Preparation and evaluation of Eudragit gels. IV: Rectal gel preparations for sustained release and avoidance of first-pass metabolism of propentofylline.

Formulations of a high-viscosity acrylic resin gel (Eudispert hv) containing propentofylline, a new cerebral microcirculation-improving agent, were prepared and tested for avoidance of the first-pass metabolism of propentofylline through the liver and for sustained release of propentofylline. The absolute bioavailability of propentofylline after oral administration was only 4% in rabbits. The relative bioavailabilities of propentofylline from polyethylene glycol (M(r), 2000) and Witepsol H-15 suppositories were approximately 8- and 16-fold, respectively, compared with oral administration. Furthermore, the absolute bioavailability of propentofylline from Eudispert hv hydrogel and xerogel preparations was approximately 100%. The results indicate that, in principle, drug loss caused by first-pass metabolism may be avoided completely by placing Eudispert hv hydrogel and xerogel formulations in the lower part of the rectum for long periods.

Involvement of ATP in noxious stimulus-evoked release of glutamate in rat medullary dorsal horn: a microdialysis study.

Our electrophysiological studies have shown that both purinergic and glutamatergic receptors are involved in central sensitization of nociceptive neurons in the medullary dorsal horn (MDH). Here we assessed the effects of intrathecal administration of apyrase (a nucleotide degrading enzyme of endogenous adenosine 5-triphosphate [ATP]), a combination of apyrase and 1,3-dipropyl-8-cyclopentylxanthine (DPCPX, an adenosine A1 receptor antagonist), or 2,3-O-2,4,6-trinitrophenyl-adenosine triphosphate (TNP-ATP, a P2X1, P2X3, P2X2/3 receptor antagonist) on the release of glutamate in the rat MDH evoked by application of mustard oil (MO) to the molar tooth pulp. In vivo microdialysis was used to dialyse the MDH every 5 min, and included 3 basal samples, 6 samples after drug treatment and 12 samples following application of MO. Tooth pulp application of MO induced a significant increase in glutamate release in the MDH. Superfusion of apyrase or TNP-ATP alone significantly reduced the MO-induced glutamate release in the MDH, as compared to vehicle. Furthermore, the suppressive effects of apyrase on glutamate release were reduced by combining it with DPCPX. This study demonstrates that application of an inflammatory irritant to the tooth pulp induces glutamate release in the rat MDH in vivo that may be reduced by processes involving endogenous ATP and adenosine.

Drug-eluting stent for delivery of signal pathway-specific 1,3-dipropyl-8-cyclopentyl xanthine.

1,3-Dipropyl-8-cyclopentyl xanthine (DPCPX) is a highly selective antagonist of the adenosine A(1) receptor (A(1)R). The A(1)R mediates mitogenic effects of adenosine in coronary artery smooth muscle cells (CASMC). DPCPX plays a role as an antimitogen and reduces CASMC proliferation by the blockage of A(1)R. A drug-eluting stent (DES) loaded with DPCPX was prepared. The water solubility of DPCPX is 1.6 microg/mL at pH 3-9, and 38.1 +/- 2.3 microg/mL at pH 11. A series of DPCPX-eluting stents were formulated in polyurethane (PU) films with different dose densities and film thicknesses. The release of DPCPX from the PU-coated stents was nearly linear. The release rate and duration were effectively controlled by adjusting the film thickness with the same drug concentration. The eluted DPCPX from the PU films was effective in preventing CASMC proliferation, regardless of stimulation by 2-chloro-N-6-cyclopentyladenosine (CCPA), a highly selective A(1)R agonist. A(1)R specific antagonist DPCPX was effective in preventing CASMC proliferation and holds great promise for intracoronary delivery from DESs to test the role of the A(1)R signaling pathway for prevention of in-stent restenosis.

Drug release from hydrocolloid embeddings with high or low susceptibility to hydrodynamic stress.

PURPOSE: The subject of the study was the influence of hydrodynamic stress on the drug release from direct compressed hydrocolloid embeddings. Additionally a correlation between the release kinetics and different polymer characterising parameters was attempted. METHODS: The drug release was fitted to an expanded Korsmeyer equation to describe the release kinetics. The influence of the stirring Dissolution Time (MDT) was expressed as quotient of the MDT's at the stirring rate of 200 and 100 min-1. RESULTS: If the drug release followed the square root of time kinetics, nearly no effect of the agitation speed on the release rate was observed. To achieve this diffusion controlled drug release the developing gel layer had to be hydrated very well and resistant against erosion (viscosity of at least 4000 mPa.s of the 2% polymer solution and a small expansion of the swelling gel especially at the beginning of the release). The erosion controlled zero order release was generally much affected by the hydrodynamic stress except for some hydrocolloids with incomplete swelling. Thus, it was possible to define a new release mechanism, the polymer particle erosion. The drug release was controlled by the attrition of partially swollen polymer particles and not by the polymer dissolution or drug diffusion. CONCLUSIONS: Polymer particle erosion or diffusion control should be the release controlling mechanisms for negligible influence of hydrodynamic stress.

Absorption of enprofylline from the gastrointestinal tract in healthy subjects.

Enprofylline, a new potent bronchodilator xanthine drug, was given orally as an aqueous solution to 6 healthy subjects in single doses of 2, 4 and 6 mg/kg. The two lower doses produced plasma concentrations in the range 1-4 mg/l, i.e. in the assumed "therapeutic interval" according to previous animal studies. A high 24 h urine recovery of unchanged drug, with mean values for the three dose levels ranging from 85 to 91% of the given dose, indicated good absorption and little metabolism. The dose-corrected area under the plasma concentration-time curve rose with dose as the latter was increased from 2 to 6 mg/kg. This indicates that the elimination of enprofylline is capacity-limited at high doses. Double peaks in the plasma concentration-time curves at the higher dose levels suggested intermittent and delayed gastric emptying as a possible explanation. This hypothesis was confirmed by studies in 6 other healthy subjects, who received the drug solution by three different routes; by mouth, via a catheter in the duodenum, and rectally via a catheter in the colon. The corresponding time to peak values (mean +/- SEM) were 32.5 +/- 8.7, 13.3 +/- 2.5, and 157 +/- 23 min.

Modification of subcutaneous adipose tissue by a methylxanthine formulation: a double-blind controlled study.

BACKGROUND: Excessive subcutaneous adipose tissue is typically treated by physically removing the fat through liposuction, but cost and accessibility have popularized alternative treatments for reducing adipose tissue thickness. OBJECTIVE: The purpose of this study was to test the absolute and relative effectiveness of a liposome-encapsulated caffeine-based cream in modifying subcutaneous adipose tissue. METHODS: Forty-one patients consented and completed the double-blind, single-center, placebo-controlled study. Caliper measurements, tape measurements, and photographs were taken over a 2-month period. RESULTS: Both concentrations of the cream were found to significantly reduce the thickness of the adipose tissue in all areas of the body. In addition, the more concentrated cream was significantly more effective than the less concentrated cream in the areas of the hips and the triceps. CONCLUSION: The caffeine-based liposome-encapsulated cream significantly reduced the thickness of the subcutaneous fat over a 2-month period.