Reduction of cisplatin hepatotoxicity by procainamide hydrochloride in rats.

In preceding papers, we proposed that procainamide hydrochloride, a class I antiarrhythmic agent, was able to protect mice and rats from cisplatin-induced nephrotoxicity and that it could exert its action through accumulation in kidneys followed by coordination with cisplatin (or its hydrolysis metabolites) and formation of a less toxic platinum compound similar to the new platinum(II) triamine complex cis-diamminechloro-[2-(diethylamino)ethyl 4-amino-benzoate, N4]-chlorideplatinum(II) monohydrochloride monohydrate, obtained by the reaction of cisplatin with procaine hydrochloride. Hepatotoxicity is not considered as a dose-limiting toxicity for cisplatin, but liver toxicity can occur when the antineoplastic drug is administered at high doses. Here, we report that procainamide hydrochloride, at an i.p. dose of 100 mg/kg, reduces cisplatin-induced hepatotoxicity, as evidenced by the normalization of plasma activity of glutamic oxalacetic transaminase and gamma-glutamyl transpeptidase, as well as by histological examination of the liver tissue. Twenty-four hours after i.p. treatment with the combination of 7.5 mg/kg cisplatin and 100 mg/kg procainamide, a significant increase of procainamide (+56%, P<0.05), total platinum (+31%, P<0.05), platinum-DNA adducts (+31%, P<0.05) and percent DNA-DNA interstrand cross-links (+69%, P<0.02) was found in liver tissue, as compared to animals treated with cisplatin alone. Moreover, in accordance with these findings, we also observed a slightly lower concentration and cumulative excretion of platinum in the feces. Since mitochondrial injury is considered a central event in the early stages of the nephrotoxic effect of cisplatin, the distribution of platinum in these subcellular organelles obtained from hepatocytes was determined after treatment with cisplatin with or without procainamide hydrochloride, together with platinum concentration in their cytosolic fraction. Our data show that the coadministration of procainamide hydrochloride produced a rearrangement of subcellular platinum distribution in hepatocytes with a slight decrease in mitochondria (-15%, P<0.10) and a slight increase in the cytosolic fraction (+40%, P<0.10) of platinum content, compared to the treatment with cisplatin alone. In analogy with our previous results in the kidney, confirmed here by our data in vitro, we suggest that the hepatoprotective activity of procainamide hydrochloride is linked to the formation of a less toxic platinum complex, which leads to inactivation of cisplatin itself and/or its highly toxic hydrolysis metabolites and to a different subcellular distribution of platinum.

Pharmacokinetic and pharmacodynamic analysis of platinum after combined treatment of cisplatin and procainamide hydrochloride in mice bearing P388 leukemia.

BACKGROUND: Our previous studies showed that procainamide hydrochloride may be an important modulator of cisplatin toxicity and antitumour activity. This study was performed in order to investigate if procainamide hydrochloride may influence the therapeutic index of cisplatin by inducing modifications of its pharmacokinetics and pharmacodymanics in vivo. MATERIALS AND METHODS: The pharmacokinetic profile of cisplatin administered either in the presence or absence of procainamide hydrochloride was investigated in BDF1 female mice bearing 6-day P388 leukemia. Procainamide hydrochloride was administered i.v. at the dose of 50 mg/kg, immediately before cisplatin which, in turn, was administered i.p. at the dose of 8 mg/kg. RESULTS: The combined administration of the antiarrhythmic drug and cisplatin caused significant differences in the pharmacokinetic profiles of Pt in plasma, ascites fluid and tissues. Filterable Pt was significantly increased both in plasma and ascites fluid in animals given the combined treatment. Similarly, a small increase was also found for total plasma Pt. These differences caused some changes of the pharmacokinetic parameters of filterable (plasma: AUC0-1 h = +16%, t1/2 alpha = +29%, t1/2b = +14%, K2p = -32%; ascites fluid: AUC0-1 h = +23%, t1/2 alpha = +78%, t1/2 beta = -49%, and total Pt (plasma: AUC0-1 h = +19%, t1/2 alpha = +27%, t1/2 beta = -22%; ascites fluid: AUC0-1 h = +6%, AUC0-infinity = +43%, t1/2 alpha = +30%). The analysis of tissue Pt content showed the general increase of Pt concentration in the main organs of animals treated with cisplatin and procainamide hydrochloride, with AUC0-24 h increased by 95%, 22%, 90% and 28% in kidney, liver, spleen and lung, respectively. The analysis of binding of Pt to DNA and percent interstrand cross-links (%ISCL) in P388 tumour cells showed that the % ISCL (10.44 +/- 3.81% vs. 3.51 +/- 0.01%) and the efficiency of ISCL formation (0.51 +/- 0.14 vs. 0.17 +/- 0.02 %ISCL.microgram DNA/pg Pt) were significantly greater when cisplatin was administered in association with procainamide hydrochloride. CONCLUSION: Our results show that procainamide hydrochloride may alter the pharmacodynamics and the pharmacokinetics and distribution of Pt in tumored mice treated with cisplatin.

