SAKK 21/12: a phase II trial of transdermal CR1447 in breast cancer patients.

Objective: CR1447, a novel transdermal formulation of 4-hydroxytestosterone, has aromatase-inhibiting and androgen receptor (AR)-modulating properties (IC504.4 nM) with antitumor effects against AR-positive tumor cells in vitro. This trial investigated the efficacy and safety of CR1447 for patients with metastatic estrogen receptor-positive (A) and AR-positive triple-negative breast cancers (B). Design and methods: (A) included patients with at most one prior endocrine therapy line without progression ≥6 months, whereas (B) included patients with ≤2 prior chemotherapy lines, all displaying advanced signs of disease. The primary endpoint was disease control at week 24 (DC24). The null hypothesis was DC24 ≤30% (A) and ≤15% (B). Thirty-seven patients were recruited (29 in (A) and 8 in (B)); accrual was stopped following an interim analysis demonstrating futility in (A) and slow accrual in (B). Results: DC24 was attained in 5/21 (95% CI: 8.2-47.2) patients in (A) and none in (B). The median progression-free survival was 5.1 months (95% CI: 2.5-5.6) in (A) and 2.5 months (95% CI: 0.7-2.6) in (B). The median overall survival was 24.6 months (95% CI: 22.9-not applicable) in (A) and 10.8 months (95% CI: 3.3-10.9) in (B). CR1447 had a favorable safety profile without treatment-related grade 3-5 toxicities in (A). Especially no side effects linked to androgenic effects were observed. Conclusions: Despite this trial being negative, the 24% DC24 rate in a second-line setting, and the prolonged partial response experienced by a patient, indicate activity. Further evaluation of CR1447 in endocrine-sensitive patients or combination trials appears warranted.

Synthesis, structure-activity relationship, and antimalarial activity of ureas and thioureas of 15-membered azalides.

Azithromycin, a first member of the azalide family of macrolides, while having substantial antimalarial activity, failed as a single agent for malaria prophylaxis. In this paper we present the first analogue campaign to identify more potent compounds from this class. Ureas and thioureas of 15-membered azalides, N''-substituted 9a-(N'-carbamoyl-ß-aminoethyl), 9a-(N'-thiocarbamoyl-ß-aminoethyl), 9a-[N'-(ß-cyanoethyl)-N'-(carbamoyl-ß-aminoethyl)], 9a-[N'-(ß-cyanoethyl)-N'-(thiocarbamoyl-ß-aminoethyl)], 9a-{N'-[ß-(ethoxycarbonyl)ethyl]-N'(carbamoyl-ß-aminoethyl)}, and 9a-[N'-(ß-amidoethyl)-N'-(carbamoyl-ß-aminoethyl)] of 9-deoxo-9-dihydro-9a-aza-9a-homoerythromycin A, were synthesized and their biological properties evaluated. The results obtained indicate a substantial improvement of the in vitro activity against P. falciparum (up to 88 times over azithromycin), particularly for compounds containing both sugars on the macrocyclic ring and aromatic moiety on 9a-position. The improved in vitro activity was not confirmed in the mouse model, likely due to an increase in lipophilicity of these analogues leading to a higher volume of distribution. Overall, with increased in vitro activity, promising PK properties, and modest in vivo efficacy, this series of molecules represents a good starting platform for the design of novel antimalarial azalides.

Novelty detection--recognition and evaluation of exceptional water reflectance spectra.

The aim of environmental surveillance is to monitor known phenomena as well as to detect exceptional situations. Synoptic monitoring of large areas in coastal waters can be performed by remote sensing using multispectral sensors onboard satellites. Many methods are in use which enable the detection and quantification of 'standard algae' or specific algae blooms using their known spectral response. The present study focusses on the detection of spectra outside the known range and which are referred to as exceptional spectra. In a first step observations from a one-year period were used to establish the parameterisation of what is defined as 'normal.' In a second step observations from a different period were used to test the novelty detection application, i.e. to look for features not occurring in the first period.

Practical test of a point-source integrating cavity absorption meter: the performance of different collector assemblies.

A prototype point-source integrating cavity absorption meter (PSICAM) is presented and compared with spectrophotometric absorption measurements. Different light collector assemblies of the PSICAM were tested regarding their capability to determine the absorption of water constituents accurately over a wide range of concentrations and scattering properties. The PSICAM setup with a radiance-type sensor showed the best performance. It was compared with a photometric absorption determination using nonscattering dye solutions. The mean difference between both methods was less than 2.4% in the spectral range of 400-700 nm. The absorption determination with the PSICAM, when equipped with a radiance sensor as a light collector, was only little affected by scattering and temperature. We conclude that the PSICAM can be used to determine the absorption of natural seawater samples at ambient temperatures.

Novel antifungal beta-amino acids: synthesis and activity against Candida albicans.

A series of novel beta-amino acids has been synthesized and tested for their in vitro antifungal activity against Candida albicans. A steep SAR was observed. beta-Amino acid 21 (BAY 10-8888/PLD-118) revealed the most favourable activity-tolerability profile and was selected for clinical studies as a novel antifungal for the oral treatment of yeast infections.

A neutral trehalase gene from Candida albicans: molecular cloning, characterization and disruption.

A neutral trehalase gene, NTC1, from the human pathogenic yeast Candida albicans was isolated and characterized. An ORF of 2724 bp was identified encoding a predicted protein of 907 amino acids and a molecular mass of 104 kDa. A single transcript of approximately 3.2 kb was detected by Northern blot analysis. Comparison of the deduced amino acid sequence of the C. albicans NTC1 gene product with that of the Saccharomyces cerevisiae NTH1 gene product revealed 57% identity. The NTC1 gene was localized on chromosome 1 or R. A null mutant (delta ntc1/delta ntc1) was constructed by sequential gene disruption. Extracts from mutants homozygous for neutral trehalase deletion had only marginal neutral trehalase activity. Extracts from heterozygous mutants showed intermediate activities between extracts from the wild-type strain and from the homozygous mutants. The null mutant showed no significant differences in pathogenicity as compared to the wild-type strain in a mouse model of systemic candidiasis. This result indicates that the neutral trehalase of C. albicans is not a potential target for antifungal drugs.