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Biomedical subjects

A Gennari

Publications and source records attributed to A Gennari.

At least 37 records · Page 2Linked to original sources
PubMed1999

Cardiotoxicity of epirubicin/paclitaxel-containing regimens: role of cardiac risk factors.

PURPOSE: To evaluate the incidence of clinically relevant cardiac toxicity after treatment with epirubicin/paclitaxel-containing regimens in patients with metastatic breast cancer and to identify high-risk patients in whom the benefit of chemotherapy may be negated by the occurrence of congestive heart failure (CHF). PATIENTS AND METHODS: A total of 105 patients who were referred for epirubicin/paclitaxel treatment were included in this study. Treatment regimens were as follows: (1) epirubicin 90 mg/m(2) plus paclitaxel 135 to 225 mg/m(2) over 3 hours (n = 76); and (2) gemcitabine 1,000 mg/m(2) on days 1 and 4 plus epirubicin/paclitaxel (n = 29). The occurrence of CHF was detected by physical examination, and left ventricular function was evaluated by bidimensional echocardiography to support the diagnosis. Cardiac risk factors examined in this study included age, prior radiotherapy to the chest, hypertension, and diabetes. RESULTS: No patient experienced CHF while on treatment. Nine patients (9%) developed CHF after cumulative epirubicin doses of 1,080 mg/m(2) (n = 4), 720 mg/m(2) (n = 2), 630 mg/m(2) (n = 1), and 540 mg/m(2) (n = 2). One of the two patients who developed CHF after a cumulative epirubicin dose of 540 mg/m(2) had received consolidation with high-dose chemotherapy. Median time to appearance of cardiologic symptoms was 3 months after the end of treatment (range, 3 to 6 months). Overall, the incidence of CHF was 13% and 4% in patients with or without cardiac risk factors, respectively. The cumulative risk of developing CHF was estimated as 7.7% at a cumulative doses of 720 mg/m(2) and 48.7% at a cumulative dose of 1,080 mg/m(2). CONCLUSION: This study shows that the incidence of CHF after an epirubicin/paclitaxel regimen is low up to cumulative epirubicin doses of 990 mg/m(2), thus allowing the safe administration of this regimen even in patients who received epirubicin in the adjuvant setting. However, the risk of developing CHF increases when a cumulative dose exceeding 990 mg/m(2) is reached, concomitantly with the presence of an additional cardiac risk factor.

Adult↗
PubMed1998

Paclitaxel plus epirubicin in advanced breast cancer.

This phase I-II study aimed to determine the maximum tolerated dose (MTD) of paclitaxel (Taxol), infused over 3 hours, when combined with a fixed dose (90 mg/m2) of epirubicin. Other aims were to investigate the combination's plasma pharmacokinetics, toxicity, and activity in 50 patients with previously untreated metastatic breast cancer, as well as its ability to mobilize peripheral blood stem cells (PBSCs). The initial dose of paclitaxel, 135 mg/m2, was increased by 20 mg/m2 in subsequent cohorts of six patients until dose-limiting toxicity (DLT) occurred. The DLT of the combination was febrile neutropenia in two of eight patients who received paclitaxel at 225 mg/m2. The concentration of epirubicinol, the major metabolite of epirubicin, decreased from 47.3 +/- 9.4 ng/mL at 175 mg/m2 of paclitaxel to 37.9 +/- 7.5 ng/mL at the 225-mg/m2 dose. The most relevant toxicity was grade 4 neutropenia (61% of all the courses). Cardiac toxicity included three patients (6%) developing congestive heart failure responsive to therapy. Among 49 evaluable patients, 41 responses (84%) were observed (95% confidence interval [CI], 70% to 92%) and 9 (19%) of these were complete. In 21 patients, we evaluated the mobilization of PBSCs after this regimen plus a colony-stimulating factor. The median number of CD34+ cells was 61.7/microL (range, 6.8 to 201/microL), and a median of 6.3 x 10(6)/kg of CD34+ cells have been harvested with a single leukapheresis.

Antibiotics, Antineoplastic↗
PubMed1997

Organotin-induced apoptosis as observed in vitro is not relevant for induction of thymus atrophy at antiproliferative doses.

