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From the 13 January 1997 issue of Smart Drug News [v5n6]. Copyright (c) 1997, 2009. All rights reserved.
Smart Drug Update:
by Gavin Lee
Adaptogens are named for their ability to increase peak performance and general adaptation to stress. Although the popularity of adaptogens is a relatively recent phenomenon in the West, they have a much longer history of use in Eastern medicine and Soviet athletics. The unusual and heretofore unappreciated properties of adaptogens are now attracting increasing popular attention in the US where sales and use of adaptogens is increasing. Advertisements for adaptogens are currently appearing on prime-time television shows.
Adaptogens belong to the category of phytomedicines, natural product remedies based on plants (whole plant, or extracts of varying strength and purity) [Grünwald, 1995]. Most phytomedicines were discovered through empirical study of herbal treatments. Scientific development of phyto-medicinals (and adaptogens) came from Chinese and Japanese medicine, and from the application of Western models of drug isolation and pharmacology to the herbal remedies of Asian cultures.
Plants and plant extracts have been used for medicinal purposes for millennia. The oldest surviving written records of drug therapy have been found 1) on a Sumerian clay tablet (circa 2100 BC) [Sneader, 1990], 2) in Babylon in the Code of Hammurabi (circa 1770 BC), and 3) in ancient Egypt (circa 1550 BC) [Tempesta and King, 1994]. Many of these applications entail the use of the whole plant, but some have involved processing for many specialized and diverse uses (including arrow poisons, religious rituals and even cosmetic formulations).
Other examples of natural products from plants are opium, belladonna, ergot, nutmeg, calabar bean, foxglove, and squill. Some of these old folk medicines have become incorporated into Western medicine. The skeletal muscle relaxant d-tubocurarine, derived from curare (a South American arrow poison), is routinely used in surgical procedures. Modern quinine-based anti-malarials are derived from fever bark (Cinchona), used by inhabitants of the Andean forest of Ecuador, Bolivia, and Peru [Tempesta and King, 1994]. Some folk remedies have been abandoned as drugs while others have been adopted, depending on the efficacy of the active principles isolated [Foye, 1995].
Plant-based medicinals can be grouped into two different categories: 1) complex mixtures containing a large range of compounds (e.g., infusions, essential oils, tinctures, and extracts the forms of most adaptogens and phytomedicines); or 2) pure, chemically defined, biologically active compounds (the forms of most pharmaceutical drugs) [Hamburger et al., 1991].
Scientists try to isolate pure compounds when the active components of a medicinal plant require an accurate and reproducible dosage (i.e., they have strong biological activity and/or a small therapeutic index). Examples of natural products that have become useful as purified compounds are the cardiotonic glycosides of Digitalis (digoxin, digitoxin and lanatoside C) and the poppy alkaloids (morphine, codeine, noscapine, papaverine, etc.) [Hamburger et al., 1991].
Perhaps the best example of a plant-based remedy which has made the transition from millennia of use in traditional medicine to modern use of isolated compounds in Western medicine is ma huang (Ephedra plant species), the herbal source of the drug ephedrine. Used in Traditional Chinese Medicine (TCM) for over 5000 years [Foye, 1995], the ephedra plant is used for colds, flus, fever, chills, headache, nasal congestion, bronchial asthma, lack of perspiration, edema, aching joints and bones, and coughs and wheezing [Blumenthal and King, 1995]. In TCM terms, it releases the exterior, disperses cold, and facilitates the movement of lung qi [Blumenthal and King, 1995].
Ma huang contains a total of 0.5-2.5% of several alkaloids, known collectively as ephedra alkaloids. The predominant alkaloid is ephedrine, which comprises 30-90% of the ephedra alkaloids depending upon the species [Blumenthal and King, 1995]. The next most prevalent alkaloid is pseudoephedrine.
Ephedrine was first isolated from ma huang in 1887 by N. Nagai, a Japanese chemist. In 1924, K. K. Chen of the Eli Lilly Company began to publish pharmacological studies of the isolated compound. Soon after, physicians in the United States began to use the isolated alkaloid as a nasal decongestant, CNS stimulant, and bronchial asthma treatment [Blumenthal and King, 1995].
Several purified ephedra alkaloids have been approved by the FDA for over-the-counter (OTC) use as nasal sprays (for nasal congestion) and bronchodilator inhalers (for mild asthma). Approved forms include ephedrine hydrochloride, ephedrine sulfate, and racephedrine hydrochloride.
