Intrapulmonary and intravenous administrations of dihydroergotamine mesylate have similar cardiovascular effects in the conscious dog.

BACKGROUND AND PURPOSE: The effects of intrapulmonary artery (i.p.a.) administration of dihydroergotamine mesylate (DHE) were evaluated. EXPERIMENTAL APPROACH: Conscious beagle dogs (n=4) were given DHE via the i.p.a. or i.v. route as two 0.014 mg kg(-1) doses and a 0.14 mg kg(-1) dose given 60 min apart. A recovery period of > or =45 h occurred before crossover to the alternative route. Physiological parameters were monitored by telemetry or direct measurement, and venous blood samples were collected for pharmacokinetic assessments. KEY RESULTS: No meaningful differences between i.v. and i.p.a. treatments were observed for heart rate, systemic pressures and vascular pressures. Aortic resistance increased 8, 27 and 70%, respectively, following three doses of i.v. DHE compared with 11, 37 and 57%, respectively, with i.p.a. DHE. Carotid artery resistance increased 22, 40 and 87%, respectively, following three doses of i.v. DHE, compared with 17, 45 and 67%, respectively, following i.p.a. DHE. Increases in coronary artery resistance were of similar magnitude following i.v. and i.p.a. DHE administration. Increases in left ventricular systolic and diastolic pressures were seen following all doses of i.v. and i.p.a. DHE. Changes following DHE 0.014 mg kg(-1) were minimal and not clinically significant. With DHE 0.14 mg kg(-1) by either route, emesis was the most common adverse event. CONCLUSIONS AND IMPLICATIONS: DHE has comparable effects delivered via simulated deep inhalation (i.p.a.) or i.v. administration. The risk of cardiovascular complications is unlikely to be greater following inhalation of DHE.

Aerosol delivery of ergotamine tartrate via a breath-synchronized plume-control inhaler in humans.

OBJECTIVE: To compare systemic delivery of ergotamine tartrate (ET) via a breath-synchronized, plume-control inhaler (BSPCI) (Tempo ET) with a sublingual ergot preparation and a commercial inhaler. METHODS: Study 1 determined plasma ET concentrations in seven healthy subjects after administration of ET by a 2 mg tablet (Lingraine) and a BSPCI delivering 258 microg of ET. Study 2 determined plasma ET concentrations in 16 healthy subjects after administration via an ET metered dose inhaler (ME) (Medihaler) delivering 2052 microg of ET and a BSPCI delivering 129 microg of ET. Gamma scintigraphy with (99m)Tc validation was used to quantify lung deposition. RESULTS: For both studies, ET C(max) was higher with the BSPCI (study 1: sublingual ET 134 pg/mL at 37 min; BSPCI 3743 pg/mL at 3 min; study 2: metered-dose inhaler 1109 pg/mL at 4 min; BSPCI 1210 pg/mL at 2.5 min). Mean dose normalized AUC was several-fold higher with the BSPCI compared with sublingual ET and ME dosing. Lung deposition of ET with the BSPCI was 33.5, 8.9, 11.4, and 13.2% for whole, central, intermediate, and peripheral lung, respectively, with a 1.5 peripheral : central ratio. CONCLUSION: Based on these open-label studies, the BSPCI allows rapid delivery of potentially therapeutic plasma concentrations of ET at approximately 1/15th the dose of comparators.

Effect of dry powder inhaler resistance on the inspiratory flow rates and volumes of cystic fibrosis patients of six years and older.

Several inhaled drugs for use by cystic fibrosis (CF) patients are formulated for nebulizer use only. This therapy is time consuming and includes the risk of contamination of the nebulizers. Dry powder inhalers (DPI) can be an attractive alternative for CF drugs. Inhaled flow rate and volume, and the device resistance are important determinants for optimal dispersion of drug from a DPI. It is important to understand how these variables interact in the CF population in order to properly design a new DPI formulation targeted for these patients. The objective of this study was to assess the inspiratory variables of a representative population of CF subjects 6 years and older with varying degrees of lung disease while inhaling through resistances that simulate DPI devices. Ninety-six stable CF patients were enrolled, ages 6-54 years, FEV(1) 19-126% predicted. Subjects inhaled forcefully through four different resistances (0.019, 0.024, 0.038, and 0.048 kP(0.5)/LPM, respectively), while inspiratory time (IT(DPI)), peak inspiratory flow (PIF(DPI)), and volumes (V(DPI)) were measured. For any resistance, inspired V(DPI) increased with the older age groups; PIF(DPI) was similar between adults and adolescents but lower in the children. Subjects with lower FEV(1) had lower V(DPI) and PIF(DPI). As resistance increased, PIF(DPI) decreased, IT(DPI) increased, with no significant change in V(DPI). At the lowest resistance mean PIF(DPI) was 105 LPM (range 45-163) for all patients; 112 LPM (range 75-163) in adults; and 89 LPM (45-126) in children. Mean inspired V(DPI) was 1.75 L for all patients; 2.2 L (0.8-3.7) in adults; and 1.2 L (0.5-1.8) in children. At the lowest resistance a minimal flow rate of 30, 45, and 60 LPM was attained in 100%, 99%, and 96% of all patients. Volumes of 1.0, 1.5, and 2.0 L were attained by 85%, 57%, and 30% of the patients. At the highest resistance mean PIF(DPI) was 52 LPM (range 26-70) for all patients; 55 LPM (40-70) in adults; and 47 LPM (26-62) in children. Mean inspired V(DPI) was 1.5 L in all patients; 1.9 L (0.9-3.5) in adults and 1.1 L (0.5-2.3) in children. At the highest resistance, a minimal flow rate of 30, 45, and 60 LPM was attained in 99%, 80%, and 22% of all patients. Volumes of 1, 1.5, and 2 L were attained in 84%, 45%, and 23% of the patients. We defined ranges for inspiratory variables in a diverse CF population for a range of device resistances that bracket those of current DPIs. The recorded inspiratory patterns can be used on the bench to design and test new dry powder formulations and devices to target the largest proportion of the CF population.