. 1) infarct size probably is not the only factor able to induce heart failure during AMI; 2) infarct size can be equally calculated from both HBDH or CK values, though some considerations may make preferable the choice of CK; 3) the more prolonged release of HBDH during heart failure suggests the hypothesis that lactate accumulation is an important factor influencing the appearance of this compliance.
Adult↗
[The protective effects of glucose in ischaemia, anoxia and reoxygenation (author's transl)].
In the present study we used a model of underperfusion or anoxia followed by reperfusion to assess the role of glycolysis by substituting pyruvate or mannitol for glucose as substrate. Hearts were removed from male Sprague-Dawley rats (250-400 g) and perfused by the technique of Langendorff. The perfusate was Krebs-Henseleit bicarbonate buffer gassed with 95% O2, 5% CO2 or with 95% N2, 5% CO2 mixture and containing substrates as can be seen in the figures. The mild ischemia was obtained by reducing the perfusion pressure by 70%, from 60-70 cm H2O to 10-20 cm H2O. The coronary flow was rapidly reduced to 0.8 +/- 0.03 ml/min within the first 5 minutes. After mild ischemia anaerobic glycolysis was accelerated because lactate production in ischemic hearts perfused with glucose (36.2 +/- 15.3 microM/g/min-1) was higher than in the ischemic hearts perfused with mannitol (6.8 +/- 1.9 microM/g/min-1). During mild ischemia or anoxia there was little difference in the rate of release of creatin-kinase for all the substrates tested, but major differences become apparent on reperfusion. In that period the highest values of CK release were found in mannitol perfused hearts, the lowest in glucose perfused hearts. These results suggest that the rate of glycolytic flux during mild ischemia or anoxia may prevent enzyme release. The beneficial effect of glucose has been observed also during reperfusion. In fact enzyme release was higher in hearts reperfused with glucose than with pyruvate. When pyruvate is the only exogenous substrate available for isolated oxigenated hearts, tissue levels of citric acid cycle intermediates are high and oxidation of these substrates can account for 100% of the oxygen consumption. Therefore we suppose that oxidation of noncarbohydrate substrates such as pyruvate in reperfusion is complicated by the high mitochondrial damage. As a consequence anaerobic glycolytic pathway may play a special role in the maintenance of the membrane integrity also in the early phases of reperfusion.
Animals↗
[Protective effect of glucose and pyruvate in ischemia and reperfusion].
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Animals↗
[Glycolytic enzymes in post-infarct cardiac decompensation].
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Clinical Enzyme Tests↗
Salvage chemotherapy for non Hodgkin's lymphoma of unfavourable histology with a combination of CCNU and vinblastine.
Twenty patients with relapsed or refractory, intermediate or high grade non Hodgkin's lymphoma were treated with a combination of CCNU and vinblastine. Complete responses occurred in four patients (20 per cent), partial responses in eight (40 per cent), for an overall response rate of 60 per cent. The regimen was more effective in patients with high grade lymphoma, absence of constitutional symptoms, better response to prior treatment. Duration of response was 4, 8, 16, 30 months for complete responders; 2, 2, 6, 6, 6, 8, 9, 14 months for partial responders. This combination regimen seems at least as effective as most of other regimens utilized in salvage treatment of non Hodgkin's lymphomas, with a very acceptable toxicity.
Adult↗
CAVBP/DEP alternating chemotherapy for the treatment of intermediate and high grade non Hodgkin's lymphoma: final results of a pilot study.
Between May 1984 and September 1986, 40 patients with intermediate or high grade non Hodgkin's lymphoma were treated with a novel protocol, which alternated a conventional regimen consisting of cyclophosphamide, doxorubicin, vincristine, bleomycin, and prednisone (CAVBP) with a second chemotherapy regimen, including two drugs with newly discovered activity against lymphomas, such as cis-platin, etoposide, and prednisone (DEP). Twenty-one patients (52.5 per cent) achieved a complete response, 11 patients (27.5 per cent) had a partial response. Eight of the 21 complete responders (38 per cent) relapsed 5 to 24 months after completion of treatment. With a median follow-up of over 40 months, 22 patients are alive, six with disease and three in a second complete response after salvage chemotherapy. Factors negatively associated with response included 'B' symptoms, advanced stage of disease, bulky tumour, poor performance status, number of extranodal sites of disease. 'B' symptoms, bulky tumour, and poor performance status were also negatively associated with survival. Toxicity was modest, with no treatment-related deaths and only six cases of severe leukopenia. The results of this pilot study do not justify comparison of CAVBP/DEP with more efficacious regimens in prospective, randomized trials.
Adult↗
Side effects of prostacyclin in patients with angina pectoris and coronary artery disease.
