Drug repositioning of antipsychotic drugs for cisplatin-induced pica behavior in mice.

We aimed to clarify whether various antipsychotics ameliorate cisplatin-induced pica behavior in mice using a drug repositioning approach. Mice were administered cisplatin (12.5 mg/kg, i.p.) with or without olanzapine (1 mg/kg, i.p.), asenapine (4 mg/kg, i.p.), mirtazapine (5 mg/kg, i.p.) or standard three-drug antiemetics (granisetron [0.5 mg/kg, i.p.], fosaprepitant [25 mg/kg, i.p.], and dexamethasone [3 mg/kg, i.p.]). Kaolin, food, and water intake, and spontaneous motor activity on the day before and seven consecutive days after the cisplatin administration were measured using a telemetry system. At the primary endpoint, kaolin intake was significantly higher at day three in the cisplatin group than in the pre-treatment and saline groups ( p < 0.05). Additionally, kaolin intake was not significantly higher in cisplatin with olanzapine, asenapine, and mirtazapine groups for seven days than in the pre-treatment group. At the secondary endpoint, cisplatin decreased the food and water intake, and spontaneous motor activity in a time-dependent manner. Three antipsychotics failed to improve the cisplatin-induced decrease in food and water intake, and spontaneous motor activity. The findings suggest that prophylactic administration of antipsychotics besides olanzapine may improve cisplatin-induced nausea and vomiting in a delayed phase and de-escalate standard 3-drug antiemetics.

Suppression of infliximab antibody levels by azathioprine in patients with rheumatoid arthritis.

In rheumatoid arthritis (RA) treatment, the concomitant use of methotrexate has been shown to reduce the incidence of antibodies to infliximab (ATI), on the other hand, it is unclear whether azathioprine can reduce ATI production. We enrolled a total of 10 Japanese adult patients with RA who were treated with infliximab concomitantly with methotrexate or azathioprine. Serum concentrations of infliximab and ATI of these patients were measured. The mean serum infliximab concentrations was 1.6±1.3 µg/ml in patients with methotrexate and 1.0±0.5 µg/ml in patients with azathioprine. Serum ATI concentrations were below the limit of quantitation in 4 of 5 patients in each group. The results from the present study suggest that azathioprine suppresses ATI production.

Effect of genetic polymorphisms of azathioprine-metabolizing enzymes on response to rheumatoid arthritis treatment.

Azathioprine (AZA) is increasingly being prescribed to rheumatoid arthritis (RA) patients. Following oral administration, AZA is converted into its active form. Inflammatory bowel disease (IBD) and systemic lupus erythematosus (SLE) patients with low thiopurine (S)-methyltransferase (TPMT) activity tend to respond well to AZA therapy. In a previous study of Japanese SLE patients under low-dose AZA therapy, the group with the 94C>A mutation in inosine triphosphatase (ITPA) showed greater improvement in their disease activity index. However, it is not yet clear how genotypes relate to responsiveness to RA treatment. The genotypes ITPA 94C>A, TPMT*3C, NUDT15 595C>T, GST-M1, GST-T1 and MRP4/ABCC4 2269G>A of Japanese patients with RA were determined. The relationship between these genotypes and response to AZA therapy was evaluated using the Disease Activity Score 28 (DAS28) and various medical data. Of the 22 patients 15 had the ITPA 94C/C genotype, 7 had the ITPA 94C/A genotype, none had the TPMT*3C mutation, 4 had the NUDT15 595C>T mutation, 8 had the GST-M1 and T1 null genotypes and 9 had the MRP4/ABCC4 2269G>A mutation. Changes in DAS28 at 6 months after baseline were similar in both ITPA genotype groups. However, the maintenance dose of AZA was significantly lower in the C/A group than in the C/C group (0.85±0.30 mg/kg/day vs. 1.2±0.46 mg/kg/day, respectively; p = 0.043). The ITPA 94C/A group showed the same response to RA treatment as the C/C group, but at a lower dose. This demonstrates that RA patients with the ITPA 94C>A mutation are more responsive to AZA.