AN OVERVIEW OF HERBAL FORMULATIONS: FROM PROCESSING TO PHARMACOVIGILANCE

AN OVERVIEW OF HERBAL FORMULATIONS: FROM PROCESSING TO PHARMACOVIGILANCE

Neha Singh, Meenakshi Garg * and Rajni Chopra

Department of Food Technology, Bhaskaracharya College of Applied Science, Dwarka, New Delhi, Delhi, India.

ABSTRACT: Herbs have been a surviving unit since we were born on this planet. Currently, they are the most probed topic in the food industry or pharmacotherapy due to their multidimensional approach where one herb targets various diseases and proffers a wide range of health benefits. Moreover, some herbal supplements are merchandised globally, and people are devouring these products blithely to extract additional benefits. But taking any herbal formulation under unsupervised conditions may be subject to herbal toxicity. Hence, providing safe herbal supplements is a daunting challenge for various reasons: availability of unstandardized, contaminated, adulterated, loosely available, and unlabeled products, scanty regulations, herb-herb, and herb-drug interaction, and many others. The present article is enriched with past and most recent literature on processing crude herbs, the necessity of standardization of herbal products, the health benefits of standardized herbal medicines, and the toxicity of herbal formulations. The literature has also discussed a case study linked to herbal products, the importance of the pharmacovigilance system, and the challenges associated with the safety monitoring of herbal medicines, as reliable data on these aspects is still lacking. Thus, more investigation is needed for in-depth clarity. This review may provide an instructive insight that no therapeutic agents are free of toxic effects and may be associated with risk and beneficial effects. The article might be helpful for herbal users or other health practitioners and may serve as a stepping stone to promote further research.

Keywords: Herbal products, Herbal preparation, Standardization, Herbal toxicity, Herb-drug interaction, Pharmacovigilance system

INTRODUCTION: Plant-based therapy can contribute to attaining overarching Sustainable Development goal 3 (SDG 3) that, assures healthy lives and encourages the well-being of every individual.

Hence, integrating the safe and efficacious herbal medicinal system with the conventional pharmaceutical system could provide additional benefits to construct and strengthen the primary healthcare services.

The survey conducted in Germany illustrated that discontentment with allopathic treatment, a multidimensional or synergistic effect of herbal medicines, traditional use, and individualistic knowledge were some of the key reasons for using herbal medicines among all age groups regardless of an expert consultation.

Therefore, the government, physicians, pharmaceutical industry and concerned bodies should put some steps to create awareness among herbal users ¹. Emerging outbreaks such as SARS-COV-2 and fungal infection (Mucormycosis) have recently increased the burden on the conventional medication system. Due to this, interest in the domain of Phytotherapy is going under resuscitation to robust the existing healthcare system to counteract the current malicious pandemic. Thus, the inclusion of immunity-modulating herbs, herbal products, and AYUSH formulations in a daily regimen could serve as prophylactic measures. Depending on the traditional knowledge, in-vivo and in-vitro examination, positive influence, and preceding clinical evidence, the multi-pronged botanical formulations, particularly aqueous extract of Guduchi and pippali (Tinospora cordifolia + Piper longum), AYUSH 64 and Guduchi aq. extracts are endorsed as a standard code of practice in mild to moderate and asymptomatic COVID -19 patients.

Similarly, aqueous extracts of ashwagandha (Withania somnifera) and Guduchi are put forward as prophylactic treatment against COVID-19 ². The active compound 'Withaferin A' possibly served as a potential therapeutic vehicle to avert the progression of viral infection ³. The clinical studies have also devised that ashwagandha root extract is safe to use, but long-term examination and different dosage range needs to be evaluated further ^{4, 5}.

Above all, with the commencement of novel technologies, herbs usage is not limited to drug formulation. However, they could be served as valuable fortificant in the food industry (like in the dairy industry) for the development of functional foods (i.e., dairy products) with enhanced nutraceutical value. Alongside, botanicals incorporation makes fortified foods more appealing and attractive, which paved the way for deploying underutilized herbs ⁶. The recent literature has also delineated that merging various herbs in different dairy products eventually revamps their nutritional and therapeutic value. For example, fortification of Labneh (Condensed yogurt), cheese with Moringa oleifera, or its extract in varying ratios had improved their antioxidant power, total LAB count, antimicrobial properties, and extended the shelf-life of the products ^{7, 8}. Even bioactive compounds from botanicals are the pioneering material for nutraceuticals and are widely ingested by the inhabitants to impede the health challenges of the 21^st century.

As with the benefits of herbal formulation, some drawbacks are associated with their use and may expose you to various mild to severe health complications, most often liver injury. Many a time, adverse events of herbal medication remain underreported. The underlying rationale behind the adverse events/health risks associated with herbs/herbal formulations is the availability of unstandardized or unlabeled herbal products, contamination with noxious substances, substandard product quality, adulteration or substitution, herb-drug contraindications, presence of inherently toxic compounds and anti-nutritional factors. Further, a lack of knowledge regarding the frequency and duration of taking herbal supplements by self-medicated people or unqualified practitioners has created additional noise on health issues. Therefore, processing, standardization, and characterization of herbal products are imperative for the purity, identification, and quality assurance of herbal ingredients or for producing a more consistent product.

In this regard, the WHO has formulated standard procedures and methods for standardizing herbal medicines. Despite conventional techniques outlined in the WHO document, novel techniques including barcoding, protein chip, metabolomics, genomic fingerprinting, analytical compound examination, spectroscopy and so, on have been arriving in the last decades for the herbs/herbal product standardization ⁹. The work in this field is still in a progressive stage to develop a more effective technique to investigate the purity, authenticity and identity of raw herbs more concisely and to manufacture a more consistent phytopharmaceutical drug. Next in a row are ambiguous standards and regulations among different regions of the world, which poses a significant challenge to the herbal supplement's manufacturer to synthesize a standardized herbal product globally. Other challenges include safety monitoring of herbal formulations merchandising globally. Elsewhere, WHO and other concerned regional bodies, namely, ASEAN, European Union (EU), United States of America (USA), and United Kingdom (UK), are taking collaborative maneuvers to establish a single regulatory framework for the safety, efficacy, and standardization of herbal medicinal product ¹⁰.

As per the updated survey on Traditional and Complementary Medicine (T & CM), 124 WHO member states had laws or regulations on herbal medicines. Amongst, few member states have exclusive regulations for herbal medicines. In contrast, others either have partially the same regulations as for conventional pharmaceuticals or the same regulations as for conventional medications. For instance, South Africa and Mexico have the same regulations as conventional pharmaceuticals. Even some countries, such as New Zealand, still have no specific regulatory framework for herbal products. However, these products are regulated via other frameworks, i.e., under Dietary Supplement Regulations 1985 ¹¹.