The organotin compounds di-n-butyltin dichloride (DBTC) and tri-n-butyltin chloride (TBTC) selectively cause thymus atrophy. Previously, DBTC and TBTC were shown to inhibit proliferation of immature thymocytes, but other studies demonstrated that TBTC but not DBTC increased apoptosis in vitro and also in vivo. In this study, we examined whether apoptosis is increased in vitro by DBTC and TBTC at various concentrations and periods of incubation and whether apoptosis is involved in the induction of thymus atrophy at selective antiproliferative doses. In vitro, DBTC or TBTC at a concentration of 3 microM significantly increased DNA fragmentation in freshly isolated rat thymocytes after preincubation for 10 min followed by a 22-hr culture period. After continuous exposure for 22 hr, apoptosis was observed to be optimum at 1 microM TBTC and 0.3 microM DBTC and lower or absent at higher concentrations. Apparently, apoptosis induced by organotins in vitro depends on both duration and concentration of exposure. Selective antiproliferative doses of DBTC nor TBTC increased apoptosis on day 1 or 2 after single oral exposure. In contrast, the corticosteroid dexamethasone caused a depletion of both small and large thymocytes and a marked increase of apoptosis on both days 1 and 2 after dosing. Thus, although apoptosis is involved in the in vitro cytotoxic effects of both organotin compounds, it seems not involved in thymus atrophy at a dose that selectively inhibits immature thymocyte proliferation.

Animals↗
PubMed1997

Dose-finding study and pharmacokinetics of epirubicin and paclitaxel over 3 hours: a regimen with high activity and low cardiotoxicity in advanced breast cancer.

PURPOSE: To determine the maximum-tolerated dose (MTD) of paclitaxel over 3 hours with a fixed dose of epirubicin, to investigate the plasma pharmacokinetics of this combination, and to evaluate the toxicity and the activity in previously untreated metastatic breast cancer patients. PATIENTS AND METHODS: Fifty patients with metastatic breast cancer, measurable disease, and normal left ventricular ejection fraction (LVEF) were eligible. Epirubicin was administered as an intravenous (I.V.) bolus at the fixed dose of 90 mg/m2 before the infusion of paclitaxel over 3 hours. The initial dose of paclitaxel was 135 mg/m2 and was increased by 20 mg/m2 in subsequent cohorts of six patients until dose-limiting toxicity (DLT). Plasma pharmacokinetics of paclitaxel and epirubicin was performed at cycle 1 in at least two patients per dose level of paclitaxel (175 up to 225 mg/m2). RESULTS: The DLT of this combination was febrile neutropenia in two of eight patients who received paclitaxel at 225 mg/m2. The mean peak plasma concentration of paclitaxel ranged between 5.1 and 6.2 micromol/L at doses of 175 to 225 mg/m2. The concentration of epirubicinol decreased from 47.3 +/- 9.4 to 37.9 +/- 7.5 ng/mL in patients treated with paclitaxel 175 and 225 mg/m2. The most relevant toxicity was grade 4 neutropenia (61% of all courses). The pharmacokinetic data of paclitaxel, in particular the time above the threshold level of 0.05 micromol/L, were not significantly related to myelosuppression. Cardiac toxicity was mild: three patients (6%) developed mild congestive heart failure that was responsive to therapy. Among 49 assessable patients, 41 responses (84%; 95% confidence interval [CI], 70% to 92%) were observed, and nine (18%) of these were complete. CONCLUSION: Our study demonstrates that (1) the MTD is epirubicin 90 mg/m2 and paclitaxel 200 mg/m2; (2) no clear relationship exists between pharmacokinetic data of paclitaxel and myelosuppression, while the increase in the dose of paclitaxel is associated with a reduction in epirubicinol plasma levels; and (3) the association is feasible, with low cardiotoxicity, and has a high activity in metastatic breast cancer.

Adult↗
PubMed1996

Paclitaxel and vinorelbine in anthracycline-pretreated breast cancer: a phase II study.

BACKGROUND: Paclitaxel and vinorelbine are active in advanced breast cancer pretreated with anthracyclines We therefore conducted a phase II study to define the toxicity and activity of paclitaxel and vinorelbine administered in combination. PATIENTS AND METHODS: Our patient population consisted of 37 patients with metastatic breast cancer, 35 of whom had received prior chemotherapy including anthracyclines. The treatment regimen included vinorelbine (25 mg/m2 i.v.) followed by paclitaxel (135 mg/m2 i.v. as a 3-hour infusion) on day 1; vinorelbine was repeated on day 8 in the first 14 patients and on day 3 in the remaining 23 patients. RESULTS: Because of grade 4 neutropenia, the second dose of vinorelbine was reduced or omitted in 88% of the courses on the days 1 and 8 schedule and in 48% of the courses on the days 1 and 3 schedule. As a consequence the administered dose intensity of vinorelbine was significantly higher on the days 1 and 3 schedule (13 mg/m2/wk versus 8.3 mg/m2/ wk, P = 0.005). The overall response rate was 38% (95% CI: 22-55); four responses have been observed in the ten patients with absolute anthracycline resistance. The median duration of response was 6.5 months. CONCLUSIONS: The combination of paclitaxel and vinorelbine is a feasible and active salvage regimen in advanced breast cancer patients pretreated with anthracyclines.

