The anthracyclines: will we ever find a better doxorubicin?

Excretion and ecotoxicity of pharmaceutical and personal care products in the environment.

Mitoxantrone is a dihydroxyanthracenedione derivative which as intravenous mono- and combination therapy has demonstrated therapeutic efficacy similar to that of standard induction and salvage treatment regimens in advanced breast cancer, non-Hodgkin's lymphoma, acute nonlymphoblastic leukaemia and chronic myelogenous leukaemia in blast crisis; it appears to be an effective alternative to the anthracycline component of standard treatment regimens in these indications. Mitoxantrone is also effective as a component of predominantly palliative treatment regimens for hepatic and advanced ovarian carcinoma. Limited studies suggest useful therapeutic activity in multiple myeloma and acute lymphoblastic leukaemia. Regional therapy of malignant effusions, hepatic and ovarian carcinomas has also been very effective, with a reduction in systemic adverse effects. Mitoxantrone inhibits DNA synthesis by intercalating DNA, inducing DNA strand breaks, and causing DNA aggregation and compaction, and delays cell cycle progression, particularly in late S phase. In vitro antitumour activity is concentration- and exposure time-proportional, and synergy with other antineoplastic drugs has been demonstrated in murine tumour models. Leucopenia may be dose-limiting in patients with solid tumours, whereas stomatitis may be dose-limiting in patients with leukaemia. Other adverse effects are usually of mild or moderate severity although cardiac effects, particularly congestive heart failure, may be of concern, especially in patients with a history of anthracycline therapy, mediastinal irradiation or cardiovascular disease. Mitoxantrone displays an improved tolerability profile compared with doxorubicin and other anthracyclines, although myelosuppression may occur more frequently. Thus, mitoxantrone is an effective and better tolerated alternative to the anthracyclines in most haematological malignancies, in breast cancer and in advanced hepatic or ovarian carcinoma. Further studies may consolidate its role in the treatment of these and other malignancies.

Mitoxantrone. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential in the chemotherapy of cancer.

There is general agreement that most chemotherapy agents achieve only relatively low concentrations in the normal central nervous system, that the blood-brain barrier is variably disrupted in malignant brain tumors, and that the concentration of chemotherapy drugs in the brain adjacent to tumor is intermediate between concentrations achieved in brain tumors vs normal brain. However, there is substantial controversy regarding the role of the blood-brain barrier in resistance to chemotherapy of intracerebral tumors. Many chemotherapy agents achieve concentrations in brain tumors that are comparable to those in extracerebral tumors, and drugs that cross the intact blood-brain barrier only poorly may be active against intracerebral tumors. Furthermore, the hypothesis that the brain is a pharmacological sanctuary where metastases may grow while tumor is responding in other parts of the body may be flawed: there are only 2 or 3 types of malignancies (out of all those that are sensitive to chemotherapy) in which the risk of isolated central nervous system relapse is moderately high, and even in these 2 or 3, effective central nervous system prophylaxis has minimal or no impact on overall survival. Furthermore, drugs that cross the BBB do not appear to be more effective than other drugs at reducing the risk of brain metastases, and brain metastases at the time of diagnosis do not necessarily convey a worse prognosis than metastases to various other sites. While average drug concentrations in brain adjacent to tumor are lower than those within brain tumors, very small numbers of tumor cells may be capable of inducing local leakiness in blood vessels, and there is little information on drug concentrations achieved in individual tumor cells within the brain adjacent to tumor. Furthermore, any limitation of uptake of drugs into brain tumors could be at least partially due to increased tissue pressure within tumors rather than being due to blood-brain barrier phenomena. This distinction could be important, since strategies that one might use to increase drug delivery to brain tumors might differ depending on whether the reduced delivery were due to barrier phenomena vs blood flow phenomena. The role of the blood-brain barrier in resistance of intracerebral tumors to chemotherapy remains unclear: while it may well play some role (and perhaps even a major one), self-fulfilling prophecies and unintentional bias in data selection and interpretation may have previously made it appear more important than it actually is. The feeling by many investigators that the blood-brain barrier is a major factor in brain tumor resistance to chemotherapy may at times have unnecessarily delayed and limited the exploration of new chemotherapy drugs and strategies in the treatment of human brain tumors. While antineoplastic drug pharmacology is important in the treatment of all malignant tumors, intrinsic drug cytotoxicity may well be a much more important factor in treatment outcome than is any limitation of drug uptake by the blood-brain barrier.

