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James A. Duke 1993. Medicinal plants and the pharmaceutical industry. p. 664-669. In: J. Janick and J.E. Simon (eds.), New crops. Wiley, New York.

Medicinal Plants and the Pharmaceutical Industry

James A. Duke

  1. CLASSIFYING MAJOR DRUGS
  2. PRODUCTS OF AMERICA'S LARGEST PHARMACEUTICAL FIRMS
    1. Reanalysis of Farnsworth and Bingel (1977)
    2. Analysis of Sittig's Encyclopedia
    3. Analysis of Canadian OTC Evidence
  3. SCORING PHYTOMEDICINALS
    1. Natural Product Patents
  4. REFERENCES
  5. Table 1
  6. Table 2
  7. Table 3
There is a trend for synthetics to replace natural compounds in Prescription and Over the Counter (OTC) Pharmaceuticals. Today, ephedrine, salicylates, vitamins, and xanthines are mostly synthetic and steroids are often semisynthetic. While agreeing with Farnsworth and Bingel (1977) that 25% of modern prescription drugs contain at least one phytochemical, I suspect that only about 10% or our leading drugs (excluding the illicit drugs, cocaine, crack, hashish, heroin, marijuana, and opium) now contain phytochemicals still extracted directly from the higher plants.

I draw on four major sources to support this contention: (1) Products of America's largest pharmaceutical firms listed in the Physicians Desk Reference (PDR 1991), (2) Reanalysis of Farnsworth and Bingel (1977), (3) Canadian OTC Drugs (CPA 1988), and (4) Sittig's Encyclopedia (1988).

CLASSIFYING MAJOR DRUGS

If only about 10% of the 100 most important major drugs (Sittig 1988) and the PDR-listed drugs (PDR 1991) of major drug companies contain major compounds still derived from plants, we must clarify the 25% figure (Farnsworth and Bingel 1977) that conservationists have quoted and misquoted for twenty years. Emphasizing the constancy of this 25%, Farnsworth et al. (1985) reported: "In the USA, for example, 25% of all prescriptions dispensed from community pharmacies from 1959 to 1980 contained plant extracts or active principles prepared from higher plants. This figure (25%) did not vary by more than ±1.0% in any of the 22 years surveyed ... and in 1980 consumers in the USA paid more than $8,000 million for prescriptions containing active principles obtained from plants." However, about 15% of those 25% are now produced synthetically or semisynthetically and thus, no longer derived directly from natural sources. Farnsworth and Bingel's (1977) estimate remains correct if phrased as: 25% of modern prescription drugs contain at least one compound now or once derived or patterned after compounds derived from higher plants.

American consumers want natural drugs, believing natural drugs are safer than synthetics. The pharmaceutical firms seem to prefer synthetics or semisynthetics, in part due to proprietary economic reasons. The health of the drug company by necessity must concern the drug company before the health of the consumer. As noted in a recent International Trade Commission Study, "Between 1976 and 1990, the cost of developing a pharmaceutical product in the US increased from $54 million to $231 million. Only one out of every 4,000-10,000 compounds discovered can be marketed commercially--after which a company has less than ten years to partially recoup its R&D investment before its patent expires and generic manufacturers enter the market or a me-too drug is created by a competitor" (Chemical Marketing Reporter 1991). Such investments may lead pharmaceutical firms to prefer a proprietary synthetic or semisynthetic to a relatively less proprietary herbal or natural product. American pharmaceutical firms often seek the semisynthetic and avoid the natural compound, when, at least in some cases, the natural compound might be best. The pharmaceutical firm must consider several attributes including, safety, efficacy, reproducibility of results, patentability, and profitability. With at least $7,000 in public relations directed to each physician in this country by the pharmaceutical firms, the physicians may reflect the same priorities as the pharmaceutical firms. Consumers, National Institute of Health, Food and Drug Administration, and the government as a whole should seek the safest, cheapest, most efficacious drugs. Often, these could prove to be standardized herbs or relatively unpatentable natural products, placing the drug companies and the consumers and government's interests in conflict. More than 10% of Americans can't even afford modern medicine and/or insurance. Farnsworth (1990) estimates that about 64% of the world's population or 3.2 billion people use plants as drugs (largely unable to afford modern medicine). If their drugs are worth as much to them economically as modern medicine is to Americans, these plants are worth trillions of dollars.