Adult↗
PubMed1996

A dose-finding study of epirubicin in combination with paclitaxel in the treatment of advanced breast cancer.

We performed a dose escalation study to evaluate the maximum tolerated dose of paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) given over 3 hours plus bolus epirubicin 90 mg/m2. The starting dose of paclitaxel, 135 mg/m2, was escalated by 20-mg/m2 increments in cohorts of three to six patients. Courses were repeated every 3 weeks. Filgrastim (5 micrograms/kg/d) was administered to shorten the duration of grade 4 neutropenia lasting longer than 72 hours. Twenty-nine patients have been treated, 86% of whom had failed adjuvant chemotherapy (with anthracyclines in 14 cases). One hundred forty-eight courses have been administered, and the paclitaxel dose has been escalated to 225 mg/m2 without reaching the maximum tolerated dose. The most frequent dose-related toxicity has been grade 4 neutropenia, which occurred in 59% of courses. The median duration of grade 4 neutropenia was 4 days, which was shortened with filgrastim only in patients treated with paclitaxel 225 mg/m2. Eleven episodes of febrile neutropenia (7% of courses) have been observed. Nonhematologic toxicities were mild or moderate: grade 1 or 2 peripheral neuropathy was reported by 41% and 10% of patients, respectively. The cardiac toxicities of this regimen were surprisingly low: median left ventricular ejection fraction was 57% at study entry and 56% after six courses. Only two patients showed a decrease of left ventricular ejection fraction below 50% after six courses, and no signs of anthracycline-induced congestive heart failure were noted. The activity of this novel combination is encouraging: the overall response rate is 80%, with 16% complete responses. We have demonstrated that the combination of epirubicin plus paclitaxel given over 3 hours is feasible with acceptable toxicities, does not appear to be associated with clinically relevant cardiotoxicity, and is active in a population of patients who have failed adjuvant chemotherapy.

Adult↗
PubMed1996

Paclitaxel in combination with vinorelbine in pretreated advanced breast cancer patients.

This phase II study combined paclitaxel (Taxol; Bristol Myers Squibb Company, Princeton, NJ) 135 mg/m2 by 3-hour infusion on day 1 and vinorelbine 25 mg/m2 on days 1 and 8 (in the first 14 patients) or on days 1 and 3 (in the subsequent 20 patients). The courses were repeated every 3 weeks. The second vinorelbine dose (on days 3 or 8) was reduced or omitted according to the toxicities encountered. Thirty-four patients have been treated to date; 21 had received one prior regimen of chemotherapy, 11 had two prior regimens, and two had three prior regimens. Only two patients (6%) had not been exposed to anthracyclines. One hundred twenty-six courses have been administered: 52 with vinorelbine given on days 1 and 8, and 74 with vinorelbine administered on days 1 and 3. The most frequent toxicity was grade 4 neutropenia, which occurred in 64% of the courses; 13 episodes of febrile neutropenia have been reported in eight patients. Filgrastim was administered in 43% of the courses because of febrile neutropenia or delayed recovery (> 72 hours) from grade 4 neutropenia. Mucositis was observed in 18% of the courses (12% grade 1, 3% grade 2, and 3% grade 3). The dose of vinorelbine was reduced or omitted in 86% of courses with the days 1 and 8 schedule, and in 48% of courses with the days 1 and 3 schedule. Among 28 evaluable patients, two complete and 10 partial responses have been observed (response rate, 43%, 95% confidence interval, 19% to 51%). Median duration of response is 5+ months (range, 1 to 15 months). In conclusion, this combination is active and has acceptable toxicities in anthracycline-pretreated breast cancer patients. The delivered dose intensity of vinorelbine is higher with the schedule adopted later in the study, with vinorelbine given on days 1 and 3.

Adult↗
PubMed1996

Paclitaxel combinations as front-line and salvage chemotherapy regimens in advanced breast cancer.

Thirty-two patients with advanced breast cancer have been treated with epirubicin 90 mg/m2, immediately followed by paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) infused over 3 hours, every 21 days. The starting paclitaxel dose was 135 mg/m2, increased in subsequent triplets of patients until the maximum tolerated dose was reached at 200 mg/m2. One hundred seventy-six courses have been administered; dose-related grade 4 neutropenia was observed in 66% of the courses, with 12 episodes of febrile neutropenia. Two patients showed a decline of left ventricular ejection fraction below 50% after six courses, but no signs of congestive heart failure have been reported. The response rate is 76% (95% confidence interval, 56% to 90%), with 14% complete remissions. This level of activity is encouraging considering that 84% of the patients had failed adjuvant chemotherapy (with anthracyclines in 14 cases), and 19 had progressive disease following hormone therapy for metastasis. In another study, the toxicity and activity of a salvage regimen consisting of paclitaxel 135 mg/m2 over 3 hours plus vinorelbine 25 mg/m2 in an intravenous bolus on day 1 were evaluated; vinorelbine was given again on day 8 (in 14 patients) or on day 3 (in 20 patients), and the courses were repeated every 3 weeks. Thirty-four previously treated patients with advanced breast cancer entered the study; 20 had received one prior line of chemotherapy, II had two lines, and three patients had three lines. Thirty-two patients had been exposed to anthracyclines. Grade 4 neutropenia was observed in 64% of the courses, with 13 episodes of febrile neutropenia; four episodes of grade 3 mucositis have been reported with vinorelbine days 1 and 3. A delay in the administration of chemotherapy was necessary in 17% of the courses with vinorelbine days 1 and 8 and 16% of the courses with vinorelbine days 1 and 3; moreover, the vinorelbine dose was reduced or the drug omitted on day 8 in 86% of the courses and on day 3 in 16% of the course. An objective response was achieved in 43% of the patients. In conclusion, the combination of paclitaxel plus vinorelbine is an active salvage regimen and can be administered at greater dose intensity with the day 1 and 3 schedule.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1995

Aging and endothelial function in normotensive subjects and patients with essential hypertension.

BACKGROUND: Experimental data from normotensive and hypertensive animals indicate that aging is associated with impaired endothelium-dependent relaxations to acetylcholine, and this possibility appears to be confirmed in the human coronary artery. In the present study, we evaluated the effect of age on endothelial responsiveness in the forearm vessels of either normotensive control subjects or essential hypertensive patients. METHODS AND RESULTS: Within the normotensive or hypertensive group (n = 53 and n = 57, respectively), subjects were selected with similar blood pressure, plasma cholesterol, and glucose values, and hypercholesterolemic subjects, diabetics, and smokers were excluded. We evaluated forearm blood flow (by strain-gauge plethysmography) modifications induced by intrabrachial acetylcholine (0.15, 0.45, 1.5, 4.5, and 15 micrograms/100 mL per minute), an endothelium-dependent vasodilator, and sodium nitroprusside (1, 2, and 4 micrograms/100 mL per minute), an endothelium-independent vasodilator. Acetylcholine caused a dose-dependent vasodilation that was significantly (P < .01) lower in essential hypertensive patients than in normotensive control subjects. However, a significant negative correlation was observed between acetylcholine-induced vasodilation and patient age in both normotensive (r = -.86, P < .001) and hypertensive (r = -.85, P < .001) patients. In contrast, vasodilation to sodium nitroprusside was similar in normotensive control subjects and essential hypertensive patients with a poorer inverse correlation with patient age (normotensive control subjects, r = -.37; hypertensive patients, r = -.36) compared with acetylcholine. CONCLUSIONS: The present data indicate that there is a blunted response to acetylcholine with advancing age in both normotensive control subjects and essential hypertensive patients, suggesting that aging is associated with reduced endothelium-dependent vasodilation in humans.

Acetylcholine↗
PubMed1995

The relationship between systemic oxygen uptake and delivery during moderate hypothermic cardiopulmonary bypass: critical values and effects of vasodilation by hydralazine.

