Tralement

Uses

Cupric sulfate is a compound used as an intravenous copper supplement for Total Parenteral Nutrition (TPN).

Elemental use in copper deficiency

Copper and copper containing compounds are broadly used in medical practice. Metallic copper is used already for many years in dental fillings and in copper intrauterine devices (IUD) for reversible contraception. Ointments containing copper, which release copper ions that are absorbed by the skin in the management of cramps, disturbances of renal function, peripheral, venous hypostatic circulatory disturbances, rheumatic disease and swelling associated with trauma. There are also cosmetic facial creams containing copper as their main active ingredient .

Selenious acid is an ingredient found in supplements, vitamins, parenteral nutrition, and dandruff shampoo.

Selenium injection is indicated for use as a supplement to intravenous solutions given for total parenteral nutrition (TPN). Administration of selenious acid in TPN formulas helps to maintain plasma selenium levels and also to maintain endogenous stores to prevent deficiency .

Selenium compounds, such as selenium sulfide, are used topically in anti-dandruff shampoos and in cases of seborrhea .

For the purpose of brevity, selenite will the focus of discussion, and more information about selenium can be obtained at Selenium.

Tralement is also used to associated treatment for these conditions: Copper Deficiency, Skin disinfectionSelenium Deficiency, Parenteral Nutrition, Selenium Supplementation

How Tralement works

This drug is an essential trace element for the functioning of many metalloenzymes including ceruloplasmin, ferroxidase II, lysyl oxidase, monoamine oxidase, Zn-copper superoxide dismutase, tyrosinase, dopamine-β-hydroxylase, and cytochrome-c-oxidase.

It is involved in erythropoiesis & leukopoiesis, bone mineralization, elastin and collagen cross-linking, oxidative phosphorylation, catecholamine metabolism, melanin formation & antioxidant protection of cells .

Cupric sulfate may also have a role in iron turnover, ascorbic acid metabolism, phospholipid metabolism, myelin formation, glucose homeostasis, and cellular immune defense .

After the metal passes through the basolateral membrane it is transported to the liver, attached to serum albumin. The liver is the critical organ for the homeostasis of copper. The copper is then prepared for excretion through the bile or incorporation into various proteins. The transport of copper to the peripheral tissues is accomplished through the plasma attached to serum albumin, ceruloplasmin or low-molecular-weight complexes .

In the dermis, copper promotes dermal fibroblasts proliferation, upregulates collagen (types I, II, and V) and elastin fiber components (elastin, fibrillins) production by fibroblasts, through the induction of TGF-β, promotes heat shock protein-47, important for collagen fibril formation, serves as a cofactor of LOX enzyme required for extracellular matrix protein cross-linking, stabilizes the skin ECM once formed, as increased crosslinking of collagen and elastin matrices occurs in a copper dose dependant manner, serves as a cofactor of superoxide dismutase, an antioxidant enzyme in the skin, essential for protection against free radicals, inhibits cellular oxidative effects such as membrane damage and lipid peroxidation, acts as a cofactor of tyrosinase, a melanin biosynthesis essential enzyme responsible for skin and hair pigmentation .

In reference to its role as a biocide, copper is an essential nutrient for many organisms. It acts as a cofactor in respiration, and therefore copper is required for aerobic metabolism. Accumulation of copper ions or intracellular release of free copper ions from proteins lead to cell damage. Copper catalyzes reactions that result in the production of hydroxyl radicals through the Fenton and Haber-Weiss reactions. The highly reactive oxygen intermediates lead to lipid peroxidation and oxidation of proteins. Free copper ions oxidize sulfhydryl groups, such as cysteine, in proteins or the cellular redox buffer glutathione. In particular, copper ions inactivate proteins by damaging Fe-S clusters in cytoplasmic hydratases .

Sodium selenite likely has the same mechanism of action as Selenium.

The most important physiological role of sodium selenite is associated with its presence as an active component of many enzymes and proteins, in addition to its antioxidative role. Selenium has been shown to activate anticancer agents, prevent heart and vascular diseases, exhibit anti-proliferative and anti-inflammatory properties, and to stimulate the immune system .

Its anticancer properties may be explained by the oxidation of free sulfhydryl groups. Tumor cells express free sulfhydryl groups (–SH) on the surface of their cell membranes and contribute to uncontrolled cell division. Only those compounds that can oxidize these groups to disulfides (S–S) may inhibit this process. Some organic forms of selenium, including selenocysteine, methylseleninic acid, and Se-methylselenocysteine have been established to be antioxidants. However, their anticancer mechanism is still not well understood .

Selenious acid, during an in vitro study, was found to stimulate hemoglobin synthesis in three different malignant erythroleukemia cell lines (MEL) . It has also been shown to increase the release of interleukin 2 in a dose-dependent manner . Interleukin-2 is made by a type of T lymphocyte (white blood cell). It increases the growth and activity of other T-lymphocytes and B-lymphocytes and this contributes to the development of the immune system .

Toxicity

Acute oral toxicity (LD50): 300 mg/kg in rats .

Copper sulfate ingestion (accidental or deliberate) is a rare form of poisoning usually limited to the Indian subcontinent. Though the rates are on the decline, it is essential that physicians are aware of its lethal complications and management strategies. The main complications of copper sulfate ingestion include intravascular hemolysis, methemoglobinaemia, acute kidney injury, and rhabdomyolysis .

Severe gastrointestinal effects may occur with acute overdosage. In extreme or long-term overdosage, symptoms may be similar to those of Wilson's disease, a disease in which the liver does not filter copper adequately and copper accumulates in the liver, brain, eyes, and other organs. Gradually, high copper levels may cause life-threatening organ damage .

