Effect of dietary supplementation with polyunsaturated fatty acids on bronchial hyperreactivity in subjects with seasonal asthma.

Dietary supplementation with omega-3 essential fatty acids results in the production of uniqe 5-lipoxygenase and cyclooxygenase products which are biologically less active and may inhibit the production, or actions, of the eicosanoids produced when arachidonic acid is the substrate for 5-lipoxygenase and cyclooxygenase, rather than omega-3 essential fatty acids. Since airway inflammation may play a central role in the pathophysiology of asthma, we studied the effect of omega-3 essential fatty acids on bronchial responsiveness in 7 atopic patients suffering from seasonal asthma due to airborne allergens, and positive to intracutaneous skin reaction to two or more allergens. Bronchial responsiveness to ultrasonically nebulized distilled water (UNDW) was determined 30 days from the initial ingestion of 3 g/day of omega-3 essential fatty acids and 30 days after stopping dietary supplementation. Flow volume curves and Raw were recorded before the provocation test, at the end of inhalation, and at 10-, 20-, 30- and 60-min intervals. The maximum fall in forced expiratory volume in 1 s (FEV1) and the maximum increase in airway resistance (Raw) were chosen as the main outcome parameters. After 30 days of dietary supplementation, bronchial responsiveness to UNDW was significantly improved (in fact maximum fall in FEV1 was -11% vs. -28% before treatment, and maximum increase in Raw was +37% vs. +265% before treatment). The challenge test repeated 30 days after stopping dietary supplementation was the same as that recorded before treatment. The present data strongly suggest the hypothesis that dietary supplementation with omega-3 essential fatty acids could decrease bronchial hyperreactivity in atopic patients.

Early cardiac toxicity of 4'-iodo-4'-deoxydoxorubicin.

4'-iodo-4'-deoxydoxorubicin was administered intravenously to 35 patients with advanced malignant neoplasms. The doses were escalated as follows: 2, 4, 6, 7, 10, 14, 19, 26, 52, 70, 80 and 90 mg/m2. Myocardial function was assessed by Holter monitoring and echocardiography. The prevalence of arrhythmias that could be attributed to the drug in the 24 h following infusion was 14.3% (supraventricular) and 10.6% (ventricular). Echocardiographic heart function variables were unchanged at 24 h and 21 days from drug injection. The data indicate the absence of significant, acute cardiotoxic effects of 4'-iodo-4'-deoxydoxorubicin.

Detection of cardiac arrhythmias and ischaemic events in combination chemotherapy with cisplatin, etoposide and bleomycin for testicular cancer.

Ten patients treated with combination chemotherapy regimen containing Cisplatin, Bleomycin and Etoposide (PEB) were submitted to Holter monitoring during the first cycle of treatment. No modifications of heart rate, ST-T segment were observed and only a slight increase of incidence of sopraventricular ectopic beats was recorded. One patient developed a transient second degree atrio-ventricular block in the first day during episodes of vomiting. These data suggest that combination chemotherapy with PEB, at least during the first cycle of treatment, has no significant arrhythmogenic effect.

Evaluation of cardiac toxicity of idarubicin (4-demethoxydaunorubicin).

Cardiac toxicity of idarubicin (4-demethoxydaunorubicin), a new daunorubicin derivative, was tested in 49 phase II patients with advanced malignancies. In 26 patients the drug was given intravenously at a dose of 13 mg/m2 and in 23 orally at a dose of 45 mg/m2. Cardiac toxicity was evaluated by means of electrocardiography, left ventricular systolic time intervals, echocardiography and radionuclide cineangiography. The type and incidence of ECG abnormalities were comparable to those observed with other anthracycline analogs. Other functional parameters, serially measured to evaluate delayed cardiotoxicity in patients who received more than 65 mg/m2 intravenously or 225 mg/m2 orally, were not significantly different from pretreatment values. No patient developed clinical congestive heart failure. Only one patient exhibited a drop in the left ventricular ejection fraction of more than 15% from pretreatment values. These data indicate that idarubicin given orally or intravenously at the tested doses has no significant cardiotoxic activity in the range of the cumulative doses attained.

Clinical evaluation of the cardiac toxicity of 4'-deoxy-doxorubicin.

4'-deoxy-doxorubicin, a new doxorubicin analog, was tested in 65 phase II patients with advanced malignancies. Cardiac toxicity evaluation was performed by means of electrocardiography (ECG), left ventricular systolic time intervals, echocardiography and radionuclide left ventricular ejection fraction. ECG abnormalities were observed in a lower percentage of patients (23%) compared to that described for doxorubicin and other anthracycline analogs such as 4'-epi-doxorubicin and 4-demethoxy-daunorubicin. Other functional parameters serially measured to evaluate chronic cardiotoxicity in 23 patients, who received more than 200 mg/m2 were not significantly different from mean pretreatment values. No patient developed congestive heart failure but some of them exhibited a fall of left ventricular function parameters more than 15% from pretreatment values. These data suggest that this new analogue is probably less cardiotoxic than the parent compound doxorubicin but not completely devoid of cardiotoxicity.

Cardiac function evaluation in AMSA-treated patients.

