History

Ephedra, and other medicinal plants have been identified at European neanderthal burial sites dating from 60,000 BCE (1). Thousands of years later, Pliny accurately described the medicinal uses of ephedra. But thousands of years before Pliny, traditional Chinese healers used ephedra extracts. Chinese texts from the 15 th century recommended ephedra as an antipyretic and antitussive. In Russia, around the same time, extracts of ephedra were used to treat joint pain; and though recent laboratory studies confirm that ephedra might be useful for that purpose (2), additional trials and studies have not been forthcoming. In the 1600s, Indians and Spaniards in the American Southwest used ephedra as a treatment for venereal disease (3). That idea might also have had some merit, as some studies show that ephedra contains compounds with antibiotic activity called transtorines (4). Whether the transtorines will prove to be clinically useful has not been determined.

In 1885, Nagayoshi Nagi, a German-trained, Japanese-born chemist, isolated and synthesized ephedrine. Nagi's original observations were confirmed by Merck chemists 40 years later (5). Merck's attempts at commercializing ephedrine were unsuccessful, at least until 1930, when Chen and Schmidt published a monograph recommending ephedrine as the treatment of choice for asthma (3). During the 1920s and 1930s, epinephrine was the only effective oral agent for treating asthma. Epinephrine, which had been available since the early 1900s was (and still is) an effective bronchodilator, but it has to be given by injection, or administered with special nebulizers. Ephedrine was nearly as effective as epinephrine, and could be taken orally. As a result, ephedrine became the first-line drug against asthma. It was displaced from that front during the late 1970s and early 1980s, when aerosolized synthetic P-agonists were introduced.

Unlike most of the other alkaloids contained in ephedra (methylephedrine and cathinone are both psychoactive, but the amount contained in unadulterated ephedra is too low to be of clinical significance), ephedrine is also a potent central nervous system (CNS) stimulant (6). Injections of ephedrine, called philopon (which means "love of work") were given to Japanese kamikaze pilots during World War II. A major epidemic of ephedrine abuse occurred in postwar Japan, when stockpiles of ephedrine accumulated for use by the Army were dumped on the black market. Abusers in Tokyo, and other large Japanese cities, injected themselves with ephedrine (then referred to as hirapon), in much the same way that methamphetamine is injected today (7). In the Philippines, a mixture of ephedrine and caffeine called shabu was traditionally smoked for its stimulating effect. In the late 1980s, shabu smoking gave way to the practice of smoking methamphetamine ("ice"). In what is perhaps a tribute to the past, some "ice" is sold under the philopon name.

The chemistry and nomenclature of these compounds are somewhat confusing, and are best understood by reference to the synthetic route used by plants to make ephedrine. All ephedra plants contain phenylalanine-derived alkaloids. Plants use phenylalanine as a precursor, but incorporate only seven of its carbon atoms. Phenylalanine is metabolized to benzoic acid, which is then acetylated and decarboxylated to form pyruvic acid. Transamination, results in the formation of forms (-)-cathinone.

Reduction of one carbonlyl group leads to the formation of either (-)-norephedrine (phenylpropanolamine is the name used to refer to the synthetic mixture of ± norephedrine), or norpseudoephedrine (called cathine). N-methy-lation of (-)-norephedrine results in the formation of (+)-ephedrine. N-methy-lation of cathine leads to the formation of (+)-pseudoephedrine (8).

Coping with Asthma

Coping with Asthma

If you suffer with asthma, you will no doubt be familiar with the uncomfortable sensations as your bronchial tubes begin to narrow and your muscles around them start to tighten. A sticky mucus known as phlegm begins to produce and increase within your bronchial tubes and you begin to wheeze, cough and struggle to breathe.

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