Alkaloids ephedra

Ephedrine and ist isomer pseudoephedrine are alkaloids in Ephedra species. Brochmann-Hans-sen and Baerheim Svendsen reported the first gas chromatographic separation of these two alkaloids in a study on the separation and identification of 11 sympathomimetic amines on a 1.15 % SE-30 packed column at 104°C. However, ephedrine and pseudoephedrine could not be separated as such, but were separated as their oxazolidine derivatives after treatment with acetone. A typical chromatogram is given in Tale 13.1. 

Reproduced from j. Phami. sci., 51 (1962) 938, with the permission of the copyright owner. 

Parker et al. applied gas chromatography for the separation and identification of some sympathomimetic amines. They used a packed column of 5 % Carbowax 20 M on firebrick treated with 5 potassium hydroxide, at a column temperature of 170°C or 190°C. Ephedrine and pseudoephedrine were not separated, however. 

In a couple of papers, Beckett and Testa3described the gas chromatographic separation 

RETENTION INDICES OF DIASTEREOMERIC EPHEDRINES5 as N-acetyl-O-trimethylsilyl ether derivatives 

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Ephedra, also known as Ma-Huang, is a central nervous system stimulant that is similar to amphetamine. Ephedra alkaloids (a material found in plants) with the active ingredient ephedrine have been used for medicinal purposes in China for... 

Jacob P III, Haller CA, Duan M, Yu L, Peng M, et al. 2004. Determination of ephedra alkaloid and caffeine concentrations in dietary supplements and biological fluids. J Anal Toxicol 28 152. 

Pyruvic acid Ephedra alkaloids Phenyl C Cathine Cathinone Ephedrine Norephedrine... 

C) The FDA recommends that ephedra alkaloids be limited to no more than 8 mg per dose. 

Haller CA, Benowitz NL. Adverse cardiovascular and central nervous system events associated with dietary supplements containing ephedra alkaloids. N Engl J Med 2000 343 1833-1838. 

A number of other types of compounds have been used as chiral catalysts in phase-transfer reactions. Many of these compounds embody the key structural component, a P-hydroxyam-monium salt-type structure, which has been shown to be crucial to the success of the above described cinchona-derived quats. Although they have not been as successful as the cinchona catalysts, the ephedra-alkaloid derived catalysts (see 20, 22, 23 and 25 in Charts 3 and 4) have been used effectively in several reactions. In general, quats with chirality derived only from a single chiral center, which cannot participate in a multipoint interaction with other reaction species, have not been effective catalysts [80]. 

McCooeye, M., Ding, L., Gardner, G. J., Fraser, C. A., Lam, J., Sturgeon, R. E., and Mester, Z. (2003). Separation and quantitation of the stereoisomers of ephedra alkaloids in natural health products using flow injection-electrospray ionization-high field asymmetric waveform ion mobility spectrometry-mass spectrometry. Anal. Chem. 75 2538-2542. 

Andraws R, Chawla P, Brown DL. Cardiovascular effects of ephedra alkaloids a comprehensive review. Prog Cardiovasc Dis. 2005 47 217-225. 

As of January 2002, the maximum allowable dosage of ephedra is 8 mg per dose, or 32 mg per day. Most ephedra supplement products advise users to take two or three doses per day. What the product label says and what the actual content of the product is may be different. A research study published in 2000 tested the amount of ephedra alkaloids in dietary supplements and compared the results to the product label. The researchers found that more than half of the supplements did not list the ephedra alkaloid content or had a significant difference between the amounts listed on the label and the actual ephedra alkaloid content. The labels of most ephedra supplements state that the product is not intended for users less than 18 years old. 

Another interesting feature of polymer-supported catalysts containing quaternary ammonium salts involves the development of enantioselective catalysis using salts derived from cinchonia or ephedra alkaloids.11341 The first application of such chiral supported catalysts in the Michael reaction between methyl 1-oxoindan-2-carboxylate and methyl vinyl ketone revealed a high chemical yield in condensation product (60-100 %) although the enantioselectivities were only moderate (ee <27 %). 

