The calcitonin gene-related peptide (CGRP) receptor antagonist BIBN4096BS reduces neurogenic increases in dural blood flow.

In an in vivo preparation of the exposed rat cranial dura mater electrical field stimulation causes increases in blood flow that are mainly due to the vasodilatory effect of calcitonin gene-related peptide (CGRP) released from meningeal afferents. In this preparation the effect of BIBN4096BS, a non-peptide competitive antagonist of CGRP receptors, was examined. Additionally, in an in vitro preparation of the hemisected rat skull the effect of BIBN4096BS on CGRP release stimulated by activation of meningeal afferents was analysed. Injection of BIBN4096BS at cumulative doses of 300 microg/kg and 900 microg/kg caused dose-dependent inhibition of the electrically evoked blood flow increases. The basal blood flow and vital parameters were not significantly changed by any dose. In the hemisected skull BIBN4096BS at 10(-6) M did not alter the CGRP release evoked by depolarizing K(+) concentrations or antidromic electrical stimulation of the trigeminal ganglion. We conclude that neurogenic increases in dural blood flow are reduced by BIBN4096BS without changing basal vascular parameters. This peripheral effect may be important with regard to CGRP receptor inhibition as an antimigraine strategy.

Inhibition of stimulated meningeal blood flow by a calcitonin gene-related peptide binding mirror-image RNA oligonucleotide.

Calcitonin gene-related peptide (CGRP) released from trigeminal afferents is known to play an important role in the control of intracranial blood flow. In a rat preparation with exposed cranial dura mater, periods of electrical stimulation induce increases in meningeal blood flow. These responses are due to arterial vasodilatation mediated in part by the release of CGRP. In this preparation, the effect of a CGRP-binding mirror-image oligonucleotide (Spiegelmer NOX-C89) was examined. Spiegelmer NOX-C89 applied topically at concentrations between 10(-7) and 10(-5) M to the exposed dura mater led to a dose-dependent inhibition of the electrically evoked blood flow increases. The highest dose reduced the mean increases in flow to 56% of the respective control levels. A nonfunctional control Spiegelmer (not binding to CGRP) was ineffective in changing blood flow increases. Intravenous injection of NOX-C89 (5 mg kg(-1)) reduced the evoked blood flow increases to an average of 65.5% of the control. The basal blood flow was not changed by any of the applied substances. In addition, an ex vivo preparation of the hemisected rat skull was used to determine CGRP release from the cranial dura mater caused by antidromic activation of meningeal afferents. In this model, 10(-6) M of NOX-C89 reduced the evoked CGRP release by about 50%. We conclude that increases in meningeal blood flow due to afferent activation can be reduced by sequestering the released CGRP and thus preventing it from activating vascular CGRP receptors. Moreover, the Spiegelmer NOX-C89 may inhibit CGRP release from meningeal afferents. Therefore, the approach to interfere with the CGRP/CGRP receptor system by binding the CGRP may open a new opportunity for the therapy of diseases that are linked to excessive CGRP release such as some forms of primary headaches.

Dentist-time expenditure for two different adhesive all-ceramic systems.

OBJECTIVES: The purpose of this clinical investigation was to compare a chair-side adhesive all-ceramic system to a laboratory processed adhesive all-ceramic system with respect to quality and time expenditure for the dentist. METHODS: The same dentist treated 10 patients, who were each to receive two large posterior single tooth restorations of similar location and extent. One restoration was made in the laboratory by using the IPS Empress system [LAB], the other one was done chair-side by utilizing the Cerec system [CHAIR]. The time expenditure was measured for [LAB] and [CHAIR] and compared by the Wilcoxon signed rank test. The restorations were also evaluated according to the USPHS criteria. RESULTS: The mean time expenditure for the dentist with low-level assistance was 111:03 min [S.D.+/-24:09 min] for [LAB] and 115:31 min [S.D.+/-15:54 min] for [CHAIR]. Time expenditure with medium level assistance for the operator was 100:53 min [S.D.+/-23:59] for [LAB] and 105:50 [S.D.+/-15:28] for [CHAIR]. Assuming a high level of assistance, the mean time values were 53:11 min [S.D.+/-14:29] for [LAB] and 54:29 min [S.D.+/-09:21] for [CHAIR]. The baseline investigation according to the modified USPHS criteria did not reveal any differences between [CHAIR] and [LAB]. CONCLUSION: There were no statistical significant differences with respect to time expenditure or quality between [LAB] and [CHAIR] in this study.