Herbal remedies toxicity & regulation seminar ppt

This file contains information about herbal toxicity and different regulatory guidelines from different countries for its regulation and control

1. Herbal remedies toxicity & regulation Submitted by- Sk Azizuddin Submitted to- Dr.Ozair Alam Course- M.Pharm Department- Pharmaceutical A nalysis Year- 2020-2022 College name- Jamia Hamdard 1

2. Contents Introduction Herbal medicine(Definition) Toxicity of H erbal drugs Toxic ingredients Regulation of herbal drugs Regulation of herbal drugs in India New Regulatory Guidelines of Ayush Problems to Remote in Regulation of Herbal Drugs Conclusion References 2

3. Introduction Plants have been used since time immemorial for diverse purposes in the life of mankind particularly as food, and medicines for nutrition and the treatment of diseases, respectively, in both humans and animals. They are used in all cultures of the world and have been relied upon for several millennia to support, promote and restore human health. They form a vital component of traditional medicine (TM) and their use for the maintenance of health and wellbeing is a common practice in all African societies. They are used as remedies for the prevention and treatment or management of a plethora of disease conditions including relatively new ones such as HIV/AIDS. Traditional medicine used to be the only health-care system available to the whole of the African population prior to the introduction of allopathic or conventional medicine . The practice received international recognition after the 1978 Alma Ata Conference Declaration, which aimed to achieve primary health care for all by the year 2000 through the use of traditional medicine . TM, especially herbal medicine, still forms the backbone of rural health care in Africa, supporting an estimated 80–90% of the population . Not only in Africa but also in the whole world. 3

4. Herbal medicine Herbal medicine is also known as phytochemicals or botanical medicine. According to World Health Organization (WHO), herbal medicine includes ‘herbs , herbal materials, herbal preparations and finished herbal products, that contain active ingredient parts of plants or other plant materials or combinations thereof ’ . Herbal medicine is generally considered as an integral part of dietary supplement. There is a growing interest in herbal medicine due to its long history of application and general belief that herbs are natural and intrinsically safe. According to WHO, approximately 4 billion of people, 80% of the world population, rely on traditional herbal medicine for their primary health care In recent years, utilisation of herbal remedies as a dietary supplement for disease prevention or as alternative/complementary medicine (CAM) for disease treatment has become increasingly popular. A wide variety of herbal medicine/products are readily available in the market all over the world. It is estimated that a significant percentage of population in developed countries such as Canada (70%), France (49 %), Australia (48%), USA (42%) and Belgium (31%) have used CAM at least once for health care 4

5. Toxicity of herbal drugs Herbal remedies are plant-based, as in fact are many orthodox drugs - some 25% of present pharmaceutical preparations contain at least one active ingredient extracted from plant sources (Farnsworth , 1981). Moreover, thousands of our present drugs were originally derived from plants , including digitalis (foxglove), aspirin (willow and meadowsweet) and paclitaxel ( Taxol).However , in the case of orthodox drugs the active ingredient is isolated from the plant, chemically standardized, subjected to critical clinical assessment and then often replaced with a synthetic analogue. In contrast, the herbalist uses mixtures of diverse herbal ingredients of varying potency. Potency depends on the part of the plant used - for example root, stem, leaves or fruits - the time of the year it is picked, and the actual species of plant used: for example, ginseng may refer to many Panax and Eleutherococcus species . Because potency refers to the amount of drug required evoking a response, if the potency of the formulation of the herbal remedy is unknown it is difficult to know what dose to prescribe to get the desired effect without causing problems of toxicity. An example of this problem is provided by mistletoe, the popular name for 1300 species of evergreen, including the European variety Viscum album . Mistletoe is used as an antispasmodic, diuretic and hypotensive, and some claim it has anti-cancer properties. Mistletoe extract contains at least three types of potentially toxic compounds: alkaloids - some of which may be cytotoxic - viscotoxins and lectins, which have hemagglutinin and mitogenic actions . 5

