RA Drugs Linked to Slight Skin Cancer Risk

People taking rheumatoid arthritis drugs such as etanercept (Enbrel) or infliximab (Remicade) may be at a slightly increased risk for skin cancer, researchers report.

However, the risk is probably not significant enough to outweigh the benefits of these drugs, the researchers said.

These so-called biologic treatments work by blocking tumor necrosis factor alpha (TNF-alpha), which previous studies had found to be linked with increased risk of skin, lung and blood cancers.

"The risk of skin cancer is marginally increased among people with rheumatoid arthritis," said lead researcher Dr. Frederick Wolfe, a clinical professor of internal medicine at the University of Kansas School of Medicine. "But it's nothing that anybody should be worried about," he added.

For the study, Wolfe and his colleagues collected data on 13,001 patients with rheumatoid arthritis included in the National Data Bank for Rheumatic Diseases and the U.S. National Cancer Institute SEER (Surveillance, Epidemiology, and End-Results). The researchers found a total of 623 cases of skin cancer and 537 cases of other cancers.

They also found that anti-TNF-alpha medications were associated with a slight increased risk of skin cancer. But, they did not find any increased risk for other cancers, according to the report in the September issue of Arthritis & Rheumatism.

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Methcathinone is a structural analogue of methamphetamine and cathinone. It is potent and it, along with the parent compound, are easily manufactured.

They are sold in the U.S. under the name CAT. It is distributed as a white to off-white chunky powdered material and is sold in the hydrochloride salt form. Outside of the U.S., methcathinone is known as ephedrone and is a significant drug of abuse in Russia and some of the Baltic States.



Methcathinone was permanently placed in Schedule I of the Controlled Substances Act in October 1993. Prior to its scheduling, two federal cases were effectly prosecuted in Ann Arbor and Marquette, Michigan, utilizing the analogue provision of the Controlled Substances Analogue and Enforcment Act of 1986.

PHENETHYLAMINES

The class of compounds with the largest number of individual compounds on the illicit drug market is the Phenethylamines. This class of compounds consists of a series of compounds having a phenethylamine skeleton. Phenethylamines are easily modified chemically by adding or changing substituents at various positions on the molecule.

Phenethylamines fall into one of two categories in terms of physiological effects — these compounds are either stimulants or hallucinogens. Phenethylamines are suitable for clandestine laboratory production. The parent compound in the phenethylamine series is amphetamine, a central nervous system stimulant(CNS). With this molecule, the modifications begin by adding a methyl group to the nitrogen on the side chain. The resulting structure is the most popular clandestinely produced controlled substance in the U.S. in 1995 — methamphetamine

Like amphetamine, methamphetamine is also a CNS stimulant. It is easily produced in clandestine laboratories using two basic synthetic routes. The traditional route used by “methcooks” began with phenyl-2-propanone; however, when bulk sales were limited by law, most clandestine chemists began using ephedrine as a precursor, although some now synthesize their own supply of phenyl-2-propanone, and still other routes are possible New legislation has now limited bulk purchases of ephedrine in the U.S., though not in neigboring countries. And the chemical structure is such that further molecular synthetic modifications are easily accomplished resulting in a number of homologues and analogues. Few of the synthetic modifications of phenethylamines by clandestine laboratory “chemists” are novel. Most have been documented either in the scientific literature or in underground scientific literature. And the Internet now provides answers to anyone tenacious enough to search for a simple method to synthesize any analogue or homologue of a phenethylamine.

The parent compound of a second set of phenethylamine homologues and analogues is 3,4-methylenedioxyamphetamine (MDA). This compound was first reported in the literature in 1910.14 In the mid-1980s, the N-methyl analogue of MDA came into vogue and was known then and is still referred to as “Ecstasy”.

The synthesis of 3,4-methylenedioxymethamphetamine (MDMA) follows the same synthetic protocols as the less complicated phenethylamines. The clandestine laboratory operator or research chemist selectively adds one N-methy group, an N,N-dimethyl group, an N-ethyl group, an N-propyl, an N-isopropyl group, and so on. In 1985 the N-hydroxy MDA derivative was reported.

