Pharm 100 - Lesson E.3

• In the past decade, there has been an increase in the availability and use of herbal preparations. This phenomenon is driven by at least two forces – the desire of the general public to use natural productswhich they believe are safer than conventional or allopathic medications, and by manufacturers and retailers who promote these products for financial gain. It should be recognized that the practise of medicine prior to the 1940’s depended on a large number of natural products. These were opium,cascara, digitalis leaf, and numerous tinctures, to name a few.
• The 1950’s heralded the era of thepurified natural product; that is, the use of digoxin replaced digitalis leaf preparations, and in addition,the pharmaceutical industry developed thousands of synthetic drugs. These two sources of drugs arestill the major sources of drugs in 1998.
• Herbal medicines are more widely used in Europe than in North America. It is estimated that more than 40% of the practising physicians in Europe prescribe plant-derived pharmaceuticals or herbal medicines. In Europe, the regulations controlling the manufacture and testing of herbal products are more stringent than in Canada. In 2004 Canada introduced new regulations that should begin theprocess of better regulations to ensure the efficacy and safety of these products.
• While the use of these products is gaining popularity in Canada, it should be noted that two-thirds of the world’s populationis reported to rely on herbal products. The estimated sales in Canada are between one and two billiondollars annually

Drugs used by mainstream medicine. These drugs have a drug identificationnumber (DIN) from Health Canada and have undergone full testing for safety and efficacy.

Plant products sold as medicine (no DIN); often crude mixturesand evaluation is lacking.

They have a DIN. Full status as a drug and meet allrequirements of a drug, i.e. full safety and efficacy evaluation

Drug obtained from plants, purified, and used at therapeutic doses andwith scientific evidence of efficacy and documented toxicity, e.g. digitalis (digoxin), quinine,cocaine, atropine, tubocurarine.

This is a herbal product used at one-quarter the proposed therapeutic dose.

• 1. The public has expressed concern over the side effects of allopathic medicines. While most herbal products do not appear to be harmful, a number have significant toxicities, and indeed some herbal products are toxic.
• 2. The cost of the allopathic medicines, especially newer agents, are high. The public has the perception, probably justified, that herbal drugs are less expensive than allopathic drugs.
• 3. There is a lack of faith in allopathic drugs. Not all allopathic medicine are effective and anumber that are effective have serious toxicities associated with their use. The concept that “what is natural is best” seems to prevail.
• 4. There is often hope that somehow a herbal or natural product will cure a chronic or terminal disease. A patient with terminal cancer will cling to the faintest hope of surviving, and often that hope includes herbal medicines. In the 1970’s and 1980’s, Canadians and Americans flocked to Mexico to receive an experimental cancer treatment, Amygdalin. The drug was obtained from apricot pits, was not effective, but had serious toxicities and cost thousands of dollars.
• 5. There is a general belief that herbals are not toxic. Pharmacologists and toxicologists have known for a long time that both natural and human-made chemicals can be toxic. The source is certainly no assurance of safety. Botulinum toxin, produced by a microorganism, is one of the most toxic substances known to science.

Plants have a number of uses in the preparation of both herbal and allopathic drugs. They are asource of direct therapeutic agents, e.g. digoxin or taxol. They provide a source of raw material forthe manufacture of more complex semisynthetic compounds, e.g. taxol, estrogens. A plant estrogen isused as the starting material in the preparation of ethinyl estradiol, the estrogen in the oralcontraceptives. The structure of plant substances can be used as a model for new compounds. Chemists will modify the active ingredient in a plant product and obtain a drug which is moreeffective than the original compound.

