Melanie Johns Cupp

Doxorubicin Dosage Guidelines in a Patient with Hyperbilirubinemia of Gilbert's Syndrome

OBJECTIVE: To reconcile dosage modification guidelines for doxorubicin in a patient with hyperbilirubinemia of Gilberts syndrome (GS). CASE SUMMARY: A 62-year-old white man with concurrent diagnoses of large-cell non-Hodgkins lymphoma and GS was treated with standard doses of a doxorubicin-containing chemotherapy regimen. No increase of end-organ toxicity was observed during four treatment cycles. DISCUSSION: The relative prevalence of GS coupled with the rising incidence of non-Hodgkins lymphoma increases the probability that both disorders will be present in the same individual. A MEDLINE search (1966 through July 1997) revealed little, and often conflicting, information pertaining to drug metabolism and disposition in GS. In addition, no information has been reported regarding the metabolic fate of doxorubicin in these patients. It is important to emphasize that the lack of enhanced extramedullary toxicity in this patient is not conclusive evidence that the hepatic abnormality of GS had no effect on doxorubicin metabolism. CONCLUSIONS: Based on information regarding mechanisms for hepatic clearance, dosage modification of doxorubicin may not be necessary in hyperbilirubinemia of GS.

γ—Hydroxybutyric Acid (GHB), γ-Butyrolactone (GBL), and 1,4-Butanediol (BD)

γ-hydroxybutyric acid (GHB) was synthesized in 1960 by the French physician Henry Labroit (Ropero-Miller and Goldberger, 1998). Because of its then reported low toxicity and lack of side effects, the use of GHB in anesthesia and psychiatry was initially endorsed (Labroit, 1964), but it soon fell out of favor as an anesthetic owing to its unpredictable actions and adverse effects (Ropero-Miller and Goldberger, 1998). GHB has also been studied as a treatment for opioid and ethanol withdrawal; as a treatment for narcolepsy; and in the management of shock. In the 1980s, GHB was promoted in the United States as a growth hormone stimulator (Chin et al., 1998). After the Food and Drug Administration (FDA) banned the over-the-counter sales of l-tryptophan in 1989, GHB was promoted as a replacement sleep aid (Ropero-Miller and Goldberger, 1998). Beginning in 1990, the FDA began an investigation into several reports of GHB-associated vomiting, dizziness, tremors, and seizures resulting in hospitalization and death (FDA, 1997). GHB gained public notoriety with the death of actor River Phoenix, which was purportedly associated with GHB use. At that time, GHB was popular in Los Angeles nightspots, where it was commonly found in powder form. GHB then began appearing on college campuses, first in Florida and Georgia (Minai, 2001). The FDA and the Department of Justice took action against several manufacturers, distributors, and promoters of GHB. Through these actions and the use of embargos and public education campaigns, the distribution and abuse of GHB began to decrease. There was then a resurgence in the use of GHB and accompanying reports of GHB-associated adverse effects and deaths with the creation of clandestine labs (FDA, 1997). Subsequently, the GHB precursors γ-butyrolactone (GBL) and 1,4-butanediol (BD) began to be marketed as natural, nontoxic dietary supplements (FDA 1999a, b).

Coenzyme Q10 (Ubiquinone, Ubidecarenone)

Moore and colleagues identified coenzyme Q10 in 1940 (Greenberg and Frishman, 1988). In 1957, coenzyme Q10 was isolated from beef heart by Dr. Frederick Crane. Karl Folkers, a scientist at Merck Sharpe and Dohme, elucidated its chemical formula the following year. In 1972, Dr. Folkers and an Italian researcher identified a deficiency of coenzyme Q10 in human heart disease (Sinatra, 1999). Based on data from only a small number of patients, the Japanese government approved coenzyme Q10 for the treatment of congestive heart failure in 1974 (Khatta et al., 2000). In 1978 a Nobel Prize was awarded for the discovery of coenzyme Q10’s role in energy transport. The 1980s saw an increase in the number of clinical studies of coenzyme Q10 (Sinatra, 1999). From 1977 through 1991, Dr. Folkers and other researchers published Biomedical and Clinical Aspects of Coenzyme Q, a work of six volumes in which much often-cited coenzyme Q10 research was published. Coenzyme Q10 capsules were advertised to health care professionals by Doctor’s Mutual Service Company of California in the late 1980s. Promotion of coenzyme Q10 to consumers in the U.S. began in the late 1990s.

