Antinociceptive activity of the novel fentanyl analogue iso-carfentanil in rats.

A large number of fentanyl analogues have been synthesized so far, both to establish the structure-activity-relationship (SAR) and to find novel, clinically useful antinociceptive drugs. In this study, the newly synthesized fentanyl analogue 3-carbomethoxy fentanyl (iso-carfentanil) was compared to fentanyl for its antinociceptive activity (tail-immersion test) in rats. It was revealed that the introduction of a 3-carbomethoxy group in the piperidine ring of fentanyl skeleton reduced the potency and shortened the duration of action of the parent compound, i.e., fentanyl. The antinociceptive potency of 3-carbomethoxy fentanyl is influenced mainly by the steric factor (voluminosity of the carbomethoxy group and the cis/trans isomerism), while the chemical nature of the group is probably irrelevant. This is in agreement with SAR studies of other 3-substituted fentanyl analogues. In contrast to potency, the duration of action is not affected by cis/trans isomerism. It is assumed that the time course of action of 3-carbomethoxy fentanyl is influenced by the nature of the carbomethoxy group. Since the potency and the duration of action of this novel antinociceptive compound are interesting from the aspect of SAR studies and have potential promise for clinical application, 3-carbomethoxy fentanyl deserves to be extensively evaluated.

Higher environmental temperature potentiates cataleptic effect of fentanyl in rats.

The influence of higher environmental temperature (HET=30/-1 degrees C) on fentanyl-induced behavior was studied in unrestrained rats. Subacute exposure (3 days) of rats to HET significantly (P<0.01) increased the cataleptic effect of fentanyl citrate (0.5 mg/kg), in comparison to the corresponding exposure to normal environmental temperature (NET=22+/-1 degrees C). Also, the hyperthermic response of rats to a low dose of fentanyl citrate (0.2-0.5 mg/kg) was significantly (P<0.01) potentiated, and the hypothermic response to a high dose of fentanyl citrate (1.5 mg/kg) was significantly (P<0.05) attenuated after exposure to HET. Fentanyl-induced hyperexcitability, loss of righting reflex, loss of corneal reflex and analgesia were not significantly affected by HET. This study provides the first evidence on the influence of environmental temperature on drug-induced catalepsy. HET-induced potentiation of the cataleptic response to fentanyl could be the result of an interference with behavioral thermoregulation.

Randomized study of zorubicin versus zorubicin-cisplatin in undifferentiated carcinoma of the nasopharynx (UCNT)

BACKGROUND: The most active chemotherapy regimens in UCNT were those combining anthracyclines (doxorubicin or epirubicin) and cisplatin. Our previous pilot study on 37 patients treated with the zorubicin-cisplatin combination with a RR of 67% and literature data about other anthracyclines such as epirubicin achieving a response rate of over 50% were the basis of this randomized study comparing efficacy and toxicity of the combination vs. zorubicin as monotherapy. PATIENTS AND METHODS: A total of 80 patients entered the study. The diagnosis of UCNT was confirmed by two independent pathologists. All patients had their primary tumors in the nasopharynx. The patients were randomized in two groups: group A (zorubicin 325 mg/m2, day 1), and group B (zorubicin 250 mg/m2, day 1 and cisplatin 30 mg/m2, days 2-5). The inter-cycle interval was four weeks. The two groups were well balanced according to sex, age, stage Ho and TNM stage. RESULTS: Group A: 40 patients included, 34/40 evaluable for activity. Activity on evaluable patient basis: CR 4/34 (11.75%), PR 4/34, SD 14/34, PD 12/34, response rate 8/34 (23.5%); response rate on intent to treat basis 8/40 (20%). TOXICITY: granulocytopenia grade 3-4 6/40, thrombocytopenia grade 3-4 2/40, no febrile neutropenias, nausea/vomiting any grade 3/40, cardiac toxicity any grade (rhythm) 3/40 other toxicities minor or absent. Group B: 40 patients included, 36/40 evaluable for activity. Activity on evaluable patient basis: CR 10/36 (27.78%), PR 17/36, SD 3/36, PD 6/36, response rate 27/36 (75%); response rate on intent to treat basis 27/40 (67.5%). TOXICITY: granulocytopenia grade 3-4 10/40, thrombocytopenia grade 3-4 8/40, two febrile neutropenias, nausea/vomiting any grade 13/40, other toxicities mild or absent. Of the group of patients achieving a CR, four relapsed following 7, 11, 22 and 23 months, one was lost to follow-up, one died after six months from fulminant hepatitis B and eight are in complete remission lasting for 30+ to 66+ months. Following CR achievement none received any consolidation radiotherapy, and the projected five years of freedom from relapse for complete responders is about 60%. CONCLUSION: Zorubicin is an effective drug in UCNT and its combination with cisplatin has a significant activity and an acceptable toxicity.

Randomised study of high-dose epirubicin versus high-dose epirubicin-cisplatin chemotherapy for advanced soft tissue sarcoma.

