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.

Comparison of in vitro and in vivo efficiencies of a novel unit-dose liquid aerosol generator and a pressurized metered dose inhaler.

Gamma scintigraphic imaging was employed in 10 healthy volunteers to compare the total and regional lung deposition of aerosols generated by two delivery platforms that permitted microprocessor-controlled actuation at an optimal point during inhalation. An aqueous solution containing 99mTc-DTPA was used to assess the deposition of aerosols delivered by inhalation from two successive unit-dosage forms (44 microl volume) using a prototype of a novel liquid aerosol system (AERx Pulmonary Delivery System). This was compared with aerosol deposition after inhalation of two 50 microl puffs of a 99mTc-HMPAO-labeled solution formulation from a pressurized metered dose inhaler (MDI). The in vitro size characteristics of the radiolabeled aerosols were determined by cascade impaction. For the AERx system, the predicted lung delivery efficiency based on the product of emitted dose (60.8%, coefficient of variation (CV)=12%) and fine particle fraction (% by mass of aerosol particles <5.7 microm in diameter) was 53.3% (CV=13%). For the solution MDI, the emitted dose was 62.9% (CV=13%) and the predicted lung dose was 44. 9% (CV=15%). The AERx system demonstrated efficient and reproducible dosing characteristics in vivo. Of the dose loaded into the device, the mean percent reaching the lungs was 53.3% (CV=10%), with only 6. 9% located in the oropharynx/stomach. In contrast, the lung deposition from the solution MDI was significantly less (21.7%) and more variable (CV=31%), with 42.0% of the radiolabel detected in the oropharynx/stomach. Analysis of the regional deposition of the radioaerosol indicated a homogeneous pattern of deposition after delivery from the AERx system. A predominantly central pattern of distribution occurred after MDI delivery, where the pattern of deposition was biased towards a central zone depicting the conducting airways. The AERx system, in contrast to MDIs, seems highly suited to the delivery of systemically active agents via pulmonary administration.

Morphine pharmacokinetics after pulmonary administration from a novel aerosol delivery system.

BACKGROUND: Successful pharmacotherapy of pain often depends on the mode of drug delivery. A novel, unit dose, aqueous aerosol delivery system (AERx Pulmonary Drug Delivery System) was used to examine the feasibility of the pulmonary route for the noninvasive systemic administration of morphine. METHODS: The study had two parts: (1) a dose-ranging study in four subjects with three consecutive aerosolized doses of 2.2, 4.4, and 8.8 mg (nominal) morphine sulfate pentahydrate at 40-minute intervals, and (2) a crossover study, on separate days, in six subjects with 4.4 mg (nominal) aerosolized morphine sulfate administered over 2.1 minutes on three occasions and intravenous infusions of 2 and 4 mg over 3 minutes. Subjects were healthy volunteers from 19 to 34 years old. Arterial blood was sampled for a total of 6 hours and plasma morphine concentrations were measured by gas chromatography-mass spectrometry. RESULTS: In part 1, plasma morphine concentrations were proportional to dose. In part 2, the mean +/- SD peak plasma concentration (Cmax) occurred at 2.7 +/- 0.8 minutes after the aerosol dose, with mean values for Cmax of 109 +/- 85, 165 +/- 22, and 273 +/- 114 ng/ml for the aerosol and 2 and 4 mg intravenous doses, respectively. The bioavailability [AUC(0-360 min)] of aerosol-delivered morphine was approximately 100% relative to intravenous infusion, with similar intersubject variability in AUC for both routes (coefficient of variation < 30%). CONCLUSION: The time courses of plasma morphine concentrations after pulmonary delivery by the AERx system and by intravenous infusions were similar. This shows the utility of the pulmonary route in providing a noninvasive method for the rapid and reproducible systemic administration of morphine if an appropriate aerosol drug delivery system is used.