Evaluation of antinociceptive effects of Galipea longiflora alkaloid extract and major alkaloid 2-phenylquinoline.

The present study evaluated the antinociceptive properties of an alkaloid extract and 2-phenylquinoline obtained from the bark of Galipea longiflora Krause (Rutaceae) against different models of pain in mice. The results demonstrate that the alkaloid extract caused a pronounced antinociceptive effect with the main alkaloid detected, 2-phenylquinoline, exhibiting moderate activity. The alkaloid extract had a calculated ID50 value of 20.3 mg/kg i.p. and less than 50 mg/kg p.o. against the writhing test which proved to be more effective than the reference drugs when administered by both routes. The ID50 of 2-phenylquinoline was 52.8 mg/kg i.p. with an inhibition of 24.5% when administered orally at 100 mg/kg. In the formalin test the alkaloid extract, but not 2-phenylquinoline, significantly inhibited both phases of pain (neurogenic and inflammatory) at 10 mg/kg i.p. with inhibitions of 37.4% and 58.3%, respectively. The alkaloid extract and 2-phenylquinoline caused only a modest effect in the capsaicin and glutamate tests. In the hot plate test, the alkaloid extract increased the latency time by 25.6% at 10 mg/kg i.p. compared to 2-phenylquinoline which was less effective. It appears that the antinociceptive effects of this plant may be attributed, at least in part, to the presence of some antinociceptive alkaloids in minor concentrations.

[Updating in occupational health for health care workers]. / Aggiornamenti in tema di tutela della salute occupazionale dei lavoratori della sanità.

The board of the Thematic Section on Preventive Medicine for Health Care Workers of the Italian Society of Occupational Medicine and Industrial Hygiene (SIMLII) programmed a national conference on occupational risks of health care workers to be held in late 2009. Main topics will be: a) biohazards; b) biomechanical risk; c) psychosocial factors. Three different working groups were established to tackle critical aspects and suggest practical recommendations to occupational health professionals. Preliminary issues are presented while final results will be presented at the conference on September 2009.

Switching to anastrozole versus continued tamoxifen treatment of early breast cancer. Updated results of the Italian tamoxifen anastrozole (ITA) trial.

BACKGROUND: Tamoxifen, for many years the 'gold standard' in the adjuvant setting for the management of endocrine sensitive early breast cancer, is associated with an increased risk of endometrial cancer and other life-threatening events. Moreover, many women relapse during or after tamoxifen therapy due to the development of resistance. This provided the rationale for a switching trial with anastrozole, the updated results of which are reported here. PATIENTS AND METHODS: This trial investigated the efficacy of switching to anastrozole for women already receiving tamoxifen. After 2-3 years of tamoxifen treatment, postmenopausal, node-positive, ER-positive patients were randomized to receive either anastrozole 1 mg/day or to continue tamoxifen, 20 mg/day, giving a total duration of 5-years treatment. The primary end point was disease-free survival and secondary endpoints were event-free survival, overall survival and safety. RESULTS: A total of 448 patients were enrolled. At a median follow-up time of 64 months (range 12-93), 63 events had been reported in the tamoxifen group compared with 39 in the anastrozole group [HR 0.57 (95% CI 0.38-0.85) P = 0.005]. Relapse-free and overall survival were also longer in the anastrozole group [HR 0.56 (95% CI 0.35-0.89) P = 0.01 and 0.56 (95% CI 0.28-1.15) P = 0.1]. However, the latter difference was not statistically significant. Overall more patients in the anastrozole group experienced at least one adverse event (209 versus 151: P = 0.000). However, numbers of patients experiencing serious adverse events were comparable (37 versus 40, respectively: P = 0.7). CONCLUSIONS: Switching to anastrozole after the first 2-3 years of treatment was confirmed to improve event-free and relapse-free survival of postmenopausal, node-positive, ER-positive early breast cancer patients already receiving adjuvant tamoxifen.

