Toxins


Chantixby James J. Galligan, Ph.D., Associate Chair,
Department of Pharmacology and Toxicology

Chantix (Varenicline) is one of the most popular smoking cessation drugs available by prescription.  However, a number of problems with this drug have been identified and this has led to many restrictions on its use.  These problems include an increased incidence of depression, suicidal thoughts, lightheadedness and fainting.

Results of a recent study published in the Canadian Medical Association Journal add another potential problem for Chantix.  These investigators conducted a meta-analysis of 14 published papers describing the beneficial and negative effects associated with Chantix when used to treat nicotine addiction.  The investigators included only double-blind randomized controlled trials in their analysis.  This means that subjects and investigators did not know who was receiving Chantix vs. placebo (simply a sugar pill with no active ingredients) and subjects were assigned to the Chantix or placebo group randomly.  This reduces the chance that subjects at risk for cardiovascular problems were assigned more frequently to the Chantix group.  The investigators analyzed data from 8,216 subjects.  Their study revealed a small but statistically significant increase in the risk for cardiovascular problems such as heart attacks or strokes in the subjects taking Chantix.  Although there was a difference, it was small.  In the Chantix group 52 of 4908 (1.06%) subjects experiences a so called adverse cardiovascular event while in the placebo group 27 of 3308 (0.82%) subjects experienced the same kind of event.

There are some points worth discussion here.  Firstly, it is not surprising that Chantix might be associated with cardiovascular complications.  Chantix is a nicotine replacement therapy.  Therefore, Chantix shares many of the same pharmacological actions of nicotine.  Cigarette smoking does increase the risk of cardiovascular disease partly because cigarette smoke contains nicotine (cigarette smoke also contains carbon monoxide and other toxins which are not present with Chantix).  Nicotine increases blood pressure and increase blood clots which can cause heart attacks and strokes and Chantix may do this as well.  Secondly, although the increased risk for adverse events in the Chantix group was small, the overall sample size was also small (<5,000 subjects).  Worldwide, there are millions of people using Chantix to help kick the smoking habit and therefor a much larger number of patients might be at risk worldwide.

Finally, it is important to remember that all drugs cause side effects (some worse than others).  When deciding whether or not a drug should be used, the doctor and patient must consider the risk vs. the benefit.  Chantix might produce a small increase in the risk for a heart attack or stroke in a patient trying to kick the nicotine habit.  But, what is the heart attack/stroke risk for that patient if he/she continues to smoke?  Many smokers become former smokers without the need for drugs like Chantix but there are also many smokers who have quit hundreds of times.  This is the subset of people who are most likely to benefit from nicotine replacement treatments.  Larger studies will likely reveal the real risk/benefit ratio of Chantix when used to treat nicotine addiction.

In the meantime, the wise person will discuss these issues with their doctor before using Chantix to help kick the smoking habit.

 

Additional information available can be found at:

NuclearExplosionJapan

by James J. Galligan, Ph.D., Associate Chair,
Department of Pharmacology and Toxicology

The recent earthquake and tsunami in Japan has caused severe destruction and has damaged a nuclear power plant.  This poses the danger of release of radioactive materials into the atmosphere and subsequent exposure to the people living near the damaged plant.  You may have heard on the continuous news coverage of this catastrophe that medical personnel are providing potassium iodine to people at risk for radiation exposure.

Why is potassium iodine useful for protection against radiation toxicity?  To answer this question we first need to discuss the thyroid gland.  The thyroid gland produces thyroid hormone which is released into the circulation to regulate metabolism of cells throughout the body.  Cellular metabolism generates body heat and energy utilization.  Thyroid hormone contains iodide and without iodide there is not thyroid hormone and this disrupts normal cell metabolism.  Normally iodine comes from dietary sources (including iodized salt) and this is sufficient to maintain normal thyroid function.  One of the toxic substances released from a damaged nuclear reactor is radioactive iodine.  When people breathe in radioactive iodine contaminated air, they are giving themselves a dose of this toxic substance.  Radioactive iodine accumulates in high concentrations in the thyroid gland and the radiation can then damage the thyroid or cause thyroid cancer.  IOSAT Photo

Interestingly, radioactive iodine is used to treat thyroid cancer as the radiation will kill off the tumor cells and iodine accumulates in the thyroid gland.  Anyway, people who are at risk will be protected against accumulation of radioactive iodine in the thyroid gland by potassium iodine supplements.  Potassium iodine fills up the thyroid stores of iodine leaving no room for radioactive iodine to accumulate.  Because potassium iodine is safe and non-toxic, there is no risk to using this preventative treatment.