Although the exposure of human subjects to prostacyclin (PGI2) infusion has been broad, no systematic approaches have been made in order to investigate the dose-related side effects in patients with angina pectoris and coronary artery disease (CAD). We studied 25 patients with typical chest pain and overt CAD. All patients underwent a cycloergometer stress testing (25 W increments at 2-min intervals). PGI2 was infused in scalar doses up to 10 ng/kg/min. During the infusion 25 patients (100%) had facial flushing, 7 (28%) moderate headache and one (4%) had nausea. In addition, 4 patients experienced the typical chest pain and had significant (greater than or equal to 0.1 mV) ST segment depression at 8.10 ng/kg/min infusion rates. These patients had lower tolerance to exercise (6.7 +/- 1.7 vs. 8.8 +/- 1.9 min; p less than 0.05) and coronary artery lesions more severe than those observed in patients without drug-induced angina pectoris. Our data therefore indicate that PGI2 at therapeutic doses may induce myocardial ischemia in patients with angina pectoris, low tolerance to exercise and severe CAD. In patients with mild to moderate degree of CAD, PGI2 was found to be well tolerated. These findings suggest that patients with angina pectoris and low tolerance to exercise should be excluded from clinical studies directed at elucidating the effectiveness of PGI2 in cardiovascular disorders.
Angina Pectoris↗
Activity and toxicity of gemcitabine and gemcitabine + vinorelbine in advanced non-small-cell lung cancer elderly patients: Phase II data from the Multicenter Italian Lung Cancer in the Elderly Study (MILES) randomized trial.
BACKGROUND: Following the demonstration that vinorelbine improves survival and quality of life compared with best supportive care in elderly patients with advanced non-small-cell lung cancer (NSCLC), we started the three-arm prospective Multicenter Italian Lung Cancer in the Elderly Study (MILES) trial of vinorelbine, gemcitabine and gemcitabine + vinorelbine. DESIGN: Within the randomized phase 3 trial, pilot single-stage phase 2 studies were planned for gemcitabine and for gemcitabine + vinorelbine. Eligible patients are aged 70 or more, with stage IV or IIIb (with metastatic supraclavear nodes or malignant pleural effusion) NSCLC. Single-agent gemcitabine is given at 1200 mg/m(2) on days 1 and 8; in the combination, gemcitabine is given at 1000 mg/m(2) and vinorelbine at 25 mg/m(2), both on days 1 and 8, every 3 weeks. RESULTS: As planned 49 patients were enrolled in each group. Median age was 74 in both groups. Two-thirds of patients had stage IV disease. The response rate was 18.4% (95% exact CI 8.8-32.0) with both treatments. With single-agent gemcitabine main toxicities were grade 4 thrombocytopenia and grade 2 hepatic toxicity, in one patient each, and grade 2 pulmonary toxicity in two patients. With gemcitabine + vinorelbine combination there were grade 4 neutropenia and thrombocytopenia (one patient each), grade 3 anemia requiring red blood cell transfusion (two patients), and grade 4 fever in two patients. Four patients, with severe cardiac comorbidities, suffered grade 3 heart toxicity with atrial flutter or fibrillation, followed by congestive heart failure responsive to treatment. CONCLUSION: Both single-agent gemcitabine and the gemcitabine + vinorelbine combination are sufficiently active and tolerable to allow continuation of the MILES study.
Age Factors↗
The role of granulocyte growth factors in the treatment of non small cell lung cancer.
In the past years granulocyte growth factors have been introduced in clinical practice. Their use is intended to reduce the risk of infection related to chemotherapy and to increase the dose-intensity of chemotherapy agents. Very few randomized trials have been reported in advanced non small cell lung cancer on chemotherapy plus or minus granulocyte-macrophage colony-stimulating factor or granulocyte colony-stimulating factor. No benefit for granulocyte growth factors use was observed in terms of response rate and survival. Recently, several investigators used growth factors to support new promising drug combinations including vinorelbine, gemcitabine, taxol or taxotere. However, outside controlled clinical trials the role of granulocyte growth factors in the treatment of non small cell lung cancer should be within the American Society of Clinical Oncology guidelines.
Adult↗
Single-agent gemcitabine as second-line treatment in patients with advanced non small cell lung cancer (NSCLC): a phase II trial.
