Tetrachlorodecaoxide Research Articles

Naringin, a flavanone glycoside, promotes angiogenesis and inhibits endothelial apoptosis through modulation of inflammatory and growth factor expression in diabetic foot ulcer in rats

Chronic, unhealed diabetic foot ulcer (DFU) is one of the most severe complications of diabetes mellitus (DM). Naringin, a flavanone glycoside antioxidant, was reported to have antidiabetic and anti-apoptotic properties. In the present study DM was induced experimentally by streptozotocin (STZ, 55mg/kg, i.p.). In surgically introduced wounds on the dorsal surface of the hind paw of rats, the healing potential of naringin was investigated. Rats were treated with naringin (20, 40 and 80mg/kg, p.o.), insulin (10IU/kg, s.c.) and tetrachlorodecaoxide (TCDO) (1 drop, twice a day, topically) for 16days. The wound area was measured every second day, and on day 17 various biochemical parameters were determined in serum, wound tissue, and histopathological examination of the wound was performed. Naringin (40 and 80mg/kg) significantly (P<0.05) improved wound area, serum glucose level, glycated Hb and serum insulin. Naringin treatment at 40 and 80mg/kg resulted in significant (P<0.05) up-regulation of mRNA expression of growth factor (IFG-1, TGF-β and VEGF-c), Ang-1 and collagen-1 whereas mRNA expression of inflammatory mediators (TNF-α, IL-1β and IL-6) was down-regulated. Furthermore, naringin significantly (P<0.05) attenuated STZ-induced apoptosis and stimulated angiogenesis in the wound tissue. Further results suggest that angiogenesis was improved via naringin-mediated inhibition of hyperglycemia, oxidative stress, down-regulation of inflammatory mediator expression and up-regulation of growth factor expression, leading to improved wound healing of DFU.

Development of Novel Oral Formulations Prepared via Hot Melt Extrusion for Targeted Delivery of Photosensitizer to the Colon

Colon-residing bacteria, such as vancomycin-resistant Enterococcus faecalis and Bacteroides fragilis, can cause a range of serious clinical infections. Photodynamic antimicrobial chemotherapy (PACT) may be a novel treatment option for these multidrug resistant organisms. The aim of this study was to formulate a Eudragit®-based drug delivery system, via hot melt extrusion (HME), for targeting colonic release of photosensitizer. The susceptibility of E. faecalis and B. fragilis to PACT mediated by methylene blue (MB), meso-tetra(N-methyl-4-pyridyl)porphine tetra-tosylate (TMP), or 5-aminolevulinic acid hexyl-ester (h-ALA) was determined, with tetrachlorodecaoxide (TCDO), an oxygen-releasing compound, added in some studies. Results show that, for MB, an average of 30% of the total drug load was released over a 6-h period. For TMP and h-ALA, these values were 50% and 16% respectively. No drug was released in the acidic media. Levels of E. faecalis and B. fragilis were reduced by up to 4.67 and 7.73 logs, respectively, on PACT exposure under anaerobic conditions, with increased kill associated with TCDO. With these formulations, photosensitizer release could potentially be targeted to the colon, and colon-residing pathogens killed by PACT. TCDO could be used in vivo to generate oxygen, which could significantly impact on the success of PACT in the clinic.

Tetrachlorodecaoxide does not jeopardize anastomotic healing: an experimental study in animals.

Tetrachlorodecaoxide (TCDO) is a negatively-charged complex of chlorine and oxygen commonly used for the treatment of infected external wounds. However, it displays antiadhesive properties when applied intra-abdominally. In rats, small-bowel and a large-bowel anastomoses were performed and one-half of the animals received TCDO. It was found that TCDO did not alter the bursting pressures of small and large-bowel anastomoses at 1, 3 and 9 days postoperatively.

A double-blind, placebo-controlled, randomized trial to evaluate the role of tetrachlorodecaoxide in the management of chemotherapy-induced oral mucositis

We conducted a double-blind, placebo-controlled, randomized trial to evaluate the efficacy and safety of tetrachlorodecaoxide (TCDO) in patients with chemotherapy-induced mucositis. Sixty-two patients with World Health Organization grade II–IV oral mucositis were eligible for the study. They were randomized to receive TCDO or placebo, 10 mL twice daily, swish and swallow, for 7 days. Patients were evaluated for oral pain, dysphagia, and oral intake. Downgrading and total duration of mucositis were documented. Thirty-two were randomized to receive TCDO. Thirty received the placebo. All were evaluable. Both arms were well matched for age, gender, type of underlying neoplasm, and prior history of oral mucositis. Intensity of initial symptoms, degree of mucositis, and time period between delivery of chemotherapy and development of mucositis were also similar. Post-therapy evaluation revealed no significant difference in the mean grade of oral and esophageal pain, or dysphagia between TCDO and placebo. Downgrading or total duration of mucositis did not differ between the two groups. Oral intake improved significantly in patients taking TCDO. Time to subjective improvement in oral pain was significantly shorter with TCDO (3.1 versus 3.6 days). Evaluation on day 3 revealed that 77% of those receiving TCDO were free of oral pain in comparison to 46% receiving placebo ( P = 0.05). These results indicate that TCDO may be helpful in palliating some of the symptoms related to oral mucositis. The therapeutic benefit, however, is small and needs to be confirmed in a larger trial.