Further, herbal medicines were categorized under eight possible regulatory categories as of 2012 (i.e., Second survey), namely, prescription medicines, herbal medicines, non-prescription medicines (OTC or self-medication), dietary supplements, functional foods, health foods, general food products, and others ¹¹. In India, the Department of Ayurveda, Yoga, Unani, Siddha, and Homeopathy (AYUSH) is responsible for regulating herbal medicines, which are governed under the aegis of the Ministry of Health. Later, in 2014 Ministry of AYUSH was established ¹¹.

Herbal medicines in India are sold as prescribed and non-prescribed medicines ¹¹ still, a vast range of herbal products sold in India are not subjected to any clinical trials before being allocated in the market, and a majority of people are taking these herbal supplements regardless of their safety. Therefore, herbal products/medicines should be substantiated as safe, effective, and of acceptable quality before allocating to the public. In recent decades, evidence has been available on herbal therapy's therapeutic effects and clinical efficacy. Still, the new thrust area is investigating the synergy of composite herbal formulation and their interaction with chemical drugs. The main objectives of the current literature underlined processing techniques requisite for manufacturing herbal formulation, the health benefits/clinical efficacy of standardized products, the necessity of standardization, and health risks associated with herb toxicity. The study has also delineated several case reports on herbal supplements/ayurvedic medicines such as slimquick, aloe vera pills, etc. In the last section, pharmacovigilance of herbal products is summarized and remarked on its importance in mitigating the adverse events/effects/health risk contributed by any of the attributes of herbal formulations.

Processes Involved in the Preparation of Herbal Formulation: Herbal materials or finished herbal products have already been recognized in international trade and commerce, which upsurges their economic value and significance. Therefore, herbs/herbal products are lucrative for the Indian market. However, a range of adverse effects has been stated to the regulatory authorities regarding the use of herbal formulations, which are usually associated with the abysmal quality of crude material, variability in the source herbal material, inherent toxicity of herbal medicines, and manufacturing and processing factors. Thus, correct identification of source plant species and collecting appropriate parts to prepare herbal products are some of the fundamental steps to assure their safety, quality, and effectiveness ¹².

Herbal processing involves post-harvest procedures applied to crude plant materials to produce herbal materials, preparation, and finished herbal products. Post-harvest processing of raw herbs or herbal materials is imperative to assure maximum safety and efficacy and enhance the therapeutic activity and quality of finished herbal products. Therefore, Good Herbal Processing Practices (GHPP), along with Good Agricultural and Collection Practices (GACP) and Good Manufacturing Practices (GMP), have formulated a series of processing methods for the production and manufacturing of herbal medicines ¹². The "processing" of herbal materials encompasses primary and secondary processing, as shown in Fig. 1. However, herbal processing may vary from herb to herb.

Hence, specific primary processing includes various simple prerequisite procedures such as washing, cleaning, sorting, size reduction, garbling, parboiling (blanching), leaching, and drying. In addition to primary processing, a myriad of herbal materials requires "specific processing" prior to direct use as decocting material for the instant therapeutic activity or as starting material for producing finished herbal products. These processes include cutting, sectioning, comminution (fragmentation), sweating/aging, roasting, boiling or steaming, stir-frying, and fumigation. Secondary processing will ensure the purity of raw herbs and ameliorate their therapeutic profile, such as reducing toxicity or improving clinical efficacy ¹³. For example, Aconite root is processed either by boiling in water or steaming before consumption as it contains toxic compounds (aconitine and related alkaloids) if taken in its crude form. Research has indicated that decocting Aconitum tuber in boiling water reduced the highly toxic metabolic compound diester-diterpenoid alkaloids (i.e., aconitine) into less toxic alkaloid compounds, i.e., benzoylaconine and aconine ¹⁴. "Herbal materials" consist of herbs and other crude botanical ingredients, viz. gums, resins, exudates, and balsams. In contrast "Herbal preparation" are produced when botanical ingredients are subjected to various physical or biological processes such as extraction (in water, alcohol, supercritical CO_2, or other solvents), fractionation, purification, concentration, fermentation, and many other techniques. They can also be formulated by steeping or heating herbal material in alcoholic beverages, honey, or other media. The resulting herbal preparation may contain fragmented or powdered herbal material, extracts, tinctures, essential oils, decoction, expressed plant juices, and cold and hot infusions. From the above concept, herbal material could serve as a starting material, and herbal preparation might be considered an intermediate material for manufacturing finished herbal products or herbal dosage forms for therapeutic use. Finished herbal products contain either one or more herbal preparation formulated from one or more herbs. The products composed of various plant materials are known as "mixture herbal products ¹⁵.

FIG. 1: REPRESENT STEPS INVOLVED IN THE PROCESSING OF HERBS/HERBAL MATERIAL

Standardization of Herbal Formulations: Herbal preparations are extensively available "over the counter," and large chunks of the population are gulping down these herbal preparations without knowing their safety, quality, purity, and clinical efficacy. Standardization and quality control of herbal supplements/products are mandatory before being allocated in the marketplace to circumvent serious health complications. However, unlike synthetic/chemical medicines, specifications and methods to control the quality of final herbal products, especially those containing a mixture of herbs, are much more complex because the quality of finished products depends on the quality of herbal raw material procured ¹⁵.

So, for that purpose, WHO has devised four documents that give technical guidance in the critical areas where quality control is necessary for the production of herbal medicines, are as follows: WHO guidelines on good agricultural and collection practices (GACP) for medicinal plants ¹³, WHO guidelines on assessing the quality of herbal medicines concerning contaminants and residues ¹⁶, Good processing practices for herbal materials (in preparation) and Analytical methods for chemical identification of ingredients/ constituents for quality control of herbal medicines ¹⁵.

As per European Pharmacopoeia, "standardization means adjusting the herbal substance/herbal preparation to a defined content of a constituent or a group of a constituent with known therapeutic activity respectively either by adding excipients or by blending batches of the herbal substances or herbal preparation like standardized extracts ¹⁷.

Even the content of constituents "with known therapeutic activity" in standardized herbal preparation should be specified with the lowest possible tolerance (both upper and lower limits). If powdered herbal substances are standardized, then the quantity of herbal substance or original preparation must be represented as a range according to a prescribed amount of constituents with known therapeutic activity ¹⁷. Standardized herbal substances/ herbal preparations have been prioritized over unstandardized extracts as they ensure the identification "that the herb is what it is claimed to be."

Additionally, herbal medicinal products with a defined content could be considered a prerequisite for clinical trials. Nevertheless, advancements in chemical and biological techniques provide the scientific basis for manufacturers to produce standardized herbal products.

