Something Old, New, Borrowed, Blue: Anthracenedione Agents for Treatment of Multiple Sclerosis.

Objective: This study aimed to present anthracenedione agents that have been used to treat multiple sclerosis (MS), problems related to their use, and knowledge gained from our experiences using these agents to develop more efficacious drugs with fewer adverse effects.

Methods: We review preclinical and clinical data during the development mitoxantrone, an anthracycline, for the treatment of MS; benefits and potential risks; and strategies to reduce complications of anthracyclines.

Results: Mitoxantrone had unacceptable and greater-than-anticipated toxicity for use in a chronic disease such as MS.

A novel aza-anthrapyrazole blocks the progression of experimental autoimmune encephalomyelitis after the priming of autoimmunity.

Mitoxantrone is one of the few FDA-approved drugs available to treat rapidly progressing forms of multiple sclerosis; however, its utilization is compromised by a cardiotoxic potential and the risk of mitoxantrone-induced leukemia. BBR3378, a novel aza-anthrapyrazole, is structurally similar to mitoxantrone, but lacks the ring hydroxyls that may contribute to cardiotoxicity. Here, we investigated the therapeutic activity of BBR3378 in a C57BL/6 mouse model of multiple sclerosis.

Verapamil, but not probenecid, co-administration can convert desloratadine to a sedating antihistamine in mice.

The possibility that non-sedating antihistamines could elicit sedation in mice due to drug-induced inhibition of brain PgP was evaluated by measuring the ability of desloratadine alone or in combination with verapamil to cause ataxia in mice. Also, the concentrations of desloratadine in plasma and in brain homogenates were measured by liquid chromatography-mass spectrometry. Relative to methylcellulose (control) treatment, verapamil plus desloratadine decreased rotarod performance of mice.

The hemodynamic effects of diaspirin cross-linked hemoglobin in dopamine-resistant endotoxic shock in swine.

As the blood substitute Diaspirin Cross-linked Hemoglobin (DCLHb) has potent vasopressor activity, we assessed its hemodynamic effects in a clinically relevant dopamine-resistant endotoxic shock model in swine. In a randomized and controlled study, E. coli LPS was administered to anesthetized and invasively monitored swine.

Characterization of anthracenediones and their photoaffinity analogs.

In an attempt to overcome the cardiotoxicity and cross-resistance problems caused by the anticancer drugs anthracyclines and anthracenediones during chemotherapy, we have developed a series of aza-anthracenedione compounds by modifying the chromophore and the side arms of anthracyclines and anthracenediones. One of these aza-anthracenediones, 6,9-bis[(2-aminoethyl)amino]benzo[g]isoquinoline-5,10-dione (BBR 2778), which is currently under phase II clinical trials, showed remarkable antitumor activity and appeared to lack a cardiotoxic effect in preclinical studies. However, it was still cross-resistant against multidrug resistance (MDR) cells expressing P-glycoprotein (P-gp).