Cardiac function was monitored by means of ECG and systolic time intervals in 13 patients submitted to treatment with 4'-(9-acridinylamino) methanesulfon-m-aniside (AMSA) without the classical reconstitution vehicle N1N-dimethylacetamide. ECG changes were represented by flattening of T waves (100%), sporadic atrial extrasystoles (23%), and sporadic or coupled ventricular premature beats (7.6%). These alterations were transient and not dose related. The systolic time interval ratio, recorded at the end of infusion and 2 h after drug administration, did not change significantly from pretreatment values. Systolic time intervals recorded in 6 patients after the mean cumulative dose of 550 mg/m2, and in 3 patients after the mean cumulative dose of 1000 mg/m2, did not change from mean basal values. Present data failed to confirm the occurrence of a significantly cardiotoxic activity of AMSA.

Preliminary evaluation of myocardial toxicity of 4'-deoxydoxorubicin: experimental and clinical results.

4'-deoxydoxorubicin (4'-deoxy-DXR), a new doxorubicin (DXR) analogue with interesting antineoplastic activity, was tested for its cardiotoxicity in guinea pigs and humans. In experiments on isolated guinea pig heart, which is considered a highly predictive model of acute anthracycline cardiotoxicity in humans, 4'-deoxy-DXR was found to be significantly less cardiotoxic than DXR. This effect was correlated with a lower degree of inhibition of the fast-exchanging calcium compartment and of the low affinity sarcolemmal calcium-binding sites. The preliminary study on 4'-deoxy-DXR in humans was conducted on 117 patients affected by advanced malignancies resistant to conventional chemotherapy. The drug was administered by bolus i.v. injection in doses ranging from 10 to 40 mg/m2 in the phase I study and in doses of 35 mg/m2 in the phase II study, which is still ongoing. Cardiologic evaluation consisted of recording of EKG, left ventricular systolic time intervals (STI), echocardiography and radionuclide ejection fraction. Preliminary data indicated a lower percentage of EKG abnormalities in comparison not only with DXR but also with other anthracycline analogues. Analysis of STI recorded 1 h after different doses of 4'-deoxy-DXR failed to show the dose-dependent effect on left ventricular function which has been described for DXR, thus confirming the lower acute cardiotoxic effect. Functional parameters serially measured to evaluate chronic cardiotoxicity in 15 patients who received more than 200 mg/m2 were not significantly different from basal values.

Possible enhancement of the cardiotoxicity of doxorubicin when combined with mitomycin C.

Forty-six patients with recurrent metastatic breast cancer were treated with a combination chemotherapy including doxorubicin and mitomycin C. Myocardial contractility was monitored by means of echocardiography. During therapy there was a progressive deterioration of myocardial function, and this phenomenon was found to be linearly correlated to the cumulative dose of doxorubicin. Six patients (13.8%) developed congestive heart failure during therapy; it occurred after the median cumulative dose of 322 mg/m2 (range 135-472). Possible risk factors of cardiomyopathy could be identified in only two patients. These results suggest that mitomycin C could enhance the cardiotoxicity of doxorubicin.

Relationship between pulmonary function tests and morphologic changes in the lung in bleomycin-treated patients.

The transfer factor of the lung for carbon monoxide (TLCO) and the respiratory response to moderate exercise were determined in 16 patients with pulmonary metastasis pretreated with bleomycin who underwent pulmonary partial resection. The results of pulmonary function tests were related to histologic findings. No significant correlation was found between pulmonary morphologic changes and the TLCO: this questions the usefulness of TLCO as a predictive method for detecting subclinical bleomycin pulmonary toxicity. No significant correlation was found between morphologic findings and cumulative dose of bleomycin: this confirms the limit of a dose limitation strategy. In contrast, evaluation of pulmonary response to exercise seemed to improve the sensitivity of monitoring such patients for clinical evidence of latent pulmonary toxicity; however, it seems that critical morphologic changes must occur before pulmonary performance begins to deteriorate.

Preliminary echocardiographic and polygraphic evaluation of cardiac toxicity of 4'-epi-doxorubicin.

Data recorded by ECG, poly ECG, and echocardiography in 101 cancer patients treated with 4'-epi-doxorubicin are reported and compared with those previously obtained in a comparable group of 78 patients treated with doxorubicin. 4'-Epi-doxorubicin was administered by i.v. route in doses ranging from 50 to 90 mg/m2 in a three-weekly regimen; the maximum cumulative dose was 630 mg/m2. The results obtained demonstrate that this new antitumor anthracycline develops a lower acute cardiotoxic effect and suggest that 4'-epi-doxorubicin is endowed with a reduced chronic cardiotoxicity as compared to doxorubicin.

Evaluation of doxorubicin cardiotoxicity in patients treated intermittently with beta-methyldigoxin.

Twenty-one patients with various advanced neoplasms were treated with 60 to 75 mg/m2 of doxorubicin every 3 to 4 weeks and monitored by ECG and systolic time intervals (PEP/LVET) with the aim to establish whether a pretreatment with beta-methyldigoxin, administered intermittently, could prevent doxorubicin-induced cardiotoxicity. It was found that until patients received digitalis pretreatment the PEP/LVET ratio did not change significantly from mean basal values even after the highest cumulative dosages of doxorubicin. However, after interruption of the therapy with both drugs, PEP/LVET increased reaching a value not significantly different from that observed in a comparable group of patients treated only with doxorubicin. Moreover, of 9 patients who reached the cumulative limiting dose, 2 developed congestive heart failure. These results question the possibility that digitalis administered according to an intermittent treatment scheme may prevent doxorubicin cardiomyopathy.