FENTANYL

Fentanyl [the technical nomeclature is N-(1-phenethyl-4-piperidyl)propionanilide] is a synthetic narcotic analgesic approximately 50 to 100 times as potent as morphine.6 The drug had its origin in Belgium as a synthetic product of Janssen Pharmaceutica.7

In the 1960s in Europe and in the 1970s in the U.S., it was introduced for use as an anesthesia and for the relief of post-operative pain. Almost 70% of all surgical procedures in the U.S. use fentanyl for one of these purposes.

Fentanyl has been called “synthetic heroin”. This is a misnomer. Victims of fentanyl
overdoses were often heroin abusers with “tracks” and the typical paraphenalia. The fentanyls as a class of drugs are highly potent synthetic narcotic analgesics with all the properties of opiates and opinoids.9 However, the fentanyl molecule does not resemble heroin. Fentanyl is strictly a synthetic product while the morphine used in heroin production is derived from the opium poppy.

Beginning in the late 1970s with -methylfentanyl,10 nine homologues and one analogue
(excluding enantiomers) of fentanyl appeared in the illicit marketplace.11 The degrees of potency vary among the fentanyl homologues and analogues. The potencies of the fentanyl derviatives are much higher than those of the parent compound. But the high potencies cited above explain why even dilute exhibits result in the deaths of users who believe they are dealing with heroin. Another name used by addicts when referring to Fentanyl and its derivatives is “China White”. This term was first used to described substances seized and later identified as alpha-methylfentanyl in 1981.

There are many fentanyl homologues and analogues . Because of the size and complexity of fentanyl derivatives, the interpretation of IR, MS, and NMR spectral data prove very valuable in elucidating specific structural information required for the identification of the material.

PHENCYCLIDINE (PCP)

The chemical nomenclature of phencyclidine is phenylcyclohexylpiperidine. The term “PCP” is used most often used when referring to this drug. The acronym PCP has two origins that are consistent. In the 1960s phencyclidine was trafficked as a peace pill (“PeaCePill”). PhenylCyclohexylPiperidine can also account for the PCP acronym.



PCP was first synthesized in 1926.3 It was developed as a human anesthetic in 1957, and found use in veterinary medicine as a powerful tranquilizer. In 1965 human use was discontinued because, as the anesthetic wore off confusional states and freightening hallucinations were common. Strangely, these side effects were viewed as desirable by those inclined to experiment with drugs. Today even the use of phencyclidine as a primate anesthetic has been all but discontinued. In 1978, the commercial manufacture of phencyclidine ceased and the drug was transferred from Schedule III to Schedule II of the Controlled Substances Act. Small amounts of PCP are manufactured for research purposes and as a drug standard.

The manufacture of PCP in clandestine laboratories is simple and inexpensive. The first clandestinely produced PCP appeared in 1967 shortly after Parke Davis withdrew phencyclidine as a pharmaceutical.4 The clandestine laboratory production of PCP requires neither formal knowledge of chemistry nor a large inventory of laboratory equipment. The precursor chemicals produce phencyclidine when combined correctly using what is termed “bucket chemistry”.

The opportunities for a contaminated product from a clandestine PCP are greatly enhanced because of the recognized simplicity of the chemical reactions in the production processes. The final product is often contaminated with starting materials, reaction intermediates, and by-products.

Clandestine laboratory operators have been known to modify the manufacturing processes to obtain chemically related analogues capable of producing similar physiological responses. The most commonly encountered analogues are N-ethyl-1-phenylcyclohexylamine (PCE), 1-(1-phenylcyclohexyl)- pyrrolidine (PCPy), and 1-[1-(2-thienyl-cyclohexyl)]-piperidine (TCP).

In the 1960s, PCP was distributed as a white to off-white powder or crystalline material and ingested orally. In recent years, PCP has been encountered as the base and dissolved in diethyl ether. The liquid is then placed into small bottles which are recognized to hold commercial vanilla extract. This ether solution is then sprayed on leaves such as parsley and smoked. PCP is commonly encountered on long thin dark cigarettes (“Sherms”) which have been dipped in the PCP/ether solution.