6. Adverse reactions & Allergic Reactions Adverse reactions- Modern drugs generally undergo extensive formal testing for therapeutic and adverse effects before being licensed. In this way drug regulatory bodies ensure that the risk of adverse effects is small and within acceptable limits. No such controls exist for the majority of herbal remedies, however . They do not come under the aegis of the regulatory bodies and are not required to undergo systematic testing. Consequently our knowledge of their potential adverse effects and interactions is limited. In the UK and the USA herbal remedies are considered as dietary supplements rather than as drugs. Consequently companies selling them cannot make any claims about their therapeutic effects and they give no advice about their adverse effects or contraindications gives examples of some known medically serious adverse effects of herbal preparations. Allergic reactions- Like orthodox drugs, herbal preparations can result in hypersensitivity reactions, which can range from dermatitis through to anaphylactic shock. For example, tea tree oil - widely used as a topical disinfectant - or chamomile can cause allergic reactions Mutagenic reactions Anthranoid laxatives such as aloe, cascara, rhubarb and Senna have Genotoxic potential and have been associated with colorectal cancer in epidemiological studies in humans. Chaparral may also be mutagenic. One case has been described where a patient developed cystic renal cell carcinoma after regularly drinking Chaparral tea. 6

7. Drug interactions & Contamination Drug interactions- Most consumers believe herbal medicines are harmless, so they have no qualms with taking them in along with prescribed conventional medicines. In addition, many immigrants to the UK have their own traditional medicines, which they may combine with orthodox medical care ( D'Arcy, 1993 ). Both these practices can lead to harmful herb-drug interactions. This problem is exacerbated because at least 30% of patients do not tell their doctor that they are using them (Eisenberg et al, 1993; Yoon and Horne, 2001). This is either because patients do not consider herbal remedies as 'drugs', and so when asked for a history of their medications do not mention them , or because they are reluctant to mention them for fear of a negative response from the practitioner . It is therefore vital that clinicians include questions about herbal remedies in their routine drug histories, and be informed rather than judgmental about their use . Contamination- Herbal medicines are not required to undergo the same quality checks as conventional drugs and so they may be contaminated or adulterated. For example, many Asian and Indian herbal remedies have been found to contain heavy metals such as lead, arsenic and mercury. One of the worst examples of contamination causing adverse effects occurred in the USA in 1989, where there was an outbreak of eosinophilia-myalgia syndrome associated with the use of Tryptophan, an over-the-counter dietary supplement used for weight loss (Anon, 1999). More than 1500 cases were reported, including 38 deaths. More than 95% of the cases were traced to an individual Japanese supplier. Researchers found some trace-level impurities, suggesting that a contaminated batch of L-tryptophan contributed to the outbreak. 7

8. False authentication False authentication can occur inadvertently or deliberately. An example of this is Ginseng preparations . Only Asian ginseng contains the active compounds ginsenosides, but commercial preparations often do not make this clear. More seriously, ingredients may be included which are not identified, including potent orthodox drugs such as digitalis, steroids, active oestrogens, phenacetin and glibenclamide. Finally, one ingredient can be replaced with another. This led to an outbreak of fibrosing interstitial nephritis in Germany and France when ' Guang fangi ‘ containing nephrotoxic aristolochic acids was substituted for the Chinese drug ' Fangji . The use of herbal medications in the United States over the past decade has increased dramatically and there are over 29,000 products on the market. In the United States, as many as 65 percent of the population report the use of complementary and alternative medical (CAM) therapies . Women are more likely to use complementary medicine, and non-Hispanic whites are more likely than other racial groups. Use is highest in persons between the ages of 35 and 55 years. In 1997, the out-of-pocket cost for all complementary and alternative therapies was estimated to be $ 27 billion while $19 billion was spent for dietary supplements .Use of herbal medications can be traced back as far as ancient China, India, and Sumeria, and formulations have been expanded upon over the centuries .Many patients consider "natural" herbal remedies to be completely free of unwanted side effects. This is concerning since many herbal products have biological activity that can lead to severe toxicity. Fewer than 40 percent of patients disclose to their physician that they are using these products. 8

