A phase I study of monohydroxyethylrutoside in healthy volunteers.

The flavonol monohydroxyethylrutoside (monoHER) has demonstrated protection against doxorubicin-induced cardiotoxicity in in vitro and in vivo studies without affecting the antitumor effect. In the present phase I study, the possible side effects and the pharmacokinetics of monoHER were evaluated in healthy volunteers with the aim to develop a safe and feasible dose to be evaluated in cancer patients treated with doxorubicin. The study was performed as a single blind, randomized trial in healthy volunteers (age between 19 and 56 years). At each dose level, six subjects received monoHER and three placebo. MonoHER was solubilized in 100 ml dextrose 5% and administered as an i.v. infusion in 10 min. The placebo consisted of 100 ml dextrose 5%. The starting dose of monoHER was 100 mg/m(2). Dose escalation by 100% of the preceding dose took place after finishing each dose level until the protecting pharmacokinetic values for C (max) and AUC(infinity) (as observed in mice after 500 mg/kg monoHER i.p.) were reached and/or serious side effects were observed. The dose was escalated up to 1,500 mg/m(2). The mean values of C (max) and AUC(infinity) were 360+/-69.3 microM and 6.8+/-2.1 micromol min/ml, respectively. These values were comparable to the C (max) and AUC(infinity) observed under the protecting conditions in mice. No serious side effects occurred during the entire study. Thus, 1,500 mg/m(2) is a feasible and safe dose to be evaluated in a phase II study to investigate the protective properties of monoHER against doxorubicin-induced cardiotoxicity in cancer patients.

Dose-finding and pharmacokinetic study of cisplatin, gemcitabine, and SU5416 in patients with solid tumors.

PURPOSE: To investigate the feasibility and pharmacokinetics of the combination cisplatin, gemcitabine, and SU5416. PATIENTS AND METHODS: Patients received cisplatin 80 mg/m(2) on day 1, gemcitabine 1,250 mg/m(2) on days 1 and 8, repeated every 3 weeks, and SU5416 (85 and 145 mg/m(2)) intravenously twice weekly. Pharmacokinetics of all three agents, side effects, and antitumor response were investigated in patients with solid tumors amenable to therapy with cisplatin/gemcitabine. RESULTS: In the first cohort of three patients entered at the 85 mg/m(2) dose, no dose-limiting toxicities were observed. In the next cohort (145 mg/m(2)), three patients developed a thromboembolic event. After entry was restricted to patients with low thromboembolic risk, three additional patients enrolled at 145 mg/m(2) developed a thromboembolic event. The dose was then reduced to 85 mg/m(2) in all patients still on the study, and three additional patients were entered on this dose level. In 19 treated patients, eight patients developed nine thromboembolic events (three transient ischemic attacks, two cerebrovascular accidents, and four deep venous thromboses). The most common toxicities observed were those previously reported for SU5416 alone (headache and phlebitis) and for this chemotherapy regimen (nausea, thrombocytopenia, and leucopenia). No significant pharmacologic interaction among the three drugs was observed. Response rates were similar to those expected in the patient population selected for this study. Analysis of variables of the coagulation cascade and of vessel wall activation was performed in three patients and showed significant increases in thrombin generation and endothelial cell perturbation in a treatment cycle-dependent manner. CONCLUSION: The incidence of thromboembolic events, possibly related to the particular regimen tested in this study, discourages further investigation of this regimen.

The chemical reactivity of BNP7787 and its metabolite mesna with the cytostatic agent cisplatin: comparison with the nucleophiles thiosulfate, DDTC, glutathione and its disulfide GSSG.

