Drugs Isolated From Plants A Artemisinin

In the 1970s the antimalarial properties of extracts of annual or sweet wormwood (Artemisia annua L.), a traditional Chinese drug for fevers and malaria, were discovered and this led to the isolation of the active principle, artemisinin, which is also called qinghaosu. It is an endoperoxide found in the dried aerial parts of the plant in concentrations ranging from 0.01 to 0.86%, depending on the origin of the plant (2). Artemisinin is an antimalarial agent that is selectively toxic to various species of Plasmodium (falciparum, vivax, ovale) in vitro and in vivo, including chloroquine-resis-

tant strains. Synthetic efforts have yielded active derivatives, including a-and /3-artemethers, artether, and artesunate. Artemisinin and its derivatives are sparingly soluble in water and lipidic phases and are therefore administered in aqueous or oily suspension, tablets, or suppositories. The use is reserved to geographical areas with multiresistant falciparum, by prescription (2).

B. Cardiac Glycosides

Two of the Digitalis genus, D. purpurea L. (purple foxglove) and D. lanata Ehrh. (Grecian foxglove), are used for the extraction of digitoxin and di-goxin. The purple foxglove contains 0.2-0.4% cardenolide glycosides and is cultivated in the Netherlands for extraction of glycosides or, more rarely, collected from natural habitats. The Grecian foxglove is cultivated in the Netherlands and France. The leaves are collected and must be rapidly dried at a temperature as low as possible. The Grecian foxglove is used industrially for the extraction of digoxin and digitoxin as well as derivatives of its secondary glycosides, e.g., desacetyl-lanatoside C. Purple foxglove contains about 30 glycosides, divided into three series: the A series, with digitoxi-genin as aglycone (primary glycoside is purpurea glycoside A); the B series, with gitoxigenin as aglycone; and the E series, with gitaloxigenin as aglycone. Varieties in which series A predominates (>50%) are preferred. The constituents of the Grecian foxglove are called lanatosides and are divided into five series; the A, B, and E series; the C series, with the primary glycoside lanatoside C; and the D series (2). The cardenolide glycosides are still important drugs in the treatment of heart insufficiency, although synthetic drugs, e.g., /3-blockers, are also used.

C. Opium

The all-time classic of plant-derived drugs is certainly opium. According to the European Pharmacopoeia, raw opium is the air-dried latex obtained by incision from the unripe capsules of opium poppy, Papaver somniferum L.

o artemisinin o artemisinin

It contains not less than 10.0% morphine and not less than 2.0% codeine. Raw opium is intended only as starting material for the manufacture of galenical preparations (3).

The cultivation of the opium poppy may be divided into production of opium, mostly in India, and production of the straw for extraction of alkaloids, mostly in temperate climates. Legal opium cultivation is restricted to the following countries: Bulgaria, Greece, Iran, India, Russia, Turkey, and the former Yugoslavia. However, great amounts are illegally cultivated in Southeast Asia and Mexico (4). The opium production involves a great deal of manual work: cutting of the capsules to release the latex and later, when it has dried and turned brown, collecting (2). One capsule gives about 20 mg of opium (4). The latex is air dried and shaped into cakes of about 5 kg. In order to isolate alkaloids directly from the capsules, poppy varieties optimized for alkaloid production have been developed and cultivation methods optimized. The harvest may be conducted at complete maturity, which yields "straw," or before maturity, which yields "green poppy," rich in alkaloids. The capsules are dried and alkaloids may be extracted (2).

Morphine is the main alkaloid of opium and is known as a powerful analgesic that acts via the central nervous system. This means that it has many adverse effects as well as the risk of tolerance and dependence. Still, morphine is the drug of choice for severe pain, for instance, in cancer patients. Morphine is isolated from opium in a process that begins with mixing opium and calcium chloride to a thin paste, which releases the alkaloids from their salts and precipitates meconic acid. Morphine is solubilized as calcium morphinate. The next step is the purification of morphine by adding ammonium chloride, which makes morphine precipitate. The precipitate is collected, washed, and dried (2,4). The total synthesis of morphine was published in 1956, but it is still isolated from the plant (5). Over 90% of the morphine obtained is used for codeine production.

Codeine is present in small amounts in opium (about 2%) and can be extracted, but it is usually produced by semisynthesis, i.e., methylation, from morphine. Codeine is an antitussive agent (4). Dihydrocodeine is an analgesic (2).

Noscapin is one of the main alkaloids in opium (about 6%) and is obtained as a by-product in the isolation of morphine. It has antitussive properties (4).

Other semisynthetic derivatives of morphine are ethylmorphine, the 3-ethylether of morphine, and pholcodine, 3-morpholinyl-ethylmorphine, which are both antitussives. Diacetylmorphine (= heroin) has no use in therapeutics but has great abuse potential. Morphine antagonists are also prepared from morphine and include /V alIy 1 normorphine (= nalorphine), which is a partial antagonist, and /V-cyclopropylmethyl-14-hydroxynordi-

hydromorphinone (— naltrexone) and /V-allyl-14-hydroxynordihydromor-phinone (= naloxone), which are pure antagonists (2).

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