Prevention of Postoperative Adhesions by Single Intraperitoneal Medication

Postoperative adhesions account for a significant morbidity after abdominal, gynecological, or cardiac surgery. A large number of compounds have been suggested to prevent such adhesions, but none is generally accepted. We have compared eight different substances that could be beneficial for the prevention of postoperative adhesions in a new standardized rabbit model with measurement of the areas of adhesion. In 10 groups of 20 rabbits an area of abrasion of the serosa of the ileum, the appendix, and the abdominal wall measuring 10,000 mm 2 was created by an emery piston during celiotomy. The controls received no medication. The treatment groups received a single intraperitoneal administration of 1 ml per 100g body wt of normal saline (NaCl), 5 mg taurolidine (T), 0.5 U plasmin/300 U DNase (PD), 2000 IU streptokinase/500 IU streptodornase (SS), 7 mg phosphatidylcholine (PC), 4 mg hyaluronic acid (HA), 7 mg sphingolipid (SL), 7 mg galactolipid (GL), or 0.5 ml tetrachlorodecaoxide (TCDO), respectively. Ten days later the extent of adhesions was quantified by morphometry. The total area of adhesions (±SEM) was found to be 1998 ± 124 mm 2 in controls. The application of NaCl reduced the adhesions to 1368 ± 58 mm 2, of T to 1012 ± 48 mm 2, of PD to 673 ± 33 mm 2, of SS to 360 ± 44 mm 2, of PC to 335 ± 84 mm 2, of HA to 328 ± 76 mm 2, of SL to 278 ± 80 mm 2, of GL to 261 ± 67 mm 2, and of TCDO to 240 ± 45 mm 2. The effects of PD, SS, PC, HA, SL, GL, and TCDO were significant in comparison to controls and NaCl. Our experimental data suggest that the two new lipid substances, SL and GL, are the most likely candidates for routine clinical use in the prevention of postsurgical adhesions.

Influence of tetrachlorodecaoxide (Ryoxon) on the development of leukemia after total-body gamma-irradiation.

The effect of tetrachlorodecaoxide (TCDO) treatment after total-body irradiation (TBI) with gamma-rays (single dose, about LD 50) on the development of radiation-induced leukemia was tested in rats. TCDO was applied intravenously from day 4 through day 11. The control group was exposed to the same dosage of X-rays (TBI), but received physiological saline solution instead of TCDO. Compared to the control group, TCDO therapy initially markedly increased the survival rate: 72 versus 44% (6 months after TBI) and 36 versus 20% (1-year survival rate). The overall survival, however, was not significantly prolonged. TBI caused leukemia in 36% of the rats in the irradiation control group without TCDO treatment, however, none of 24 rats treated with TCDO after X-ray exposure developed leukemia. Since in this study TCDO was only administered for 8 days during the acute phase of radiation syndrome, we suppose that additional TCDO treatment at various times later on would lead to even better results.

Stimulation of Hematopoietic Cell Recovery by Tetrachlorodecaoxide in Sublethally Irradiated Mice

This study investigated whether tetrachlorodecaoxide (TCDO), a potent wound-healing agent, promotes recovery of hematopoietic tissue of mice depleted by sublethal X irradiation. Mice were exposed to 3 Gy total-body irradiation and were given 1 ml/kg TCDO intravenously daily from day 1 to 5 or day 4 to 8 after irradiation. The effect was assessed by the change in the total number of nucleated cells in bone marrow and spleen, endogenous spleen colony formation, and 30-day mouse lethality. In the spleen there were profound effects on spleen weight, total organ cellularity, and endogenous colony formation. The TCDO produced radiation dose-modifying factors between 1.4 and 1.5 for endogenous spleen colony formation in mice primed with 3 Gy and reirradiated 4 days after treatment. This stimulated cellular recovery resulted in an increased protection of mice from lethality caused by subsequent total-body irradiation by factors of 1.12-1.18. The results show that TCDO is a potent stimulator of cellular recovery in the spleen of sublethally irradiated mice.

