A phase I study of the p-glycoprotein antagonist Tarquidar in combination with Vinorelbine.

P-glycoprotein (Pgp) antagonists have had unpredictable pharmacokinetic interactions requiring reductions of chemotherapy. We report a phase I study using tariquidar (XR9576), a potent Pgp antagonist, in combination with vinorelbine. EXPERIMENTAL DESIGN: Patients first received tariquidar alone to assess effects on the accumulation of (99m)Tc-sestamibi in tumor and normal organs and rhodamine efflux from CD56+ mononuclear cells. In the first cycle, vinorelbine pharmacokinetics was monitored after the day 1 and 8 doses without or with tariquidar. In subsequent cycles, vinorelbine was administered with tariquidar. Tariquidar pharmacokinetics was studied alone and with vinorelbine. RESULTS: Twenty-six patients were enrolled. Vinorelbine 20 mg/m(2) on day 1 and 8 was identified as the maximum tolerated dose (neutropenia). Nonhematologic grade 3/4 toxicities in 77 cycles included the following: abdominal pain (4 cycles), anorexia (2), constipation (2), fatigue (3), myalgia (2), pain (4) and dehydration, depression, diarrhea, ileus, nausea, and vomiting, (all once). A 150-mg dose of tariquidar: (1) reduced liver (99m)Tc-sestamibi clearance consistent with inhibition of liver Pgp; (2) increased (99m)Tc-sestamibi retention in a majority of tumor masses visible by (99m)Tc-sestamibi; and (3) blocked Pgp-mediated rhodamine efflux from CD56+ cells over the 48 hours examined. Tariquidar had no effects on vinorelbine pharmacokinetics. Vinorelbine had no effect on tariquidar pharmacokinetics. One patient with breast cancer had a minor response, and one with renal carcinoma had a partial remission. CONCLUSIONS: Tariquidar is a potent Pgp antagonist, without significant side effects and much less pharmacokinetic interaction than previous Pgp antagonists. Tariquidar offers the potential to increase drug exposure in drug-resistant cancers.

Ferromagnetism in DyRh and DyRhX (X = Fe, Ni, Co, Gd) thin films

In an effort to achieve large high-field magnetization and increased Curie temperature, polycrystalline DyRh, (DyRh)95X5 and (DyRh)85X15 (X = Fe, Co, Ni, Gd) thin films have been prepared via ultra-high vacuum DC co-sputtering on SiO2 and Si wafers, using Ta as seed and cap material. A body-centred cubic CsCl-like crystal formation (B2 phase) was achieved for DyRh around the equiatomic equilibrium, known from single crystals. The maximum in-plane spontaneous magnetization at T = 4K in fields of μ0H = 5T of was found to be μ0MS,4K = (1.50 ± 0.09)T with a ferromagnetic transition at TC = (5 ± 1)K and a coercivity of μ0HC,4K[D] = (0.010 ± 0.001)T (at T = 4K) for layers deposited on substrates heated to 350°C. Samples prepared at room temperature exhibited poorer texture, smaller grains and less B2-phase content; this did impact on the Curie temperature which was higher compared to those layers with best crystallisation; however the maximal magnetization stayed unaffected. Ferromagnetic coupling was observed in ternary alloys of DyRhGd and DyRhNi with an increased Curie temperature, larger initial permeability, and
high-field magnetization which was best for (DyRh)85Gd15 with μ0MS,4K[Gd15] = (2.10 ± 0.13)T. DyRhFe and DyRhCo showed antiparallel coupling of the spontaneous magnetic moments.