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Cytotoxic chemotherapy using docetaxel, estramustine, and mitoxantrone is often employed to treat men with hormone-refractory prostate tumors. More recently, oral satraplatin has been studied as an alternative to docetaxel-based therapies. These cytotoxic agents have diverse mechanisms of action and disposition. Moreover, there is often wide interindividual variation in the pharmacokinetics, toxicity, and clinical outcome following administration of these agents in patients with prostate cancer. This chapter summarizes what is known about the basic clinical pharmacology of these agents and discusses the mechanisms and implications of interindividual variation in treatment. [ABSTRACT FROM AUTHOR]

Mitoxantrone (dihydroxyanthracenedione, DHAD) is an anthracenedione derivative developed in the 1970s in an effort to find a less cardiotoxic doxorubicin derivative. Although the exact mechanism of action remains unclear, mitoxantrone intercalates between base pairs of the DNA double helix, resulting in cross links, strand breaks, and inhibition of nucleic acid synthesis. Early studies with mitoxantrone demonstrated a low potential for drug–drug interactions, other than a significantly increased risk of infection when administered concomitantly with live vaccines. Currently, there are five black box warnings described in the US package insert. Initially approved in 1987 for treatment of acute non-lymphocytic leukemia (ANLL – now AML) in adults, mitoxantrone was approved in 1996 for use in combination with corticosteroids as initial chemotherapy for the treatment of patients with pain related to advanced castration-resistant prostate cancer (CRPC). For this indication, the recommended dosage is 12–14 mg/m2 every 3 weeks, as a 30-min intravenous infusion. In multiple large randomized studies, mitoxantrone plus prednisone was shown to reduce pain and increase quality of life for patients with CRPC, though it does not extend survival. Subsequent to the approval of docetaxel as a treatment for CRPC, mitoxantrone has primarily been used as a second-line therapy. [ABSTRACT FROM AUTHOR]

New therapies challenge the very definition of multiple sclerosis (MS). By classic definitions, MS is a chronic neurological disease characterized by plaques or scars in the central nervous system (CNS) as a result of demyelization and atrophy of neuronal axons. However, for most diagnosed with MS, symptoms and progression are much more heterogeneous than that definition would imply. For most with MS, the initial symptoms include a relapsing and remitting inflammatory phase (RR-MS), which responds to immunotherapy. Natural history studies of clinical relapse rates, a primary endpoint used in most phase III treatment trials, report incidence of relapses from 0.5 to 2 per year (Weinshenker and Ebers, 1987). With time, most RR-MS patients transition to what has been characterized as a non-inflammatory secondary progressive form of the disease (SP-MS). Immunotherapies that target the inflammatory phase of MS may not be effective once the transition occurs. In addition, a proportion of those diagnosed with MS exhibit a more aggressive form of MS that does not show significant remission cycles nor respond to the same therapies. This aggressive form of the disease was termed primary progressive (PP-MS) using consensus data from an international survey of clinicians for standard definitions of these common clinical MS courses (Lublin and Reingold, 1996). [ABSTRACT FROM AUTHOR]