In vitro anti-HIV-1 activity of chondroitin polysulphate.

Three chondroitin sulphates and five chondroitin polysulphates, with molecular weights ranging from 3000 to 30,000 daltons, were evaluated applying the MT-4 cell-culture assay for inhibition of HIV-1 replication. These results were compared with those obtained with compounds of known in vitro antiretroviral activity, namely, dermatan sulphate, heparin, dextran sulphate, pentosan polysulphate, zidovudine (AZT) and suramin. Chondroitin polysulphate with a molecular weight (MW) of 9000 daltons (CPS 9000) was the most effective polyanionic compound studied. In contrast with zidovudine, this CPS 9000 was not toxic for MT-4 cells up to a concentration of 500 micrograms/ml. Moreover, CPS 9000 is highly specific for inhibition of HIV-1 reverse transcriptase.

Magnetic resonance first-pass perfusion imaging: overview and perspectives.

The data from clinical studies with quantitative MR first-pass perfusion imaging suggests that this technique outperforms SPECT--widely available clinical imaging tool--in sensitivity and specificity. Moreover, MRFP imaging may be combined with the assessment of global and segmental function of the heart and regional wall thickening, and in addition, performed with pharmacological stress agents. The inter- and intra-observer reproducibility of quantitative MRFP is comparable with clinically used nuclear medicine techniques. MRFP measurements can discern collateral myocardium and are able to identify small changes in myocardial blood flow and myocardial perfusion reserve (the ratio of stress blood flow over resting). MRFP imaging has been mainly used in context of coronary artery disease but many other exciting areas in clinical cardiology are awaiting of new insights that can be accomplished with this technique. Trials are needed to obtain the approval of the contrast agent (Gd-DTPA) and perfusion sequences by the Food and Drug Administration and to establish reimbursement procedures with the third-party insurance companies and health maintenance organizations.

[Transcutaneous absorption of non-steroidal antirheumatics. Clinical study under a new model for investigation of pharmacokinetics]. / Transkutane Resorption von nicht-steroidalen Antirheumatika. Klinische Studie über ein neues Modell zur Untersuchung der Pharmakokinetik.

The feasibility of the bilateral vein stripping model for the investigation of the transcutaneous absorption of a non-steroidal antirheumatic drug (NSAID) was examined. After application of a 1% solution of indomethacin (Elmetacin, CAS 53-86-1) at one leg (steady state) plasma and vein tissue of both sides was taken at the same time. The mean indomethacin plasma levels of 19 female patients were 7 ng/ml, in the vein tissue of the application side 280 ng/g and at the opposite side 80 ng/g. The tissue levels in the veins are in the same range as in the target tissues of transcutaneous antirheumatic therapy. Therefore the model is considered useful for the investigations of the pharmacokinetics of topically applied NSAID.

[Heparin and mucopolysaccharide polysulfuric acid ester permeate human skin]. / Heparin und Mucopolysaccharidpolyschwefelsäureester (MPS) permeieren die menschliche Haut.

After topical application of commercial preparations containing heparin and heparinoids (MPS) in concentrations of 30,000 up to 150,000 IE/100 g, the individual layers of the skin show more or less increased heparinization, which can be traced by means of the permeation chamber technique. The average concentration of heparin and MPS in the dermal layers containing capillaries is about 0.1-0.5 IE/ml and 400-40,000 ng/ml, respectively, depending on the quality of the horny layer. We did not find any evidence for the permeation being activated either by DMSO, urea, or other accelerators. Repeated exposition to the preparation within 4 hours, however, resulted in increased permeation of heparin and MPS. The amount of the gel or ointment applied was of no significance.

Permeation of the human skin by heparin and mucopolysaccharide polysulfuric acid ester.

Punched samples of different specimens of human skin were treated with 5 mg/cm2 of commercially available topical preparations of heparin (50,000 IU/100 g, i.e. 0.35% w/w) or mucopolysaccharide polysulfuric acid ester (MPS, 1.4 and 0.45% w/w, respectively; active ingredient of Hirudoid). Heparin and MPS were labelled with tritium. The skin samples were fixed into a perfusion chamber. Perfusion fluid and skin were analysed 180 to 360 min later. The concentrations found in the corium varied from 0.005 to 0.1 IU heparin per g (i.e. 0.03 to 0.64 micrograms/g) and from 1.05 to 3.14 micrograms/g of MPS. While in normal skin the single administration of heparin and MPS resulted in levels of the same relative magnitude, skin with thinner epidermis and decreased horny layer (keloids) absorbed MPS to a higher degree. Repeated administration of a 1.4% MPS cream (0 and 90 min, measurement after 180 min) resulted in markedly enhanced levels, which were out of proportion especially in the deeper skin layers. This effect was confirmed with a 0.45% MPS cream. The direct comparison to the heparin cream resulted in higher heparin levels in the epidermis but higher MPS levels in all deeper skin layers, when calculated to the same concentration in the cream. The heparin in the dermal layers and in the perfusion chamber fluid was determined by molecular binding to protamine loaded sepharose 4B.