• 1. Lack of efficacy data. Current efficacy is based on empirical evidence, not controlled studies.
• 2. Lack of data on safety. All drugs should be evaluated for safety.
• 3. Lack of standardization. Often there is poor quality control. Active ingredient varies inconcentration from batch to batch.
• 4. Undeclared ingredients. The consumer is not assured of the content of the herbal drug.
• 5. Intentional adulteration. This is the addition of substances other than the herbal. One producthad hydrocortisone added, a drug under the Food and Drug Act. Also, dihydroepiandrosterone,heavy metals, cocaine, NSAIDs, and estrogens have been found in some herbals.
• 6. Source is questionable. There is a lack of control at the source point, e.g. foreign countries. Manufacturing facilities and processes are not inspected.
• 7. Confusing literature – who to believe. The literature aimed at the general public often overstatesthe efficacy of a herbal preparation. There is a lack of good controlled trials.
• 8. Toxicities? Some are innocuous, others can be lethal, e.g. some herbal teas contain coltsfoot and butterbur – ingredients which cause liver damage.
• 9. Drug interactions with allopathic medicines. Patients often take herbal medicines withprescription drugs. A number of drug-drug interactions have been reported, some serious. It canbe argued that a patient has the right to choose their own source of drug. On the other hand, for their own safety, their physician should be told what medications/drugs they are selfadministering. A recent survey revealed that two-thirds of patients who use herbals do not telltheir physicians.

Drugs derived from plants can be described with a “scale of effectiveness”. The chart below listsa target organ and a series of drugs which affect that organ. Drugs can be mild or potent. The potentdrugs are only available on a physicians prescription

The main use is as a sedative and hypnotic. It is a drug of choice for herbalists in the treatmentof nervous tension and panic attacks. It is often termed the Valium of the 19th century. The active ingredients are a group of compounds known as Valepotriates. Preparations of Valerian have beenshown to have CNS depressant activity. They are clearly less effective than the benzodiazepines(Valium) but have less adverse effects. Controlled studies have examined the effect of Valerian onsleep. There was an increase in slow wave sleep, but no change in REM sleep. There was no difference in the onset or duration of sleep. There was no difference in rating of quality of sleep versus placebo. Other studies have observed a small increase in the quality of sleep. Valerian products may be useful in mild insomnia, but further clinical trials are necessary to determine its true value over placebo. A number of toxicities have been reported with Valerian. Hepatotoxicity may be a significant problem. The CNS depressant properties of Valerian may impair the ability to operate a motor vehicle. Vigilance is disrupted.

It is purported to be an antipyretic, antispasmodic, emmenogogue, a carminative and anantithelmintic. Modern use is in the treatment of migraine. The herb contains sesquiterpene lactones. In the treatment of migraines, some studies reported a 24% reduction in migraines. This study waswell designed and it can be concluded that feverfew may be useful for mild migraines. Researchersnoted that some batches or capsules contained very little active ingredient while other batchescontained the proper amount. Toxicities occurred in 20% of users; 11% of users had mouthulcerations. Dermatitis was also a problem.

The herb contains allatoin and rosmarinic acid. It also contains pyrrolizidine alkaloids which arehepatotoxic if taken chronically. They are also carcinogenic. Allatoin is most likely the activeingredient when the drug is used topically for wound healing. Efficacy of the drug is questionable. It must be recognized that the cream or ointment base will have an effect. Comfrey was once used internally for ulcers, ulcerative colitis, bronchitis and digestive disorders, but due to its hepatotoxicand carcinogenic potential, it should not be used internally. Comfrey would be one herbal product toavoid.

• Extracts of harpogophytum procumbens (Devil’s Claw) is recommended by herbalists for thetreatment of inflammatory conditions, including rheumatoid arthritis. The active ingredient isbelieved to be a class of compounds known as glucoiridoids, a plant steroid. A number of studies have examined the effect of Devil’s Claw on the production of inflammatory producing substances (prostaglandins) in healthy volunteers. Devil’s Claw lacked the biochemical effects expected of antiinflammatory drugs of the non-steroidal type (e.g. ibuprofen).
• In a similar study in animals, doses 100 times that recommended for human consumption,extracts of Devil’s Claw were found to be ineffective in suppressing inflammation.
• Review of relevant clinical trials suggests that the drug does not compare favourably with drugs such as ibuprofen. It is possible that the glucoiridoids have some anti-inflammatory properties;however, a recent study suggests that they are inactivated in the acid milieu of the stomach.

