Anti-inflammatory properties of a novel wound healing and immunomodulating agent, tetrachlorodecaoxygen complex (TCDO).

The first phase of the healing process is characterized by the development of an inflammatory reaction involving migration of inflammatory cells and release of inflammatory mediators. In a previous study, we have demonstrated that the water soluble tetrachlorodecaoxygen complex (TCDO), first synthetized to promote wound healing, inhibits polymorphonuclear (PMN) migration. The aim of the present study was to investigate the activity of TCDO on the progression of an acute non-specific inflammatory reaction, on the release of 6-keto-PGF1 alpha and PGE2 and on PMN oxidative metabolism in the rat. Injected in the pleural cavity, TCDO (15 mumoles/rat) significantly decreased the number of exudative cells while 1.5 mumoles/rat inhibited PMN oxidative metabolism ex vivo (assessed by chemiluminescent assay and measurement of O2- generation) after stimulation of the cells by opsonized zymosan. Similar observations were made in vitro after incubation of PMNs with various concentrations of TCDO (300 to 3 microM). The effect was dose-related and highly significant up to the concentration of 3 microM. In parallel, TCDO decreased the amounts of 6-keto-PGF1 alpha and PGE2 in exudates harvested 1 hour after the intrapleural injection of isologous serum. Effects were significantly different from control levels, from 1.5 to 0.03 mumoles/rat for 6-keto-PGF1 alpha and from 1.5 to 0.01 mumoles/rat for PGE2. This effect was observed when TCDO was injected at the same time or 1 hour before the isologous serum but not later. TCDO also inhibited LTB4 generation in vitro after PMN stimulation by calcium ionophore A23187, at concentrations up to 150 microM. The effects of TCDO in vivo and in vitro on rat PMN functions and inflammatory mediator release mimic certain activities of anti-inflammatory drugs. These properties may be beneficial in the very early stages of the wound healing process.

[Prevention of extravasation necroses as a complication following intravenous cytostatic drug therapy. Results of an open pilot study]. / Verhinderung von Extravasatnekrosen als Komplikation nach intravenöser Zytostatikatherapie. Ergebnisse einer offenen Pilotstudie.

Extravasation of some cytostatics applied i.v. can often cause local edema with skin redness, thrombophlebitis and not infrequently skin necrosis with chronic ulcera. Local treatment is usually ineffective, and so far surgical excision of ulcera is the only curative approach. Tetrachlorodecaoxygen anion complex (TCDO) has shown high activity in healing chronic leg ulcera, by increasing pO2 in hypoxic wound tissue and stimulating phagocytosis as one of anti-inflammatory processes To study the local activity of TCDO in tissue necrosis and chronic ulcera caused by cytostatic extravasation, 23 patients with local skin complications underwent local treatment with TCDO, made as isotonic water solution. Seventeen patients experienced only local edema with redness, while 6 patients showed deep chronic ulcera. All the skin changes were complications after i.v. doxorubicin, cisplatinum, dactinomycin or vinblastine application. The treatments with TCDO followed 1-3 months after ulcera appeared, while skin inflammations were treated 1-8 days after they occurred. TCDO was applied locally twice a day by impregnated cotton tissue for 4-6 weeks. Evaluable were only measurable lesions. From 17 patients with only skin inflammation 3 patients obtained complete resolution, 8 partial resolution and 6 had stable lesions. Thus, overall response was recorded in 65% of patients (11/17). In 6 patients with deep chronic ulcera a longer treatment (6 weeks) was needed, and in 5 of them the complete epithelization and resolution occurred. One patient had a partial wound healing. No side effects of treatment were observed. The effect of locally applied TCDO in chronic ulcera seems to be preferable to surgical treatment. A controlled study will show the exact therapeutic value of this new anti-inflammatory compound.

Rationale for and results from a randomised, double-blind trial of tetrachlorodecaoxygen anion complex in wound healing.

Local tetrachlorodecaoxygen anion complex (TCDO) had three therapeutic effects in difficult wounds, substantiated on day 14 in a multicentre double-blind randomised clinical trial on 271 inpatients with 0.9% saline as control. Wound cleansing was intensified, the formation of new tissue (granulations, epithelium) was promoted, and, irrespective of the different wound types, wound surfaces decreased more quickly, by a factor of 2.4. A novel quantity (eta) was derived as an indicator of wound healing promotion. eta NaCl (= -0.14) did not differ among different wound diagnoses. eta TCDO values were significantly better in relation to wound diagnosis, to smear (detritus), and to epithelialisation. Local TCDO was well tolerated.

Decrease of metastatogenic potential by pregraft treatment of Lewis lung carcinoma cells with proteinase and protein kinase affinity labels.