PURPOSE: BNP7787 is a new chemoprotective agent presently under clinical investigation to protect against cisplatin-induced toxicities, especially nephrotoxicity and neurotoxicity. In the kidneys BNP7787 is postulated to undergo selective conversion into mesna, which can locally detoxify cisplatin. The reactivity of cisplatin with this new chemoprotective agent and with its metabolite mesna was investigated at clinically observed plasma concentrations and compared with the nucleophiles thiosulfate (TS) and DDTC, and with the endogenous compounds glutathione (GSH) and oxidized glutathione (GSSG). METHODS: Reaction kinetics experiments were performed at 37 degrees C and pH 7.4 in the presence of a high chloride concentration (0.15 M). The degradation of cisplatin was measured over time using HPLC with off-line flameless atomic absorption spectrophotometry. RESULTS: The degradation half-lives of cisplatin (13.5 microM) with 17.2 m M BNP7787, 340 microM mesna and 17.2 m M mesna were 124 min, about 790 min and 73 min, respectively. Cisplatin reacted at least 9.5 times more slowly with 17.2 mM BNP7787 and 5.5 times more slowly with 17.2 mM mesna than with 17.2 mM of the modulating agents DDTC or TS (i.e. half-lives 11 and 13 min, respectively). The half-lives of cisplatin with 17.2 m M GSH and GSSG (i.e. 122 and 115 min, respectively) were comparable with the half-life obtained with BNP7787. The thiol mesna was shown to be a stronger nucleophile than its corresponding disulfide BNP7787. CONCLUSIONS: The much slower relative reactivity of BNP7787, the short residence of BNP7787 (approximately 2 h) and the much lower concentration of mesna in the circulation following BNP7787 administration precludes chemical inactivation of cisplatin in the circulation, and thus the antitumor activity of cisplatin is maintained.

The cardioprotector monoHER does not interfere with the pharmacokinetics or the metabolism of the cardiotoxic agent doxorubicin in mice.

PURPOSE: Monohydroxyethylrutoside (monoHER) has proved to be a good protector against doxorubicin-induced cardiotoxicity without interfering with the antitumor effect of doxorubicin. The aim of the present study was to determine whether there is a pharmacokinetic interaction between monoHER and doxorubicin which may be involved in monoHER cardioprotection. METHODS: Mice were treated with monoHER (500 mg x kg(-1) i.v.) alone, monoHER 5 min after doxorubicin (10 mg x kg(-1) i.v.), doxorubicin alone and doxorubicin 5 min after monoHER. The levels of monoHER and doxorubicin(ol) in plasma and heart tissue were measured by HPLC 24 h and 48 h after monoHER and doxorubicin administration, respectively. RESULTS: The areas under the concentration-time curves (AUCs) of monoHER and doxorubicin(ol) were not affected by the coadministered drug. No changes were observed in pharmacokinetic parameters such as initial and final half-lives, mean residence time, clearance and volume of distribution of monoHER and doxorubicin(ol) after single or combined administration. CONCLUSION: The cardioprotection of monoHER in mice is not caused by a pharmacokinetic interaction between monoHER and doxorubicin.

Bioavailability and pharmacokinetics of the cardioprotecting flavonoid 7-monohydroxyethylrutoside in mice.

PURPOSE: The pharmacokinetics and bioavailability of monoHER, a promising protector against doxorubicin-induced cardiotoxicity, were determined after different routes of administration. METHODS: Mice were treated with 500 mg.kg(-1) monoHER intraperitoneally (i.p.), subcutaneously (s.c.) or intravenously (i.v.) or with 1000 mg.kg(-1) orally. Heart tissue and plasma were collected 24 h after administration. In addition liver and kidney tissues were collected after s.c. administration. The levels of monoHER were measured by HPLC with electrochemical detection. RESULTS: After i.v. administration the AUC(0-120 min) values of monoHER in plasma and heart tissue were 20.5+/-5.3 micromol.min.ml(-1) and 4.9+/-1.3 micromol.min.g(-1) wet tissue, respectively. After i.p. administration, a mean peak plasma concentration of about 130 microM monoHER was maintained from 5 to 15 min after administration. The AUC(0-120 min) values of monoHER were 6.1+/-1.1 micromol.min.ml(-1) and 1.6+/-0.4 micromol.min.g(-1) wet tissue in plasma and heart tissue, respectively. After s.c. administration, monoHER levels in plasma reached a maximum (about 230 microM) between 10 and 20 min after administration. The AUC(0-120 min) values of monoHER in plasma, heart, liver and kidney tissues were 8.0+/-0.6 micromol.min.ml(-1), 2.0+/-0.1, 22.4+/-2.0 and 20.5+/-5.7 micromol.min.g(-1), respectively. The i.p. and s.c. bioavailabilities were about 30% and 40%, respectively. After oral administration, monoHER could not be detected in plasma, indicating that monoHER had a very poor oral bioavailability. CONCLUSIONS: MonoHER was amply taken up by the drug elimination organs liver and kidney and less by the target organ heart. Under cardioprotective conditions (500 mg/kg, i.p.), the Cmax was 131 microM and the AUC(infinity) was 6.3 microM.min. These values will be considered endpoints for the clinical phase I study of monoHER.