Ingestion of more than 15 mg of copper has been reported to be toxic to humans. In a survey of human clinical case studies, 5.3 mg/day was the lowest oral dose at which local gastrointestinal irritation was seen. Ingestion of gram quantities of copper sulfate resulted in death by suicide, whereas less severe effects were reported from estimated copper doses of 40 to 50 mg from ingestion of carbonated beverages in contact with copper containers. Limited data are available on the chronic toxicity of copper. The hazard from dietary intakes of up to 5 mg/day appears to be low .

Treatment of cupric sulfate toxicity is symptomatic and may involve the use of a chelating agent (e.g. penicillamine, trientine and zinc) to remove any excessive metal that has been absorbed. In addition, dialysis may be useful .

The toxicity of selenium has been consistently well documented. However, some early studies reported that selenium may be a carcinogen. Nelson et al. (1943) showed that rats fed diets containing Se as seleniferous wheat developed hepatic tumors and low-grade carcinomas in 11 out 53 study animals .

Selenium at high doses (15-30 mcg/egg) has been reported to have significant adverse embryological effects on developing chickens. There currently no adequate and well-controlled studies in pregnant women. Selenious acid injections should be used during pregnancy only when the potential benefits justify the potential risk to the growing fetus .

The presence of selenium in the placenta and the umbilical cord blood has been reported in humans .

Overdosage symptoms with selenious acid include:

Acute Brick red–color gastric mucosa, cerebral edema, coma, death, fulminating peripheral vascular collapse, garlic or sour breath odor, gastrointestinal disturbance, hemolysis, hypersalivation, internal vascular congestion, liver necrosis, muscle spasms, pulmonary edema, and restlessness .

Chronic Dental defects, dermatitis, garlic odor of breath and/or sweat, gastrointestinal disorders, hair loss, mental depression, metallic taste, nervousness, nausea, vomiting, weak nails .

Volume of Distribution

The body of a 70 kg healthy individual contains approximately 110 mg of copper, 50% of which is found in the bones and muscles, 15% in the skin, 15% in the bone marrow, 10% in the hepatic system, and 8% in the brain .

The distribution of copper is affected by sex, age, and the amount of copper in the diet. Brain and liver have the highest tissue levels (about one-third of the total body burden), with lesser concentrations found in the heart, spleen, kidneys, and blood. The iris and choroid of the eye have very high copper levels .

Erythrocyte copper levels are generally stable, however, plasma levels fluctuate widely in association with the synthesis and release of ceruloplasmin. Plasma copper levels during gestation may be 2-3 times levels measured before pregnancy, due to the increased synthesis of ceruloplasmin .

Following oral intake and absorption, selenium from sodium selenite is found in the highest concentrations in the liver and kidneys of humans and animals .

In one study, tissue samples taken at autopsy from 46 healthy individuals killed in accidents and from 75 corpses of victims of various diseases to analyze selenium levels and distribution . The per-weight-unit basis of selenium levels ng/gm in wet in tissues decreased in the following order: kidney (469) > liver > spleen > pancreas > heart > brain > lung > bone > skeletal muscle. The highest proportion of body selenium was found in skeletal muscles (27.5%) , . Significantly less selenium was measured in bones (16%) and blood (10%). In the tissues of cancer corpses, the selenium levels were lower than levels in the control group. The lowest selenium concentrations were measured in alcoholic livers .

Elimination Route

Primarily absorbed in the small intestine .

Based on studies with radioactive isotopes of copper, most copper is absorbed from the stomach and duodenum of the gastrointestinal tract.

Maximum blood copper levels are observed within 1 to 3 hours following oral administration, and about 50 percent of ingested copper was absorbed. Copper absorption is proposed to occur by two mechanisms, one energy- dependent and the other enzymatic. Factors that can interfere with copper absorption include competition for binding sites with zinc, interactions with molybdenum and sulfates, chelation with phytates, and inhibition by ascorbic acid (vitamin C) .

Copper absorbed from the gastrointestinal tract is transported rapidly to blood serum and deposited in the liver bound to metallothionein .

From 20 to 60% of the dietary copper is absorbed .

The absorption of selenite following oral administration approximately 40-70% of an oral dose, based on studies done in humans .

Selenoprotein P, the plasma form of selenium, contains at least 40% of the total selenium in plasma . Deletion of the gene for selenoprotein P in mouse models alters the distribution of selenium in body tissues suggesting that selenoprotein P is necessary for selenium transport .

Half Life

The biological half-life of copper from the diet is 13-33 days with biliary excretion being the primary route of elimination .

30 days in beagle dogs .

Elimination Route

This drug is 80% eliminated via the liver in bile. Minimal excretion by the kidney . Metabolism studies show that persons with daily intakes of 2-5 mg of copper per day absorbed 0.6 to 1.6 mg (32%), excreted 0.5 to 1.3 mg in the bile, passed 0.1 to 0.3 mg directly into the bowel, and excreted 0.01 to 0.06 mg in the urine. As the data indicate, urinary excretion plays a negligible role in copper clearance, and the main route of excretion is in the bile. Other nonsignificant excretory routes include saliva, sweat, menstrual flow, and excretion into the intestine from the blood .

Selenium is eliminated mainly in the urine. However, significant endogenous losses through the feces can also occur . The rate of excretion varies with the chemical form of selenium used in supplementation and the route of administration. Other minor routes of elimination are lungs and skin .

Analysis of 72-hour urine sampling from a study of 48 Norwegian women given a 200 μg supplement of selenium in the form of selenite indicated approximately 50% absorption of selenite .

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