Dihydroergotamine: discrepancy between arterial, arteriolar and pharmacokinetic data

Abstract

Aims To investigate the peripheral vascular effects and pharmacokinetics of dihydroergotamine (DHE) 0.5 mg after a single subcutaneous administration in humans. Methods A double-blind, placebo-controlled cross-over study was performed in 10 healthy male subjects. A wash-out period of 2 weeks separated the two study periods. During each period, just before and at regular intervals after drug administration, vascular measurements were performed and venous blood samples were drawn. Vessel wall properties were assessed at the brachial artery, by ultrasound and applanation tonometry. Blood pressure and heart rate were recorded with an oscillometric device. Forearm blood¯ow was measured with venous occlusion plethysmography. For all parameter-time curves the area under the curve (AUC) was calculated. Differences in AUC after placebo and DHE (DAUC) were analysed and the time-course of the difference assessed. DHE pharmacokinetics were analysed according to a two-compartment open model with an absorption phase. Results AUC for blood pressure, heart rate and forearm vascular resistance did not change after DHE. Brachial artery diameter and compliance decreased (P<0.01); DAUC (95% con®dence interval) equalled x8.81 mm h (x12.97/x4.65) and x0.98 mm 2 kPa x1 h (x1.61/x0.34), respectively. Diameter decreased (P<0.05) from 1 until 24 h after DHE (peak decrease 9.7% at 10 h); compliance from 2 until 32 h (24.8% at 2 h). Time to reach maximum plasma concentration of DHE averaged 0.33t0.08 h (ts.e.mean); terminal half-life was 5.63t1.15 h. Conclusions DHE decreased diameter and compliance of the brachial artery whereas forearm vascular resistance remained unchanged. Thus, DHE acts on conduit arteries without affecting resistance arteries. Furthermore, a discrepancy was demonstrated between the plasma concentrations of DHE which rapidly reach peak levels and quickly decline, and its long lasting vasoconstrictor activity.

Efficacy endpoints in migraine clinical trials: the importance of assessing freedom from pain

“…In a double-blind comparison of conventional subcutaneous sumatriptan 6 mg with subcutaneous dihydroergotamine 1 mg in the acute treatment of a single migraine attack (n ¼ 295), significantly more patients treated with subcutaneous sumatriptan had relief 2 hours postdose than did patients treated with subcutaneous dihydroergotamine (85% versus 73%, p ¼ 0.002); however, headache recurred within 24 hours among 45% of patients treated with conventional subcutaneous sumatriptan compared with 18% of patients treated with subcutaneous dihydroergotamine (p 0.001) 30 . Dihydroergotamine is rapidly and efficiently absorbed when administered subcutaneously, with time to maximum concentration t max ¼ 15-45 minutes and approximately 100% bioavailability 31,32 .…”

Kinetics of 5-HT2BReceptor Signaling: Profound Agonist-Dependent Effects on Signaling Onset and Duration

“…In vivo, many ergot derivatives have extraordinarily long durations of action that are not easily attributed to circulating levels of parent drug (de Marées et al, 1986;de Hoon et al, 2001). For some derivatives this may be partially explained by the presence of circulating active metabolites with extended plasma dx.doi.org/10.1124/jpet.113.207670. half-lives.…”

Design of an implantable active microport system for patient specific drug release

“…This pressure range was specified with respect to the expected maximum arterial pressures for intravascular administration of drugs. Pharmacologically relevant arterial blood pressures (Ferrara et al 1987;Rossen et al 1976) vary between 13.3 and 17.4 kPa (100-130 mmHg) whereas central venous pressures (Barendsen and van den Berg 1976;de Hoon et al 2001) range between 0.199 and 1.197 kPa (1-9 mmHg). All measurements were carried out with waterbased fluids.…”