Prospective randomized trial of docetaxel versus doxorubicin in patients with metastatic breast cancer.

PURPOSE: This phase III study compared docetaxel and doxorubicin in patients with metastatic breast cancer who had received previous alkylating agent-containing chemotherapy. PATIENTS AND METHODS: Patients were randomized to receive an intravenous infusion of docetaxel 100 mg/m(2) or doxorubicin 75 mg/m(2) every 3 weeks for a maximum of seven treatment cycles. RESULTS: A total of 326 patients were randomized, 165 to receive doxorubicin and 161 to receive docetaxel. Overall, docetaxel produced a significantly higher rate of objective response than did doxorubicin (47.8% v 33.3%; P =.008). Docetaxel was also significantly more active than doxorubicin in patients with negative prognostic factors, such as visceral metastases (objective response, 46% v 29%) and resistance to prior chemotherapy (47% v 25%). Median time to progression was longer in the docetaxel group (26 weeks v 21 weeks; difference not significant). Median overall survival was similar in the two groups (docetaxel, 15 months; doxorubicin, 14 months). There was one death due to infection in each group, and an additional four deaths due to cardiotoxicity in the doxorubicin group. Although neutropenia was similar in both groups, febrile neutropenia and severe infection occurred more frequently in the doxorubicin group. For severe nonhematologic toxicity, the incidences of cardiac toxicity, nausea, vomiting, and stomatitis were higher among patients receiving doxorubicin, whereas diarrhea, neuropathy, fluid retention, and skin and nail changes were higher among patients receiving docetaxel. CONCLUSION: The observed differences in activity and toxicity profiles provide a basis for therapy choice and confirms the rationale for combination studies in early breast cancer.

Phase III randomized study of fluorouracil, epirubicin, and cyclophosphamide v fluorouracil, doxorubicin, and cyclophosphamide in advanced breast cancer: an Italian multicentre trial.

From February 1983 to January 1985, 497 patients with advanced breast cancer were randomly allocated to receive either epirubicin or doxorubicin in the following combination chemotherapy regimen: fluorouracil (5-FU) 500 mg/m2 intravenous (IV) on days 1 and 8; epirubicin or doxorubicin 50 mg/m2 IV on day 1; cyclophosphamide 500 mg/m2 IV on day 1 (FEC or FAC). Cycles were repeated every 21 days until progression or to cumulative doses of 700 mg/m2 for epirubicin and 550 mg/m2 for doxorubicin. Dose reductions were applied according to the standard criteria. Activity was evaluated in 443 patients (222 in the FEC arm and 221 in the FAC arm). The two experimental groups were comparable in age, performance status, menopausal status, histology, previous treatments, and site of the disease. The overall response rate (complete response and partial response [CR + PR]) was not significantly different: 53.6% for FEC and 56.5% for FAC. The median time to progression was 273 days for FEC and 314 days for FAC; the median survival time was 591 and 613 days, respectively. Leukopenia, anemia, nausea, and vomiting were significantly lower in patients treated with FEC. As for cardiotoxicity, four cases of congestive heart failure (CHF) were recorded among patients treated with FAC while only one was observed in the FEC group. These results indicate that epirubicin in a combination chemotherapy regimen is as active as doxorubicin and is significantly less toxic.

Analgesic potential of marrubiin derivatives, a bioactive diterpene present in Marrubium vulgare (Lamiaceae).

Marrubiin, a furane labdane diterpene, is the main analgesic compound present in Marrubium vulgare, a medicinal plant used in Brazil and other countries to treat several ailments. Considering its important pharmacological action, as well as its high yield, some structural modifications were performed in order to obtain more active compounds. Success was obtained in reducing the lactonic function, in the formation of marrubiinic acid and two esterified derivatives, which exhibited significant analgesic effect against the writhing test in mice. Marrubiinic acid showed better activity and excellent yield, and its analgesic effect was confirmed in other experimental models of pain in mice, suggesting its possible use as a model to obtain new and potent analgesic agents.

