Yet another fluoridated drug was withdrawn from the global market this week.
"Baycol" (made by Bayer AG) - a cholesterol-lowering drug taken by 700,000 Americans - was pulled off the market on Wednesday, August 8th. It had been linked to 31 U.S. deaths. Bayer would not disclose the total number of deaths worldwide, but at least nine more fatalities abroad are known.
Baycol had been found to cause muscle destruction - a condition known as rhabdomyolysis - and displayed compounded toxicity when used with other drugs.
On August 9th, the European Medicines Evaluation Agency announced a safety review of other drugs in the same class as Bayer 's "Baycol".
COMMENT (by Andreas Schuld and Wendy Small):
This is not the only recent withdrawal of a fluorinated drug.
The pulling of Baycol follows the earlier withdrawal of other fluorinated "weight-reducing" drugs such as Redux, Fen-Phen and Pondimin (September 1997).
Regarding the once very popular drug combination Fen-Phen, it is important to note that only the fluorinated compound ("Fen" - fenfluramine) was withdrawn, while Phentermine ("Phen") was not pulled.
Concerning rhabdomyolysis - other fluorinated medications have shown the same adverse effect.
Since 1988 - their introduction on the market - many cases of tendonitis and rhabdomyolysis have also been reported due to fluoroquinolone antibiotics, which are used in the treament of a large variety of infections.
In October 1994 the Japan Pharmaceutical Affairs Bureau amended the product information for Enoxacin, Fleroxacin, Norfloxacin, Sparfloxacin and Tosufloxacin to state that rhabdomyolysis may occur. (Reference: Information on Adverse Reactions to Drugs No.128, October 1994.)
In 1996, the Sri Lanka Drug Evaluation Sub-Committee decided that the product information of fluoroquinolone antibiotics should include a warning stating: "The onset of tendon pain calls for immediate withdrawal of fluoroquinolone antibiotics." (Reference: 27th Meeting of the Drug Evaluation Sub-Committee, Ministry of Health, Colombo, 26 November 1996.)
"Baycol" (Cerivastatin) is yet another drug containing a fluorophenyl compound. Prozac and Paxil are some other well-known drugs containing fluorophenyl compounds, as are pesticides including Flusilazole and Fluorbenside.
Starting in the 1930s, fluorophenyl compounds were used as successful agents in the treatment of hyperthyroidism. Originally used mainly in the dye and pesticide industries, it had been found by IG Farben (Bayer) and Knoll's scientists that all fluoride compounds - organic or inorganic - interfere with thyroid hormone activity.
[It is important to realize that this disturbance is not caused by the thyroid gland itself. Any effects on the actual gland are a secondary effect and a result of the severe disturbance caused elsewhere in peripheral tissue, particularly the liver and brain.]
Organic fluoride compounds undergo extensive transformation in the liver, mainly via a process called oxidative demethylation, involving the thyroid hormone (T3) mediated P-450 enzyme system.
In many instances the resulting metabolites may have higher activity and/or greater toxicity than the original compound.
Ironically, an example often used as textbook case to demonstrate of how more-toxic metabolites are produced after passing through the liver, is a compound called "Sevoflurane", which is one of many fluorinated agents used in anesthesia.
Inorganic fluoride is a normal metabolite of Sevoflurane and thought to be responsible for the renal failure observed.
Fluvoxamine (Luvox) transforms to at least 9 metabolites.
The activity of organic fluoride compounds on the P-450 enzyme system is also important as it relates to the elimination of many other drugs. Inhibition of these enzymes can cause other drugs to accumulate to dangerous levels in the body, and many cases implicating fluorinated medications are documented in hundreds of studies on MEDLINE.
As just one example, fluoxetine (Prozac) increased up to 13 times the concentrations of thioridazine and its metabolites in the plasma when both medications were administered (Daniel et al, 1999).
Drug interaction was also part of the reason for the Baycol withdrawal.
Liver damage is often observed when fluorinated agents are used. This, again, is true for all organic fluoride compounds.
In 2000, 3M announced a phase-out of "Scotchgard"
discovering that the product's primary ingredient-a fluorinated compound called perfluorooctanylsulfonate (PFOS) -- was found in all tested blood bank examinations.
PFOS and related compounds are known to cause liver dysfunction and liver cancer.
Paxil and Prozac are also known to cause liver disease.
Fluoxetine (Prozac) has been shown to cause severe liver dysfunction such as hepatitis (Cai et al, 1999; Johnston & Wheeler, 1997; Mars et al, 1991; Friedenberg & Rothstein, 1996).
Fluoxetine has also shown tumor-promoting activity in the liver (Lin et al, 1999).
Tolrestat (fluorinated anti-diabetic) was withdrawn in 1997 after the appearance of severe liver toxicity.
All fluoride compounds interfere with thyroid hormones.
Example: Prozac (fluoxetine)
Several studies show that fluoxetine causes a decline inT3 levels and affects T3 production (Eravci et al, 2000; Lin et al, 1999; Baumgartner et al, 1994; Shelton et al, 1993).
In rat brain, fluoxetine has also been
shown to interfere with T3
metabolism (Eravci et al, 2000; Baumgartner et al, 1994).
In 1983 Golstein et al. stated that, "the major effect of the drug seems to be stimulation of TSH synthesis and release via the inhibition of T4-mediated thyroid-pituitary feedback. Additionally, fluoxetine could exert a minor direct central stimulatory effect on TSH secretion".