The relationship between oxygen delivery (DO2) and uptake (VO2) has been studied during moderately hypothermic cardiopulmonary bypass (CPB) in 15 patients undergoing myocardial revascularization. As soon as nasopharyngeal temperature was lowered to 32 degrees C, blood flow was decreased from 2.4 to 2.0 l/min/m2. Arterial and mixed venous blood gas analyses were performed five and eight minutes later and DO2 and VO2 were calculated; VO2 stabilized in five minutes after changing blood flow and neither DO2 nor VO2 values changed three minutes later (DO2: 217 +/- 19 versus 215 +/- 17 ml/min/m2; VO2: 63 +/- 12 versus 66 +/- 14 ml/min/m2). Blood flow then was increased to 2.3 l/min/m2 and DO2 and VO2 were determined again, five minutes later; they both increased significantly, to 243 +/- 20 and 74 +/- 13 ml/min/m2, respectively. However, a further blood flow increase to 2.6 l/min/m2 which caused DO2 to increase to 277 +/- 24 ml/min/m2, did not affect VO2 which was unchanged five minutes later (76 +/- 13 ml/min/m2); VO2 dependence on DO2 values higher than 243 +/- 20 ml/min/m2 was consequently ruled out. Ten patients, having a mean arterial pressure higher than 80 mmHg, were eventually vasodilated with hydralazine, 0.1 mg/kg intravenously, and DO2 and VO2 were determined after five and ten minutes. As blood flow did not change, DO2 was unaffected while a slight increase in VO2 mean values was observed which was not statistically significant (prior to hydralazine: 78 +/- 15 ml/min/m2; five minutes later: 82 +/- 17 ml/min/m2; 10 minutes later: 76 +/- 18 ml/min/m2). In conclusion, during hypothermic CPB at 32 degrees C, VO2 plateau ranges between 48 and 102 ml/min/m2 (mean +/- 2 SD) in 95% of patients, corresponding to 66 and 141 ml/min/m2 at 37 degrees C; this finding closely matches other literature reports. Consequently, lower VO2 values suggest inadequate oxygen supply to tissues. Critical DO2 at 32 degrees C is lower than 283 ml/min/m2 in 97.5% of patients. Finally, arterial vasoconstriction does not seem to play a significant role in tissue hypoperfusion.

Adult↗
PubMed1992

Modulation of desynchronized sleep through microinjection of alpha 1-adrenergic agonists and antagonists in the dorsal pontine tegmentum of the cat.

Noradrenaline is involved in the regulation of the sleep/waking cycle by acting through various receptor types. In previous studies we investigated the role of beta- and alpha 2-adrenergic receptors through local microinjections of various drugs into the dorsal pontine tegmentum (DPT) of the cat. This region is known to be crucially involved in desynchronized sleep execution. In this study we examined the role of alpha 1-adrenergic receptors. The alpha 1-agonist methoxamine and the alpha 1-antagonist prazosin were injected into the DPT of freely moving, unanaesthetized cats. We found that methoxamine notably reduced desynchronized sleep, and that this effect was both dose-dependent and site-specific. These effects were prevented by the subsequent injection of prazosin. On the other hand, the injection into the DPT of prazosin alone produced scarce or inconsistent effects on the sleep/waking cycle.

Animals↗
PubMed1991

Microinjections of alpha 1- and alpha 2-noradrenergic substances in the cerebellar vermis of decerebrate cats affect the gain of the vestibulospinal reflexes.

1. In addition to mossy and climbing fibers, the Purkinje (P)-cells of the cerebellar cortex receive noradrenergic (NA) afferents which originate mainly from the locus coeruleus. Since these fibers impinge also on the vermal cortex of the cerebellar anterior lobe, which receives a labyrinth input and projects to the lateral vestibular nucleus, experiments were performed in precollicular decerebrate cats to find out whether unilateral injection of alpha-adrenergic substances into the vermal cortex of the cerebellar anterior lobe exerted some influence on posture as well as on the dynamic characteristics of vestibulospinal (VS) reflexes evaluated by recording the multiunit EMG responses of the forelimb extensor triceps brachii of both sides to roll tilt of the animal at 0.15 Hz, +/- 10 degrees. 2. Unilateral injection into the vermal cortex of the culmen of the alpha 1-adrenergic agonist metoxamine or the alpha 2-adrenergic agonist clonidine (0.25 microliters at the concentration of 4 micrograms/microliters of saline) produced a postural asymmetry, characterized mainly by a slight decrease of the extensor tonus in the ipsilateral forelimb and an increased tonus in the contralateral forelimb. The same substances significantly increased the gain (imp./sec/deg) of the first harmonic component of the EMG responses of the ipsilateral and the contralateral triceps brachii to animal tilt. The crossed effects were more prominent for the alpha 2- than for the alpha 1-agonist. However, no significant changes in the phase angle of the responses were observed in both instances. The effects described above occurred within 5-10 min after the injection, reached the peak values after 15-20 min, and disappeared within 2 hours. 3. The postural and reflex changes described above were not due to irritative events following the injection, since they were not observed in control experiments after injection of 0.25 microliter of saline into the same corticocerebellar area prior to the administration of the alpha 1- or the alpha 2-adrenergic agonist. Moreover, the resulting effect were dose-dependent. 4. Both the ipsilateral as well as the contralateral effects induced by the alpha 1- or the alpha 2-adrenergic agonist metoxamine or clonidine were impaired by previous injection into the same corticocerebellar area of the corresponding alpha 1- or alpha 2-adrenergic antagonist prazosin or yohimbine, respectively (0.25 microliter at the concentration of 8-16 micrograms/microliters in both cases).(ABSTRACT TRUNCATED AT 400 WORDS)

Adrenergic alpha-Agonists↗