Comparison of temsirolimus pharmacokinetics in patients with renal cell carcinoma not receiving dialysis and those receiving hemodialysis: a case series.

BACKGROUND: Intravenous temsirolimus, an inhibitor of the mammalian target of rapamycin (mTOR), is approved for the treatment of advanced renal cell carcinoma (RCC). Sirolimus, the principal metabolite of temsirolimus in humans, also exhibits mTOR inhibitory activity. OBJECTIVE: The purpose of this study was to compare the pharmacokinetics of temsirolimus and its metabolite, sirolimus, among patients with RCC not receiving dialysis and those receiving hemodialysis. METHODS: This was a single-center, unblinded, single-dose study. Patients with histologically confirmed metastatic RCC were eligible. A single 25-mg dose of temsirolimus was administered as a 30-minute intravenous infusion during the first round of chemotherapy. Blood samples were drawn at 0 (predose), 0.5 (end of infusion), 1.5, 2.5, 5.5, 24, 72, and 144 hours after infusion. In patients receiving hemodialysis, an additional blood sample was drawn 1 hour after each treatment to compare pre- and postconcentration. Temsirolimus concentrations were assayed in blood using HPLC coupled to mass spectrometry. Pharmacokinetic parameters (C(max), T(max), t((1/2)), AUC(0-infinity), total body clearance, volume of distribution at steady state, AUC ratio [the ratio of sirolimus to temsirolimus AUCs], and AUC sum [the algebraic sum of temsirolimus and sirolimus AUCs]) were calculated and analyzed statistically. RESULTS: In total, 13 consecutive patients (11 men and 2 women; 11 not receiving dialysis and 2 receiving hemodialysis) were included. No patient refused to participate in the study. Of those not receiving dialysis, the median age was 54 years (range, 36-77 years), and of those receiving hemodialysis, the median age was 60.5 years (60-61 years). There were no significant between-group differences in the pharmacokinetic parameters of temsirolimus and sirolimus. Moreover, in patients receiving hemodialysis, blood drug concentrations assessed immediately before hemodialysis were similar to those assayed 1 hour after the treatment. CONCLUSION: This study found that after single-dose administration of 25 mg of temsirolimus as a 30-minute intravenous infusion, neither temsirolimus nor sirolimus concentrations were significantly affected in these patients with RCC receiving hemodi-alysis compared with those not receiving dialysis.

Inhibition of cell growth, induction of apoptosis and mechanism of action of the novel platinum compound cis-diaminechloro-[2-(diethylamino) ethyl 4-amino-benzoate, N(4)]-chloride platinum (II) monohydrochloride monohydrate.

Cis-diaminechloro-[2-(diethylamino) ethyl 4-amino-benzoate, N(4)]-chloride platinum (II) monohydrochloride monohydrate (DPR) is a new platinum triamine complex obtained from the synthesis of cisplatin and procaine. In this paper we analyzed, adopting a disease-oriented strategy, the tumour selectivity of this compound, its ability to induce apoptosis and its mechanism of interaction with DNA. The inhibition of cell proliferation was evaluated by the MTT assay using a panel of 51 tumour cell lines. Some of them were also evaluated for the induction of apoptosis by 4'-6-diamidine-2'-phenylindole (DAPI) staining, Western blot of p53 protein and agarose gel electrophoresis of ladder DNA. Finally, interstand cross-links (ISCL) were evaluated by ethidium bromide fluorescence technique. When evaluated by the MTT assay, DPR showed a high selective activity for neuroblastoma, small cell lung cancer (SCLC), ovarian cancer and leukemia cell lines. The comparison of mean graphs of DPR and cisplatin suggested that our compound possesses a mechanism of action similar to that, at least in part, of its parent compound. Moreover, DPR showed itself to be a good trigger of programmed cell death, as demonstrated by DAPI staining, activation of p53 protein and agarose gel electrophoresis of ladder DNA. Finally, the study of the formation of ISCLs demonstrated that DPR, despite being a monofunctional platinum compound, is able to form bifunctional adducts through the release of procaine residue. Data presented here suggest that DPR is an antitumour agent able to trigger apoptosis, and that it is endowed with a peculiar mechanism(s) of action and a special selective activity against two tumours, namely neuroblastoma and SCLC, which are still characterized by a low incidence of long-term survivors.