Three synthetic irreversible enzyme inhibitors (75 microM di-iso-propylphosphorofluoridate (DFP), 310 microM N alpha-p-tosyl-L-lysine (TLCK) and 240 microM L-1-tosylamide-2-phenylethyl (TPCK) chloromethyl ketone), as well as the transition state analogue chymostatin, inhibit the development of Lewis lung adenocarcinoma (3LL) in C57 BI/6 mice, when 3LL cells are treated once and for a limited period (60 min) prior to grafting. These compounds demonstrate divergent protease specificity and, in the case of TLCK and TPCK, convergent reactivity toward the highly conserved protein kinase catalytic subunit. Using 200 microM chymostatin and low doses (25-40 microM) of the irreversible enzyme inhibitors, the antimetastatogenic effect is revealed to be specific, as primary tumor development is not affected. Although no direct experimental evidence can be forwarded, our results fit with the concept that the motile metastatogenic 3LL cells may constitute a phenotype which, in contrast to the resident cells from the primaries, responds to these enzyme inhibitors in a highly sensitive manner.

Hydrogen bond catalysis of mononucleotide ethylation supports non-random DNA alkylations by N-ethyl, N-nitrosourea.

The axial (ax.) and equatorial (eq.) diastereomeric forms of phosphate triesters resulting from reactions of N-ethyl, N-nitrosourea with 3 cyclic mononucleotides were analyzed by column liquid chromatography (CLC). Evidence is presented that the 2'OH group of 3', 5'cAMP essentially contributes to the stereoselective eq. alkyl substitution, most probably by hydrogen bonding catalysis. The neighboring group direction of ethylation gives substantial support to non-random DNA alkylations by NEU.

[Stimulation of wound healing by tetrachlordecaoxide. Results of a randomized double-blind study]. / Stimulation der Wundheilung durch Tetrachlordecaoxid (TCDO). Ergebnisse einer randomisierten Doppelblindstudie.

In 38 patients with chronic therapeutically resistant wounds, which, in 25 cases, had been existing for more than one year, Tetrachlorodecaoxide ( TCDO ) in a water solution containing glycerin was analyzed for its capacity to induce wound healing and compared in this respect to the standard in moist wound treatment, physiological sodium chloride. The results of the clinical trial demonstrate that the TCDO solution is significantly superior to physiological saline in local wound treatment regarding the degree of wound smear reduction, the formation of wound granulation tissue, the stimulation of epithelisation on the wound borders and the shrinking of the wound surface. The differences in therapeutic efficiency are so large that, in spite of the relatively small patient samples (21 + 17) it was possible to verify the superiority of a method for wound treatment in a randomized double blind clinical trial.

Bone marrow genotoxicity of N-methyl, N-nitrosourea (NMU): n-alkanols as sister chromatid exchange (SCE) anti-inducers.

The in vivo SCE test was used to demonstrate significant inhibition of NMU bone marrow genotoxicity by pretreatment of Chinese hamsters with n-alkanols. Our findings exclude a loss of intracellular DNA alkylation potential through a competitive direct reaction of NMU with the weakly nucleophilic polar end of the n-alkanols, but not through methylations of nucleophilic membrane sites possibly liberated by structural modifications which the membrane-active amphiphilics induce.

Receptors for bradykinin in murine peritoneal macrophages: modulation of short-term spreading.

The order of potency of bradykinin (bk) and four analogues, with respect to their modulation of peritoneal macrophage short-term spreading, suggests the presence of two peptide receptors in these cells which are responsible for antagonistic effects. Spreading inhibition and stimulation are mediated by the B1- and B2-types respectively. The implications of these results are highlighted in view of the hypothesis that the anti-inflammatory compound of the 1500--1000 molecular weight peptide fraction purified from malignant cell culture supernatants could be a kinin metabolite and a feedback mediator of inflammatory reactions.

Steady-state fluorescence polarization (FP) of 1,6-diphenyl-1,3,5-hexatriene (dph)-labelled platelets in the presence of bradykinin (bk).

Steady-state fluorescence polarization (FP) decreases, when 1,6-diphenyl-1,3,5-hextriene (dph) labelled platelets are exposed to bradykinin (bk). At pH 8, the dose-response curve is bell-shaped with an optimum bk effect at 10(-7) M. In contrast to the ricinoleic-acid ester of glycerin-polyethyleneglycol, cremophor EL (CEL), bk is no more effective when platelets are pretreated with 10(-5) M p-bromophenacylbromide (B phi B). These results suggest that platelets are target cells for the peptide bk, which induces an FP decrease indirectly by stimulating the release of non-saturated fatty acids in the platelet membrane.

On the stereochemistry of activation of phenylalanine by phenylalanyl-tRNA synthetase from baker's yeast.

Because of its chiralic alpha-phosphorus atom adenosine 5'-O-(1-thiotriphosphate) (ATPalphaS) exists in two diastereomeric forms, arbitrarily named (A) and (B). For phenylalanyl-tRNA synthetase ATPalphaS (A) is a substrate whereas ATPalphaS (B) is neither a substrate nor an inhibitor. During the ATPalphaS (A)/PPi exchange reaction with phenylalanyl-tRNA synthetase the configuration at the alpha-phosphorus is retained. The mechanistic implications of these findings are discussed. Preliminary investigations with several other aminoacyl-tRNA synthetases show that the stereochemical requirement with respect to the alpha-phosphorus of ATP is not identical for all aminoacyl-tRNA synthetases.