LYSERGIC ACID DIETHYLAMIDE (LSD)

LSD is an hallucinogenic substance produced from lysergic acid, a substance derived from the ergot fungus (Clavica purpurea) which grows on rye. It can also be derived from lysergic acid amide which is found in morning glory seeds.1 LSD is also refered to as LSD-25 because it was the twenty-fifth in a series of compounds produced by Dr. Albert Hofmann in Basel, Switzerland.

Hoffman was interested in the chemistry of ergot compounds, especially their effect on circulation. He was trying to produce compounds that might improve circulation without exhibiting the other toxic effects associated with ergot poisoning. One of the products he produced was Methergine™, which is still in use today.

When LSD-25 was first tested on animals, in 1938, the results were disappointing. Five years later, in 1943, Hoffman decided to reevaluate LSD-25. The hallucinogenic experience that ensued when he accidentally ingested some of the compound led to the start of experimentation with “psychedelic” drugs.

LSD is the most potent hallucinogenic substance known to man. Dosages of LSD are
measured in micrograms (one microgram equals one-one millionth of a gram). By comparison, dosage units of cocaine and heroin are measured in milligrams (one milligram equals one-one thousanth of a gram). LSD is available in the form of very small tablets (“microdots”), thin squares of gelatin (“window panes”), or impregnated on blotter paper (“blotter acid”).

The most popular of these forms in the 1990s is blotter paper perforated into 1/4 inch squares. This paper is usually brightly colored with psychedelic designs or line drawing. There have been recent reports of LSD impregnated on sugar cubes.2 These LSD-laced sugar cubes were commonplace in the 1970s. The precursor to LSD, Lysergic Acid, is a Schedule III controlled substance. LSD is classified as a Schedule I controlled substance.

PSILOCYBIN MUSHROOMS

The naturally occuring indoles responsible for the hallucinogen properties in some species of mushrooms are psilocybin and psilocin. 12 The use of hallucinogenic mushrooms dates back to the 16th century occuring during the coronation of Montezuma in 1502.8 In 1953, R. G. Wassen and V.P. Wasson were credited with the rediscovery of the ritual of the Indian cultures of Mexico and Central America. 13 They were able to obtain samples of these mushrooms. The identification of the mushrooms as the species Psilocybe is credited to the French mycologist, Roger Heim. 14

Albert Hofmann (the discoverer of lysergic acid diethlamine) and his colleagues at Sandoz laboratories in Switzerland are credited with the isolation and identification of psilocybin (phosphorylated 4-hydroxydimethyltryptamine) and psilocin (4-hydroxydimethyltryptamine).15

Psilocybin was the major component in the mushrooms, and psilocin was found to be a minor component. However, psilocybin is very unstable and is readily metabolized to psilocin in the body. This phonomenon of phosphate cleavage from the psilocybin to form the psilocin occurs quite easily in the forensic science laboratory. This can be a concern in ensuring the specifity of identification.

The availability of the mushroom has existed worldwide wherever proper climactic conditions exist — that means plentiful rainfall. In the U.S., psilcoybib mushrooms are reported to be plentiful in Florida, Hawaii,16 the Pacific Northwest, and Northern California.17 Mushrooms that are analyzed in the forensic science laboratory confirm the fact that the mushrooms spoil easily. The time factor between harvesting the mushrooms and the analysis proves to be the greatest detriment to successfully identifying the psilocybin or pscilocyn. Storage prior to shipment is best accomplished by drying the mushrooms. Entrepreneurs reportedly resort to
storage of mushrooms in honey to preserve the psychedelic properties.18

Progressing through the analytical scheme of separating and isolating the psilocybin and psilocin from the mushroom matrix, cleavage of the phosphate occurs quite easily. Prior to beginning the analysis, drying the mushrooms in a desicator with phosphorous pentoxide ensures a dry starting material. In many instances, the clean-up procedure involves an extraction process carried out through a series of chloroform washes from a basic extract and resolution of the components by TLC.

The spots or, more probably, streaks are then scaped from the plate, separated by a back-extraction, and then analyzed by IR. Direct analysis by GC is very difficult because both psilocybin and psilocin are highly polar and not suitable for direct GC analysis. Derivatization followed by GC/MS is an option except in those instances where the mushrooms have been preserved in sugar.19 With the development and availability of HPLC, the identification and quatitation of psilocybin and psilocyn in mushrooms are becoming more feasible for many forensic science laboratories. 20