A critique of the role of the blood-brain barrier in the chemotherapy of human brain tumors

Complications of intravesical chemotherapy

A total of 9 patients entered in a phase I trial who received oral idarubicin daily for 3 days took part in pharmacokinetic studies, and bioavailability studies were performed on 13 additional patients receiving single doses of oral idarubicin alternating with i.v. treatment. The data were best fit by a two-compartment model (distribution and elimination compartments for i.v. drug and absorption and single-phase elimination for oral drug). For different idarubicin doses in the phase I and bioavailability studies, the median values for the terminal half-life of idarubicin varied from 5.6 to 11.6 h. High concentrations of the active metabolite idarubicinol were formed. Idarubicinol was climinated more slowly than was the parent compound, with median half-lives for different dose levels varying from 8 to 32.7 h. Although most pharmacokinetic parameters were similar in plasma and whole blood, peak concentrations and AUCs in whole blood were about 3–4 times those calculated in plasma for idarubicin and about 1.5–2 times those determined in plasma for idarubicinol, indicating fairly extensive uptake into erythrocytes. Oral bioavailability was determined by comparing oral idarubicin to i.v. drug with respect to the combined idarubicin and idarubicinol plasma AUCs, and it varied from 12%–49% (median, 29%). Bioavailability was essentially the same (30%) when whole-blood values were used. Urinary excretion of the drug was <5% of the delivered dose by 96 h. Granulocytopenia correlated with plasma idarubicinol “estimated” clearance and steady-state volume of distribution, with whole-blood idarubicinol AUC, area under the moment curve (AuMC), and “estimated” clearance and volume of distribution, and with whole-blood combined idarubicin and idarubicinol AUCs. This suggests that drug contained in erythrocytes plays a major role in toxicity and that idarubicinol may play a larger role in toxicity than does the parent compound.

Bioavailability and pharmacology of oral idarubicin.

Phase I and Pharmacology Study of Intravesical Mitoxantrone for Recurrent Superficial Bladder Tumors

Autopsy-tissues were obtained from eight patients who had last received menogaril (total cumulative dose, 175-1080 mg/m2) intravenously (one patient) or orally (seven patients) from 1 to 285 days prior to death. Tissue samples were assayed for menogaril and its metabolities by high-pressure liquid chromatography. Unchanged menogaril was found only in a single lung-tissue sample from a patient who had died < 24 h after receiving his last treatment. N-Demethylmenogaril was found in two lung-tissue samples and in single samples of the thyroid, lymph node, pancreas, cerebellum, and tumor. The major menogaril metabolite found in human autopsy-tissues was 7-deoxynogarol. The highest 7-deoxynogarol concentrations were found in the large bowel (median, 201 ng/g), liver (median, 183 ng/g), and lung (median, 177 ng/g). The heart ranked as the 9th of 18 organs in median 7-deoxynogarol concentration, after the large bowel, liver, lung, tumor, thyroid, skeletal muscle, adrenal gland, and kidney. The lowest concentrations were detected in brain tissue. Our results suggest that the low degree of cardiac toxicity and the possible pulmonary toxicity of menogaril may be related to relative tissue concentrations of menogaril metabolites. Tumor 7-deoxynogarol concentrations were comparable with those in normal tissues, except that concentrations in intracerebral tumors were higher than those in the normal brain. Tissue 7-deoxynogarol concentrations appeared to be directly related to the cumulative dose and inversely related to the time from the last treatment to death; the value obtained by dividing dose by time correlated (P < 0.05) with tissue 7-deoxynogarol concentrations.

Human autopsy-tissue distribution of menogaril and its metabolites

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Bioavailability and pharmacology of oral idarubicin.

Phase I and Pharmacology Study of Intravesical Mitoxantrone for Recurrent Superficial Bladder Tumors

Human autopsy-tissue distribution of menogaril and its metabolites