by Hubert J. Karreman, VMD, FACVBM
Pharmacognosy is the branch of knowledge concerned with medicinal drugs obtained from plants or other natural sources. Organized veterinary medicine has been using products derived from plants since its inception. Both in veterinary schools and in practice, botanical medicines were of primary importance for a myriad of commonly encountered conditions. This can be seen by simple perusal of veterinary textbooks dating between 1890 – 1940 (just prior to the advent of synthetic pharmaceuticals). Many well-known pharmaceutical companies such as Bayer, Boehringer-Ingelheim, Parke-Davis, Merck, Lilly, and Wyeth got their start by processing plants into medicinal products. Botanical medicines were at their zenith in veterinary practice in the 1930’s. The United States Pharmacopeia (USP) and the National Formulary (NF), of which entries are considered Official by FDA, began in the early 1800’s in order to set forth standards of identity for raw materials and standardized potencies for the manufacture of finished botanical medicines. The current edition of the USP/NF has about 60 botanical entries.
Beginning in the latter half of the 1800’s, organic chemists began to isolate active ingredients from plants i.e. salicylic acid from Salix alba and digoxin from Digitalis purpurea. Once an active ingredient could be identified and isolated, its synthesis eliminated the need for time consuming meticulous inspections of plants arriving from distant shores as well as unscrupulous harvesters that substituted cheaper similar looking plants for the genuine article. Advances in organic chemistry fueled the development of modern pharmacy.
Many medically important drugs were alkaloids such as strychnine and brucine (Strychnos nux vomica), atropine (Atropa belladonna) and aconitine (Aconitum napellus), to name but a few. These plants and their constituents are considered completely toxic as taught to modern veterinary students. However, prior to 1950, veterinary students studied Materia Medica, in which the identification, medicinal preparation, indications, therapeutics, toxicology and antidotes of plants and their active constituents were learned in great detail. The standard veterinary curriculum of the day even included learning the Latin apothecary language for prescription writing. Students used textbooks such as: “Veterinary Materia Medica and Therapeutics” (Winslow 1919, 8th ed.) “Veterinary Pharmacology Materia Medica and Therapeutics” (Milks 1930, 2nd ed.), “Veterinary Doses and Prescription Writing” (Fish 1930, 6th ed.) and “The Practice of Veterinary Medicine” (Udall 1943, 10th ed).
Veterinarians, armed with a deep knowledge of pharmacognosy and associated therapeutics, graduated and worked primarily with horses, cattle and hogs with a smaller portion of work with dogs and cats. Busy practitioners no doubt put to use the pharmacognosy they learned in detail from veterinary schools. They also bought commercially prepared drug products from pharmaceutical manufacturers of the day. In the years prior to the first antibacterials (~1935), veterinary science was limited to identifying bacterial pathogens and, in the case of dairy cows, tracking transmission to formulate control programs. Actual treatment against bacterial infection consisted of injections of antisera and autogenous bacterins including intramammary infusions of various botanical and antiseptic solutions. Except for holding out obviously bad milk, there was no mention of withholding times in textbooks.
Drugs first became regulated by the Pure Food and Drug Act of 1906. The Act prohibited the sale of adulterated and misbranded food and drugs in interstate commerce. All types of commercially available medicine were covered by the Act, whether for human or veterinary use. “Patent medicines” - those nostrums that derived most of their effect not by what the label necessarily indicated but usually by the alcohol contained in them or the opium undeclared in them - were a main target of the Act. Importantly, the Act specified that any product’s main drug (now termed Active Pharmaceutical Ingredient - API) must conform to the definition for it set forth in the USP or NF, unless “the standard of strength, quality, or purity be plainly stated upon the bottle, box, or other container thereof although the standard may differ from that determined by the test laid down in the United States Pharmacopoeia or National Formulary”.