[In vivo study of the distribution, affinity for cartilage and metabolism of glycosaminoglycan polysulphate (GAGPS, Arteparon)]. / In vivo Studie über Verteilung, Knorpelaffinität und Metabolismus von Glykosaminoglykanpolysulfat (GAGPS, Arteparon).

37 patients suffering from osteoarthritis and 10 arthritic patients received intramuscular (i.m.), partly also intraarticular (i.ac.) injections of GAGPS; whereupon pharmacokinetics in serum, synovial fluid, urine, and cartilage were investigated. Cartilage was obtained during endoprosthetic hip surgery. The concentrations were determined by radiochemistry, partly after gel chromatography and electrophoresis respectively. Serum levels in patients with osteoarthritis after i.m. administration of 50 mg were 0.55 microgram/ml 3 hrs later, and 0.11 microgram/ml 24 hrs later. Patients with arthritis showed similar serum levels which were slightly higher after i.ac. injection, and which rose proportionally when the dosage was increased to 125 mg. With the arthritic patients, also the concentrations in the synovium were comparable, in the cases with osteoarthritis concentrations were slightly higher, which in both cases suggests that the synovial membrane is promptly penetrated. However, the concentrations in cartilage following a dosage of 50 mg within 24 hours rose as high as 1.45 micrograms/g which corresponds roughly to three times the serum level 3 hours after application. According to biochemical data, injections of 1 to 2 micrograms/ml should yield chondroprotective effects. Hitherto therapy has relied mainly on i.ac. injections; it may now be expanded by the i.m. route of administration. GAGPS was bound to serum proteins, in the synovia, however, it was found unbound. The main portion of the compound excreted via urine within 12 hrs (30 to 40 percent) was mainly unaltered; later, a partial degradation of the chain length and of the degree of sulfation was observed. Animal experiments on rats showed an increased affinity of GAGPS to inflamed tissues (Freund's adjuvant, carageenan edema).

[Distribution and excretion of a glycosaminopolysulfate in the rabbit after parenteral application (author's transl)]. / Verteilung und Ausscheidung eines Glykosaminoglykanpolysulfats nach parenteraler Applikation beim Kaninchen

The pharmacokinetics of unlabelled and tritium-labelled glycosaminoglycan polysulfate (GAGPS) was examined by gel chromatography, electrophoresis and radiometry. The compound was given i.m. and, for comparison, i.v. In both cases (dose: 7.5 mg/kg) blood levels after 1 h reached maxima of approx. 6 mug/ml and remained between 2.0 and 1.5 mug/ml for between 24 and 48 h. The question of threshold-limited excretion is discussed. The concentration curves of the synovia were almost identical to those of the blood. The cartilage of the joint had a comparable level after 48 h (1.7 mug/g), whilst the level was lower in rib cartilage (1.1 mug/g). Urinary excretion within 24 h amounted to 45% of almost unchanged GAGPS. A further 10% were excreted within the following 24 h. The residue was distributed chiefly in the kidneys, liver, skin, spleen, gut, and bone marrow. In the course of the elimination time the excreted substnace showed a lower molecular weight as was found by gel chromatography.

[Glycosaminoglycanpolysulfate (GAGPS, Arteparon) for basic therapy of arthrosis. III. Biochemical-diagnostic and clinical studies on the intramuscular use of GAGPS]. / Glykosaminoglykanpolysulfat (GAGPS, Arteparon) zur Basistherapie der Arthrose. III. Biochemisch-diagnostische und klinische Untersuchungen zur intramuskulären Anwendung von GAGPS.

Investigations using 3H-Arteparon (3H-glycosaminoglycan polysulfate, 3H-GAGPS) showed that in humans with degenerative joint disease an intramuscular administration of 125 mg GAGPS (0.5 ml Arteparon forte) produces GAGPS concentrations within the joint, which in a biochemical assay inhibit cartilage degrading lysosomal enzymes. The dosage was determined from animal experiments that had indicated the relationship between the applied quantity of the drug and the resulting biological concentrations. Preliminary results of treatment with 0.5 ml Arteparon forte in 15 patients are reported.