Although ma huang is also available over the counter as raw herb and extracts, the FDA has expressed an interest in removing it from the market. However, the recent passage of the Dietary Supplement, Health and Education Act of 1994 (DSH&EA) protects herbs by defining them as dietary supplements and classifying them as foods. This legal protection extends to extracts and concentrates of herbs as well.
Western models of disease focus on the biochemical and cellular causes of conditions. Our drug and pharmacology models are based on the interaction between compounds and receptors. This is usually described by a lock-and-key analogy, where the active compound (the substance or drug in question) is the key and the receptor (the biological macromolecule acted upon) is the lock. Just as the right key will turn the lock that opens the door, a specific substance can bind to the receptor to initiate a biological process. Receptors can be proteins (including enzymes), lipoproteins or glycoproteins (the most common type), or nucleic acids. They can bind to organic compounds, proteins, peptides, RNA, DNA, fats, lipids, steroid hormones, and metal ions.
Receptors may be located on enzymes, which can catalyze chemical reactions. For example, the essential amino acid tryptophan binds to the enzyme tryptophan hydroxylase which attaches a hydroxyl group to produce 5-hydroxytryptophan. This transformation initiates the biosynthesis of the neurotransmitter serotonin and the neurohormone melatonin.
Receptors may also be located on transport proteins. Tryptophan gets through the blood-brain barrier by binding to a receptor on a neutral amino acid transport protein (which also binds phenylalanine and tyrosine). A glucose receptor on a transport protein is responsible for the cellular (and intestinal) absorption of glucose.
Receptors control and regulate countless biological processes in the body. The electrical firing of nerves is triggered by receptors in transmembrane ion channel proteins. The proteins which pump ions across nerve membranes have receptors; an example is the Na+/K+-ATPase receptor which binds the cardioactive digitalis glycosides. Interneuron communication takes place with postsynaptic neurotransmitter receptors. Neurotransmitter recycling uses presynaptic neurotransmitter receptors. Even structural proteins have receptors. Tubulin, for example, binds colchicine, an anti-inflammatory agent extracted from Colchicum autumnale seeds [Bourne and Roberts, 1989].
The Western approach to pharmacology is to quantify the dynamics between receptors and drugs (meaning all substances that bind to receptors, including pharmaceuticals, herbal compounds and nutrients alike). How much affinity does the drug have for the receptor? How many receptors are present? How much drug does it take to saturate the receptors to 50% of capacity? 90%? Or 100%? What degree of receptor saturation does it take to produce a clinical effect? A toxic effect?
One of the powerful technologies resulting from the Western approach is in the area of drug design. By studying the similarities and differences between different drugs molecular size, shape, and electrical charge distribution (see adjacent sidebar), new drugs can be designed to optimize affinity for particular receptors and minimize affinity for others. This approach can lead to drugs with higher efficacy, lower toxicity and/or more selectivity.
In 1878, John N. Langley first came up with the idea that drugs act upon receptors by studying the opposing actions of pilocarpine and atropine upon the flow of saliva in the cat [Albert, 1985]. In 1907, Paul Erlich, the Nobel Prize-winning microbiologist (who pioneered chemo- and immunotherapy) is generally credited with coining the term receptive substance or receptor. He noticed that various organic compounds produced antimicrobial effects with a high degree of selectivity. This observation led to his 1913 lock-and-key concept which described the interaction of a drug with its receptor.
Erlichs idea was that only certain endogenous or exogenous organic compounds could fit properly into a receptor and activate it. In actuality, there is usually a fairly wide range of drugs that will have some degree of affinity for particular receptors. Few drugs interact only with their intended receptors. Most interact with multiple receptors which may partly explain the existence of multiple side effects of most drugs [Maher, 1995].
Chemicals which bind to receptors and stimulate a biological response are called agonists. Bromocriptine is a dopamine (D2) agonist and adrafinil is an adrenergic (alpha5) agonist. Chemicals which bind but do not cause any biological response are called antagonists or inhibitors. Many useful drugs turn out to be inhibitors [Bourne and Roberts, 1989]. GH3 is a mild, competitive MAO inhibitor while deprenyl is a strong, irreversible MAO inhibitor with selectivity for type B MAO. The new antidepressant SSRI drugs (Prozac, Paxil, Zoloft, etc.) are selective serotonin reuptake inhibitors.
Drugs from plant sources were a major research interest of European pharmaceutical companies and scientists in the 1980s. Due to recent advances in synthetic and computational chemistry programs, plant screening for biological activity has diminished in most US pharmaceutical companies [Hamburger et al., 1991]. Medicinal plant consumption in Western Europe almost doubled between 1980 and 1990. In addition, 25% of all prescribed medicines come from higher plants [Hamburger et al., 1991], which include at least 119 drugs from 90 different plant species [Farnsworth, 1994].