What can be done to determine which natural alternatives are relatively safe, efficacious, and affordable to the majority of the world's citizenry? There must be some economic incentive for drug firms to investigate natural alternatives. Clearly, it would not make sense for a drug firm to invest $231 million proving that a widely grown ornamental could prevent migraine, when the drug firms are already reaping millions of dollars in the sale of proprietary migraine medications. If, on the other hand, drug companies by mandate, compared new synthetic drugs not only with placebo, but with one of the best herbal alternatives, e.g. feverfew for migraine, those drug companies could be given some marketing exclusivity on natural alternatives that the companies prove efficacious. As a society, we would feel safer in the knowledge that home-grown herbs had been proven efficacious, at least under the experimental conditions.

American consumers are calling for greater use of natural products (certainly they prefer natural antioxidants, cosmetics, dyes, food colors, and pesticides, if not medicines) while the pharmaceutical firms have moved towards the synthetic. It is hard to document the disdain for the natural compound among the druggists. Farnsworth notes, however (1990):

"Of all the pharmaceutical companies I know in the US that are interested in research on plant materials--and that's probably only four--none is interested in discovering active chemical structures which will be patented and marketed as drugs per se. They are looking for lead structures from which they would prepare analogues."

The only pharmaceutical firms that I know in the United States that are interested in natural products are Merck Sharp & Dohme (West Point, Pennsylvania), Eastman Pharmaceuticals (Rochester, New York), SmithKline Beecham (Pittsburg, Pennsylvania), and Glaxo (Research Triangle Park, North Carolina). There are several small start-up companies, getting into this area either from a mass screening viewpoint or from looking to ethnobotany e.g. Shaman Pharmaceuticals (see King 1991), to provide leads. This is a new trend: five years ago, there wasn't a single pharmaceutical company in the United States that had any interest in developing drugs from higher plants." (Farnsworth 1990).

PRODUCTS OF AMERICA'S LARGEST PHARMACEUTICAL FIRMS

Green consumerism has not yet reached the pharmaceutical industry. One might define a "green" pharmaceutical as one containing as its major ingredient a compound still commercially extracted from a higher plant. Estimated percentages of "green" products produced by some major pharmaceutical firms are tabulated in Table 1. Their drugs, as listed in PDR (1991), were evaluated to see what percentage still contained natural products as one of the major ingredients. The average for these firms is less than 10% "green." If all the once-natural compounds, or compounds patterned after once-natural, and excipients, such as acacia, candellila, carnauba, guar, tragacanth, are included, then more than 50% of their drugs contain some naturally occurring phytochemical. Thus, a sensu stricto interpretation (only still-natural phytochemicals as major ingredients), finds fewer that 10% natural or "green" pharmaceuticals. A sensu lato interpretation (containing a now-natural or once-natural phytochemical as a major or minor ingredient), finds more than half of modern pharmaceuticals are at least partially "green."

Reanalysis of Farnsworth and Bingel (1977)

Table 2, modified from Farnsworth and Bingel (1977) lists the major plant-derived phytochemicals in United States prescriptions two decades ago. Steroids are clearly the largest items in Table 2. From mare's urine as a source of steroids, we moved to temperate Dioscorea villosa, and then to tropical "barbasco" (Dioscorea spp.). After too many price hikes in the barbasco, the steroid industry largely went to semisynthetic modification of the phytosterols from temperate soybeans. In general, most modern steroids are now semisynthetic. Codeine, atropine, hyoscyamine, digoxin, digitoxin, pilocarpine, and quinidine are still derived from plants. Reserpine, pseudoephedrine, and ephedrine, count for 3% of those prescriptions cited by Farnsworth and Bingel (1977), and are sometimes produced synthetically, sometimes natural. Two-thirds of American ephedrine is synthetic, one-third from German, one-third from American factories, the other third being natural ephedrine from China. The relative share of the synthetic will probably increase in the future. Assume that half of our ephedrine, pseudoephedrine, and reserpine are synthetic and that all the steroids are now semisynthetic, subtract and find that, accepting these assumptions and no change in percentages, only 6.4% of our drugs have these natural ingredients, synthetic or semisynthetic compounds having replaced the natural compounds.