BACKGROUND: Although the use of salvage chemotherapy in advanced non-small cell lung cancer (NSCLC) is controversial, pretreated symptomatic patients often need some kind of treatment to achieve symptoms relief. Gemcitabine is one of the most active new drugs in advanced NSCLC and preliminary reports suggest that it is active also in patients previously treated with platinum compounds. AIM: to evaluate activity and toxicity and the effect on quality of life of gemcitabine in platinum-pretreated patients with advanced NSCLC. METHODS: single-stage phase 2 trial with p0 = 5%, p1 = 20%, alfa = 5%, beta = 10%; 34 patients required and 4 objective responses expected to warrant further studies. Gemcitabine was administered at dose of 1000 mg/m2, i.v., d 18-15, every 4 weeks, for a maximum of 6 cycles. Quality of life was measured by EORTC C-30 and LC-13 questionnaires. RESULTS: from September 1996 to July 1998, 30 patients have been enrolled. There were 6 (20% exact 95% CI 8-39%) partial responses (2 responses were in pts with brain metastases and 2 in patients progressed during first-line chemotherapy). All patients (but one died because myocardial infarction, progressed; median time to progression was 10 weeks (95% CI 7-12); 28 patients died; median survival was 22 weeks (95% CI 17-29). Quality of life analysis showed no significant change but for the improvement of cough after 3 cycles of chemotherapy. There was no severe toxicity. CONCLUSION: gemcitabine is active as second line for patients with advanced NSCLC who received platinum-based first line treatment. In view of such results randomized trials comparing gemcitabine versus best supportive care are warranted.
Adult↗
[Topotecan, a recent discovery and prospects for treating tumors of the lung].
Topotecan is a new active drug in the treatment of lung cancer. In advanced non small cell lung cancer (NSCLC) it showed 0-15% of objective response (OR) with 15% in the largest phase II study performed on 40 patients at the M.D. Anderson Cancer Center. Interesting results have been reported in combination chemotherapy with new drugs, in particular with gemcitabine. However, the role of topotecan in NSCLC must be developed in further trials. Topotecan is one of the most active drug in small cell lung cancer (SCLC). Particularly, it showed active in sensitive pretreated patients with 14%-38% OR. In a phase III randomized trial performed in pretreated patients, single agent topotecan showed similar OR and survival but better palliative effect compared to the CAV regimen (cyclophosphamide + adryamicin + vincristine). In first line chemotherapy topotecan showed 39% OR as single agent. Interesting results have been showed in combination chemotherapy in particular with taxol. Several studies are ongoing. Topotecan as first line chemotherapy could be developed in old doublet combinations (such as cisplatin or carboplatin + topotecan), new doublet combinations (such as taxol or vinorelbine or gemcitabine + topotecan), triplet chemotherapy combinations (such as cisplatin or carboplatin + taxol + topotecan) and sequential or alternate chemotherapy regimens. Topotecan reaches high drug concentration in the brain. It showed activity in brain metastases of SCLC with 40%-63% OR and 13%-43% of complete response in pretreated patients. This particular activity could be considered in first line chemotherapy as prophylaxis of brain metastases or to treat patients with brain metastases at diagnosis. Oral topotecan is a very interesting drug. It showed 36% OR in outfit untreated SCLC patients and 23% in pretreated patients, respectively. Oral formulation seems to induce less toxicity when compared to the intravenous drug. In the future topotecan should be developed as first line combined radio-chemotherapy treatment to make the best of its radiosensitizer effect. The activity on brain metastases also must be developed. Oral formulation is interesting because it is less toxic and could be considered in less toxic regimens in particular in outfit or elderly patients. However in the next years the role of topotecan will be better defined performing phase III randomized trials.
Administration, Oral↗
Single agent docetaxel plus granulocyte-colony stimulating factor (G-CSF) in previously treated patients with advanced non small cell lung cancer. A phase II study and review of the literature.
The use of salvage chemotherapy in advanced non small cell lung cancer (NSCLC) is controversial. However, many patients need to be treated in order to achieve relief of their symptoms. Docetaxel (taxotere) is one of the most active drugs for the treatment of advanced NSCLC and several studies have also shown its effectiveness in pretreated patients. In the present study, 23 patients were treated in order to evaluate both the effectiveness and toxicity of the single agent docetaxel. Furthermore, granulocyte-colony stimulating (G-CSF) factor was administered in order to reduce neutropenia related to docetaxel. Docetaxel was administered intravenously at a dose of 100 mg/m2, on day 1, and it was repeated every 3 weeks. G-CSF was administered for primary prophylaxis of neutropenia at the standard dose of 30 mg/day from day 4 to day 10 of each cycle. The treatment was tolerated well and 5 (21.7%) partial responses were obtained. The median time to progression and the median survival time were 3 and 5 months, respectively. The main side effect noted was fatigue, the intensity of which was grade 2 in 43.4% of cases and grade 3 in 8.7% of patients, respectively. One patient (4.3%) had grade 4 cutaneous toxicity. No cases of grade 4 neutropenia were reported. In conclusion, docetaxel is active when used for salvage chemotherapy in advanced NSCLC whilst concurrent primary prophylactic administration of granulocyte-colony stimulating factor seems to decrease severe neutropenia.
Adult↗