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Ulcer and Wound-Healing Activities of Copper Complexes

It has been demonstrated that copper complexes such as copper aspirinate and copper tryptophanate, markedly increase healing rate of ulcers and wounds. For example, copper complexes heal gastric ulcers five days sooner than other reagents. Further, it has been shown that, whereas non-steroidal anti inflammatory drugs, such as ibuprofen and enefenamic acid suppress wound healing, copper complexes of these drugs promote normal wound healing while at the same time retaining anti inflammatory activity.The skin of pigs is considered the closet model to human skin in terms of the anatomical and physiological charactaristics of skin. This was examined: the possible adverse effects of applying the test dressings on wounds by using a prcine partial-thickness wound model. An independent laboratory performed this experiment using a large, white, Landrace female pig weighing 50kg.

Test sites comprised a total of 12 evenly bilateral allocated punch biopsy partial-thickness wounds each measuring approximately 12 mm in diameter and 5mm in depth. Immediately after wounding, six randomly chosen wounds were covered with test dressings and the remaining six wounds with control commercial sterile dressing pads. Comparable assessments of the test dressing and control dressing covered wound sites at day 3 and 7 post-wounding were conducted by macroscopic examination and scoring of local dermal reactions (crythema, edema and crust formation), and by microscopic examination following biopsy harvest. In addition to assessing the direct effects at the wound sites, blood samples were collected at the pre test stage (baseline control) and at the time of the two respective biopsy harvest sessions on study days 3 and 7 post wounding to resolve any potential treatment effects on clinical pathology parameters. The Results:

Antibacterial and antifungal efficacies of test dressings.

Both the envelope fabric (2.3% copper oxide impregnated polypropylene nonwoven fabric) and the internal fabric (containing 3% copper oxide plated fibers) of the test dressings have potent antibacterial (gram positive and gram negative bacteria) and antifungal properties. The damage to microorganisms is exerted within minutes of their exposure to the copper oxide containing fabrics. The test dressings exerted similar potent biocidal efficacy when repeatedly spiked for 5 consecutive days with high titers of bacteria. When the biocidal efficacy against Enterococcus faecalis of the test dressing was compared in two separate experiments with a popular silver containing wound dressing K pneumoniwere were exposed to fabrics containing only 1% copper dress- oxide (one third of the amount found in the test dressings) for 24 hours with 2 log of the bacteria killed, the surviving bacteria that were propagated and re-exposedagain for 5 consecutive times to the 1% copper oxide containing fabrics, were as sensitive to the fabrics as their parent bacteria. At least 2 log of the bacteria were killed in each of the consecutive exposures, without development of tolerance.

Skin sensitization.

One of the animals exposed to the internal or exterior fabric of the test dressings showed any dermal reactions throughout the entire 72 hour observation period. There was no evidence of erythema, thema, eschar, or edema formation. The calculated guideline-based Primary Irritation Index (PII) was 0.0 (ie, the test item is classified as a nonskin irritant item under ISO10993 international standard). Additionally, systemic clinical signs in reaction to treatment were not evident in any of the animals and unusual changes in body weight also were not noted. In the porcine experiment, the weight of the pig remained the same during the 7 day study. No noticeable clinical signs of adverse effects in the pig were evident throughout the entire study period in reaction to treatment. Macroscopic examination of the wound sites revealed no significant differences between the control and test dressings in erythema, edema, and crust formation at 3 and 7 days post-wounding.The present study analyzed the copper dressings invitro biocidal properties and safety in animal models. Their capacity to enhance wound closure, increase gene and in-situ upregulation of proangiogenic factors (eg, placental growth factor and VEGF), and increase blood vessel formation when compared to control dressings (without copper) or commercial wound dressings containing silver in wounds inflicted in genetically engineered diabetic mice, is reported elsewhere.29Copper oxide was incorporated into the dressings since it is the most common naturally occurring form of copper and copper oxide is both non-soluble and a very powerful biocide. These properties allow a very slow and steady release of copper ions,34 which permit an increased shelf life of the wound dressings, and more significantly, increased capacity of the wound dressing forprolonged and stable biocidal and wound healing properties.

