In patients with advanced/metastatic cancer, brivanib demonstrates promising antiangiogenic and antitumor activity and manageable toxicity at doses ≤800 mg orally q.d., the recommended phase II study dose.

Recently, extensive behavioral research has been conducted on the benztropine (BZT) analogs with the goal of developing successful therapeutics for cocaine abuse. The present study was conducted to characterize the contribution of dispositional factors in mediating the behavioral differences among the chloro BZT analogs and to identify cytochrome P450 enzymes involved in their metabolism. Bidirectional transport and efflux studies of four of the chloro BZT analogs were conducted. Screening with a panel of human and rat Supersomes was performed for 4Ј,4Љ-diCl BZT. In addition, pharmacokinetic and brain distribution studies for 4Ј-Cl and 4Ј,4Љ-diCl BZT in Sprague-Dawley rats were conducted. The permeability of the chloro analogs ranged from 8.26 to 32.23 and from 1.37 to 21.65 ϫ 10 Ϫ6 cm/s, whereas the efflux ratios ranged from 2.1 to 6.9 and from 3.3 to 28.4 across Madin-Darby canine kidneymultidrug resistance 1 (MDCK-MDR1) and Caco-2 monolayers, respectively. The P-glycoprotein (P-gp) inhibitor verapamil reduced the efflux ratios and enhanced the absorptive transport of the chloro BZT analogs. 4Ј,4Љ-diCl BZT was a substrate of human CYP2D6 and 2C19 and rat 2C11 and 3A1. The brain uptake for 4Ј-Cl and 4Ј,4Љ-diCl BZT was comparable and higher than previously reported for cocaine (brain-to-plasma partition coefficient ϭ 4.6 -4.7 versus 2.1 for cocaine). The rank order for t 1/2 was 4Ј,4Љ-diCl BZT Ͼ Ͼ 4Ј-Cl BZT Ͼ cocaine and for steadystate volume of distribution was 4Ј-Cl BZT Ͼ 4Ј,4Љ-diCl BZT Ͼ Ͼ cocaine. In conclusion, the chloro analogs differ significantly in their clearance and duration of action, which correlates to their behavioral profiles and abuse liability. Furthermore, these results suggest that the distinctive behavioral profile of these analogs is not due to limited brain exposure.The psychostimulant effects of cocaine are thought to be mediated mainly through inhibition of dopamine uptake via the dopamine transporter (DAT) (Ritz et al., 1987;Volkow et al., 1997). Accordingly, the DAT has been regarded as one of the key targets for the development of cocaine agonist therapeutics (Carroll et al., 1999;Rothman et al., 2005). Benztropine (BZT) is a potent dopamine uptake inhibitor that is not subject to significant abuse in humans (Rothman, 1990). As such, BZT was used as the pharmacophore for the design of a series of BZT analogs with the purpose of enhancing the potency and selectivity toward DAT (Newman and Kulkarni, 2002;Zou et al., 2003;Kulkarni et al., 2004). The overall goal of these studies has been to better understand the role of DAT in cocaine addiction and to guide the design of ligands that may serve as medications for the treatment for cocaine abuse. Article, publication date, and citation information can be found at http://jpet.aspetjournals.org. doi:10.1124/jpet.106.111245. ABBREVIATIONS:DAT, dopamine transporter; BZT, benztropine; 4Ј-Cl BZT, 4Ј-chloro-3␣-(diphenylmethoxy)tropane; 4Ј,4Љ-diCl BZT, 4Ј,4Љ-dichloro-3␣-(diphenylmethoxy)tropane; 3Ј-Cl BZT, 3Ј-chloro-3␣-(diphenylmethoxy)...

The results suggest that caffeine administered in the gum formulation (Stay Alert chewing gum) via a multiple dosing regimen provides an effective and convenient means of maintaining effective concentrations of caffeine that would in some operational scenarios be desirable for maintaining alertness and performance in sleep deprived individuals.

Background:The objectives of this phase I study were to determine the safety, pharmacokinetics (PK), pharmacodynamics and efficacy of brivanib combined with full-dose cetuximab in patients with advanced gastrointestinal malignancies.Methods:Patients with advanced gastrointestinal malignancies who had failed prior therapies received brivanib (320, 600 or 800 mg daily) plus cetuximab (400 mg m–2 loading dose then 250 mg m–2 weekly). Assessments included adverse events, PK, tumour response, 2[18F]fluoro-2-deoxyglucose positron-emitting tomography and K-Ras mutation analyses.Results:Toxicities observed were manageable; the most common treatment-related toxicities (>10% of patients) were fatigue, diarrhoea, anorexia, increase in aspartate aminotransferase and alanine aminotransferase, acneiform dermatitis, headache, mucosal inflammation, nausea, dry skin, vomiting, hypertension, pruritus, proteinuria and weight loss. Of 62 patients, 6 (9.7%) had objective radiographic partial responses, with an overall response rate of 10%. Median duration of response was 9.2 months; median progression-free survival was 3.9 months.Conclusions:The acceptable toxicity profile and efficacy of brivanib observed in this study were promising. These findings are being further evaluated in a phase III study of brivanib plus cetuximab vs cetuximab alone in patients previously treated with combination chemotherapy for K-Ras wild-type advanced metastatic colorectal cancer.

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