The Antiviral Activity of Tetrachloro Decaoxide against Herpes Simplex Virus Type 1 and the Virucidal Effect of the Drug

At the recommended clinical dose for direct application to infected wounds tetrachloro decaoxide (TCDO) (1.0 × concentration TCDO) alone or in combination with haemoglobin proved to be cytotoxic for BHK and Flow 2002 cells, but at ≤0.1 TCDO/haem concentration BHK-21 cells tolerated treatment with the drug for 24 h retaining ≥80% cell viability. The in vitro cytotoxic effect is only partially reversible; but this could not explain the strong antiviral effect of TCDO/haem against herpes simplex virus type 1 (HSV-1) growing in BHK cells. The antiviral effect produces both a reduction in the number of virus particles assembled, and a lowering of their relative infectivity (i.e. reduced virus quality). The antiviral effect was active throughout the HSV-1 replication cycle. The quality of the viral DNA that was packaged into particles was unimpaired but unpackaged DNA was less infectious than controls. The reduction in particle numbers appeared to be due to both lowered protein synthesis and reduced virus particle assembly. TCDO/haem exhibits potent virucidal activity against HSV-1; HSV-2; Semliki Forest virus; Germiston virus; Reovirus type 3; Influenza virus type A; Feline leukaemia virus; Adenovirus type 5 and Polio virus type 1. Enveloped viruses, though varying over a wide sensitivity range were more sensitive than non-enveloped viruses. The magnitude of the virucidal effect against HSV-1 in suspension could be reduced by addition of BSA. The HSV-1 virucidal effect stems mainly from an effect of the drug on virion polypeptides. We propose that the effects of TCDO/haem result from the nonspecific chemical oxidation of susceptible chemical linkages both within and between individual proteins located intracellularly (antiviral and cytotoxic effects) or on the surface of virions (virucidal effect).

Radiosensitization by tetrachlorodecaoxide (TCDO): Influence of concentration

Radiosensitization by tetrachlorodecaoxide (TCDO): Influence of concentration

Regenerative Effects of Tetrachlorodecaoxide in BD IX Rats after Total-Body γ Irradiation

Tetrachlorodecaoxide (TCDO) was tested for its effects in BD IX rats when combined with a single dose nearing LD50 of total-body irradiation (gamma rays, 60Co). In pilot tests we found that TCDO administrations prior to or immediately after irradiation led to a very high mortality rate (up to 90%), whereas the initiation of TCDO treatment on Day 2, 3, or 4 after irradiation lowered the death rate noticeably, with optimum results when TCDO application was started on Day 4. In our major experiment on 100 BD IX rats, it was demonstrated that the following treatment schedule considerably decreased the death rate (from 44 to 4%): 15.5 mumol TCDO/kg body wt/day on Days 4-6 after irradiation and 7.75 mumol/kg body wt/day on Days 7-11. The animals treated with TCDO showed only mild anemia in the peripheral blood, accompanied by reticulocytosis and low-grade leukocytopenia. Examination of the bone marrow on Day 12 after irradiation revealed X-ray-induced agranulocytosis in the animals that had received only physiological saline solution, whereas in the bone marrow of the animals treated with TCDO there was erythropoiesis as well as myelopoiesis. In addition, the degree of hair loss and depigmentation occurring about 1 month after irradiation was considerably reduced by TCDO. From these results it can be postulated that TCDO has two different effects: as an oxygen donator it causes radiosensitization in the tissue when given before or immediately after irradiation; as an agent stimulating phagocytes and tissue regeneration, it promotes regeneration very effectively when damage is already evident in the tissue.

Improvement of tumor spheroid oxygenation by Tetrachlorodecaoxide

The benefit of Tetrachlorodecaoxide (TCDO) in improving tumor tissue oxygenation has been tested using multicellular tumor spheroids. Measurements of oxygen tension (Po 2) values with O 2-sensitive microelectrodes re vealed a distinct enhancement of the spheroid oxygenation after both, bolus injection or continuous infusion of TCDO into the medium surrounding the spheroids. The effect of TCDO on local oxygenation appeared to be less pronounced in spheroid regions with low initial Po 2 values compared to well-oxygenated areas of these cellular aggregates. By continuously infusing TCDO into the measuring system, a sustained increase of local Po 2 was obtained which was proportional to the local steady state concentration of TCDO in the medium surrounding the tumor spheroids. During experiments with TCDO in vivo, this substance should, therefore, be tested for its potential of improving the oxygenation status of solid tumors, and hence, of sensitizing tumors to classical treatments, such as radiotherapy.

Time kinetics of hemoglobin and myoglobin activation by tetrachlorodecaoxide (TCDO).