The general process of drug discovery usually follows ethnobotanical research. Ethnopharmacologists investigate the pharmacological uses of plants by various native peoples, focusing on plants used in medicine or religious or sacred rites. The process can also be done by a Western-trained physician providing health care to an indigenous population. He or she merely asks the patient or local healer (sometimes a shaman) to describe plants used to treat various disease conditions (e.g., wounds, fevers, or other complaints). Plant samples of these remedies are then collected for future analysis [Tempesta and King, 1994].
After the samples are brought to a university or pharmaceutical lab, a team of botanists, pharmacognosists, chemists, pharmacologists, and toxicologists take over. They then: 1) determine botanical identity, 2) prepare various crude extracts (with preliminary TLC and HPLC analyses), 3) screen the extracts for biological and pharmacological activity, 4) separate individual components when activity is found, 5) verify purity of isolated compounds, 6) determine thestructure by physicochemical and chemical means (usually IR, NMR, and GC/MS), 7) synthesize the chemical, 8) synthesize derivatives and analogs that may be patentable, 9) study the chemical and analogs for structure-activity relationships (to find the best analog), 10) develop large-scale isolation and production methods for further pharmacology and toxicology studies [Hamburger et al., 1991].
In the West, most natural products are screened for the 4 disease scourges: cardiovascular heart disease (26%), cancer/neoplasm (18%), nervous system conditions (14%), and microbial diseases (14%). These diseases get 72% of every drug-research dollar, and are unique to Western societies and not native cultures [Cox, 1994]. For an aging population like the US, other top priorities are diabetes, arthritis and psychiatric conditions [Stinson, 1996].
In 1987, 10,000 compounds were able to be screened per year [Hamburger et al., 1991], but today, due to automated in vitro assays with computer technology, 1,000,000 compounds can be tested annually [Bevan et al., 1995]. With 500,000 compounds in the inventory of major pharmaceutical companies, many promising leads often get lost, totally ignored, or screened for the wrong condition.
Most drugs are only marginally profitable. Most sales come from the top 25% of all drug compounds. 55% of pharmaceutical profit comes from 10% of all drugs. Only three out of ten drugs recover their development costs after taxes over the lifetime of a product. For drugs introduced in the US in the 1970s, 23 years were required after product launch to get a profit on the average research and development (R&D) investment. Currently, market conditions change so quickly that newer drugs have shorter lifetimes. Because most NCEs (new chemical entities) will not recover their costs, most successful drug companies must have an occasional blockbuster to cover R&D.
Economically, drugs can be categorized by the amount of sales they generate. Blockbusters achieve annual worldwide sales in excess of $300-400 million. These include Genentechs TPA (tissue plasminogen activator), and Amgens erythropoietin. Major products generate annual sales of $200-400 million and include Genentechs human growth hormone (rhGH), Lillys human insulin, some colony stimulating factors. Minor drugs bring in $50-200 million and include wound healing growth factors and streptokinase drugs. Finally, marginal products have sales of less than $50 million (which includes alpha-interferon) [Lee, 1993]. Because of these sales figures, three factors influence a drug companys decision to enter a field of research: 1) medical need, 2) commercial potential, and 3) scientific resources [deStevens, 1990].
Drug company R&D expenditures peaked at 16.5% in 1989 and have leveled out at 16% currently. Factors which have raised costs include inflation, environmental protection, new technologies, regulations and more stringent worker safety laws [Anderson, 1996].
In the past, drug choices were made by physicians, pharmacists and opinion leaders based primarily on drug properties and not cost. Now, drug choices are being strongly influenced by the economic concerns of outside groups. Drug choices are now influenced by government reimbursement regulations and price controls, third-party (insurance company) requirements, managed health care organizations (HMOs and PPOs), consumer and patient advocacy groups, and media coverage. This influence has increased competition by generics, contained overall drug prices, and forced drug companies to adjust their pricing and marketing strategies.
Drug companies must now pay close attention to competitive pressure from: 1) other drugs of the same therapeutic class, 2) generic drugs (after patent expiration), 3) alternative treatments, herbal remedies and nonprescription products used to treat the same disease or medical condition, and 4) the refusal of third-party payers to reimburse for the drug [Bleidt, 1996].
Preclinical testing involves studies of: 1) acute toxicity (effects of large single doses up to the lethal level), 2) chronic toxicity (effects from continuous use important if chronic use in humans is intended), 3) teratogenicity (reproductive toxicity), 4) carcinogenicity, 5) mutagenicity, and 6) investigative toxicology (toxicity mechanisms) [Katzung and Berkowitz, 1989].