Treatment of advanced non-small cell lung cancer (NSCLC): the "Umbria" cooperative study.

One hundred fifty-six patients with metastatic or locally advanced non-small cell lung cancer (NSCLC) were randomized to 3-week cycles of treatment with either: (A) cisplatin (120 mg/m2 on day 1); (B) cisplatin (120 mg/m2 on day 1) plus etoposide (VP-16) (100 mg/m2 on days 1-3; and (C) the cisplatin plus etoposide (VP-16) regimen plus mitomycin C (10 mg/m2 on days 1, 21, and 42; then every 6 weeks for a maximum dose of 100 mg). The overall objective response rates for the combination regimens (30% with two drugs and 26% with three drugs) were superior to that obtained with one drug (4%). Likewise, the median duration of survival with the combination therapy arms (8 to 9 months) was superior to that obtained with the single agent (5 months). Both performance status and limited disease were correlated with response in all groups, and with survival in the combined chemotherapy arms. The dose-limiting toxicity was myelosuppression, especially for the group receiving the three-drug regimen. In summary, combination chemotherapy using cisplatin and etoposide (VP-16) appears to be the most active and safest regimen in NSCLC.

Intracranial hypertension in head injury: management and results.

OBJECTIVE: (1) To describe the pattern of intracranial pressure (ICP) and cerebral perfusion pressure (CPP) in a group of severe head-injured patients, (2) to quantify complications of ICP monitoring, and (3) to describe a management protocol and its results. DESIGN: Prospective observational study. SETTING: General intensive care unit in a teaching hospital. PATIENTS: 138 comatose patients, selected according to the following criteria: age > 16 years, coma [Glasgow Coma Scale (GCS) < or = 8] with at least one pupil reactive after resuscitation, digital recording of intracranial and arterial pressure, and jugular saturation measurements. MEASUREMENTS AND RESULTS: Median GCS was 5, and 62 patients had significant extracranial injuries; 71 had intracranial hematomas, which were urgently evacuated. Mean ICP was 20.5 mmHg (SD 8.34), mean CPP was 71.86 mmHg (SD 11.22); cerebral extraction of oxygen averaged 29 %. Medical therapy was used to control ICP in 130 cases; 93 patients required hyperventilation. Vasopressors were infused in 16 cases; in 14 cases a barbiturate infusion was started. In 6 patients all pharmacological treatments failed and surgical decompression was done. The only complication of ICP monitoring was meningitis in 3 patients. Outcome at 6 months was a good recovery and moderate disability for 82 patients (59.4%), severe disability and vegetative status for 37 (26.8%), and 19 patients died (13.7%). The severity of intracranial hypertension was related to poorer results at 6 months. CONCLUSIONS: Intracranial hypertension is very frequent in severe head injury but can be reasonably well controlled by combined surgical and medical therapy.

A randomized trial fo three cisplatin-containing regimens in advanced non-small-cell lung cancer (NSCLC): a study of the Umbrian Lung Cancer Group.