Analysis of Sittig's Encyclopedia

In his first Table, Sittig (1988) lists the top 100 generic pharmaceuticals in the United States in 1976. The top four items had sales over $100 million; the cutoff after 100 was at the 10 million sales level. Total United States sales of the top 100 was about $3 billion. Among the top 25 of Sittig, only one (4%), is clearly derived largely from higher plants, digoxin from temperate Digitalis as number 4. Theophylline once derived from subtropical Camellia (and possibly tropical Theobroma), at number 21, is still used but is almost if not exclusively synthesized. Methyldopa is synthesized, but could possibly be based on the legumes like Mucuna and Vicia which contain levodopa. Likewise, the hormones norethindrone, ethinyl estradiol, and conjugated estrogens appear to be wholly synthesized or semisynthetic but they could probably be derived from starting estrogenic compounds in palm and pine pollens or pomegranates. Tartaric acid and potassium chloride, e.g., also occur in higher plants but can be viewed as phytochemicals.

Farther down Sittig's top 100, there are even fewer clearly "green" drugs. There are several estrogenic or androgenic hormones, presumably largely semisynthetic. There are several antibiotics derived from lower plants. Some have salicylic or tartaric acids or maleic-acids, coumarin, ethanol, furfurylamines, triethylamines, guanidine, benzaldehyde, proline, piperidine, heptaldehydes, and some contain semisynthetic opiates. Natural products, if they are used, are often only minor elements in a bigger formula. Stretching to accept guaifenesin (largely guaiacol which could come from a tropical tree), warfarin sodium (based largely on 4-hydroxy-coumarin, which could come from a tropical tree), and "nicotine polacrillex" (presumably based on natural nicotine which could be obtained from tropical trees (Duboisia) or weeds (Nicotiana), only about 5% of the top hundred are based primarily on higher plant phytochemicals. Ten percent are antibiotics derived from lower plants, mostly bacteria by biotechnology. Only by counting all the "iffy" odds and ends can one stretch the percentage to 25% containing at least one compound that could conceivably be derived from a higher plant.

Analysis of Canadian OTC Evidence

A fourth line of evidence (CPA 1988) confirms Farnsworth's 25% figure sensu lato. As in the United States, Canadians share a desire to take more responsibility for their own health care. An aging population and the resulting strain on health care services will force consumers to take an even greater role in years to come (CPA 1988).

The product monographs appendix of the CPA Book lists hundreds of apparently approved medicines from A&C with Codeine to Zinkosalb, both of which contain salicylic compounds which the American Indians once derived from poplars, willows, and even wintergreens. Such compounds count in the Farnsworth 25%, even though they are now synthetic.

A&C with Codeine illustrates the problems one encounters in trying to make a survey of this type. It contains three major ingredients, the now-synthetic acetylsalicylic acid, the sometimes synthesized caffeine, and the still natural codeine. Thus, it clearly contains one natural ingredient, probably the most expensive ingredient, codeine, still derived from the opium poppy. The caffeine may be synthesized or may be a by-product of decaffeinated coffee. The acetylsalicylic-acid could fall into the category called semisynthetic, if derived by acetylation of natural salicylic acid, but today it is mostly a pure synthetic, involving the utilization of no higher plant phytochemicals.

A and D Ointment is equally problematic. Vitamins A & D, as all vitamins, could come from natural products. But most are not derived from higher plants and all are synthesized (Harold Newmark pers. commun.). A and D Ointment would be scored "non-green," the lanolin of course derived from animals. Vitamins should be scored non-phytochemical ("non-green") unless the monograph specifies that the vitamin is plant derived. Absorbine contains methyl-salicylate and menthol, both natural products, now largely synthesized. Excipients like the glycine and lactose in Acetest are, of course, not scored as major ingredients. Similarly homatropine, while related to atropine, is treated here as a synthetic. How should one score ACI-JEL vaginal buffer which contains some herbal excipients like tragacanth and acacia, and compounds that do occur in plants like acetic and ricinoleic acids which are cheaper as synthetics? Resorcinol is scored synthetic though it too can be derived from umbelliferone. Pseudoephedrine and ephedrine are sometimes synthesized. Although lidocaine is said to have been patterned after gramine, it is not a phytochemical. Aloe in After Burn certainly makes it score "green." Similarly the witch hazel, not the salicylic acid in Aknoderm, makes it score "green." Listerine Antiseptic contains 21.9% alcohol, 0.09% eucalyptol (cineole), 0.06% thymol, and 0.04% menthol (all derivable from plants but probably synthetic).

