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ARSENIC

Rough file:

Methimazole (MMI) and propylthiouracil (PTU) are widely used for the treatment of Graves' disease. However, no studies have been reported on the action of these drugs on binding of L-triiodothyronine (T3) to the nuclear receptor. T3 receptors of rat liver nuclei, prepared by differential centrifugation, were extracted with 0.4 M KCl and 5 mM dithiothreitol (DTT). In the assessment of T3 binding to the DTT-reduced receptor, the hepatic nuclear extract was chromatographed on Superose 6 to remove DTT and isolate proteins of relative mass approximately 50,000 (chromatographed nuclear receptors (CNRs)), prior to the addition of [125I]T3 of high specific activity (3300 microCi/micrograms; 1 Ci = 37 GBq). MMI or PTU at 2 mM reduced specific T3 binding to CNR by 84% and 85%, respectively. The inhibitory effects of these reagents and 2 mM sodium arsenite (which complexes dithiols) were additive. arsenic and thionamides inhibit T3 binding to nuclear receptor.doc

The long-term retention of arsenic was most apparent in hair and skin, squamous epithelium of the upper gastrointestinal tract (oral cavity, oesophagus, and the oesophageal part of the stomach mucosa), the epididymis, thyroid, lens and skeleton. The accumulation in hair, skin and the upper gastrointestinal tract may be ascribed to a binding to keratin, the content of which is high in squamous epithelia. The distribution of arsenic in golden hamsters was similar to that found in mice. The significance of the findings in relation to reported adverse effects of inorganic arsenic is discussed. arsenic distribution in mice.hair.skin.thyroid.doc

Blackfoot disease is an endemic peripheral vascular disorder which is confined to a limited land area on the southwest coast of Taiwan. It has long been related to the consumption of high levels of arsenic found in the artesian well water. Humic substances have also been extracted from the well water and have been reported as a possible source of environmental goitrogen. The purpose of this study was to examine whether the prevalence of goiter is increased in the blackfoot disease-endemic area. This study covered all the children in the elementary schools of Putai and Peimen. They were divided into two groups according to the location of schools in the endemic area or non-endemic area of blackfoot disease. Thyroid enlargement was examined by palpation as recommended by the World Health Organization. Thyroid antibodies and hormones were determined in school children with a goiter and age-sex-matched normal control children using particle agglutination methods and radioimmunoassays, respectively. Aspiration cytology was done in cases with a nodular goiter. In total 4,567 school children were examined, including 2,306 males and 2,261 females. One hundred and twenty school children (2.63%) had a goiter of grade I or above. The prevalence of goiters in school children from the endemic area was higher than that from the non-endemic area (3.44 vs 2.08%, p less than 0.01). The prevalence of goiters in females from the endemic area was higher than that from the non-endemic area (4.65 vs 2.69%, p less than 0.02).arsenic increases goiter.study in blackfoot disease.doc

FDA Approves Arsenic Therapy
September 27, 2000

WASHINGTON (AP) - A form of arsenic once used as insect poison won Food and Drug Administration approval Tuesday as a leukemia treatment after studies found small doses helped patients with a rare but deadly form of the disease.

The approval of Trisenox, the brand name for arsenic trioxide, marks the first official arsenic-based therapy in the United States in over 100 years - one that came when U.S. scientists noted China was having some success with a compound much of the world had abandoned.

At issue is the rare "acute promyelocytic leukemia," or APL, which strikes about 1,500 Americans a year. About 400 will not respond to, or will quickly relapse after, standard chemotherapy. These patients have had few options but to try standard therapy again in hopes of buying some time.

But in a study of Trisenox, 28 of the 40 patients given the drug intravenously went into remission - an impressive 70 percent response rate, the FDA said. How long remission lasts varies, cautions FDA medical officer Dr. Steven Hirschfeld, but a few have lasted several years.

"To have a 70 percent response rate in patients who have failed conventional treatment is an exceptionally good result," said Dr. David Scheinberg, leukemia chief at New York's Memorial Sloan-Kettering Cancer Center, which is responsible for arsenic trioxide's comeback.

Arsenic alone is a poison and can cause cancer, but arsenic-containing compounds have been used medically for more than 2,000 years. Ninteenth-century U.S. doctors tried arsenic to treat leukemia, but abandoned it with the discovery of radiation and chemotherapy.

In the late 1970s, Chinese scientists noticed traditional Chinese practitioners were giving leukemia patients an arsenic-containing paste that in some cases seemed to work, Hirschfeld said. Those scientists eventually figured out that arsenic trioxide was the beneficial ingredient, and hunted for intravenous forms. Successful Chinese studies attracted the attention of Sloan-Kettering, which began U.S. tests in 1997.

APL is a cancer where abnormal or immature white blood cells crowd out proper white cells and red blood cells in the bone marrow and blood. Arsenic trioxide apparently works like another common APL treatment, retinoic acid: Instead of killing cells, it causes those immature white cells to mature into normal cells, Scheinberg said. Scientists now are testing whether it might help certain other cancers, too.

It can cause very serious side effects, the FDA cautioned. The sudden increase of working white blood cells can cause inflammation and fluid accumulation, especially in the heart and lungs, that can be fatal. Twenty percent of patients who tested Trisenox had the side effect, but all were successfully treated.

Trisenox also caused a heartbeat irregularity called an increased QT interval in 40 percent of patients. This irregularity can lead to arrhythmias, so the FDA urged that patients be closely monitored. Other side effects included nausea, vomiting, headache and fatigue.

Manufacturer Cell Therapeutics Inc. of Seattle said Trisenox will be available within three weeks, and a complete course of therapy will cost between $12,000 and $16,000.

The following article is from Dr. Mercola's site at www.mercola.com. arsenic is a direct antagonist of selenium and uses up selenium in the process of detoxifying arsenic. Selenium, through its action in glutathione peroxidase is one of the body's prime protectors from free radicals.  A selenium deficiency is highly correlated with the growth of cancerous tumors. Also, selenium is critical for converting T4 to T3 so arsenic can contribute to hypothyroidism by using up selenium.

Arsenic Triggers Flood Of Free Radicals

Arsenic is an important environmental contaminant, being number ONE in the EPA (Environmental Protection Agency) Superfund list.

The degree of human sufferings caused by arsenic is beyond comprehension in some other parts of the world, such as in Bangladesh and West Bengal, India where an estimated 50 million people are at risk from drinking arsenic contaminated water.

Arsenic's cancer-causing properties may stem from the production of DNA-damaging particles called free radicals.

The finding supports the use of antioxidants such as vitamin C and vitamin E, which mop up free radicals, in cancer prevention.

Researchers studied the effects of arsenic on cells grown in the laboratory.

Cells exposed to arsenic produced about three times as many damaging free radicals as other cells, the authors report, and an antioxidant cut the level of free radicals in the arsenic-exposed cells by half.

Arsenic exposure also doubled the number of cells with genetic mutations, the researchers note. And when an antioxidant blocker was added to the mix, mutated cells increased by 5 to 16 times.

Studies have already shown arsenic to be a human carcinogen, but before this study, the way arsenic caused cancer was unclear.

These results, however, clearly demonstrate that the generation of free radicals within minutes of arsenic exposure can lead to gene mutations and death of the cell, the authors conclude, and that antioxidants can block those effects.

Proceedings of the National Academy of Sciences February 13th 2001;98:1643-1648