Standardization and quality control of mono- or polyherbal formulation/blend is a very exhausting and arduous job as crude herbs are susceptible to a diverse range of variations because of different factors, primarily, the identity of the botanicals, seasonal variation, geographical location, harvesting time and procedure, method of collection, manufacturing processes (i.e., selection, drying, purification and extraction), genetic variability, diurnal variation, ecological conditions (like insect manifestation, microbial infection), and different parts of the plant. In addition, the factors mentioned above affect the plant materials’ chemical composition and therapeutic value, which causes batch-to-batch variation of herbal products ¹⁸.

Apart from that, other elements such as adulteration or contamination with microbes, heavy metals, pesticides, and any other foreign agent could alter herbal product quality, safety, and efficacy. Therefore, standardization of herbal products involves a trans-disciplinary approach that is augmented from the birth of the plant to its clinical application or final usage. Table 1 indicates some standardized herbal products available in the market with their health benefits/clinical efficacy.

TABLE 1: CLINICAL EFFICACY OF STANDARDIZED HERBAL PRODUCTS

The Necessity of Standardization: The modern medicinal system is constructed on specific standards, well-established experimental data, toxicity data, and human clinical trials. While in the case of herbal medicinal products, there is a paucity of unanimous standards, ambiguous regulatory network (i.e., varies from country to country), insufficient evidence on toxicity and a lack of human clinical studies. The dearth of standardization has myriad repercussions, such as variability in the quantity or absolute omission of the known active compound, which is known for its therapeutic activity. Investigation in this field has ventured that many herbal products commonly accessible in the market vary in their chemical constituents when scrutinized quantitatively. For example, Withania somnifera (ashwagandha) and ginseng, the herbs merchandised globally, are predisposed to variation in their active or marker compounds. A review study has inspected 507 ginseng products available in the market for authenticity. Amongst various species, Panax ginseng, P. notoginseng and P. quinquefolius are traded globally. All of the ginseng products were procured from 12 countries distributed over six continents. The scrutiny of the chemical and botanical identity of all the ginseng-containing herbal supplements proclaimed that 76% were authentic and 24% were adulterated. Correspondingly, across six continents highest adulteration was seen in South America (100%) and the lowest in Asia (21%), followed by no adulteration in Africa (0%). At the national level, Taiwan ranked highest (49%) in ginseng adulteration, whereas products purchased from the South Korean market were found authentic. Most often, Panax spp. labeled on the product were substituted with other Panax spp. In many scenarios, the therapeutic part of the ginseng plant (root) was substituted with other plant parts, i.e., flowers, leaves, and stems. One of the main reasons for the intentional adulteration is the price of the ginseng supplement, which varies according to the product's species, quality and purity ²⁴.

The latest study highlighted the variation in the concentration of four different ginsenosides (Rg 18, Rg3, Rs11, and Re7) in ginseng roots procured from different spp. The study showed that the total concentration of ginsenosides was maximum in ginseng harvested from P. quinquefolius, i.e., 186 µg/g, Geumsan, i.e., 185 µg/g, and White ginseng, i.e.,150 µg/g ²⁵.

Thus, many past and current studies have depicted that acquiring superior-quality and authentic ginseng products with proven safety and clinical efficacy is a daunting challenge for both herbal users and health care practitioners. Nevertheless, G115 is a well-characterized and standardized ginseng extract that exists in the market, having well-established clinical data on its safety and efficacy profile ²⁶.

The research has also enlisted a similar variation in commercial ashwagandha products. The authenticity of the root and powder samples of the ashwagandha product purchased from the market was done by DNA barcoding. The results stipulated that 77% of products were authentic while 22% were non-authentic products in powder format, followed by root samples (1%). As observed above, powder samples were more vulnerable to adulteration than root samples ²⁷.

FIG. 2: METHODS OF STANDARDIZATION AND QUALITY CONTROL

Besides, inadequate quality standards have led to numerous adverse events ranging from organ toxicity to death. So, considering the above investigations, standardization and characterization of herbal products must be lined in the process for identity, purity, and quality assurance of herbal ingredients and the production of a more consistent product. Three pharmacopoeial features desirable for standardization and quality assurance of herbal medicinal products are identity, purity, and assay. First, the identification section assures that the herbal medicine under scrutiny is the one mentioned on the label. It also claims that herbal raw material is authentic. Identification tests are required to confirm herbal medicine's identity, including macroscopic and microscopic evaluation, chemical analysis, DNA-based tests, and fingerprinting ²⁸. These tests will not fully authenticate the herbal product's chemical composition. However, they expected to offer some degree of assurance or confirmation that it is the one declared on the label. The second attribute, purity, assures that plant raw material is free from adulterants or malicious substances. Finally, the assay section comprises chemical and biological profiling of herbal medicine, where herbs' chemical constituents with known therapeutic activity should be assessed quantitatively. If the chemical component accounted for known therapeutic action is unknown, pharmacopeia may include tests to determine the chemical constituent that serves as the analytical or active marker ²⁸. The methods used to standardize plant-based products are depicted in Fig. 2.

Toxicological Profile of Herbs and Herbal Formulations: Even though 'Nature is curable,' 'nature may be toxic too' because taking any supplement/drug without supervision may turn into mayhem. So, this is the case with the herb Tinospora cordifolia (TC, also termed as Giloy or Guduchi), the principal herb for many ayurvedic herbal formulations that have become a part of COVID management protocol due to its immunity-boosting attribute ²⁹.

The current hospital-based observation study outlined the adverse effects of Giloy consumption faced by six patients, particularly drug-induced autoimmune-like hepatitis. Four of six patients ingested boiled extract of Giloy plant twigs, whereas the remaining two consumed it in commercially available tablet and syrup format. All subjects' median interquartile range of taking herbal formulation was 90 days. As per the updated RUCAM score, around four patients had shown possible DILI, and two had a probable drug-induced liver injury. Out of 6 patients, four female patients who experienced chronic liver damage due to Giloy ingestion were also associated with other co-morbidities such as two had type-2 diabetes, and the other two had hypothyroidism ³⁰. This study highlighted liver injury that may be either due to autoimmune-like hepatitis as a result of Guduchi consumption or due to exposure to the quiescent chronic auto-immune liver disorder. Although TC has many health benefits, it benefitted the mass of people via stimulating immune response even though it activates the auto-immune response. Hence, it is crucial to be cautious about the potential adverse effect of the Guduchi administration ³⁰.