9. Toxic ingredients Botanical supplements containing toxic constituents , such as liver toxins or carcinogens (chemicals with potential to cause cancer), do occasionally cause adverse reactions, but as a rule, these supplements are quickly withdrawn from the market once a potential problem has been identified. Some may still be sold in supplements imported from Asia or Europe. The following is a partial list of botanicals with potentially toxic constituents: Aconite, Alfa alfa , Aloevera , Borage , Calamus, Chaparrel ,Coltsfoot, Comfrey , Ephedra, Germander , Ginkgo biloba, Ginseng , Glycyrrhiza glabra ( Licorice ) Isapghul, Sassafras , Senna , Silybum marianum , St. John’s wort etc. A few of the above are briefly covered below . Aconite- Aconite alkaloids contained in the root-stocks of plants of Aconitum family are accredited with analgesic and anti-inflammatory effects within several systems of traditional medicine and are still widely proposed for the treatment of rheumatism, neuralgia and cardiac complaints . Alfa alfa- The herb widely used in Homeopathy, is said to contain vitamins A, C, E and K as well as calcium, potassium, phosphorus and iron. However it has been reported that the use of this herb can induce Systemic Lupus Erythromatosus (SLE) like syndrome in individuals predisposed to this condition . Aloevera- Seventh most widely used herb for centuries as a treatment for minor bruises and is increasingly being used in products for internal consumption. Long term use of aloe latex could results in potassium deficiency so the laxatives containing anthraquinone glycosides should not be used continuously for longer than 1-2 weeks owing to the danger of electrolyte imbalance . 9

10. Toxic ingredients(continue) Comferey : The herb was used by Greek Physicians in the first century as a safe drug in the form of poultice to heal wounds and as a tea to help knit broken bones. In late 1970,s scientists discovered that it contains pyrrolizidine alkaloids which are known to be hepatotoxic and has been associated with obstruction of blood flow to the liver, possibly leading to hepatotoxic reactions besides being a risk for cancer . Ephedra: The herb has been used in traditional Chinese medicine since antiquity for the treatment of respiratory ailments. The drug has been advertised as a supposedly safe, natural product for weight loss, body building and mood evaluation. Recently the drug became highly controversial due to its use in slimming formulas and products claiming to deliver a "legal high" resulting in serious health hazards. Ephedra has many side effects including restlessness , irritability, increased blood pressure and heart rhythm disorders . The alkaloid ephedrine contained in ephedra herb can cause serious toxic reactions ranging from liver damage to severe high blood pressure and heart problems. Ginkgo biloba : Ginkgo fruits and seeds have been used medicinally for thousands of years as a supplement to improve mental alertness and related memory problems. Researchers have shown that the extract is a potent inhibitor of platelet-activating factor and long term use has been associated with increased bleeding time, spontaneous haemorrhage and sub dural haematomas (Rowin and Lewis, 1996 ). Isapghul: Isapghul which is considered to be the safest and largely used for its demulcent and laxative properties since centuries is reported to have adverse reactions including bronchospasm , asthma and intestinal obstruction. If swallowed dried it may cause oesophageal obstruction. 10

11. Toxicity of herbal medicines Toxicity of Chinese herbal medicines-: It is estimated that there are 7000 species of medicinal plants in China and , of the 150 species most commonly used, 10 are toxic." Chan et al " report that in Hong Kong, most cases of serious poisoning by CHMare related to the use of Caowu , the root of Aconitum kusnezoffii, and Chuanwa., the main root of Aconitum carmichaeli. These herbs contain variable amounts of highly toxic alkaloids, including a conitine, which activate sodium channels and cause widespread excitation of cellular membranes . Several herbal preparations containing aconitine alkaloids, for example , Monkshood (Aconitum spp.), are commonly used in CHM to treat arthritic, rheumatic and musculoskeletal pain. The alkaloids have analgesic, antipyretic and local anaesthetic properties but they are potentially toxic and there is a narrow margin of safety between a therapeutic and toxic dose.v-" The toxic effects include severe cardiac arrhythmias , nausea., vomiting, generalised weakness, numbness and paraesthesia . There is no antidote for aconitine poisoning . A number of cases of accidental aconitine poisoning following ingestion of CHM preparations have been reported."?" Dickens et at " report 30 accidental aconitine poisonings, in Hong Kong during the period 1989-1994. In at least 17 cases, intoxication was life threatening requiring management in an intensive care unit, and three patients died. 18 All 17 patients developed symptoms of aconite toxicity within two hours of herb ingestion; most developed tachyarrhythmia's. In two cases ventricular tachycardia and fibrillation resulted in death within 12 hours of taking CHM containing aconitine. 11