Dimethylglycine (N,N-Dimethylglycine)

Dimethylglycine was discovered in 1943 (Tonda and Hart, 1992). It is found in some but not all formulations of pangamic acid (vitamin B15). Pangamic acid is not an identifiable substance because of the variety of products that have been marketed as such. One pangamic acid formulation that contains dimethylglycine is the “Russian formula,” which was patented in 1975 and contains 61.5% calcium gluconate and 38.5% dimethylglycine (Gray and Titlow, 1982a). This is not the same as the pangamic acid isolated by Krebs and associates in 1951, which was studied in the treatment of cardiovascular disease in the 1950s and is structurally distinct from dimethylglycine (Kemp, 1959). Pangamic acid has been sold as a dietary supplement in the United States at least since the late 1970s, when the lay press celebrated its benefits (Colman et al., 1980). Although pangamic acid is also known as vitamin B15, it is not actually a vitamin because no deficiency state has been identified, and it has no known nutritional value (Colman et al., 1980; Gray and Titlow, 1982a). FoodScience Laboratories was the original distributor of vitamin B15 in the United States, and the Food and Drug Administration (FDA) challenged the company in court in the early 1980s in an attempt to remove the product from the market (Gray and Titlow, 1982a). As a result of this litigation, dimethylglycine continued to be marketed, but the use of the terms “vitamin B15” and “pangamic acid” fell out of favor (Hoorn, 1989). Currently, however, products labeled as vitamin B15, pangamic acid, and diemthylglycine are available. Some Internet sites incorrectly use the terms pangamic acid and vitamin B15 as synonyms for dimethylglycine.

Glucosamine and Chondroitin

In the 1950s, in vitro studies of glucosamine demonstrated its potential to increase fibroblast production of collagen and mucopolysaccharides. These findings led to studies of glucosamine for the treatment of osteoarthritis (OA) in humans, first with an injectable product, and then with oral supplementation (McCarty, 1994). Public interest in the use of glucosamine for OA increased in the late 1990s, in some measure owing to the publication of two books for laypersons on the subject, The Arthritis Cure and Maximizing the Arthritis Cure (Thie et al., 2001).

Red Yeast Rice Extract

Red yeast rice extract is a Chinese remedy known as Hongqu that has been used for centuries (Reeder, 1998). Its use was first documented in China during the Tang Dynasty in 800 AD. It has been used for making rice wine and to preserve and enhance the taste and color of foods, including meat, fish, and soybean products (Herber et al., 1999; Ma et al., 2000). Li Shizhen, a pharmacologist of the Ming Dynasty (1368–1644), reported that red yeast rice promotes “digestion and blood circulation, can strengthen the spleen and dry the stomach” (Ma et al., 2000). Red yeast rice extract has been sold commercially in the United States since the late 1990s.

Melatonin (N -acetyl-5-Methoxytryptamine )

Melatonin was isolated in the late 1950s and had been administered intravenously by 1960. Studies of its sedative/hypnotic effects soon followed (Dawson and Encel, 1993). Melatonin promotion to the public began in the mid-1990s.

Dehydroepiandrosterone (DHEA) (Prasterone).

Dehydroepiandrosterone (DHEA) is an endogenous steroid that is produced by the zona reticularis of the adrenal cortex (Gurnell and Chatterjee, 2001). It was first isolated in 1934 from urine by Butenandt and Dannenbaum. In 1944, dehydroepiandrosterone sulfate (DHEA-S), DHEA’s sulfated metabolite, was isolated from the urine. In 1954, DHEA was isolated from the blood, and in 1959 the chemist E.E. Baulieu discovered that DHEA-S was the most abundant form of the hormone found in human plasma. In 1965, De Neve and Vermeulen reported an association between DHEA-S levels and aging; it was found that as people age, DHEA-S levels decline in a linear fashion (Lieberman, 1995; Yen, 2001). This discovery led to numerous studies that focused on the link between DHEA and DHEA-S levels and the aging process.

SAMe (S-adenosyl-l-methionine)

Because of its instability, SAMe was not investigated as a therapeutic agent until the 1970s, when Stramentinoli and colleagues developed a stable p-toluene-sulfonate complex of SAMe-sulfate (Stramentinoli and Catto, 1976). This preparation was administered parenterally. Its antidepressant effects were first described in 1970 (DeVanna and Rigamoni, 1992). An enteric-coated oral formulation was then developed, but bio-availability was poor, necessitating dosing on the order of 1 g/d compared with several hundred mg/d with the parenteral formulation (Baldessarini, 1987). More stable formulations were subsequently developed (Franzese, 2001). SAMe did not appear on the shelves of retail outlets in the United States until February 1999 (Chamberlain, 2001).

Androstenedione and Other Over-the-Counter Steroids

Androstenedione first appeared in early 1997 in body-building magazines, where it was advertised as a natural anabolic agent. It has become an attractive, legal alternative to anabolic steroids for professional and recreational athletes, particularly those engaged in “power” sports who wish to increase muscle mass and endurance (Anonymous, 1998; Anonymous, 1998, Uralets and Gillette, 1999).