Survival in patients with locally advanced (stage III Mo) and metastatic (Ml) non-small-cell lung cancer (NSCLC) is short. Phase II studies have reported objective responses ranging from 20% to 60% using cisplatin-based chemotherapeutic regimens, yet few have shown improvement in median survival. In our phase II pilot studies with cisplatin (CDDP) and etoposide (VP-16), we observed a 26% response rate; with CDDP, VP-16, and mitomycin-C, a 38% response rate was obtained in advanced NSCLC patients. A total of 156 consecutive patients with locally advanced and metastatic NSCLC were randomized to one of three treatment arms to determine whether the chemotherapy protocols had any effect on response rate and median survival in a large, randomized study. Arm 1 consisted of CDDP (120 mg/m2 x 3 weeks); arm 2, of CDDP (120 mg/m2) and VP-16 (100 mg/m2 given i.v. on days 1-3), repeated every 3 weeks; and arm 3, of CDDP (120 mg/m2) and VP-16 (100 mg/m2 on days 1-3) given every 3 weeks, plus mitomycin C (10 mg/m2 on days 1, 21, and 42, then every 6 weeks, for a maximal dose of 100 mg). After 71 patients had been enrolled in the study, we stopped accrual in the CDDP arm due to a lack of response [1 complete response (CR) in 24 patients; 4%] and continued enrollment in the two combination-chemotherapy arms. In the CDDP/VP-16 arm a 30% response rate [1 CR, 18 partial responses (PRs)] was obtained, and in the CDDP/VP-16 mitomycin C arm a 26% response rate (4 CRs, 11 PRs) was seen among a total of 150 evaluable patients. Responses were observed in 31% of patients with favorable performance status (PS) (ECOG 0-1) vs 14% in patients with a poor PS (ECOG 2-3). Of patients with locally advanced disease (III Mo), 17 (33%) obtained an objective response, compared with 20 patients (20%) with metastatic disease. Median survival was 18 weeks in the CDDP arm, 35 weeks in the CDDP/VP-16 arm, and 37 weeks in the CDDP/VP-16/mitomycin C arm. The median survival in the multimodal chemotherapy arms was significantly greater than that obtained with CDDP alone. Toxicity was predominantly myelosuppression in the mitomycin C-containing arm (27%, wtto grade 3-4). Our study shows that combination chemotherapy using CDDP/VP-16 is active and safe in the treatment of advanced NSCLC patients with a good performance status. The addition of mitomycin C did not improve the therapeutic response.

Combination of beta-interferon and tamoxifen as a new way to overcome clinical resistance to tamoxifen in advanced breast cancer.

This paper shows that the response to tamoxifen (T) can be improved and the resistance to the antiestrogen can be overcome, in advanced breast cancer, by a pretreatment with natural beta-interferon (nIFN-beta) followed by the association of nIFN-beta with T. Forty-three patients with advanced breast cancer, both progressive (group A) and stable or partially responsive (group B) to previous treatment with T received nIFN-beta i.m. 3 x 10(6) IU/day for 14 days and, subsequently, T30 mg/day and nIFN-beta once a week. The overall objective response rate was 26% (95% Confidence Interval = 13-39) with 8 PR obtained in group A and 3 CR in group B. The median duration of response was 6 months (range 3-12+). Stabilization of disease was observed in 44% of cases. Toxicity was mild.

Bioethics in nephrology: guidelines for decision-making in Italy.

In 1998, the Italian Ministry of Health urged the Italian Society of Nephrology (SIN) to draft recommendations for uniform decision-making procedures in the field of dialysis. In accordance with the Ministry's specifications, at the time the Society approved diagnostic protocols regarding clinical questions, but without fully recognizing the multiple issues arising in complex medical situations where dialysis is likely to go on for a long time. The authors propose some guidelines for ethical conduct and their application, with special regard to medico-legal dilemmas, together with the principles of clinical guidelines that would further improve the "perceived quality" of chronic dialytic treatment.

Antiemetic activity of high-dose metoclopramide combined with methylprednisolone versus metoclopramide alone in dacarbazine-treated cancer patients. A randomized double-blind study of the Italian Oncology Group for Clinical Research.

