Pharmacodynamic and Pharmacokinetic Evaluation of a New Transdermal Delivery System with a Time‐Dependent Release of Glyceryl Trinitrate

Abstract

The pharmacokinetics of glyceryl trinitrate (GTN) and its main metabolites as well as the hemodynamic effects of a new transdermal delivery system (TDS) were investigated in ten healthy male volunteers using a single blind, placebo-controlled study design with an application period of active drug of 4 successive days. The adhesive-type matrix system contains 20-mg GTN and released about 75% in a time-dependent manner. The plasma concentrations of GTN and its metabolites 1-2- and 1-3 glyceryl dinitrate reflected the time-dependent release with higher plasma concentrations during the first 12 hours than during the second 12 hours. Continuous administration of the TDS, which released 15 mg GTN/day, caused an accumulation of GTN in the plasma (about 70% greater AUC at the fourth day in comparison with the first day). The total effect per dose on the a/b-ratio of the digital pulse (height of the peak of the systolic wave divided by height of the peak of the dicrotic wave) and the reflex tachycardia were diminished by about 50% and 37%, respectively, at the fourth treatment day. The effect on systolic blood pressure measured under orthostatic conditions was blunted already 8 hours after the first application. The effect of sublingually administered GTN on digital pulse was attenuated during administration and also 1 hour after removal of the last TDS. The effect was restored 8 to 12 hours after removal of the TDS. Thus, the discontinuous release of GTN from the new system does not prevent the decline of hemodynamic efficacy during continuous therapy.

Nitric Oxide Is Released Into Circulation With Whole-Body, Periodic Acceleration * *Dr. Sackner is Chief Executive Officer and Chairman Board of Directors, Non-Invasive Monitoring Systems, Inc., and owns approximately 37% of Non-Invasive Monitoring Systems, Inc. shares. He is also a member of the Board of Directors, Vivometrics, Inc., Ventura CA. Ms. Gummels owns approximately 0.2% of Non-Invasive Monitoring Systems shares. Dr. Adams is a member of the Scientific Advisory Board and owns approximately 0.1%

“…Nitroglycerin in therapeutic sublingual, spray, ointment, and transdermal patch doses increased the a/b ratio from 26 to 89%. 14,16,18,[25][26][27][28][29][30][31] Chowienczyk et al 14 found the highest peak increase of the a/b ratio, 205% in an adult receiving nitroglycerin, 0.1 mg IV, and 124% in an adult receiving albuterol, 20 g/min IV. Since changes of the a/b ratio from the action of NO follow a dose-response curve, whole-body, periodic acceleration appears to be much more potent in accessibility to NO than organic nitrates or ␤-adrenergic agonists in terms of vasodilatation of the resistance vessels.…”

“…Similar falls in the dicrotic notch occur with therapeutic doses of organic nitrates. 16,18,24,35 Dicrotic notch position changes contrast with serum nitrite levels measured after interventions designed to increase or decrease NO release. Here, infusions of nitrite in volunteers to reproduce the serum changes for this metabolite of NO fail to effect vasodilatation as measured by forearm blood flow measurements.…”

Pharmacokinetic Characterisation of Transdermal Delivery Systems

“…Consequently, an intermittent dosage regimen, typically where the patch is removed at night, has been recommended (Physicians Desk Reference 1992). Wiegand et al (1992) recently reported that a 8-to 12-hour period of nitroglycerin withdrawal restored the full efficacy of the drug.…”

Pharmacokinetics and haemodynamic effects of ISDN following different dosage forms and routes of administration

“…The digital pulse throughout the study was recorded at the same distal phalanx using a photo electric sensor (Hellige AG, Freiburg, FRG), and the signal was amplified by an ECG-recorder (Hellige Cardiognost EK 413, Hellige AG, Freiburg, Germany). At least 20 pulse waves were recorded during each measurement and the a/b ratio was calculated, where a is the height of the systolic peak and b the high of the dicrotic wave (Imhof et al 1980;Wagner et al 1990;Wiegand 1991;1992). Ten consecutive waves were evaluated and the a/b ratios were averaged.…”