12. Regulation of herbal drugs Need for regulation of Herbal drugs- Most serious side effects originate from overuse or misuse of such medicines. The likelihood of side effects increases when the production and sale of such products is largely uncontrolled and or unregulated and the consumer is not adequately informed about their proper uses. While in some countries herbal medicines are regulated through official controls and rigorous manufacturing standards , this is not so everywhere. In Germany, for example, where herbal products are sold as "phytomedicines" they are subject to the same criteria for their safety, efficacy and quality as applicable to other drugs. Regulatory controls are therefore considered necessary to safeguard Drug interactions with herbal drugs . So it is always wise to consult a qualified medical practitioner having clinical herbal experience in case of any doubt about the compatibility of herb and the drugs you intend to take (WHO Reports, 1997, 2002 ). The current emphasis is on screening the environment for man-made genotoxic and carcinogenic compounds .They detracts from studies on the possible health hazard or beneficial effects of naturally occurring agents to which humans are daily exposed in their day to day life . The simple phenolics, belong to this category of compounds. They are ubiquitous among plants, used as food additives, and ingested daily in milligram quantities. They are also known to induce double-strand DNA breaks, DNA adducts, mutations and chromosome aberrations in a great variety of test systems . 12

13. Regulation of herbal drugs(Continue..) However, both in vitro and in vivo assays have proved that they can suppress the genotoxic activity of numerous carcinogenic compounds. Some studies on animal models revealed that , phenolics induce precancerous lesions, papillomas and cancers , act as cocarcinogens, and exert a promoting effect in various rodent assays. At the initiation and promotion stages induced by carcinogens and promoters of different molecular structures . phenolics have proved to be potent inhibitors of carcinogenesis . The extent to which a health hazard or protective activity of complex dietary mixtures is due to their phenolic content needs to be confirmed by further research. In addition, these multiple, occasionally contradictory functions of simple phenolics make it difficult to propose their use as chemo preventive agents (Stich 1991 ). In India, manufacture, sale, export and import of herbal medicines are regulated as per the Drugs and Cosmetics Act, 1940. Most of the traditional medicinal products are available as over the counter (OTC ) drugs. Duration of a license to sell herbal drugs by a pharmacy is five years from the issue/renewal of a license. For manufacturing a herbal drug, application needs to submitted to the state licensing authority . On receipt of application authority will verify the statements and will inspect manufacturing and testing establishment in accordance with the provisions of rule. If authority is satisfied the application will be forwarded to central license approving authority and license will be issued if requirements are meet. Employee requirements of a manufacturing unit include a graduate in pharmacy or pharmaceutical chemistry, a graduate in science, a graduate in medicine. 13

14. CURRENT REGULATORY PERSPECTIVE OF HERBAL DRUGS Foreign organic matter (FOM) The Foreign organic matter is a common contaminant in the herbal drugs. As per WHO, any matter or residue that is present apart from labelled description of monograph can be consider as foreign organic matter. The FOM may also be a moulds or insects, including excreta and visible contaminant such as sand or silicaceous matter, poisonous harmful foreign matter, chemical residues and animal matters such as insects and microbes, which can produce toxins, are also among the potential contaminants of herbal medicines (WHO, 2004, 2003; EMEA, 2002). FOM should be regulated in market within limit as per WHO guidelines. Even though many death issues happening due to foreign contaminants, there are no scientific evidences or documentation in form of literature or publications. Hence this became difficult for the authors to represent the clinical data in this article. Phytochemical complexity of Phyto-pharmaceuticals Plant consist diversity in its phytoconstituents, it is quite difficult to have a clear total phytochemical data that is responsible for targeted biological activity. It is mandate to know clear total phytochemical fingerprint nature of each plant. Even in 21st century after having modern tools like chromatography and spectroscopy, the modern sciences failed to document total phytochemical finger print and complex interactions between phytochemicals. Still the concept of multitargeting effect of phototherapeutics is unclear (Efferth & Koch, 2011). Even incidents like discovery of hyperforin proved that hypericin is less potent and stable than hyperforin, till 19th to 20th century, Science assume that hypericin is only the phytochemical marker responsible for various therapeutics and it was changed after discovery of hyperforin (Vollmer & Rosenson, 2004). Even for the regulatory agencies it has become a big issue to regulate and document the phytochemical complexity reactions. 14