But before formulating any generalization regarding the adversities of Giloy, one should also consider its ingestion by a large community amid a pandemic under supervised or unsupervised conditions ³¹. Even sufficient evidence of carcinogenicity in experimental animals averred that few herbs particularly, Aloe vera (Whole leaf extract), goldenseal root powder, Ginkgo biloba, kava extract, and pulegone, have been recognized as a possible carcinogen (Group 2B) in humans by the International Agency for Research on Cancer (IARC) ³². Another example of herb toxicity is aristolochic acids (AA), found in Aristolochia plants and were formerly used as an herbal remedy for various ailments, namely, pneumonia, stroke, hepatitis, arthritis, and gout. Hence, AA was extensively used in several herbal products and traditional medicines. But research has delineated inevitable adverse consequences of AA ingestion, particularly kidney failures and urinary tract cancer.

Consequently, IARC considered AA a cancer-causing compound (Group 1) based on substantial evidence. Despite this, it is widely used in regions like China, South Korea, Japan, Southeast Asia, North America, and Europe ³³.  Herbs/herbal formulations are more often consumed with pharmaceutical drugs and raise the concern of herb-drug interaction mainly occurring due to alteration in metabolic enzymes or pharmacokinetics of prescribed medication ³⁴. The research has postulated that induction or inhibition of hepatic cytochrome P450 enzyme and transport or efflux proteins are the two critical pathways involved with HDIs ³⁵. Moreover, Huges ³⁶ had reported a case of a 27-year-old man who was found intoxicated after ingesting a lethal amalgam of herb and chemical drug, namely, quetiapine and mitragynine (active component of Kratom plant, Mitragyna speciosa). The case has underlined the possible herb-drug interaction posed by the interference of mitragynine with the metabolism or clearance of quetiapine, perhaps due to the inhibitory action of mitragynine on hepatic enzymes i.e., upon different cytochrome P450 enzymes or suppression of P-glycoprotein, a cellular transport protein ³⁷. Thus, these two pathways (cytochrome P450 enzymes and P-glycoprotein) are associated with the elimination or metabolism of the drug (quetiapine) that may be hindered by concurrent use of mitragynine. Likewise, more cases of polypharmacy came ahead, which directed people's life at risk or may lead to organ injury. For example, in-vivo investigation in mice has demonstrated that administration of herb (aqueous extract of aloe vera) and synthetic drug (glimepiride) in combination was found to exert hypoglycemic effects in high intensity in contrast to taking either of two alone. Hence, it was essential to readjust the drug dose and monitor glucose levels to avert hypoglycemia ³⁸. Thereby, botanicals or their derivatives having specific pharmacological activity shall not be combined with synthetic medicines with the same pharmacological function ³⁹.

FIG. 3: TYPES OF HERB-INDUCED TOXICITY AND FACTORS AFFECTING IT

Succeeding on a ladder of toxicity is metal toxicity due to ingestion of Ayurvedic and other herbal products now become a public health problem. The study conducted by Mikulski ⁴⁰ evaluated 252 samples of Ayurvedic medicine for heavy metals and metalloids (Ag, Ba, Cd, Cr, Hg, Ni, Pb, As, and Sb), among them, lead (Pb), mercury (Hg) and arsenic (As) were found in a range 65%, 38% and 32% of the total sample respectively. Lead was the leading element detected in most samples with a maximum concentration of 43200mg/kg, followed by mercury and arsenic with the highest concentration of 279000mg/kg and 44800 mg/kg of samples, respectively. Additionally, metals like Pb, Hg, As and Cd were present in samples at a concentration exceeding the recommended daily intake. Surprisingly, the metal content was varied with the product, even though the same product proffered by the same provider contained varying levels of the same element. This problem may occur due to small producers' production of these Ayurvedic formulations by hand. Hence, issues like product consistency, purity and possible toxicity are often neglected. Moreover, this study has also highlighted the dearth of regulations in the production and purity of Ayurvedic supplements that could cause notable public health concerns. Apart from this, other factors that induce herb toxicity are depicted in Fig. 3. Two factors ascribable for the toxicity of herbal medicines are intrinsic and extrinsic; the former includes toxicity that could be caused by active chemical compounds present in the botanicals. Later toxicity may be caused by erroneous substances such as contaminants and adulterants in the herbal medicines/products. Botanical preparations are responsible for inducing different types of toxicity such as cardiotoxicity, hepatotoxicity, nephrotoxicity, neurotoxicity, skin toxicity and many others. Further, the critical analysis of the enlisted herb-induced toxicities database suggested that the incidence of hepatotoxicity and nephrotoxicity are more frequently dominated. Perhaps these organs (i.e., liver and kidney) are involved in the first-pass metabolism of toxic compounds. In addition, they are major organs included in detoxifying and filtrating drug metabolites or toxic components from the body. Table 2 underlying below outlined a few studies that indicated adverse events associated with herbal material.

TABLE 2: ADVERSE EVENTS ASSOCIATED WITH HERBAL MATERIAL

In some instances, herbs or herbal products such as aloe vera, Tinospora cordifolia are allied with drug-induced liver injury (DILI). However, the underlying mechanisms related to herb-induced liver injury (HILI) are challenging to assess because of the small fractions of reported cases. However, most DILI cases from herbal materials seem idiosyncratic instead of intrinsic type due to the dearth of well-established evidence ⁵². Moreover, assessing the etiology of idiosyncratic HILI in humans is arduous because it is sporadic, affects only susceptible people, has rare congruent relation with dosage and is more miscellaneous in its presentation ^{53, 52}. Nevertheless, systematic review and meta-analysis evidence had displayed that nearly 79 types of herbs or herbal materials were linked to herb-induced liver injury (HILI). Green tea extract, kava kava, ma huang, senna, aloe vera, Garcinia cambogia, etc., were frequently used supplements associated with HILI. Additionally, around 82.8% of patients completely recovered from liver injury. On the other hand, nearly 6.6% of cases required transplantation, while 1.5 % and 10.4% of the cases were correlated with chronic liver disease and fatality, respectively ⁵⁴. A similar case report also came ahead that was related to herbs usually found in weight-loss dietary supplements, i.e., Garcinia cambogia.

