Crystal structure of (E)-2-[(2-bromopyridin-3-yl)methyl-idene]-6-meth-oxy-3,4-di-hydro-naphthalen-1(2H)-one and 3-[(E)-(6-meth-oxy-1-oxo-1,2,3,4-tetra-hydro-naphthalen-2-ylidene)meth-yl]pyridin-2(1H)-one.

The title compounds C17H14BrNO2, (I), and C17H15NO3, (II), were obtained from the reaction of 6-meth-oxy-3,4-di-hydro-2H-naphthalen-1-one and 2-bromo-nicotinaldehyde in ethanol. Compound (I) was the expected product and compound (II) was the oxidation product from air exposure. In the crystal structure of compound (I), there are no short contacts or hydrogen bonds. The structure does display π-π inter-actions between adjacent benzene rings and adjacent pyridyl rings. Compound (II) contains two independent mol-ecules, A and B, in the asymmetric unit; both are non-planar, the dihedral angles between the meth-oxy-benzene and 1H-pyridin-2-one mean planes being 35.07 (9)° in A and 35.28 (9)°in B. In each mol-ecule, the 1H-pyridin-2-one unit participates in inter-molecular N-H⋯O hydrogen bonding to another mol-ecule of the same type (A to A or B to B). The structure also displays π-π inter-actions between the pyridyl and the benzene rings of non-equivalent mol-ecules (viz., A to B and B to A).

Phase I and pharmacokinetic study of XRP6258 (RPR 116258A), a novel taxane, administered as a 1-hour infusion every 3 weeks in patients with advanced solid tumors.

PURPOSE: To assess the feasibility of administering XRP6258, a new taxane with a low affinity for the multidrug resistance 1 protein, as a 1-hour i.v. infusion every 3 weeks. The study also sought to determine the maximum tolerated dose and the recommended dose, to describe the pharmacokinetic (PK) behavior of the compound, and to seek preliminary evidence of anticancer activity. EXPERIMENTAL DESIGN: Twenty-five patients with advanced solid malignancies were treated with 102 courses of XRP6258 at four dose levels ranging from 10 to 25 mg/m(2). Dose escalation was based on the occurrence of dose-limiting toxicity (DLT) at each dose level, provided that PK variables were favorable. The maximum tolerated dose was defined as the dose at which at least two patients developed a DLT at the first course. RESULTS: Neutropenia was the principal DLT, with one patient experiencing febrile neutropenia and two others showing prolonged grade 4 neutropenia at the 25 mg/m(2) dose level. Nonhematologic toxicities, including nausea, vomiting, diarrhea, neurotoxicity, and fatigue, were generally mild to moderate in severity. XRP6258 exhibited dose-proportional PK, a triphasic elimination profile, a long terminal half-life (77.3 hours), a high clearance (mean CL, 53.5 L/h), and a large volume of distribution (mean V(ss), 2,034 L/m(2)). Objective antitumor activity included partial responses in two patients with metastatic prostate carcinoma, one unconfirmed partial response, and two minor responses. CONCLUSION: The recommended phase II dose of XRP6258 on this schedule is 20 mg/m(2). The general tolerability and encouraging antitumor activity in taxane-refractory patients warrant further evaluations of XRP6258.

Cross-reactivity among edible nuts: double immunodiffusion, crossed immunoelectrophoresis, and human specific igE serologic surveys.

BACKGROUND: As many as one third of all food allergen anaphylactic events are related to tree nut ingestion. Although concurrent allergen sensitivity to tree nuts is common, cross-reactivity among nut antigens is less well defined. OBJECTIVE: To survey serologic cross-reactivities among 7 tree nuts (walnut, pecan, hazelnut, cashew, Brazil nut, pistachio, and almond) and peanut. METHODS: Human specific IgE enzyme-linked immunosorbent assay inhibition was used to identify nut allergen cross-reactivities. Single-nut rabbit antisera were used in double immunodiffusion, crossed-line immunoelectrophoresis, and crossed immunoelectrophoresis with intermediate gel studies of nut antigen cross-reactivity. RESULTS: Nut specific IgE enzyme-linked immunosorbent assay inhibition demonstrated no cross-reactivities between peanut and tree nuts. Among tree nuts, 2 groups with allergen cross-reactivity were defined: (1) walnut, pecan, and hazelnut and (2) hazelnut, cashew, Brazil nut, pistachio, and almond. Double immunodiffusion, crossed-line immunoelectrophoresis, and crossed immunoelectrophoresis with intermediate gel results supported the same groupings of cross-reactive tree nuts and identified several less prominent nut-nut antigen cross-reactivities between groups and with peanut. CONCLUSION: With few exceptions (notably limited peanut cross-reactivity with pistachio and walnut), peanut antigens did not serologically cross-react with tree nuts. Walnut, pecan, and hazelnut form a group of strongly cross-reactive tree nuts. Hazelnut, cashew, Brazil nut, pistachio, and almond form a group of moderately cross-reactive tree nuts. Cross-reactivities between these groups are less pronounced (notably limited cross-reactivity of walnut and pecan with Brazil nut). The strongest cross-reactivities among tree nuts follow botanical family associations: (1) walnut and pecan in the family Juglandaceae and (2) cashew and pistachio in the family Anacardiaceae.

A Phase I and pharmacokinetic study of squalamine, an aminosterol angiogenesis inhibitor.

PURPOSE: The purpose of this study was to assess the feasibility and characterize the pharmacokinetics of squalamine administered as a continuous i.v. infusion daily for 5 days every 3 weeks. EXPERIMENTAL DESIGN: Patients with advanced solid malignancies were treated with escalating doses of squalamine as a 5-day continuous i.v. infusion every 3 weeks. Doses were initially escalated in 100% increments from a starting dose of 6 mg/m(2)/day, with a single patient treated at each dose level until moderate toxicity was observed, at which time additional patients were treated. RESULTS: Thirty-three patients were treated with 73 courses of squalamine at 13 dose levels ranging from 6 to 700 mg/m(2)/day. Hepatotoxicity, characterized by brief, asymptomatic elevations in transaminases and hyperbilirubinemia, was the principal dose-limiting toxicity of squalamine. At 700 mg/m(2)/day, two of three patients developed grade 4 hyperbilirubinemia, which precluded further dose escalation. At 500 mg/m(2)/day, one of seven patients experienced dose-limiting grade 4 hyperbilirubinemia and grade 3 neurosensory changes, which resolved soon after treatment. Squalamine pharmacokinetics were dose-proportional. At 500 mg/m(2)/day, the mean (percentage coefficient of variation) clearance, half-life, and volume of distribution of squalamine were 2.67 liters/h/m(2) (85%), 9.46 h (81%), and 36.84 liters/m(2) (124%), respectively, and steady-state concentrations [20.08 micro g/ml (13%)] were well above those that inhibit angiogenesis in preclinical models. CONCLUSIONS: At the recommended Phase II dose of 500 mg/m(2)/day, squalamine is well tolerated and results in plasma concentrations at least an order of magnitude higher than those required for prominent antiangiogenic effects in preclinical studies.