SCORING PHYTOMEDICINALS

This discussion illustrates the subjective nature of assigning economic values to a very complicated and widely divergent phytomedicinal industry. A generous scoring, allowing all vitamins and amino-acids, acetic acid, lactose, as major or minor ingredients or excipients would give at least 50% "green." Thus, the final percentage of plants or plant-derived extracts in modern pharmaceuticals will ultimately depend upon your definition of phytomedicinal. Should such natural compounds as alcohol, vinegar, citric acid, resorcinol, be included, then well over 50%, perhaps 75% of medicines contain plant-derived phytochemicals. Only by counting all of the following major naturals could one score the Canadian OTC's as 25% "green" (CPA 1988): allantoin, benzoin, bran, caffeine, camphor, caprylic-acid, charcoal, cineole, citric-acid, codeine, cresol, ephedrine, guaiacol, lecithin , menthol, methylcellulose, methylmorphine, pectin, phenol, pseudephedrine, salicylates, sorbitol, tartaric-acid, turpentine, and undecylinic-acid.

The score could top 50% "green" if one counts minor ingredients, all vitamins and minerals which occur in higher plants, plus these other even more marginal compounds: acetic-acid, agar and alginates, alcohols, amino acids, all vitamins (even ascorbic acid), benzocaine, benzyl alcohol, benzyl benzoate, citrates, crotamiton, danthron and casanthranol (close to anthraquinoones), dextromorphinan and complex opiates, dextrose and other refined sugars, epinephrine, guaifenesin, homatropine, homosalate, hydrocortisone, hydroquinone, lactulose, lidocaine, paba, phenylephrine, resorcinol, selenium, and other minerals like sulfur, urease, and vanillylamide.

Some argue that we would be better with more natural product medicines and fewer synthetics. If reverting to natural medicines, which also prove safe and efficacious, could also help save the rain forest, there's one more reason to consider natural drugs. The government should consider requiring pharmaceutical firms not only to prove their new drugs safe and efficacious, but compare them not only to placebo, but also to one or more of the better herbal alternatives. If energy costs remain as they are or become less expensive, we should expect even more synthetics to replace naturals, in both Prescription and OTC drugs. If energy costs get more expensive, or if "green" consumers get louder, we may reverse the trend from natural to synthetic in this country.

Natural Product Patents

With American drug firms trending away from the natural product, the Japanese are increasing their share of the world's natural product patents. Surveys (Duke 1990) over the last four years have shown the Japanese percentage of the world's natural product patents surge from 40 to 60%. In 1990, at least among those natural-product patents reported in Phytotherapy Research, Japan obtained more than five times more than did the United States (Table 3). As American consumer demand for the natural increases, the pharmaceutical dissatisfaction for the natural ironically also increases.

REFERENCES

Table 1. Some higher plants used in the drugs of major firms and estimated percentage of "green" drugs (after Valueline and Chemical Marketing Reporter).

Company Projected
earnings
($billion/1991)		 Higher plants used Natural (%)
Bristol-Myers 11.2 Mayapple, ephedra, yew <10
Merck 8.6 Rauwolfia <5
Pfizer 7.2 Rauwolfia <5
Smith Kline Beecham Pyrethrins <1
American Home Products 7.1 Opium, quinine 30
Eli Lilly 5.9 Periwinkle, curare 17
Warner Lambert 5.0 Belladonna, ephedra <5
Rhone Poulenc 3.7 Opium, rauwolfia 15
Schering-Plough 3.6 Ephedra <5
Upjohn 3.4 Belladonna <2
Marion Merrell Dow 2.8 Opium, quinine, nicotine 17
Syntex 1.8 (Barbasco formerly) <1
Johnson & Johnson Psyllium 10
G.B. Searle 1.4

Table 2. Reanalysis of common phytochemicals in the United States containing plant derived higher drugs (Modified from Farnsworth and Bingel 1977).

Phytochemical Percent of total Rxs
Steroids (95% from diosgenin) 14.7
Codeine 2.0
Atropine 1.5
Reserpine 1.5
Pseudoephedrine 0.9
Ephedrine 0.8
Hyoscyamine 0.8
Digoxin 0.7
Scopolamine 0.7
Digitoxin 0.3
Pilocarpine 0.3
Quinidine 0.2
Total 24.4

Table 3. Natural product patents.

Country Number of patents Percentage
Belgium 2 0.8
Brazil 1 0.4
China 14 5.6
Czechoslovakia 2 0.8
European 26 10.5
France 5 2.0
Germany 12 4.8
Hungary 1 0.4
International 13 5.2
Japan 148 59.6
Poland 2 0.8
United Kingdom 2 0.8
United States 13 5.2
Soviet Union 7 2.8

Last update May 16, 1997 aw