TABLE 3: CASE REPORTS OF HERBAL SUPPLEMENTS

Certain studies have reported a few complications such as acute hepatitis, hepatic failure, and acute liver injury related to intake of this herb ⁵⁵. The case report where a 35-year-old female had consumed G. cambogia extract in an amount higher than what was stated and resulted in ocular complications. She had also experienced nausea, headache, and dizziness. Albeit, the symptoms resolved after the cessation of the extract ⁵⁶. Therefore, nutritionists or physicians must consult their patients about the possible adverse effects of taking higher doses of the herbal extract. So, herbs or herbal supplements can be your friend if taken sensibly or cautiously. Otherwise, it may turn into a foe in case of overdosing. Hence, individuals should be vigilant before self-medication with herbal treatment. Numerous other case reports related to the use of herbal supplements are put forth in Table 3. Thus, toxicity tests for herbal medicines are conducted for data profiling and safety. Therefore, herbs should be tested exclusively before being included in the research to assess their toxicity. The principal goal of conducting toxicity studies is to retrieve information on the drugs' biological function and mode of action. The facts generated from experiments are used to identify the hazard and manage the risk associated with the drugs. Preclinical studies such as literature review collect information from historical use, pharmacodynamics study, and pharmacological and toxicological test are carried out to examine the safety of the medicinal products. Afterward, clinical examinations are performed to validate the safety and efficacy of traditional herbal medicines. Other cases where clinical studies may be conducted include examining the biological activity of active compounds extracted from herbal medicine to produce a new herbal drug, alter the dosage formulation, or change the delivery passage ⁶². The underlying research procedure to assess the safety and efficacy of herbal medicines is elucidated in Fig. 4.

FIG. 4: RESEARCH PROCEDURE TO ASSESS THE SAFETY AND EFFICACY OF HERBAL MEDICINES

Pharmacovigilance of Herbal Formulations: The notion that "Nature is a true healer and safer" is illusionary because certain plants or herbs known for their therapeutic property are inherently toxic in their crude form. Hence, they required specific processing to neutralize their toxic compounds before consumption. Alike all other medicines, drugs, and supplements of botanical origin could also be associated with particular side effects that may be linked to various issues, mainly substandard product quality or inappropriate use. Other associated factors include scanty regulatory measures, ungoverned distribution channels (i.e., via E-commerce route), and inadequate quality control systems. Further, the adverse events connected to the below-par quality of products involve adulterating or substituting herbal products with unlabeled ingredients and potent pharmaceutical compounds, for instance, corticosteroids and NSAIDs ⁶³.

Some other incidents may also occur due to erroneous use of incorrect plant species, improper dosing, herb-drug interaction, and use of products defiled with hazardous substances (e.g., heavy metals, pathogenic microorganisms, pesticides, and related agrochemical residues). On that account, the safety of herbal products has become a vital concern for both national health authorities and the community.

Nevertheless, other various problems countered with the use of herbal products are underlying below:

Adulteration of Herbal Products: A study conducted in China where Traditional Chinese medicines (TCM) were assessed for adulteration from 2003-2017 revealed the presence of 166 adulterants in adulterated TCM and herbal products. Amongst investigated products, 158 contaminants were detected in TCM preparations, followed by 43 in herbal supplements, and 35 adulterants were commonly found in both. They can be categorized into three main classes: substitution with non-drug compounds, illegal incorporation of non-drug element/foreign compounds, and addition of pharmaceutical drugs. TCMs primarily susceptible to adulteration belong to the following domain: sexual dysfunction, pain relief, sleep, and rheumatism ⁶⁴. Similarly, a study indicated that jamu, an antidiabetic traditional herbal medicine majorly consumed in Indonesia, has been adulterated with the pharmaceutical drug glibenclamide, a member of sulfonylurea. Out of five samples of jamu, a synthetic drug (glibenclamide) was detected in one jamu sample at a level of 1.88 µg/g when analyzed with HPLC ⁶⁵. Another study has also illustrated the adulteration of some herbal medicines that aid erectile dysfunction with PDE5 inhibitors (sildenafil) and alpha-blockers. The investigation of 12 herbal products using ambient mass spectrometry showed that three products manifested sildenafil at 0.5% to 18% levels ⁶⁶.

Misidentification and Deceitful Claims of Herbal Products: In the herbal industry, they are the major drawbacks that require vigilance to prevent or minimize adverse consequences. For example, there are many cases of intoxication reported due to misleading identification of foxgloves (Digitalis purpurea) with borage (Borago officinalis L.) as both the plant resembles and create confusion. Though, borage is consumed as a food ingredient and also a part of Italian dishes in many countries since historical eon. However, mistaken ingestion of foxgloves leads to poisoning and may also be fatal due to cardiac glycoside (probably, digitoxin).

A case study of female patients aged 55 years old experienced various symptoms like weakness, nausea, vomiting, and fatigue after ingestion of homemade savory pie prepared by leaves procured from botanical taken in a nursery as borage. Later, testing confirmed gitoxin presence could be the possible reason for clinical toxicity instead of digoxin⁶⁷.

Microbial contamination of Herbal Products: In many cases, herbal products are perhaps loaded with microbial contaminants. One such instance is outlined in the current update where the FDA has issued an alert statement to buyers and healthcare practitioners regarding the voluntary recall of all the batches of goldenseal root powder due to complaints of bacterial contamination of the product with various pathogens in high amounts ⁶⁸. Recently, a microbial contamination case was reported in Nairobi, Kenya, in 86 herbal preparations used to manage chronic diseases. Amongst, 26 herbal products were contaminated with pathogenic bacteria  coli, Salmonella spp., and Enterobacteriaceaefamily, and overall, 41 products were failed to comply with the British Pharmacopoeia (2019) specifications for microbiological quality ⁶⁹. Similarly, many cases of contamination exist in the community, but sometimes they remain underreported. Thus, there is an urgent need for strict regulatory policies on quality assurance of herbal products to protect people from contaminated and defiled herbal medicines ⁶⁹.

After considering all the adverse drug reactions (ADR) pertaining to the application of herbal medicines or herbal products, there is an underscoring need for a cohesive Pharma-covigilance system to detect disagreeable reactions and generate authentic information on the safety of herbal products. In this regard, WHO has drafted certain guidelines for the safety monitoring of herb-based supplements/drugs within the existing pharmacovigilance framework.

Pharmacovigilance is the science and actions necessary for detecting, assessing, understanding, and averting adverse events or other plausible drug-related matters. It has broadened its concerns which cover herbals, biological, traditional, and complementary medicines, vaccines, etc. The WHO International Drug Monitoring Program, unified with the WHO Collaborating Centre, the Uppsala Monitoring Centre (UMC), has installed a cogent action plan for pharmacovigilance. This plan of action includes setting up a program to exchange dialogues on safety, maintaining the global WHO database consisting of reports on adverse drug reactions (ADR), and the provision of various guidelines on monitoring the safety of drugs ⁷⁰. These guidelines acknowledge the specific challenges in monitoring the safety of herbal drugs or products and suggest strategies to overcome them. The guidelines focused on the reporting system of adverse effects linked to herbal medicines and analysis of the precipitation of the adverse reactions outlined. The action plan also includes training workshops to reinforce the national capacity for safety monitoring of herbal medicines and traditional methods ⁷⁰.