The metabolites produced by organic fluoride
compounds in the liver are tranferred to the fetus through
various pathways, including circulatory via placental passage,
gastrointestinal via fetal swallowing, and respiratory secondary
to fetal lung absorption (Hostetter et al, 2000). Numerous
congenital abnormalities have been reported due to first trimester
to Fluconsazole, a systemic antifungal agent (Pursley et al, 1996).
Infants who were breastfed by mothers
taking fluoxetine (Prozac)
demonstrated a growth curve significantly below that of infants who were breastfed by mothers who did not take the drug (Chambers et al, 1999).
This is of urgent concern. The potential for severe mental dysfunction is immense.
Other F-Drugs Recently Withdrawn:
Most of the fluorinated drugs withdrawn have shown to cause serious cardiac adverse effects, which is not surprising considering their influence on thyroid hormone activity.
(Ironically many were first held of benefit in heart disease).
1) In 2000 Cisapride ("Propulsid") was withdrawn because it caused severe cardiac side effects
2) The drug Mibedrafil ("Posicor") was withdrawn after it was shown that patients with congestive heart failure showed a trend to higher mortality (1998).
3) Flosequinan was withdrawn in 1993 after it was shown that the beneficial effects on the symptoms of heart failure did not last beyond the first 3 months of therapy. After the first 3 months of therapy, patients on the drug had a higher rate of hospitalization than patients taking a placebo.
4) Astemizole (allergy drug) was withdrawn in 1999 because it also became associated with serious life threatening cardiac adverse events.
5) Fenfluramine and dexfenfluramine were withdrawn in 1997 due to serious cardiac adverse health effects.
(Other fluorinated drugs have also shown serious cardiac toxicity, such as Halofantrine, but remain on the market with only warnings issued so far.)
6) Tolrestat (anti-diabetic) was withdrawn in 1997 after the appearance of severe liver toxicity and deaths.
7) In 1992 Abbott withdrew Temafloxacin (anti-biotic) ("Omniflox"). The drug had caused deaths, liver dysfunction, etc.
8) Grepafloxacin was removed from the market in 1999 because of serious cardiac events.
Etc., etc., etc...
This is also what we call - fluoride poisoning.
PS: Last year, U.S. District Judge Louis C. Bechtle approved a $3.75 billion national settlement of health claims stemming from "Fen-Phen". More than 9,000 lawsuits were filed against American Home Products, maker of fenfluramine.
One of the most frequently used anesthesias for general surgery is fluorinated halothane. A finding of significantly higher incidence of cardiac arrhythmias in children who were undergoing outpatient dental extraction and who were anaesthetised with halothane compared with sevoflurane, is reported on at: http://www.doh.gov.uk/cmo/cmo99_13.htm
For more information, please refer to the following:
Baumgartner A, Dubeyko M, Campos-Barros A, Eravci M, Meinhold H - "Subchronic administration of fluoxetine to rats affects triiodothyronine production and deiodination in regions of the cortex and in the limbic forebrain" Brain Res 635(1-2):68-74 (1994)
Chambers CD, Anderson PO, Thomas RG, Dick LM, Felix RJ, Johnson KA, Jones KL - "Weight gain in infants breastfed by mothers who take fluoxetine" Pediatrics 104(5):e61 (1999)
Eravci M, Pinna G, Meinhold H, Baumgartner A - "Effects of pharmacological and nonpharmacological treatments on thyroid hormone metabolism and concentrations in rat brain" Endocrinology 141(3):1027-40 (2000)
Friedenberg FK, Rothstein KD - "Hepatitis secondary to fluoxetine treatment" Am J Psychiatry 153(4):580(1996)
Golstein J, Schreiber S, Velkeniers B, Vanhaelst L - "Effect of fluoxetine, a serotonin reuptake inhibitor, on the pituitary-thyroid axis in rat" Eur J Pharmacol 91(2-3):239-43 (1983)
Hostetter A, Ritchie JC, Stowe ZN - "Amniotic fluid and umbilical cord blood concentrations of antidepressants in three women" Biol Psychiatry 48(10):1032-4 (2000)
Jackson IM, Luo LG - "Antidepressants
inhibit the glucocorticoid stimulation of
thyrotropin releasing hormone expression in cultured hypothalamic neurons" J Investig Med 1998 Dec;46(9):470-4 (1988)
Johnston DE, Wheeler DE - "Chronic hepatitis related to use of fluoxetine." Am J Gastroenterol 92(7):1225-6 (1997)
Lin X, Levitsky DA, King JM, Campbell TC - "The promotion effect of anorectic drugs on aflatoxin B(1)-induced hepatic preneoplastic foci" Carcinogenesis 20(9):1793-9 (1999)
Mars F, Dumas de la Roque G, Goissen P - "Acute hepatitis during treatment with fluoxetine" Gastroenterol Clin Biol 15(3):270-1 (1991)
Pursley TJ, Blomquist IK, Abraham J, Andersen HF, Bartley JA - "Fluconazole-induced congenital anomalies in three infants" Clin Infect Dis 22(2):336-40 (1996)
Shelton RC, Winn S, Ekhatore N, Loosen PT - "The effects of antidepressants on the thyroid axis in depression." Biol Psychiatry 33(2):120-6 (1993)
Be sure to read the other two articles on Baycol in this week's issue: