First-in-human phase 1/2a trial of CRLX101, a cyclodextrin-containing polymer-camptothecin nanopharmaceutical in patients with advanced solid tumor malignancies.

Patients with advanced solid malignancies were enrolled to an open-label, single-arm, dose-escalation study, in which CRLX101 was administered intravenously over 60 min among two dosing schedules, initially weekly at 6, 12, and 18 mg/m(2) and later bi-weekly at 12, 15, and 18 mg/m(2). The maximum tolerated dose (MTD) was determined at 15 mg/m(2) bi-weekly, and an expansion phase 2a study was completed. Patient samples were obtained for pharmacokinetic (PK) and pharmacodynamic (PD) assessments. Response was evaluated per RECIST criteria v1.0 every 8 weeks. Sixty-two patients (31 male; median age 63 years, range 39-79) received treatment. Bi-weekly dosing was generally well tolerated with myelosuppression being the dose-limiting toxicity. Among all phase 1/2a patients receiving the MTD (n = 44), most common grade 3/4 adverse events were neutropenia and fatigue. Evidence of systemic plasma exposure to both the polymer-conjugated and unconjugated CPT was observed in all treated patients. Mean elimination unconjugated CPT Tmax values ranged from 17.7 to 24.5 h, and maximum plasma concentrations and areas under the curve were generally proportional to dose for both polymer-conjugated and unconjugated CPT. Best overall response was stable disease in 28 patients (64 %) treated at the MTD and 16 (73 %) of a subset of NSCLC patients. Median progression-free survival (PFS) for patients treated at the MTD was 3.7 months and for the subset of NSCLC patients was 4.4 months. These combined phase 1/2a data demonstrate encouraging safety, pharmacokinetic, and efficacy results. Multinational phase 2 clinical development of CRLX101 across multiple tumor types is ongoing.

The impact of stress incontinence surgery on female sexual function.

OBJECTIVE: We sought to describe change in sexual function 2 years after surgery to treat stress urinary incontinence. STUDY DESIGN: This analysis included 655 women randomized to Burch colposuspension or sling surgery. Sexual activity was assessed by the Pelvic Organ Prolapse/Urinary Incontinence Sexual Questionnaire (PISQ-12) among those sexually active at baseline and 2 years after surgery. RESULTS: Mean PISQ-12 total score improved from baseline 32.23 +/- 6.85 to 36.85 +/- 5.89. After surgery, fewer subjects reported incontinence (9% vs 53%; P < .0001), restriction of sexual activity as a result of fear of incontinence (10% vs 52%; P < .0001), avoidance of intercourse because of vaginal bulging (3% vs 24%; P < .0001), or negative emotional reactions during sex (9% vs 35%; P < .0001). Women with successful surgery had greater improvement PISQ-12 scores (5.77 vs 3.79; P < .006). Sexually active women were younger, thinner, and had lower Medical, Epidemiological, and Social Aspects of Aging scores (total and urge subscale) than sexually inactive women. CONCLUSION: Sexual function improves after successful surgery and does not differ between Burch and sling.

Biochemical enrichment and biophysical characterization of a taste receptor for L-arginine from the catfish, Ictalurus puntatus.

BACKGROUND: The channel catfish, Ictalurus punctatus, is invested with a high density of cutaneous taste receptors, particularly on the barbel appendages. Many of these receptors are sensitive to selected amino acids, one of these being a receptor for L-arginine (L-Arg). Previous neurophysiological and biophysical studies suggested that this taste receptor is coupled directly to a cation channel and behaves as a ligand-gated ion channel receptor (LGICR). Earlier studies demonstrated that two lectins, Ricinus communis agglutinin I (RCA-I) and Phaseolus vulgaris Erythroagglutinin (PHA-E), inhibited the binding of L-Arg to its presumed receptor sites, and that PHA-E inhibited the L-Arg-stimulated ion conductance of barbel membranes reconstituted into lipid bilayers. RESULTS: Both PHA-E and RCA-I almost exclusively labeled an 82-84 kDa protein band of an SDS-PAGE of solubilized barbel taste epithelial membranes. Further, both rhodamine-conjugated RCA-I and polyclonal antibodies raised to the 82-84 kDa electroeluted peptides labeled the apical region of catfish taste buds. Because of the specificity shown by RCA-I, lectin affinity was chosen as the first of a three-step procedure designed to enrich the presumed LGICR for L-Arg. Purified and CHAPS-solubilized taste epithelial membrane proteins were subjected successively to (1), lectin (RCA-I) affinity; (2), gel filtration (Sephacryl S-300HR); and (3), ion exchange chromatography. All fractions from each chromatography step were evaluated for L-Arg-induced ion channel activity by reconstituting each fraction into a lipid bilayer. Active fractions demonstrated L-Arg-induced channel activity that was inhibited by D-arginine (D-Arg) with kinetics nearly identical to those reported earlier for L-Arg-stimulated ion channels of native barbel membranes reconstituted into lipid bilayers. After the final enrichment step, SDS-PAGE of the active ion channel protein fraction revealed a single band at 82-84 kDa which may be interpreted as a component of a multimeric receptor/channel complex. CONCLUSIONS: The data are consistent with the supposition that the L-Arg receptor is a LGICR. This taste receptor remains active during biochemical enrichment procedures. This is the first report of enrichment of an active LGICR from the taste system of vertebrata.