National pharmacovigilance centers operating under WHO International Drug Monitoring Program are accountable for collecting, processing, and evaluating the case reports of surmised adverse events provided by the clinician or health care practitioners ⁷⁰. In contrast, the functioning of national pharmacovigilance is coordinated and facilitated by WHO and UMC.

Additionally, in India, The Ministry of AYUSH is the governing body that tackles the quality issues and safety concerns of Ayurveda, Siddha, Unani, and Homoeopathy (ASU & H) medicines. It has launched a new Central Sector Scheme to strengthen the pharmacovigilance system for ASU & H medication, intending to inculcate the culture of reporting adverse events; manage the monitoring of the safety of AYUS&H drugs, and inspect deceptive claims conveyed by printed and electronic media.

Besides, need for unanimous regulatory standards for the pharmacovigilance of plant-based medicines. The people of this globe should also take collaborative action for the safety monitoring of botanical products. Above all, The Knife-edge of any pharmacovigilance system is dependent on how suspected adverse events are conveyed.

CONCLUSION: Since, our forefathers' era, botanical have been deployed as the first line of treatment to avert several existing or new-emerging diseases and improve humans' overall health. In recent years, advancement in scientific and technological aspects has paved the way to utilize bioactive compounds and their structural analogs as potential pioneering agents for drug discovery ⁷¹.

Indeed, herbs have exuberant beneficial effects, but ingesting any therapeutic agent beyond their limit could lead to herbal toxicity. The herb-based complications perhaps arise due to mistaken procurement of the wrong species of medicinal herbs, incorrect dosing, adulteration or substitution, contamination with impecunious substances, unstandardized herbal products, unregulated distribution channels, ineffective quality control systems, and scattered regulatory measures. Beyond that, the most prevalent herb toxicity has been caused due to herb-herb/herb-drug interactions. Therefore, it is always advised not to combine pharmaceutical drugs with herbal medicine as both may exhibit the same pharmacological activity and may eventually cause serious health complications. Nevertheless, as per the current situation, health risks due to herb toxicity require special consideration to protect public health. So, the health risks highlighted in this review taught us a noteworthy lesson that not all the therapeutic compounds taken by people can be pondered fully ‘safe’. Hence, both risk and benefits must be taken into account.

The present literature has also envisaged sufficient data on herb toxicity. However, the data on herb-drug or herb-herb toxicity and the underlying mechanism needs to be investigated, as most liver injury precipitated by herb toxicity is idiosyncratic. Hence, research must be directed to assess the principal mechanism for herb-induced liver injury or other organ injuries. Scarce human clinical trials, ambiguous regulatory measures, marketing of unstandardized herbal products, and weak pharmacovigilance systems of herbs/supplements/ formulations are perhaps new thrust areas where research is needed further.

ACKNOWLEDGMENT: This work was supported by the University Grant Commission under Junior Research Fellowship (NTA Ref. No. 190510299004), New Delhi, India.

CONFLICTS OF INTEREST: No conflict of interest

REFERENCES:

1. Welz AN, Emberger-Klein A & Menrad K: Why people use herbal medicine: insights from a focus-group study in Germany. BMC Comple and Alt Med 2018; 18(1): 1-9.
2. Ministry of AYUSH, Govt. of India. Interdisciplinary Committee for integration of Ayurveda and Yoga Interventions in the 'National Clinical Management Protocol: COVID-19'. First Report and Recommendations. 2020. Retrieved from https://www.ayush.gov.in/docs/Report%20and%20Recommendations%20of%20Interdisciplinary%20Committee.pdf OM No. A. 17020/1/2020-E.I
3. Straughn AR & Kakar SS: Withaferin A: a potential therapeutic agent against COVID-19 infection. Journal of Ovarian Research 2020; 13(1): 1-5.
4. Verma N, Gupta SK, Tiwari S & Mishra AK: Safety of Ashwagandha Root Extract: A Randomized, Placebo-Controlled, study in Healthy Volunteers. Complementary Therapies in Medicine 2021; 57: 102642.
5. Mandlik DS and Namdeo AG: Pharmacological evaluation of Ashwagandha highlighting its healthcare claims, safety, and toxicity aspects. Journal of dietary supplements. 2021; 18(2): 183-226.
6. El-Sayed SM and Youssef AM: Potential application of herbs and spices and their effects in functional dairy products. Heliyon 2019; 5(6): 01989.
7. El-Saye SM, El-Saye HS and Salama HH E SAA: Improving the Nutritional Value and Extending Shelf Life of Labneh by Adding Moringa oleifera International Journal of Dairy Science 2017; 12(2): 81–92.
8. Mohamed FA, Salama HH, El-Sayed SM, El-Sayed HS and Zahran HA: Utilization of natural antimicrobial and antioxidant of Moringa oleifera leaves extract in manufacture of cream cheese. J Biol Sci 2018; 18(2): 92-106.
9. Mukne A, Momin M, Betkar P and Joshi V: Standardization of herbal biomolecules. In Herbal Biomolecules in Healthcare Applications 2022; 643-667.
10. Ramadoss MSK and Koumaravelou K: Regulatory compliance of herbal medicines--a review. Int J Res Pharm Sci 2019; 10(4): 3127-3135.
11. World Health Organization. WHO global report on traditional and complementary medicine 2019. World Health Organization 2019.
12. World Health Organization & WHO Expert Committee on Specifications for Pharmaceutical Preparations. Fifty-second report of the WHO Expert Committee on Specifications for Pharmaceutical Preparations. 2018.
13. World Health Organization. WHO guidelines on good agricultural and collection practices (GACP) for medicinal plants. World Health Organization 2003.
14. Liu S, Li F, Li Y, Li W, Xu J and Du H: A review of traditional and current methods used to potentially reduce toxicity of Aconitum roots in Traditional Chinese Medicine. Journal of Ethnopharmacology 2017; 207: 237-250.
15. World Health Organization, & WHO Expert Committee on Specifications for Pharmaceutical Preparations. Fifty-first report of the WHO Expert Committee on Specifications for Pharmaceutical Preparations. 2017. WHO Technical Report Series, No. 1003, Annexure 1.
16. World Health Organization. WHO guidelines for assessing quality of herbal medicines with reference to contaminants and residues. World Health Organization. 2007.
17. Committee on Herbal Medicinal Products. Guideline on quality of herbal medicinal products/traditional herbal medicinal products. 2018. Retrieved fromhttps://www.ema.europa.eu/en/documents/scientific-guideline/draft-guideline-quality-herbal-medicinal-products/traditional-herbal-medicinal-products-revision-3_en.pdf.
18. Kumari R and Kotecha M: A review on the standardization of herbal medicines. International Journal of Pharma Sciences and Research, 7(2), 97-106.). A review on the standardization of herbal medicines. International Journal of Pharma Sciences and Research. 2016; 7(2): 97-106.
19. Nwidu LL, Elmorsy E and Carter WG: In‐vitro Anticholinesterases Screening and antioxidant activity of three standardized herbal products used in ethnomedicine of South‐East Nigeria. The FASEB J 2016; 30: 1191-2.
20. Alimkulova KZ and Urmanova FF. Standardization of New Herbal Composition" Flucam. European Journal of Molecular & Clinical Medicin 2020; 7(10): 2020.
21. Nausch B, Pace S, Pein H, Koeberle A, Rossi A, Kuenstle G and Werz O: The standardized herbal combination BNO 2103 contained in Canephron® N alleviates inflammatory pain in experimental cystitis and prostatitis. Phytomedicine 2019; 60: 152987.
22. Elkafrawy N, Younes K, Naguib A, Badr H, Kamal Zewain S, Kamel M and Mohamed S: Antihypertensive efficacy and safety of a standardized herbal medicinal product of Hibiscus sabdariffa and Olea europaea extracts (NW Roselle): A phase‐II, randomized, double‐blind, captopril‐controlled clinical trial. Phytotherapy Research 2020; 34(12): 3379-3387.
23. Liang P, Guo J, Li S, Guan Q, Vanderheyden T, So A and Du C: Prevention of prostate tumor development by stimulation of antitumor immunity using a standardized herbal extract (Deep Immune®) in TRAMP mice. Evidence-based Complementary and Alternative Medicine 2018; 2018.
24. Ichim MC and de Boer HJ: A review of authenticity and authentication of commercial ginseng herbal medicines and food supplements. Frontiers in Pharmacology 2021; 11: 612071.
25. Lee DG, Quilantang NG, Lee JS, Geraldino PJL, Kim HY, and Lee S: Quantitative Analysis of Dammarane-type Ginsenosides in Different Ginseng Products. Natural Product Sciences 2018; 24(4): 229-234.
26. Bilia AR and Bergonzi MC: The G115 standardized ginseng extract: an example for safety, efficacy, and quality of an herbal medicine. Journal of Ginseng Research 2020; 44(2): 179-193.
27. Amritha N, Bhooma V and Parani M: Authentication of the market samples of Ashwagandha by DNA barcoding reveals that powders are significantly more adulterated than roots. Journal of Ethnopharmacology 2020; 256: 112725.
28. World Health Organization, & WHO Expert Committee on Specifications for Pharmaceutical Preparations. Fifty-second report of the WHO Expert Committee on Specifications for Pharmaceutical Preparations. 2018. Retrieved from https://www.who.int/medicines/areas/quality_safety/quality_assurance/TRS1010annex7.pdf.
29. Rastogi S, Pandey DN and Singh RH: COVID-19 pandemic: A pragmatic plan for ayurveda intervention. Journal of Ayurveda and Integrative Medicine 2020.
30. Nagral A, Adhyaru K, Rudra OS, Gharat A and Bhandare S: Herbal Immune Booster-Induced Liver Injury in the COVID-19 Pandemic-A case series. Journal of Clinical and Experimental Hepatology 2021.
31. Rastogi S and Pandey DN: Herbal Immune Booster-Induced Liver Injury in the COVID-19 Pandemic – A Cautious Interpretation is Desired Before Any Generalization is Attempted. Journal of Clinical and Experimental Hepatology 2021.
32. IARC Working Group on the Evaluation of Carcinogenic Risks to Humans. Some Drugs and Herbal Products. IARC Monographs on the Evaluation of Carcinogenic Risks to Humans 2016; 108: 7.
33. Ang LP, Ng PW, Lean YL, Kotra V, Kifli N, Goh HP and Ming LC: Herbal products containing aristolochic acids: A call to revisit the context of safety. Journal of Herbal Medicine 2021; 28: 100447.
34. Choi YH and Chin YW: Multifaceted factors causing conflicting outcomes in herb-drug interactions. Pharmaceutics 2021; 13(1): 43.
35. Shaikh AS, Thomas AB and Chitlange SS: Herb–drug interaction studies of herbs used in treatment of cardiovascular disorders A narrative review of preclinical and clinical studies. Phytotherapy Research 2020; 34(5): 1008-1026.
36. Hughes RL: Fatal combination of mitragynine and quetiapine a case report with discussion of a potential herb-drug interaction. Forensic Science Medicine and Pathology 2019; 15(1): 110-113.
37. Meyer MR, Wagmann L, Schneider-Daum N, Loretz B, de Souza Carvalho C, Lehr CM and Maurer HH: P-glycoprotein interactions of novel psychoactive substances–stimulation of ATP consumption and transport across Caco-2 monolayers. Biochemical Pharmacology 2015; 94(3): 220-226.
38. Mondal P, Venu K, Thimmaraju MK and Chanbasha S: Herb drug interaction study between Aloe vera and glimepiride in normal and diabetic rats. Egyptian Pharmaceutical Journal 2020; 19(2): 124.
39. Suroowan, S, Abdallah HH and Mahomoodally MF: Herb-drug interactions and toxicity: Underscoring potential mechanisms and forecasting clinically relevant interactions induced by common phytoconstituents via data mining and computational approaches. Food and Chemical Toxicology 2021; 156: 112432.
40. Mikulski MA, Wichman MD, Simmons DL, Pham AN, Clottey V and Fuortes LJ: Toxic metals in ayurvedic preparations from a public health lead poisoning cluster investigation. International Journal of Occupational and Environmental Health 2017; 23(3): 187–192.
41. Hasnat M, Yuan Z, Naveed M, Khan A, Raza F, Xu D and Jiang Z: Drp1-associated mitochondrial dysfunction and mitochondrial autophagy: a novel mechanism in triptolide-induced hepatotoxicity. Cell Biology and Toxicology 2019; 35(3): 267-280.
42. Zhao W, Xiao L, Pan L, Ke X, Zhang Y, Zhong D and Chen Y: Cardiac toxicity of Triptergium wilfordii Hook F. may correlate with its inhibition to hERG Channel. Heliyon 2019; 5(10): 02527.
43. Herath N, Kodithuwakku G, Dissanayake T, Rathnathunga N and Weerakoon K: Acute Kidney Injury Following Star Fruit Ingestion: A Case Series. Wilderness & Environmental Medicine 2021; 32(1): 98-101.
44. Maduro IPDNN, Brandão ARJ and Israel KCP: Acute nephrotoxicity and neurotoxicity associated with concentrated star fruit juice consumption. BMJ Case Reports CP 2020; 13(12): 234460.
45. Zhu L, Zhang CY, Li DP, Chen HB, Ma J, Gao H, & Lin G: Tu-San-Qi (Gynura japonica): the culprit behind pyrrolizidine alkaloid-induced liver injury in China. Acta Pharmacologica Sinica 2020; 1-11.
46. Yun-Ying LI, Xiao-Yan LU, Jia-Li SUN, Qing-Qing WANG, Zhang YD, Zhang JB & Xiao-Hui FAN: Potential hepatic and renal toxicity induced by the biflavonoids from Ginkgo biloba. Chinese Journal of Natural Medicines 2019; 17(9): 672-681.
47. Yang W, Ma L, Li S, Cui K, Lei L and Ye Z: Evaluation of the cardiotoxicity of evodiamine in-vitro and in-vivo. Molecules 2017; 22(6): 943.
48. Trancă SD, Szabo R and Cociş M: Acute poisoning due to ingestion of Datura stramonium - a case report. Romanian Journal of Anaesthesia and Intensive Care 2017; 24(1), 65–68.
49. Ogunmoyole T, Adeyeye RI, Olatilu BO, Akande OA and Agunbiade OJ: Multiple organ toxicity of Datura stramonium seed extracts. Toxicology Reports 2019; 6: 983-989.
50. Bonanno G, Ippolito M, Moscarelli A, Misseri G, Caradonna R, Accurso G and Giarratano A: Accidental poisoning with Aconitum: case report and review of the literature. Clinical Case Reports 2020; 8(4): 696-698.
51. Li H, Liu L, Zhu S and Liu Q: Case reports of aconite poisoning in mainland China from 2004 to 2015: a retrospective analysis. Journal of Forensic and Legal Medicine 2016; 42: 68-73.
52. Chalasani NP, Maddur H, Russo MW, Wong RJ and Reddy KR: ACG Clinical Guideline: Diagnosis and Management of Idiosyncratic Drug-Induced Liver Injury. American J of Gastroenterology 2021; 116(5): 878–98.
53. Parlati L, Voican CS, Perlemuter K and Perlemuter G: Aloe vera -induced acute liver injury: A case report and literature review. Clinics and Research in Hepatology and Gastroenterology 2017; 41(4).
54. Ballotin VR, Bigarella LG, Brandão ABDM, Balbinot RA, Balbinot SS and Soldera J: Herb-induced liver injury: Systematic review and meta-analysis. World Journal of Clinical Cases 2021; 9(20): 5490–513.
55. Crescioli G, Lombardi N, Bettiol A, Marconi E, Risaliti F and Bertoni M: Acute liver injury following Garcinia cambogia weight-loss supplementation: case series and literature review. Internal and Emergency Medicine 2018; 13(6): 857–72.
56. Cho HK, Han YS and Park JM: Ocular complications of Garcinia cambogia extract diet pills: Case report. European Journal of Ophthalmology 2019; 30(6).
57. Yousaf MN, Chaudhary FS, Hodanazari SM and Sittambalam CD: Hepatotoxicity associated with Garcinia cambogia: A case report. World Journal of Hepatology 2019; 11(11): 735–42.
58. Ibrahim, AM, Al Sadah H, Ahmad R, Ahmad N and Naqvi AA: Clinical Uses and Toxicity of Aloe vera: An Evidence-Based Comprehensive Retrospective Review (2007-2017). Pharmacognosy Journal 2019; 11(2).
59. Ahmed OT, Patel S, Sharma B and Rossi L: S2708 Hydroxycut-Induced Autoimmune Liver Disease. Official J of the ACG 2021; 116: 1135.
60. Zheng EX, Rossi S, Fontana RJ, Vuppalanchi R, Hoofnagle JH and Khan I: Risk of Liver Injury Associated with Green Tea Extract in SLIMQUICK® Weight Loss Products: Results from the DILIN Prospective Study. Drug Safety 2016; 39(8): 749–54.
61. Gan LLY, Woon LSC, Zawawi MU and Midin M: Mania induced by steroid-adulterated herbal medicine: A case report. MANIA 2018; 11(5).
62. World Health Organization. Research guidelines for evaluating the safety and efficacy of herbal medicines. Manila: WHO Regional Office for the Western Pacific 1993.
63. Keshari P: Controversy, Adulteration and Substitution: Burning Problems in Ayurveda Practices. Pharmacognosy - Medicinal Plants [Working Title] 2021.
64. Xu M, Huang B, Gao F, Zhai C, Yang Y, Li L and Shi L: Assesment of adulterated traditional Chinese medicines in China: 2003-2017. Frontiers in Pharma 2019; 10: 1446.
65. Utami PI, Firman D and Djalil AD: Identification of glibenclamide in antidiabetic jamu by high performace liquid chromatography method: Study in Purwokerto, Indonesia. In Journal of Physics: Conference Series IOP Publishing 2019; 1402(5): 055065).
66. Moser D, Hussain S, Yaqoob M, Raine M, Jakschitz T, and Bonn GK: Fast and semiquantitative screening for sildenafil in herbal over-the-counter formulations with atmospheric pressure solid analysis probe (ASAP) to prevent medicinal adulteration. Journal of Pharmaceutical and Biomedical Analysis 2022; 214: 114720.
67. Negroni MS, Marengo A, Caruso D, Tayar A, Rubiolo P and Giavarini F: A Case Report of Accidental Intoxication following Ingestion of Foxglove Confused with Borage: High Digoxinemia without Major Complications. Case Reports in Cardiology 2019; 2019: 1–6.
68. S. Food and Drug Administration [homepage on the Internet]. FDA advises consumers not to use goldenseal root powder distributed by Maison Terre, [Updated 2020 August 19]. Available from:https://www.fda.gov/drugs/drug-safety-and-availability/fda-advises-consumers-not-use-goldenseal-root-powder-distributed-maison-terre.
69. Hassan KM, Njogu PM, Njuguna NM and Ndwigah SN: Microbiological contamination of herbal medicinal products marketed in Kenya for chronic diseases: A case study of Nairobi metropolis. Journal of Herbal Medicine 2021; 29: 100475.
70. World Health Organization. WHO guidelines on safety monitoring of herbal medicines in pharmacovigilance systems. World Health Organization 2004.
71. Atanasov AG, Zotchev SB, Dirsch VM and Supuran CT: Natural products in drug discovery: advances and opportunities. Nature Reviews Drug Discovery 2021; 20(3): 200–16.
    

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    Singh N, Garg M and Chopra R: An overview of herbal formulations: from processing to Pharmacovigilance. Int J Pharm Sci & Res 2023; 14(2): 562-78. doi: 10.13040/IJPSR.0975-8232.14(2).562-78.

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