These studies are very time consuming and expensive. During the 1980s, 2-5 years and estimates of $41M per successful drug were estimated for preclinical and toxicology studies. Although large numbers of animals are used, extrapolation of this toxicity data to humans is not completely reliable [Katzung and Berkowitz, 1989].
Federal law in the US requires that new drug compounds be tested under strict standards. Before clinical trials begin, an Investigational New Drug (IND) application is filed with the FDA, which contains: 1) composition and source of the drug, 2) manufacturing information, 3) all animal study data, 4)clinical plans and protocols, and 5) names and credentials of physicians who will conduct the trials. Four to six years are often required to complete all clinical trials [Katzung and Berkowitz, 1989].
Phase 1 studies investigate the effects of a range of drug dosages in a small number of healthy volunteers (20-80 people). They usually take less than a year to accomplish. Usually unblinded (i.e., both scientists and patients know whos getting what), these tests determine whether animals and humans show significantly different clinical responses to the drug, and test the limits of the dosage range of the drug [Katzung and Berkowitz, 1989]. Most compounds (50-70%) are abandoned during phase 1 testing due to safety or efficacy problems [Montagne, 1996].
Phase 2 studies investigate the drugs safety and efficacy in a relatively small number of patients (50-200) with the target disease. Usually single-blind (i.e., the scientists know but the patients do not), Phase 2 studies compare the efficacy of the new drug to both a placebo and an older drug used to treat the target disease. These studies usually take up to two years and approximately two out of every three new drugs is abandoned at this stage of development [Montagne, 1996].
Phase 3 studies involve a much larger patient group (sometimes thousands) and tests safety, efficacy and sometimes dosage range, usually on a double-blind basis. Usually, the dosages and protocols studied are those that are anticipated for post-approval used in medical practice. Often, patients are randomly assigned (randomized) to either the treatment or placebo control group. Sometimes, these studies feature a cross-over design (where the placebo patients get the drug, and the drug patients get the placebo half way through the study) [Katzung and Berkowitz, 1989; Rang and Dale, 1987]. These types of randomized controlled trials are considered the gold standard of drug studies [Mitchell and Lesko 1995], and those which meet these basic standards are usually published by major journals. In addition to being expensive, these studies are also time consuming, difficult to coordinate when multiple research centers are involved, and they generate vast amount of data that requires careful analysis [Katzung and Berkowitz, 1989]. About three of every four drugs is abandoned at this point [Montagne, 1996].
If Phase 3 trials are successful, a New Drug Application (NDA) is submitted to the FDA for permission to market the new drug. It includes the hundreds of volumes of all preclinical and clinical data for the reviewed drug. The NDA includes sections on chemistry, pharmacology, pharmacokinetics, microbiology, clinical and statistical analysis. Approvals usually take 2-3 years, but may be quicker for some serious diseases. Under some circumstances, controlled marketing has been permitted prior to the completion of Phase 3 trials [Katzung and Berkowitz, 1989]. The FDA approves 20-30 new medical entities yearly. Today, legal or economic reasons are cited more often in rejecting potential new drugs than scientific or therapeutic reasons [Montagne, 1996].
Phase 4 begins after marketing approval is obtained. Safety monitoring of the new drug takes place under actual conditions of use in the general population. It detects and reports idiosyncratic reactions (i.e., reactions that are so rare or that occur at such a low dosage that they were not seen in earlier, smaller studies [Rang and Dale, 1987]. For example, phenylbutazone (an anti-inflammatory drug) causes aplastic anemia in 22 out of every million treated patients and is responsible for 30 deaths annually in Wales and England [Rang and Dale, 1987].
Final FDA drug approval takes more than 5 years (usually 10-12 years) from the filing of the original patent application [Katzung and Berkowitz, 1989]. This means that the average approved drug has only 8-10 years of patent protection remaining in which to recoup the investment of developing the drug. According to Merck Company, only 1 in 10 US INDs reach NDA status and receive FDA approval [Tempesta and King, 1994; Farnsworth, 1994]. They also report that this process requires 12 years at a cost of $23 million [Farnsworth, 1994]. The failure of 9 out of 10 INDs accounts for the incredible cost of $280-330 million per approved drug [Tempesta and King, 1994]! Newer estimates put the figure at $351 million [Tyler, 1995].
Next issue will continue with a discussion of Eastern pharmacology, Chinese medicine, and the development of Russian adaptogens.
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