In the presence of peroxidase, myoglobin or hemoglobin, Tetrachlorodecaoxide (TCDO) forms an active oxygen species which is similar to the product of the polymorphonuclear leucocyte (PMNL) myeloperoxidase reaction and the 'Klebanoff Model' of phagocytosis, but it is also produced under anaerobic conditions. Randomly destructive species such as the free OH radical or singlet oxygen are not formed. The kinetics of the heme-dependent activation vary according to the heme type present. In comparison to myoglobin, blood shows a 2 h delay in the appearance of maximal activity. On the basis of known biochemical and clinical-physiological data, a hypothesis can be proposed to explain the reoxygenation observed in hypoxic tissue, induced by TCDO via this activated heme species. Under normal physiological conditions, vasodilation occurs via catalysis by xanthine oxidase or PMNL-dependent activation of fatty acids.

Biochemical Oxygen Activation as the Basis for the Physiological Action of Tetrachlorodecaoxide (TCDO)

Oxidation of methionine, 4-(methylthio)-2-oxobutyric acid (KMB), or 1-aminocyclopropane carbonic acid (ACC) are indicator reactions for activated oxygen species such as singlet oxygen (1O2), OH.-radical like oxidants, superoxide anion (O2.-), hydrogen peroxide (H2O2) or activated hemo-iron complexes like peroxidase- or catalase-"compound I". Methionine is oxidized by OH. as well as by 1O2 forming ethylene, but not by tetrachloro-decaoxygen complex (TCDO) in the absence or presence of catalytic hemoproteins such as peroxidase, hemoglobin or myoglobin. Both KMB and ACC are oxidized by TCDO under the catalysis of the above hemo-proteins where neither catalase nor superoxide dismutase are inhibitors. TCDO hemo-protein complex is an oxidant with similar properties as peroxidase-compound I and can clearly be differentiated from O2.-, H2O2, OH. and 1O2.

In vitro investigations on the antibacterial action and the influence on the phagocytic chemiluminescence of tetrachlorodecaoxide--a new, non-metallic oxygen complex.

The first non-metallic oxygen carrier, tetrachlorodecaoxide (TCDO), showed in vitro antibacterial activity among aerobic and anaerobic bacteria. The lethal dose for Escherichia coli, for example, was 150 micrograms/ml whereas 15 micrograms/ml reduced the bacterial amount after a latent period of two hours, but regrowth started after four hours. The bactericidal effect of TCDO, however, was dose-dependent and species-specific. This suggests that some aerobic bacterial species might not be able to produce sufficient amounts of protecting enzymes like catalase or superoxide dismutase. The computer controlled measurement of chemiluminescence was used as a model for the phagocytic activity. With isolated human granulocytes and opsonized zymosan as antigen no increase in peak counts per minute was observed compared with controls without TCDO. However, with human whole blood, positive effects were seen using TCDO together with zymosan as well as specific and non-specific opsonized Klebsiella pneumoniae K 17. It seems that whole blood possesses additional, but as yet unknown biocatalysers to split TCDO into oxygen and chloride.

New aspects on the pathophysiology of wound infection and wound healing--the problem of lowered oxygen pressure in the tissue.

There is a correlation between tissue oxygen tension, incidence of infection and disturbance of wound healing. Scientific investigations in recent years have documented that infection and tissue repair are processes consuming oxygen. Animal experiments have shown that oxygenation of the tissue is essential for the elimination of pathogens, the stimulation of phagocytosis as well as for the degradation of dead tissue structures and the synthesis of new tissue structures. Hypoxia and hypovolemia are of crucial significance for the impairment of organ functions. An effective therapy for disorders of oxygenation has not been feasible so far, except for clinical anesthesiological efforts to increase the oxygen saturation of hemoglobin and hyperbaric oxygen therapy. However, it has recently been possible to synthesize an oxygen carrier which supports respiratory oxygen physiologically. With tetrachlorodecaoxide (TCDO), a causal therapeutic concept for the topical treatment of infected hypoxic wounds with chronic disturbance of wound healing has been introduced for the first time.

In vitro investigations on the antibacterial action and the influence on the phagocytic chemiluminescence of tetrachlorodecaoxide — A new non-metallic oxygen complex

The first non-metallic oxygen carrier, tetrachlorodecaoxide (TCDO), showed in vitro antibacterial activity among aerobic and anaerobic bacteria. The lethal dose for Escherichia coli, for example, was 150 micrograms/ml whereas 15 micrograms/ml reduced the bacterial amount after a latent period of two hours, but regrowth started after four hours. The bactericidal effect of TCDO, however, was dose-dependent and species-specific. This suggests that some aerobic bacterial species might not be able to produce sufficient amounts of protecting enzymes like catalase or superoxide dismutase. The computer controlled measurement of chemiluminescence was used as a model for the phagocytic activity. With isolated human granulocytes and opsonized zymosan as antigen no increase in peak counts per minute was observed compared with controls without TCDO. However, with human whole blood, positive effects were seen using TCDO together with zymosan as well as specific and non-specific opsonized Klebsiella pneumoniae K 17. It seems that whole blood possesses additional, but as yet unknown biocatalysers to split TCDO into oxygen and chloride.