In a double-blind randomized trial, we compared the efficacy and tolerability of high-dose (2 mg/kg X 4) intravenous metoclopramide (MTC) versus metoclopramide plus high-dose (250 mg X 2) intravenous methylprednisolone (MP) administered for the first 2 days in untreated patients submitted to dacarbazine chemotherapy for 5 days. Thirty-four patients entered the study. Complete protection from nausea and vomiting was achieved in the majority of patients all through the study period with both antiemetic treatments, with slightly greater efficacy at day 2 for the combination. However, after suspension of the antiemetic therapy, there was a relapse of vomiting in patients. Side effects were not different between the two treatments, but extrapyramidal reactions were significantly increased on the second day of antiemetic therapy. In conclusion, high-dose MTC with or without MP can give good antiemetic protection and the combination seems to be slightly more efficacious. However, the relapse of vomiting after discontinuing antiemetic treatment and the high incidence of extrapyramidal reactions justify further studies to find a better antiemetic treatment.

Chemotherapy with cis-platin, doxorubicin, and cyclophosphamide (CAP) in patients with metastatic breast cancer.

Thirty-three evaluable patients with metastatic breast cancer (12 previously treated with adjuvant chemotherapy) were treated with a combination of cis-platin, doxorubicin, and cyclophosphamide (CAP). cis-Platin was given intravenously, 20 mg/m2, on days 1-3, doxorubicin, 40 mg/m2 i.v., on day 1, and cyclophosphamide, 200 mg/m2 i.v., on days 1-3. Cycles were repeated every 3 weeks. A complete response (CR) was obtained in 3 patients (9%) and a partial response (PR) in 18 (54%). The highest response rate was observed in soft tissue and in liver metastases. Median response duration was 48 weeks and median survival 93 weeks. Toxicity was moderate and consisted of alopecia (100%), gastrointestinal toxicity (86%), and myelosuppression (60%). We conclude that this regimen is active in the treatment of advanced breast carcinoma, with a generally acceptable tolerance, but further evaluations in Phase III studies are required.

Complications and safety associated with ICP monitoring: a study of 542 patients.

In our institution ICP was monitored in patients with GCS < or = 8 and abnormal CT scan: 362 severely head injured and 180 subarachnoid hemorrhage. Mean duration of monitoring was 103.6 hours (SD 74.96). Among 542 patients, 440 showed at least one episode of ICP above the threshold of 20 mm Hg. Among 362 head injured patients only 71 (19.3%) had an ICP lower than 20 mm Hg. In the remaining 289 (81.7%) at least one episode > or = 20 mm Hg was measured. In 13 cases (2.2%) a ventricular infection has been diagnosed. In 1 case an intraparenchimal hemorrhage related to the presence of the catheter was detected. Elevated risk of HICP and low incidence of complications have been shown in this series.

Cisplatin and low-dose cytosine arabinoside in advanced cancer.

Twenty-two patients with advanced malignancies were treated with low-dose cytosine arabinoside (ara-C) (45 mg/m2 sc every 12 h for 3 days) and cisplatin (DDP) (100 mg/m2 ev on day 2, 2 h after ara-C. Patients received 61 cycles of ara-C + DDP with a median number per patient of 2.7 cycles (range, 1-5). All patients were evaluable for toxicity and response. Overall, 6 of 22 patients (27%) obtained an objective response (2 CR + 4 PR) with a median response duration of 20 weeks. Hematologic and gastrointestinal toxicities were moderate. Our results show a low response rate with the ara-C and DDP combination compared to the interesting results obtained in vitro.

Humoral nonparathyroid hypercalcemia without evidence of bone involvement.

A case of humoral non-parathyroid hypercalcemia in a breast cancer patient is discussed. Bone metastases developed 23 months after the first clinical evidence of increased serum calcium levels and did not appear to be etiologically involved in this case of hypercalcemia. Serum levels of I-PTH and PGE2 were normal, as were urinary c-AMP levels. Furthermore, no significant response to corticosteroid therapy was observed. However, the correlation between the activity of metastatic disease and calcemia suggests that this cancer produced humoral factor(s) with calcium-mobilizing activity.

Cisplatin and VP16 in metastatic breast carcinoma as a third-line chemotherapy: a randomized study comparing low versus high doses of cisplatin.

