Materials and Methods: A total of 16 patients with carcinoma in situ refractory to bacillus Calmette-Guerin were enrolled in a phase I, open
label, single institution study. A minimum of 3 eligible patients were included per dose level. Paclitaxel-hyaluronic acid solution (ONCOFID-P-B (TM)) was administered for 6 consecutive weeks. The primary objective was to identify the maximum tolerated dose and the recommended dose. As secondary objectives the safety profile of ONCOFID-P-B, CH5183284 the pharmacokinetic profile after each instillation and the tumor response were also evaluated.
Results: No dose limiting toxicity occurred at any drug level evaluated. The plasma levels of the study drug were always below the lower limit of quantification at all tested doses after each instillation. A total of 11 adverse events were reported by 7 patients and selleck chemicals 9 (60%) showed complete treatment response.
Conclusions: Intravesical instillation of ONCOFID-P-B for carcinoma in situ refractory to bacillus Calmette-Guerin showed minimal toxicity and no systemic absorption in the first human intravesical clinical trial to our knowledge. Finally, satisfactory response rates were observed.”
“Cultures of neonatal and adult dorsal root ganglion (DRG) neurons are commonly used in in vitro models to study the ion channels and signaling events associated with peripheral sensation under various
conditions. Differential responsiveness between neonatal and adult DRG neurons to physiological or pathological stimuli suggests potential differences in their
gene expression profiles. We performed a microarray analysis of cultured adult and neonatal rat DRG neurons, which revealed distinct gene expression profiles especially of ion channels and signaling molecules at the genomic level. For example, Ca(2+)-stimulated adenylyl cyclase (AC) isoforms AC3 and AC8, PKC delta and CaMKIl alpha, the voltage-gated sodium channel beta QNZ 1 and beta 4, and potassium channels K(v)1.1, K(v)3.2, K(v)4.1, K(v)9.1, K(v)9.3, K(ir)3.4, K(ir)7.1, K(2p)1.1/TWIK-1 had significantly higher mRNA expression in adult rat DRG neurons, while Ca(2+)-inhibited AC5 and AC6, sodium channel Na(v)1.3 alpha subunit, potassium channels K(ir)6.1, K(2p)10.1/TREK-2, calcium channel Ca(v)2.2 alpha 1 subunit, and its auxiliary subunits beta 1 and beta 3 were conversely down regulated in adult neurons. Importantly, higher adult neuron expression of ERK1/2, PI3K/P110 alpha, but not of TRPV1 and TrkA, was found and confirmed by PCR and western blot. These latter findings are consistent with the key role of ERK and PI3K signaling in sensitization of TRPV1 by NGF and may explain our previously published observation that adult, but not neonatal, rat DRG neurons are sensitized by NGF. (C) 2011 Elsevier Ireland Ltd. All rights reserved.