Pharmacokinetics and enhanced bioavailability of candidate cancer preventative agent, SR13668 in dogs and monkeys

Purpose

SR13668 (2,10-dicarbethoxy-6-methoxy-5,7-dihydro-indolo-(2,3-b)carbazole), is a new candidate cancer chemopreventive agent under development. It was designed using computational modeling based on a naturally occurring indole-3-carbinol and its in vivo condensation products. It showed promising anti-cancer activity and its preclinical toxicology profile (genotoxicity battery and subchronic rat and dog studies) was unremarkable. However, it exhibited a very poor oral bioavailability (<1%) in both rats and dogs. Therefore, a study was initiated to develop and evaluate in dogs and non-human primates formulations with a more favorable oral bioavailability.

Methods

Two formulations utilizing surfactant/emulsifiers, PEG400:Labrasol^® and Solutol^®, were tested in dogs and monkeys. Levels of SR13668 were measured in plasma and blood using a high-performance liquid chromatograph–tandem mass spectrometer system. Non-compartmental analysis was used to derive pharmacokinetic parameters including the bioavailability.

Results

The Solutol^® formulation yielded better bioavailability reaching a maximum of about 14.6 and 7.3% in dogs and monkeys, respectively, following nominal oral dose of ca. 90 mg SR13668/m². Blood levels of SR13668 were consistently about threefold higher than those in plasma in both species. SR13668 did not cause untoward hematology, clinical chemistry, or coagulation effects in dogs or monkeys with the exception of a modest, reversible increase in liver function enzymes in monkeys.

Conclusions

The lipid-based surfactant/emulsifiers, especially Solutol^®, markedly enhanced the oral bioavailability of SR13668 over that previously seen in preclinical studies. These formulations are being evaluated in a Phase 0 clinical study prior to further clinical development of this drug.     

How successful is errorless learning in supporting memory for high and low-level knowledge in dementia?

Errorless learning has been shown to be very successful in the rehabilitation of memory problems particularly in patients with severe forms of memory impairment. Much of this research has focused on testing knowledge of specific details studied, ignoring any additional, higher-level knowledge that patients may have acquired during the learning process. Hence, it is pertinent to ask whether errorless learning is equally successful in the acquisition of high and low-level knowledge. In this paper, we present results of several studies comparing the effectiveness of errorless and standard trial-and-error methods in acquisition of high and low-level knowledge in people diagnosed with dementia and non-impaired controls. In Study 1, participants were asked to learn novel face-name-occupation associations; and knowledge across a range of levels, from very general (i.e., high-level) to very specific (i.e., low-level), was examined. For patients with probable Alzheimer's disease and controls there was evidence of increased benefit from errorless training in general, but the technique was most beneficial for patients attempting to retrieve specific detail. Study 2 was conducted to address the problem raised by the failure in Study 1 to manipulate learning condition at our highest knowledge level. This novel manipulation was successful, but neither of the patients received the standard benefit from errorless training. Study 3, involving a small group of dementia patients with mixed diagnoses, was conducted to replicate findings from Study 1. Results from the group analysis confirmed that the benefit obtained from errorless learning increased as a function of knowledge specificity, but again several patients failed to show a consistent effect of learning condition. Implications for use of the errorless technique are discussed.     

Patterns of memory dysfunction in current and 2-year abstinent MDMA users

The popular recreational drug MDMA or "ecstasy" is a selective serotonin neurotoxin in many species and has been found to be associated with memory dysfunction in human beings. Recent studies suggest that this impairment persists after cessation of use for periods up to at least one year. However, there is no clear indication as yet concerning which stage of memory processing is impaired as a result of MDMA use. In the current study, 31 current MDMA users and 30 MDMA users who had been abstinent for more than two years were compared with 30 controls on the WMS-III. The results suggest that MDMA use is associated with memory dysfunction and that this dysfunction persists for up to two years after cessation of use. Importantly, the findings suggest that this memory dysfunction may be due to interference at the encoding stage of memory processing.     

N-Acylthiadiazolines, a new class of liver X receptor agonists with selectivity for LXRbeta

We have identified a novel liver X receptor (LXR) agonist (2) that activates the LXRbeta subtype with selectivity over LXRalpha. LXRbeta selectivity was confirmed using macrophages derived from LXR mutant mice. Despite its selectivity and modest potency, the compound can induce APO-AI-dependent cholesterol efflux from macrophages with full efficacy. Our results indicate that it is possible to achieve significant LXRbeta selectivity in a small molecule while maintaining functional LXR activity.     

Percutaneous Gastrostomy in Patients Who Fail or Are Unsuitable for Endoscopic Gastrostomy

Purpose: Percutaneous endoscopic gastrostomy (PEG) is not possible or fails in some patients. We aimed to categorize the reasons for PEG failure, to study the success of percutaneous radiologic gastrostomy (PRG) in these patients, and to highlight the associated technical difficulties and complications. Methods: Forty-two patients (28 men, 14 women; mean age 60 years, range 18–93 years) in whom PEG failed or was not possible, underwent PRG. PEG failure or unsuitability was due to upper gastrointestinal tract obstruction or other pathology precluding PEG in 15 of the 42 patients, suboptimal transillumination in 22 of 42 patients, and advanced cardiorespiratory decompensation precluding endoscopy in five of 42 patients. T-fastener gastropexy was used in all patients and 14–18 Fr catheters were inserted. Results: PRG was successful in 41 of 42 patients (98%). CT guidance was required in four patients with altered upper gastrointestinal anatomy. PRG failed in one patient despite CT guidance. In the 16 patients with high subcostal stomachs who failed PEG because of inadequate transillumination, intercostal tube placement was required in three and cephalad angulation under the costal margin in six patients. Major complications included inadvertent placement of the tube in the peritoneal cavity. There was one case of hemorrhage at the gastrostomy site requiring transfusion and one case of superficial gastrostomy site infection requiring tube removal. Minor complications included superficial wound infection in six patients, successfully treated with routine wound toilette. Conclusion: We conclude that PRG is a safe, well-tolerated and successful method of gastrostomy and gastrojejunostomy insertion in the technically difficult group of patients who have undergone an unsuccessful PEG. In many such cases optimal clinical evaluation will suggest primary referral for PRG as the preferred option.     

骨形成蛋白与骨疾患关系的研究进展

目的：了解骨形成蛋白（ＢＭＰ）与机体骨疾患者发生发展的关系。方法：综述了近五年来ＢＭ与骨疾患关系的研究进展。结果：Ｂ屿骨发育异常、遗传性骨疾病、某些骨 异位骨化等有着直接或间接的关系。结论：搞清ＢＭＰ与机体骨疾患的关系。有助于进一步了解疾病的发病机制、病程进展和预后,为选择合适的治疗方法提供指导。