AIMS AND BACKGROUND: The study was designed to define the activity of the combination of cisplatin and etoposide as third-line chemotherapy for advanced breast cancer and to investigate the role of the dosage of cisplatin on the effectiveness of the combination. METHODS: Ninety-five eligible patients with advanced breast cancer who had failed or relapsed on two previous lines of chemotherapy were randomized to receive cisplatin at a high dose (100 mg/m2 i.v. day 1, arm A) or a low dose (60 mg/m2 day 1, arm B), combined with etoposide (100 mg/m2 i.v. days 4, 6 and 8). Cycles were repeated every 3 weeks. RESULTS: Of the 78 patients evaluable for response (39 in arm A and 39 in arm B), 9 (12%) showed complete or partial response, 5 (13%) in the high-dose arm and 4 (10%) in the low-dose arm. One complete response was seen in the high-dose arm and none in the low-dose arm. The only 2 patients with brain involvement showed an objective response (one CR in arm A and one PR in arm B). Median time to progression was 14 weeks in arm A and 10 weeks in arm B, median duration of remission 28 and 34 weeks, and survival 36 and 35 weeks, respectively. The differences were not significant. As expected, the patients in the high-dose arm experienced more severe toxicity. One toxic death was observed in each arm due to sepsis in agranulocytosis. The difference was statistically significant regarding nausea and vomiting. Neurotoxicity and ototoxicity were not relevant problems in this patient setting. CONCLUSIONS: Considering the very poor prognostic factors presented by these patients, the combination showed a certain activity, and further evaluation in earlier stages of disease is warranted. A particular responsiveness on brain metastases is suggested. The dose of cisplatin was not proven to be of significant importance.

Lonidamine in advanced colorectal cancer: a phase II study of the Italian Oncology Group for Clinical Research (GOIRC).

Twenty-one patients with metastatic colorectal adenocarcinoma, all previously treated with chemotherapy for metastatic disease, were treated with lonidamine (LDN). The major toxicity encountered was muscular (myalgias in 48%) and gastro-intestinal (nausea and/or vomiting in 52%). Other toxicities included abdominal pain, somnolence, fever, arthralgia and ototoxicity. In the 14 patients evaluable for response we observed no complete or partial remission, 8 stable disease and 6 progressive disease. LND has no clinically worthwhile activity against colorectal carcinoma refractory to conventional chemotherapy.

5-Fluorouracil, vincristine and hydroxyurea combination chemotherapy in metastatic colorectal cancer.

Twenty consecutive patients who had biopsy proven metastatic colorectal cancer were treated with combination chemotherapy. The drug regimen (FVH), in a 4 week cycle, consisted of 5-fluorouracil (600 mg/m2 i.v. on days 1, 8, 15 and 22), vincristine (1.4 mg/m2 i.v. on day 4), and hydroxyurea (2400 mg/m2 p.o. on days 3, 10, 17 and 24). Three of the 18 evaluable patients achieved an objective tumor remission (2 CR and 1 PR) and 15 patients had stable disease. The overall response rate to FVH was therefore not superior to that achieved in patients who received 5-fluorouracil alone, and the overall survival in this study was comparable to that of other studies involving patients with metastatic colorectal cancer.

[Fibrinolytic activity of the human brain after contusive injuries]. / L'attività fibrinolitica dell'encefalo umano dopo trauma contusivo

Histochemical and biochemical evaluation of cerebral tissue fibrinolysis following cranioencephalic trauma was studied in 20 cases seen at necropsy, with varying periods of survival after injury. Fibrinolysis was mainly located at the vasal intima and was very intense in areas rich in vascularised connective tissue, such as the dura mater. Its activity diminished soon after injury to reach minimum values during the first day. Thereafter it remained at very low levels in sites with gross lesions, whereas it returned to nearly normal values elsewhere on the 2nd or 3rd day. Attention is drawn to the territorial character of this pattern. Extension of these results to the fields of diagnosis and treatment, however, is considered premature.