Let’s hope that there is a quick and uneventful resolution to the current nuclear danger in Japan.  In the meantime, supplements of potassium iodine will help reduce the long term risks of exposure to any leaking radiation.

nicotine replacement therapy image

by James J. Galligan, Ph.D., Associate Chair,
Department of Pharmacology and Toxicology

Quitting cold turkey is a common regimen for kicking the cigarette smoking/nicotine habit.  Cold turkey does work for many cigarette smokers.  However, there are also many smokers who find that quitting is easy because they have done it hundreds of times.

Nicotine replacement therapy (NRT) is a common treatment for smokers in this latter category.  NRT comes in nasal sprays (very messy), chewing gum and “the patch”.  NRT involves a step down strategy over a 8-12 week period where the smoker gives up cigarettes and initially goes on a high dose nicotine treatment for 2-3 weeks followed by successive 2-3 week nicotine dose reductions.  This strategy is designed to gradually reduce the nicotine dependence and uncomfortable withdrawal symptoms (irritability, craving, disruption of sleep, etc.) until smokers no longer crave nicotine.  Studies have shown that NRT doubles the smoker’s chances of quitting by the end of the 12 week period although the success rate is still not great.  In placebo controlled studies, NRT produces about a 40% success rate while subjects on the placebo treatment quit about 20% of the time.  The big problem is that 80-90% of the quitters relapse in about 1 year. Current Food and Drug Administration (FDA) approval for NRT indicates a maximum 12 week treatment.

Part of the problem with cigarette smoking/nicotine addiction is the behavioral aspect of the addiction.  For example, the post meal coffee and cigarette is a very satisfying experience for smokers and there are strong social reinforcements associated with several smokers sharing this experience.  Studies have shown that even crack cocaine addiction has a strong behavioral-social component to the drug smoking experience and addiction.  So, unless the cigarette smoker changes his or her friends and family the smoker will continue to be exposed to the drug (nicotine)-related cues.

Drug addiction therapists and the FDA are beginning to re-think the 12 week limitation on NRT.  Nicotine raises blood pressure in some individuals but overall the data indicate that nicotine itself is not particularly dangerous to your health.  Cigarette smoking is clearly dangerous to your health as cigarette smoke contains an array of toxic chemicals.

Cigarette smoking is the major cause of lung cancer and it is also a major cause of deadly cardiovascular diseases such as high blood pressure, clogged arteries, heart attacks and strokes.  At this time, the long-term risks of NRT have not been studied in large groups of subjects.  However, the risks of cigarette smoking are unambiguous.  About 20% of Americans are cigarette smokers; this translates into 62 million people who are at great risk for lung cancer and cardiovascular disease which places a huge burden on our healthcare system.  It may be time to permit long-term NRT in an effort to reduce cigarette smoking relapse rates.  Of course this must be done with mechanisms in place to carefully monitor any unanticipated adverse effects that might appear when large numbers of people are using long-term NRT to kick the habit.

by James J. Galligan, Ph.D., Associate Chair,
Department of Pharmacology and Toxicology

The recent Associated Press news story (Monday, Jan. 11, 2010)  about the high levels of the heavy metal, cadmium, in children’s jewelry manufactured in China (http://abcnews.go.com/Health/WellnessNews/wireStory?id=9527916) is reminiscent of a story a few years ago about 1,4 butanediol in the kids toy called Aqua Dots (http://www.reuters.com/article/idUSN0741410820071108) which was also manufactured in China.  (You can also view an AP video report to the right of this post.)