Many botanicals (and /or their isolated derivatives) were Official. Here is a partial listing (Winslow, 1919): Aconitum napellus, Anacyclus pyrethrum, Atropa belladonna, Barosma betulina, Cannabis indica, Capsicum brutescens, Cephaelis ipecacuanha, Cinchona officinalis, Cinnamomum camphora, Claviceps purpurea, Coffea arabica, Commiohora molmol, Delphinium staphysagria, Digitalis purpurea, Erythoxylon coca, Eucalyptus globulus, Gelsemium sempervirens, Juniperus communis, Lobelia inflata, Mentha piperita, Phyiostigma venenosum, Pilocarpus jaborandi, Pimpinella anisum, Pinus palustrus, Salix alba, Sinapsis alba, Strophanthus hispidus, Strychnos nux vomica, Thymus vulgaris, Toluifera pereirae, Urginea maritima, Valeriana officinalis, Veratrum viride, Zingiber offinale. Most of these have been replaced by synthetics for their various physiologic actions while some are still currently being used by way of the Dietary Supplement Health and Education Act (DSHEA) and also are Generally Recognized As Safe (GRAS).
The FDA was formed when the Federal Food, Drug and Cosmetic Act was signed into law in June 1938. Where the 1906 Act was to make sure that food and drugs were what they claimed to be, the 1938 Act was to make sure that drugs were safe. It was not until 1962 that the Act was amended to ensure a drug product’s effectiveness. Products that were in commercial distribution prior to 1938 were “grand-fathered” and still allowed if formulated and labelled identically (or nearly so), but over time they needed to show effectiveness to stay in commercial distribution.
In this context, the drug thymol (found in the textbooks cited above) was known mainly for general antiseptic properties. It was utilized in veterinary (and human) medicine against hookworms and also as an infusion for cystitis (inflammation of the bladder). Its use for cystitis may have inspired another product to be developed which delivered thymol through the teat canal to the cistern of the bovine mammary gland. That product was called “H-G Intramammary Disinfectant Solution” (“A Manual of Veterinary Therapeutics”, The Haver-Glover Laboratories, Kansas City, 3rd ed. 1928, pg. 98 & 4th ed. 1932, Pg. 115). Two other API drugs, oregano and garlic, appear in only a couple old veterinary textbooks - but this does not preclude their value as medicinal substances. In fact, essence of Origanum (oregano) was also part of the “H-G Intramammary Disinfectant Solution” and garlic is listed in the USP/NF Compendium of Dietary Supplements.
Linking commercially available botanicals used formerly in mainstream veterinary medicine to current FDA categorization and regulations is challenging. Thymol, oregano and garlic are all GRAS but lack Over-The-Counter (OTC) FDA monographs. Thymol, for instance, is in many OTC human drugs for certain uses as seen in 21CFR310.545 but lack regulatory monographs. However, pharmaceutical monographs for thymol, oregano and garlic are found in the current USP/NF. Interestingly, by being GRAS they are all permitted to be in milk via the Pasteurized Milk Ordinance. Additionally, as per 40CFR180.1240, thymol is exempt from the requirement of a tolerance in or on all food commodities when used in accordance with good agricultural practices.
Even though these allowances of thymol to be in food show that it’s considered safe, that does not by itself generate an FDA-approved drug withholding time for use in food-producing species. Only with current state of the art analyses using FDA-approved methodologies can the safety of botanicals for use in veterinary medicine be affirmed. Safety studies combined with in vitro lab studies and in vivo clinical studies, as well as expert scientific opinion regarding a product, are needed to consider an “old drug” to be Generally Recognized As Safe and Effective (GRASE) for its intended label use. Indeed, thymol as studied at NC State in vitro and in vivo with resultant published articles in peer-reviewed journal articles (i.e. Journal of Dairy Science) for an intra-mammary product (PhytoMast) in dairy cows for dry-off appears to meet what is needed for a product to be considered GRASE (a letter sent to a milk processor is available on request).
Due to the complete prohibition of antibiotics in USDA NOP certified organic livestock, it is no wonder that both farmers and researchers are interested in rational alternatives to antibiotics. USDA NOP certified-organic farmers will use whatever means they can to not use antibiotics, for if they do the animal must be permanently removed from the organic system. Because of the strict rules on materials allowed to be used, it’s no stretch to say that the US certified-organic sector is leading the way globally in reducing the use of antibiotics in livestock. Studies looking at “old drugs” like thymol are foundational to public (via FDA) understanding of animal safety, food safety and effectiveness of botanical drugs and potentially reduce antibiotic use and antimicrobial resistance.