15. Regulation of herbal drugs in india In India, traditional medicines are governed by the Drugs and Cosmetics Act of 1940 and the Drugs and Cosmetics Rules of 1945. They regulate the import, manufacture, distribution and sale of drugs and cosmetics . In 1959, the Government of India recognized the traditional Indian systems of medicine and amended the Drugs and Cosmetics Act to include drugs which are derived from traditional Indian medicine. No products derived from traditional systems may be manufactured without a licence from the State Drug Control Authorities. Patent and proprietary medicines derived from the traditional systems must contain ingredients which are mentioned in the recognized books of the above systems, as specified in the Drugs and Cosmetics Act. The government is advised by a special committee and an advisory board for Ayurvedic, Siddha and Unani drugs. Pharmacopoeia committees have been constituted to prepare pharmacopoeias for all these systems. In 1993, an expert committee appointed by the Indian government developed guidelines for the safety and efficacy of herbal medicines which were intended to be incorporated into the Drugs and Cosmetics Act and rules . It was proposed that no new herbal medicines other than those authorized by the licensing authorities be allowed to be manufactured or marketed, except for those mentioned in and manufactured in compliance with the formulae given in the "authoritative" books for Ayurveda, Siddha and Unani herbal medicines. A manufacturer of a new herbal medicine must include safety data and appropriate efficacy data in the marketing authorization application. Herbal preparations are defined as natural products in which the predominant active constituents are of plant origin. A classification for herbal medicines was proposed depending on their market availability , and the nature of the herbs: 15

16. Category 1: already in use for more than 5 years Category 2: in use for less than 5 years Category 3: new medicines . The classification of herbal medicines depends on whether they contain processed or unprocessed parts of plants and whether they contain potentially poisonous plants. Requirements for safety and efficacy vary according to the classification and market availability of the product. Depending on the nature of herbs and market availability, different requirements exist for submission of clinical trial data and toxicity data. Labelling Requirements Labelling should include name of the drug, content, the name, address of the manufacturer, manufacturing licence number, batch or lot number, and date of expiry, if any. If any preparation contains not less than 3 per cent by volume of alcohol the quantity, of alcohol shall be stated in terms of the average percentage by volume of absolute alcohol in the finished products. Misbranded drugs ASU drugs are deemed to be misbranded: If coloured or coated to conceal the damage or made appear better than therapeutic value; If it is not labelled in prescribed manner; If label or container accompanying drug bears any false claim or misleading (Mukherjee et al., 2007 ) . Adulterated drugs ASU drugs are deemed to be adulterated if it consists of filthy, or decomposed material, if prepared, packed or stored under insanitary conditions; if its container contains any poisonous or deleterious substance; color other than one which is prescribed; harmful or toxic substance; if any substance mixed to reduce its quality or strength (Mukherjee et al., 2007). 16

17. Spurious drugs ASU drugs are deemed to be spurious if it is sold or offered under another name, if it is an imitation or substitute for another drug, if the label or container bears the name of an individual or company which is fictious , if it has been substituted by other drug. Central government . can prohibit manufacture of ASU if drug involves any risk to human beings or animals, drug does not have the therapeutic value claimed. Standards are to be complied with in manufacture for sale or for distribution of Ayurvedic, Siddha and Unani Drugs (Mukherjee et al., 2007 ). Import of Manufacture of New Drug for Clinical Trials or Marketing A drug, as defined in the Act including bulk drug substance which has not been used in the country to any significant extent under the conditions prescribed, recommended or suggested in the labelling thereof and has not been recognized as effective and safe by the licensing authority mentioned under Rule 21 for the proposed claims. Going by statutory provisions, there exist two types of Ayurvedic medicines- one being the classical medicine as mentioned in the authoritative books of Ayurveda and proprietary medicines. The former group of medicine is manufactured and named in accordance with the formulations described in the authoritative texts , whereas second group of medicine makes use of ingredients referred in the formulations of authoritative texts but with intellectual intervention, innovation or invention to manufacture products different from the classical medicine ( Anonymous, 2013b ). 17