Anticonvulsant Activities of Copper Complexes

The brain contains more copper than any other organ of the body except the liver, where copper is stored for use elsewhere. This fact suggests that copper plays a role in brain functions. With reports of seizures in animals and humans following the protracted consumption of copper-deficient diets, it was reasoned that copper has a role to play in the prevention of seizures. It was subsequently discovered that organic compounds that are not themselves anti-convulsants exhibit anticonvulsant activity when complexed with copper. Further, it was found that copper complexes of all anti-epileptic drugs are more effective and less toxic than their parent drugs.

Anticancer Activities of Copper Complexes

As early as 1912, patients in Germany were treated for facial epithelioma with a mixture of copper chloride and lecithin. Success of such treatment suggested that copper compounds have anticancer activity. Work at the University of Liverpool in 1913 demonstrated that subcutaneous and intravenous injections of a copper salt or colloidal copper softened and degenerated carcinomas transplanted into mice. In 1930, work in France indicated that injections of colloidal copper mobilized and expelled tumor tissue. Recent work with mice in the USA has shown that, indeed, treatment of solid tumors with non-toxic doses of various organic complexes of copper markedly decreased tumor growth and metastasis and thus increased survival rate. These copper complexes did not kill cancer cells but caused them to revert to normal cells.

Anticarcinogenic Activity of Copper Complexes

Based on work in the treatment of cancers using copper complexes, researchers have found that these same complexes may prevent or retard the development of cancers in mice under conditions where cancers are expected to be induced.

Radiation Protection and Radiation Recovery of Copper Complexes

Ionizing radiation, such as that used in the treatment of cancer, has been shown to induce massive systemic inflammation. Ideally, such radiation-induced injury might be prevented or ameliorated by chemical repair mechanisms in the body. Thus, pharmacological approaches to the repair of radiation-damaged tissue are needed. As early as 1984, copper metallo-organic complexes have been shown to have radiation protection and radiation recovery activities. They are capable of causing rapid recovery of immunocompetence and recovery from radiation induced tissue changes. The mechanism of this activity appears to be tied to the ability of certain copper complexes to deactivate the superoxide, or "free," radicals liberated by ionizing radiation. In addition, since radiation has the capability of breaking the bonds of natural copper enzymes in the body, supplementing these with non-toxic doses of pharmaceutical copper complexes restores the lost tissue-repair capability. Since these complexes may also have anticarcinogenic activity, it is suggested that there would be merit in using copper complexes in the treatment of cancer and in particular, treating patients undergoing ionizing radiation therapy for their cancer, accidental exposure to radiation, and astronauts undertaking space travel.

Heart Disease and Copper Complexes

Numerous studies have drawn attention to the relationship between copper deficiency and heart disease. First observed in rats in 1936, this effect has now been traced to both a deficiency in copper and an imbalance in the copper-to-zinc ratio in the body. Work by Dr. L.M. Klevay at the U.S. Department of Agriculture, Human Nutrition Research Center in 1973 has led to the postulation that copper has a direct effect on the control of cholesterol. In continuing work published in 1975, he theorized that a metabolic imbalance between zinc and copper - with more emphasis on copper deficiency than zinc excess - is a major contributing factor to the etiology of coronary heart disease. Subsequent work by other investigators has shown that copper complexes also can have a valuable role in the minimization of damage to the aorta and heart muscle as oxygenated blood reperfuses into tissues following myocardial infarction. This action is based on the anti-inflammatory action of copper complexes. These and other studies suggest the use of copper dietary supplements as a means of preventing and controlling such diseases as atherosclerosis (a form of arteriosclerosis), coronary heart disease, aortic aneurysms and myocardial infarction. It has been speculated that the reason that the heart attack rate in France is lower than in the rest of Europe is because of the French practice of drinking red wine. Red wine has a higher copper content than white wine because it is prepared with the skin of the grape intact. The copper originates in the wine from the copper fungicides used on the grapes in the field. Based on an abundance of historical data such as the foregoing, many researchers anticipate that copper will become an increasingly important component of tomorrow's medical treatments.

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