• Echinacea is undoubtedly one of the most widely used herbal medicines in Canada. It isrecommended for the prevention and treatment of the common cold. It is also recommended for wound healing and as an anti-inflammatory.
• Echinacea contains echinacein as the major active ingredient. The mechanism of action is purported to be exerted by stimulating the immune system. The drug presumably stimulates the cells and other elements involved in the immune process. A number of studies have found that Echinacea extracts can stimulate T-lymphocytes (a cell involved in immunity). This effect has been observed inisolated cell systems as well as humans. In a recent review of five controlled trials, the authorsreported that Echinacea was able to stimulate cells of the immune system in two of the five studies. The other three studies could not show a positive response. Cochrane reviews concluded that theremight be some small benefit from selected Echinacea preparations. Clearly there is a need forproperly controlled trials using standardized and known preparations of the herbal product.
• Toxicities with Echinacea are rare. There is a possibility of an allergic reaction. Patients whohave an auto immune disease, e.g. lupus, should not use Echinacea.

• Extracts of Aloe Vera is used topically as an aid in healing of wounds and burns. It has also been used to treat fungal infections. There is no evidence of antifungal activity.
• It is used topically as a gel or incorporated into creams. Results in terms of wound healing are conflicting; not all studies show a benefit. This inconsistency in response may be due to variability inthe products. Remember quality control is often lacking. When used topically, Aloe has caused someskin allergies.
• If taken internally, Aloe causes severe diarrhea and should not be taken internally.
• Aloe Vera has one major claim to fame – Queen Cleopatra reportedly used Aloe to protect her skin from the ravages of the Egyptian sun.

• The active ingredients in Ginseng are referred to as ginsenasides or panaxosides. People use Ginseng to increase their endurance and stamina. Advocates of Ginseng claim that it is anaphrodisiac; that it enhances memory, learning, productivity, and physical stamina, as well asenhancing the immune system. It is purported to improve health overall, reduce cholesterol, heartattacks, and blood sugar in diabetes.
• Herbalists consider this drug an adaptogen. That is a herb that restores normal balance. In otherwords, if the blood pressure is low, the herb raises it, and if the blood pressure is high, it lowers it. Pharmacologists have a great deal of difficulty with this concept.
• The efficacy of Ginseng in humans has not been established. Tests on small animals have demonstrated an increase in endurance and a reduction in stress-related ulcers as well as other responses. Proper trials in humans are lacking.
• A number of adverse effects have been observed with Ginseng. These are: headache, high bloodpressure and bleeding. Ginseng may affect platelet aggregation (sticking together to form a clot), andwill increase the effect of oral anticoagulants (blood thinners). Ginseng can also increase plasma insulin levels. The diabetic who uses insulin should not take Ginseng.
• A number of Ginseng products have been found to be adulterated. Some contain caffeine andother stimulants, and in some cases, phenylbutazone, an effective but toxic drug once used in thetreatment of rheumatoid arthritis.

• St. John’s Wort contains hypericin and is used to treat mild to moderate depression and to healwounds. Hypericin modifies a number of neuronal pathways in the central nervous system. Dopamine, serotonin, and norepinephrine containing pathways are modified. The herbal may enhance the activity of these pathways, a process not unlike other antidepressants.
• St. John’s Wort, or more correctly, hypericin, has been shown to have true antidepressantactivity. It is less effective than other antidepressants, e.g. tricyclic antidepressants or the serotoninreuptake inhibitors. It is interesting to note that several government agencies in the U.S.A. are currently developing large scale trials to test St. John’s Wort in depression. The results should beinteresting. Some studies have shown that St. John’s Wort increases the rate of healing in burns. Thebeneficial effect may be due to stimulation of growth of skin cells.
• Adverse effects to St. John’s Wort do occur. There are reports that a syndrome has been associated with the herb. The syndrome was manifested as confusion, agitation, shivering, fever,sweating, diarrhea, muscle spasms, and tremor. The herbal can also cause phototoxicity (the drug isdeposited in the skin, and sunlight breaks down the drug causing a skin reaction or rash).
• St. John’s Wort should not be taken with other antidepressants as the effect can be addictive. The user should be warned that some products contain St. John’s Wort and ephedra (phen-fen). Thisproduct should be avoided.

• 1. There is a need for appropriate regulations and standards. Products should be standardized.
• 2. There is a need to determine the efficacy of these products in controlled trials.
• 3. There is a need for valid toxicity testing