18. Drugs and Cosmetics 4th Amendment Rule 2008 (Rule 170) classifies traditional medicines into four categories to which clinical study requirement is prescribed: ASU drugs manufactured in accordance with formula as per the definition given in Section 3(a ) of DCA, medicines based on aqueous extracts of medicinal plants for indications as per approved text, Indian ethno-medicine– based drugs, and hydro alcoholic extract–based drug, whereas medicines under category III and IV need to conduct clinical trials for licensing. Although Ayurvedic medicines are known for their long history of safe and effective use, validation of safety and efficacy using scientific and evidence-based methodologies is needed for the purpose of universal acceptability, for gaining confidence of practitioners and to offer satisfaction to end users of the products. In this perspective , clinical trials on Ayurvedic medicines need to be guided according to the principle of Good Clinical Practice. ( Anonymous, 2013b ). Non-clinical studies need to be conducted. Information provided should include data relating to non clinical pharmacology and toxicology . The relevant results should be provided in summary form , stating the methodology used, the results, and a discussion of the relevance of the findings to the investigated therapeutic effects besides the possible unfavourable effects in humans . The information provided may include the following, as appropriate: Species used Number and sex of animals in each group Unit dose (mg/kg ) Dose interval Route of administration 18

19. Regulation of Herbal drugs in india(continue…) As per the rule no new drug shall be imported/manufactured, except under, and in accordance with, the permission granted by the licensing authority. An application for the grant of permission to import a new drug shall be made in to the licensing authority. The importer of a new drug when applying for permission, shall submit data as given in Appendix I to Schedule Y including the results of local clinical trials carried out in accordance with the guidelines specified in that schedule and submit the report of such clinical trials in the format given in appendix II to the said schedule . Provided further that the submission of requirements relating to toxicology, reproduction studies, teratogenic studies, perinatal studies, mutagenicity and carcinogenicity may be modified or relaxed in case of new drugs approved and marketed for several years in other countries if it is satisfied that there is adequate published evidence regarding the safety of the drug, subject to the other provisions of these rules. As per the rule no clinical trial for a new drug, whether for clinical investigation or any clinical experiment by any institution, shall be conducted except under, and in accordance with, the permission, in writing, of the licensing authority. An application for grant of permission to conduct.(a) human clinical trials (Phase-I) on a new drug shall be made to the licensing authority in Form 44 accompanied by a fee of fifty thousand rupees and such information and data as required under Schedule Y. (b) exploratory clinical trials (Phase-II) on a new drug shall be made on the basis of data emerging from Phase I trial ; (c) confirmatory clinical trials (Phase-III) on a new drug shall be made on the basis of the data emerging from Phase-II and where necessary , data emerging from Phase-I. The licensing authority after being satisfied with the clinical trials, shall grant permission 19

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24. Conclusion As globally, there is a high demand and trust towards herbal therapies and it is must to have regulatory policies in order to meet the challenges like content uniformity, stability, bio similarity, clinical toxicity issues. Hence this review is explaining the need on the modern perspectives in regulating quality, safety and efficacy of herbal medicine. The traditional medical systems are part of a time-tested culture and honoured by people still today. For more than 3,000 years , these traditions have successfully set an example of natural resource use in curing many complex diseases. Many advantages of such eco-friendly traditions exist. The plants used for various therapies are readily available, easy to transport, and have a relatively long shelf life. The most important advantage of herbal medicine is the minimal side effects, and relatively low cost compared to the synthetic medicines. The success of medicinal plants sector mainly depends on the awareness and interest of the farmers as well as its other stakeholders, supportive government policies , availability of assured markets, profitable price levels, and assess to simple and appropriate agro-techniques . To conclude, not all botanical/pharmaceutical interactions are harmful. For example, in some cases, botanicals can enhance the effect of a pharmaceuticals, thus allowing individuals to reduce their dosage Even a potent poison becomes the best drug on proper dosage administration. 24

25. References Article followed Herbal Medicine: Toxicity and Recent Trends in Assessing Their Potential Toxic Effects. POSSIBLE TOXICITY OF HERBAL REMEDIES Herbal drug toxicity and safety evaluation of traditional medicines Toxicity and Safety Implications of Herbal Medicines Used in Africa Concerns regarding the safety and toxicity of medicinal plants - An overview CURRENT REGULATORY PERSPECTIVE OF HERBAL DRUGS Regulatory Situation of Herbal Medicines A worldwide Review Regulations for Herbal Medicine-Worldwide 25