1,4 butanediol is a precursor of the synthesis of gamma hydroxybutyrate (GHB) by nerve cells in the brain.  Of course GHB is best known as a “date rape” drug.  GHB causes the victims to pass out and to develop amnesia, particularly when GHB is consumed with alcohol.  Kids playing with Aquadots were at risk of accidentally ingesting GHB and this could have acute and chronic effects on the child’s nervous system.

Cadmium has shown up in children’s jewelry (bracelets, necklaces) as a replacement for lead.  The toxicities caused by

Associate Press image of Rudolph charm

Charms from bracelets tested between 82 & 91 percent cadmium.

lead are well known.  What is less well known is that cadmium may be more toxic than lead.

Cadmium is a divalent cation ion, meaning it has two positive charges.  Cadmium has deleterious effects on the development of the nervous system which makes it very dangerous to include in the manufacturing process of children’s toys.  Cadmium is used in metallurgy (hence its use in the manufacture of jewelry), nickel/cadmium batteries and it is also used as a stabilizer in plastics manufacturing.  Cadmium is also found in cigarette smoke.

Cadmium blocks calcium channels in nerve cells.  Calcium channels are a portal for calcium to enter nerve cells from the extracellular fluids and calcium is an important signaling molecule that regulates the activity of nerve cells and their growth and maturation.  Blocking calcium channels (as can occur with cadmium exposure) would prevent calcium from entering nerves cells and therefore disrupts the normal function and maturation of nerve cells.

Cadmium also disrupts the function of many enzymes the control growth of cells, and also blocks the activity of enzymes that are responsible for DNA repair.  Both of these actions contribute to the carcinogenic effects of cadmium toxicity.

All in all cadmium exposure is not good and its’ use must be carefully monitored.  Obviously, it has no place in the manufacturing process of children’s toys.

by James J. Galligan, Ph.D., Associate Chair,
Department of Pharmacology and Toxicology

A few weeks ago, I discussed methlymercury contamination of freshwater fish in lakes scattered around the United States.  This topic was of interest because of the local expertise here in Pharmacology and Toxicology on methylmercury induced neurotoxicity.  Well, Michigan State University also has an outstanding research and training program in environmental toxicology (http://cit.msu.edu/) and another news item caught my attention that was highly relevant to the environmental toxicology expertise here at MSU (http://www.google.com/hostednews/ap/article/ALeqM5gqrMC7NvYKe4jGTjLIZM-jRqp-7QD9AVQQK04).

Cyanobacteria in Pool

Cyanobacteria in Pool

Cyanobacteria (blue green algae) blooms are contaminating many freshwater lakes in the U.S.  These algae blooms are unsightly, smelly and potentially deadly, particularly for pets.  Warm dry weather coupled with fertilizer run-off from farms are the main culprits leading to prolific growth of cyanobacteria.  The resulting blue-green sludge piles up on lakeshores and dying and decaying bacteria cause the foul odors.  This ruins the aesthetics of the lakes and certainly reduces the enjoyment for lake front property owners.  However, the real danger comes from the toxins produced by these bacteria.

Cyanobacteria produce two types of toxins: alkaloids and the peptide microcystins.  The alkaloids include saxitoxin, a sodium channel blocker that is a neurotoxin.  Microcystins are small peptides (7 amino acids) and they are predominately liver toxins.  Ingestion of contaminated water results in high levels of microcystin exposure to the intestine and then the liver.  Microcystins are phosphatase inhibitors that disrupt the protein structure of cells in the liver ultimately leading to death of liver cells (hepatocytes) and liver bleeding.  Human poisoning with cyanobacteria-produced toxins is rare because humans (at least most of them) are smart enough not to ingest the foul looking and foul smelling cyanobacteria contaminated water.  However, livestock, or the pet dog may not be so clever or lucky.

The other issue is the wildlife (waterfowl, fish, amphibians) that inhabit the contaminated lakes and who can not avoid exposure to the toxins.  Typically, the algae blooms are short lived and dissipate with rain or a nice breeze.  However, the kill off of the local inhabitants of the lake can far outlast the algae bloom and therefore the effects on the overall health of the lake can also be long lasting.

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