Hodge, P., Khoshdel, E. and Waterhouse, J. Michael reactions catalyzed by polymer-supported quaternary ammonium-salts derived from cinchona and ephedra alkaloids, J. Chem. Soc., Perkin Trans. 1, 1983, 2205-2209. 

Failure to inform physician or pharmacist of concomitant use of herbal products Incomplete and inaccurate product information (FDA analysis of 125 products containing ephedra alkaloids revealed a range of 0 to I 10 mg/dose)... 

The six optically active alkaloids ephedrine, pseudoephedrine, norephedrine, norpseudoephedrine, and the N-methylated N-methylephedrine and N-methylpseudoephedrine are described in detail in Reti s review (2). Two new alkaloids of related structure have since been identified in Ephedra species, namely, (9-benzoylpseudoephedrine (271) and the oxazolidine derivative ephe-droxane (272). The 4-quinolone derivative ephedralone, recently isolated from Ephedra alata (273), may be of similar biogenetic origin as the ephedrines. Ephedra species also contain macrocyclic alkaloids of more complex structure (275). The two major Ephedra alkaloids (—)-ephedrine and (+)-pseudoephedrine are diastereomers. (—)-Ephedrine has the erythro and (+)-pseudoephedrine has the threo configuration. 

Generally, the use of a catalyst containing a -hydroxy amine moiety, for example, cinchona and ephedra alkaloids or 4-(4-aminophenylmethyl)-l-ethyl-2-pyrrolidinol, gives addition products with higher optical purity or enantiomeric excess values (up to 88%). The use of polar solvents, concentrated reaction solutions and the presence of tetrabutylammonium salts can substantially lower the optical purity of the products88. 

A previously healthy 19-year-old man took tablets containing a total of 24 mg of Ephedra alkaloids and 100 mg of caffeine, and 15 minutes later developed severe chest pain radiating down the left arm. An electrocardiogram showed an inferolateral myocardial infarct, confirmed by creatine kinase and troponin I measurements. He made a full recovery, and coronary angiography showed only minimal atherosclerotic disease of the left anterior descending artery. 

Haller CA, Benowitz NL. Dietary supplements containing Ephedra alkaloids. New Engl J Med 2001 344 1096-7. 

Chemical/Pharmaceutical/Other Ceass Elerbal supplements Ephedra alkaloids Adrenergic agents Natural products Chemicae Eormuea C10EI15NO Chemicae Structure ... 

Many cases of serious adverse effects and even fatalities have been reported that were linked with ephedra or ephedrine administration over the last 10 years. Haller and Benowitz published a review of 140 reports of adverse events related to the use of ephedra alkaloids that were submitted to the FDA between June 1997 and March 1999. Using standardized rating system for assessing causation, 31% of the cases were considered to be definitely or probably related to the use of ephedra alkaloid-containing supplements, and another 31% were deemed to be possibly related. Among these adverse events, 47% involved in cardiovascular symptoms and 18% involved the CNS. Hypertension was the most frequent adverse effect, followed by palpitations, tachycardia, or both stroke and seizures. Ten events led to death and 13 cases produced permanent disability. 

Additive stimulant effects of caffeine Caffeine is present in many products that contain ephedra alkaloids, and those who take these products might also be consuming considerable quantities of caffeine in coffee, tea, and soft drinks. Caffeine can enhance the undesirable effects of ephedrine on the heart, blood supply system, and brain function. 

All ephedra plants contain phenylalanine-derived alkaloids, including ephedrine, pseu-doephedrine, methylephedrine, and trace amounts of phenylpropanolamine. Previously marketed herbal supplements typically stated total ephedra alkaloid content, although actual levels of individual alkaloid varied depending on raw material and production runs. 

As with other sympathomimetic agents, theoretical drug interactions with ephedra alkaloids are possible. Despite this potential, only a handful of adverse drug interactions have been reported. This is especially pertinent when considering the extensive use of both ephedra-containing supplements and ephedrine- or pseudoephedrine-containing OTC products. The most notable interaction exists between nonselective monoamine oxidase inhibitors and ephedra- or ephedrine-containing products. 

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