The 5-HT(1B/1D) receptor agonist sumatriptan is effective in aborting acute attacks of migraine and is known to cause constriction of cranial arteries as well as some peripheral blood vessels. The present study set out to investigate whether 5-HT(1B) and/or 5-HT(1D) receptors mediate contractions of the human isolated middle meningeal and temporal arteries (models for anti-migraine efficacy) and coronary artery and saphenous vein (models for side-effect potential). Concentration-response curves were made with sumatriptan (1 nm-100 microm) in blood vessels in the absence or presence of selective antagonists at 5-HT(1B) (SB224289) and 5-HT(1D) (BRL15572) receptors. SB224289 antagonized sumatriptan-induced contractions in all blood vessels, although the antagonism profile was different amongst these blood vessels. In the temporal artery, SB224289 abolished contraction to sumatriptan, whereas in the middle meningeal artery and saphenous vein sumatriptan-induced contractions were blocked in an insurmountable fashion. Moreover, SB224289 acted as a weak surmountable antagonist in the coronary artery (pK(B): 6.4 +/- 0.2). In contrast, BRL15572 had little or no effect on sumatriptan-induced contractions in the four blood vessels investigated. In situ hybridization revealed the expression of 5-HT(1B) receptor mRNA in the smooth muscle as well as endothelial cells of the blood vessels, whereas the mRNA for the 5-HT(1D) receptor was only very weakly expressed. These results show that the 5-HT(1B) receptor is primarily involved in sumatriptan-induced contractions of human cranial as well as peripheral blood vessels.
The mechanistically novel benzopyran derivative SB-220453, which is undergoing clinical evaluation in migraine, exhibits a high affinity for a selective, but not yet characterized, binding site in the human brain. It inhibits nitric oxide release and cerebral vasodilatation following cortical spreading depression as well as carotid vasodilatation induced by trigeminal nerve stimulation in the cat. The aim of our study was to investigate the contractile properties of SB-220453 on a number of human isolated blood vessels (coronary artery, saphenous vein and middle meningeal artery) as well as atrial and ventricular cardiac trabeculae. While sumatriptan induced marked contractions in three blood vessels investigated, SB-220453 was devoid of any effect. In atrial and ventricular cardiac trabeculae, neither SB-220453 nor sumatriptan displayed a positive or negative inotropic effect. Since SB-220453 did not contract the middle meningeal artery, we conclude that potential anti-migraine effects are not mediated via a direct cerebral vasoconstriction. The lack of activity of SB-220453 in coronary artery, saphenous vein and cardiac trabeculae demonstrates that the compound is unlikely to cause adverse cardiac side-effects.
Drugs Fund (CDF) reconsiderations in England. During the study period, we found 102 matched condition-intervention pairs; of which, nearly two-thirds (64/102) differ by assessment outcome. NICE recommended 85/102 (83%) of the drugs, whereas HAS and G-BA reported added benefit for 59/102 (58%, including 7/102 nonreimbursable drugs) and 72/102 (71%) treatments, respectively. Findings for matched cancer drug pairs show, however, substantial differences in assessment outcomes. While NICE recommended 42/58 (72%) cancer technologies (another 12 drugs were recommended for use in the CDF only), HAS and G-BA reported 37/58 (64%, including 5/58 non-reimbursable drugs) and 49/58 (85%, including 12 drugs with an orphan designation) treatments with added benefit, respectively. Notwithstanding that far more than half (33/58) of the cancer-related HTA outcomes differ, discrepancies by therapeutic area apparently exist. Our results confirm that different methodological choices are indeed associated with differences in HTA outcomes, which may be amplified by some well-defined exceptions in national HTA systems.
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