A randomised study was started in chemotherapy-naive patients with advanced soft tissue sarcomas who received either epirubicin 60 mg/m2/24 h (total dose for cycle 180 mg/m2) days 1, 2 and 3, (group A) or epirubicin 60 mg/m2/24 h days 1, 2 and 3 and cisplatin 30 mg/m2/24 h days 2, 3, 4 and 5 (group B). The maximal number of cycles foreseen in both groups was eight. Cardiotoxicity of the regimens was monitored by serial LVEF determinations. 106 patients entered this study, 50 (45 evaluable for activity) randomised to group A, and 56 (54 evaluable for activity) to group B. The groups were well balanced for age, sex, performance status and histological type. In group A, there was 1 complete response (CR) and 12 partial responses (PR), the overall response being 13/45 (29%); in group B, there were 7 CRs and 22 PRs, the overall response being 29/54 (54%). The difference between the overall response was statistically significant (chi 2 = 6.19, P < 0.025). The epirubicin-cisplatin regimen was found to be more toxic for platelets and more emetogenic, but cardiotoxicity, either acute or cumulative, was not found to be a major problem in both groups. However, a complete responder receiving a cumulative epirubicin dose of 1440 mg/m2 died from congestive heart failure after a disease-free interval of 27 months. The high response in group B could be the result of the synergism between high-dose epirubicin and cisplatin in patients with advanced soft tissue sarcomas.

Treatment of tumour-induced hypercalcaemia in advanced breast cancer patients with three different doses of disodium pamidronate adapted to the initial level of calcaemia.

A group of 38 female patients with advanced breast cancer experiencing the first occurrence of tumour-induced hypercalcaemia (TIH), mostly with osteolytic progressive bone metastases, were included in a prospective calcaemia-adapted study using three different doses of pamidronate (30 mg, 45 mg and 60 mg). Serum calcium normalisation was achieved in 29/38 (76%) patients. Comparison of the response rate in three therapeutic groups confirmed the need for higher doses of pamidronate in moderate TIH. Our study also emphasised the importance of effective anticancer systemic therapy.

Salivary immunoglobulins in cancer patients with chemotherapy-related oral mucosa damage.

In 40 patients with neoplastic disorders treated with chemotherapy containing anthracyclines or 5-fluorouracil, objective changes of the oral mucosa were registered in 22 patients (55%). Serum IgG and IgA levels and the mean serum IgG/IgA ratio were normal. On the contrary, the mean IgG/IgA salivary ratio was 1.27 (normally below 1.0) due to an increased salivary concentration of IgG (mean 0.095 g/l), but also due to a decreased IgA concentration (mean 0.075 g/l); the IgG/IgA ratio in saliva was higher in patients with objective changes of the oral mucosa (1.53). Values of the periodontal indices were compatible with the diagnosis of a manifest periodontal disease, which tended to be more severe than in control groups. A positive correlation between the gingival index and concentration of IgG in saliva, a non-linear correlation between the gingival index and salivary IgA and a positive linear correlation between serum IgA concentration and intensity of periodontal attachment level recession, indicate local and systemic immune responses to periodontal tissue alterations and dental plaque components. The IgA related local humoral immune response is, however, operating at a lower concentration level than in healthy individuals.

Cardioprotection with ICRF-187 (Cardioxane) in patients with advanced breast cancer having cardiac risk factors for doxorubicin cardiotoxicity, treated with the FDC regimen.

A study of cardioprotection with ICRF-187 (Cardioxane, Eurocetus) has been performed in 35 patients with metastatic breast cancer treated with the FDC regimen (5-fluorouracil 500 mg/m2 i.v., day 1; doxorubicin 50 mg/m2 i.v., day 1; cyclophosphamide 500 mg/m2 i.v., day 1). All patients had one or more cardiac risk factors for doxorubicin cardiotoxicity including 24 who had previously received left-chest-wall irradiation. Cardioxane was applied at a dosage of 1000 mg/m2 as a 15-min infusion in Ringer lactate solution 30 min before doxorubicin administration. Cardiological monitoring included left-ventricular ejection fraction (LVEF) determination by echocardiography before treatment and before each cycle following the cumulative doxorubicin dose of 200 mg/m2. Of the 35 patients, 34 were evaluable fore response, and the overall response rate was 19/34 (56%) with 3/34 complete responses and 16/34 partial responses. Statistical analysis of LVEF values in relation to increasing cumulative doxorubicin doses with Wilcoxon's test of equivalent pairs and Friedman's test has demonstrated that no cardiotoxicity was detected up to a cumulative doxorubicin dose of between 800 mg/m2 and 1000 mg/m2, except for 2 patients in whom a decrease of 20% in relation to the LVEF pretreatment level was demonstrated following a cumulative drug dose of 250 mg/m2. Thus Cardioxane provides an effective cardioprotection even in breast cancer patients with cardiac risk factors for doxorubicin cardiotoxicity treated with the FDC regimen.