Metabotropic glutamate receptor mGlu2 is resistant to homologous agonist-induced desensitization but undergoes protein kinase C-mediated heterologous desensitization.

To investigate the susceptibility of the group II metabotropic glutamate receptor mGlu2 to agonist-induced desensitization, the receptor was stably expressed in Chinese hamster ovary (CHO-mGlu2) or C6 glioma cells (C6-mGlu2). Exposure of CHO-mGlu2 cells to the group II mGlu receptor agonist (2S,1'S,2'S)-2-(carboxycyclopropyl)glycine (LCCG-1; 10 µM) for up to 15 h did not affect the subsequent ability of LCCG-1 to inhibit forskolin-stimulated cAMP accumulation. Similarly, in C6-mGlu2 cells, prolonged exposure to LCCG-1 also did not affect the subsequent ability of LCCG-1 to inhibit cAMP formation. In contrast, exposure of CHO-mGlu2 cells to the protein kinase C activator phorbol myristate acetate (PMA) suppressed the ability of LCCG-1 to inhibit cAMP formation. Using an in vitro model of group II mGlu receptor activity, the hemisected neonatal rat spinal cord preparation, the ability of the selective group II agonist (2R,4R)-4-aminopyrrolidine-2,4-dicarboxylate ((2R,4R)-APDC) to depress the fast component of the dorsal root-evoked ventral root potential (fDR-VRP) did not desensitize when applied for up to 2 h. Together these results indicate that in contrast to most G protein-coupled receptors, the mGlu2 receptor is resistant to agonist-induced homologous desensitization, and that in vitro data suggests that resistance to desensitization is a physiologically relevant property of this mGlu receptor subtype.

Lack of age and gender effects on single-dose pharmacokinetics of tomopenem (RO4908463/CS-023), a novel carbapenem.

AIMS: To investigate the effect of age and gender on the tolerability, safety and pharmacokinetics (PK) of tomopenem (RO4908463/CS-023), a novel carbapenem antibiotic, and its major metabolite. METHODS: Forty-two subjects were assigned to one of the following three groups: young men, elderly men and elderly women. The PK, safety and tolerability of an intravenous infusion of 1500 mg tomopenem and its resultant major metabolite (open beta-lactam ring) were assessed. RESULTS: Minor differences in exposure of both tomopenem and the major metabolite were seen. The area under the curve (AUC) of tomopenem was 22% higher in elderly men compared with young men, and 19% higher in elderly women relative to the elderly men. Total clearance of tomopenem decreased with decreasing creatinine clearance. In the two male groups, renal clearance values of tomopenem were similar (3.52 and 3.67 l h(-1)) and higher than in the elderly female group (2.83 l h(-1)). The mean half-lives ranged from 2.03 (healthy young men) to 2.41 h (elderly men). The difference in AUC of tomopenem can be explained by differences in the mean creatinine clearances of 116 (young men), 101 (elderly men) and 84.7 (elderly women) ml min(-1) 1.73 m(-2), respectively. CONCLUSIONS: While some PK parameters were statistically different among the three groups, the differences were mostly minor and unlikely to be clinically meaningful. The difference in the PK can be largely attributed to the difference in creatinine clearance of these groups.

Utility of serum HER2 extracellular domain assessment in clinical decision making: pooled analysis of four trials of trastuzumab in metastatic breast cancer.

PURPOSE: Trastuzumab is a humanized monoclonal antibody directed against human epidermal growth factor receptor 2 (HER2). Trastuzumab alone or in combination with chemotherapy has been shown to be effective in patients with HER2-positive early and metastatic breast cancer. The extracellular domain (ECD) of the HER2 protein may be shed into the serum and is detectable using an enzyme-linked immunosorbent assay. Correlations have been reported between raised baseline ECD levels and response to trastuzumab, suggesting that serum ECD levels may be useful in making treatment decisions in patients with HER2-positive breast cancer. We investigated this relationship, and also the effect of trastuzumab and chemotherapy on ECD levels, in patients with advanced breast cancer. METHODS: This study analyzed sequential ECD determinations on 322 patients treated with six different treatment regimens in four clinical trials. RESULTS: Baseline values were available in 296 patients, and of these, 205 (69%) had raised levels (> 15 ng/mL). No clear relationship was found between baseline ECD levels and tumor response. After initiating combination therapy, ECD levels declined irrespective of treatment received and tumor response. For trastuzumab monotherapy, some trend between changes in ECD levels in early cycles and best response was discernable, but the overlap was too broad to be clinically useful. Disease progression was not reliably predicted by rising ECD levels in the majority of patients. CONCLUSION: Based on our data, we cannot recommend using serum HER2 ECD levels to make trastuzumab or other treatment decisions for individual patients with advanced/metastatic breast cancer.

Effect of impaired renal function on the pharmacokinetics of tomopenem (RO4908463/CS-023), a novel carbapenem.

The objective of this study was to assess the impact of impaired renal function on the pharmacokinetics of tomopenem (RO4908463/CS-023), a novel carbapenem antibiotic, and its major metabolite in humans. Thirty-two subjects were enrolled in an open-label, two-center study. Subjects were evenly assigned to one of four groups, based on creatinine clearance ranges of > or =80, 50 to 79, 30 to 49, and <30 ml/min. The drug was given as a single 1,500-mg constant-rate intravenous infusion over 60 min. There were no safety concerns with increasing renal dysfunction. Renal impairment had a significant impact on exposure of both tomopenem and its metabolite. Mean (+/- standard deviation) areas under the curve for tomopenem increased with decreasing renal function, from 191 +/- 35.2 to 1,037 +/- 238 microg.h/ml. The maximum concentration of drug in plasma (C(max)) increased with a maximum difference of 44% between the severe and normal groups. In contrast, the corresponding increase in C(max) of the metabolite was much higher, at 174%. Total body clearance was linearly correlated with creatinine clearance (R(2) = 0.97; P < 0.0001). Renal clearance for tomopenem decreased with increasing severity of disease, with mean values decreasing from 4.63 +/- 0.89 to 0.59 +/- 0.19 liters/h. The results of this study indicated a strong correlation between the creatinine clearance and total clearance of tomopenem. While renal impairment appeared to have a significant effect on the pharmacokinetics of tomopenem, an even greater effect was seen on the elimination of the inactive metabolite.