EXPLOSIVE GROWTH OF HERBAL MEDICINES

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Viewed as a balanced and moderate approach to healing, herbal medicines have grown exponentially. This popularity is attributed to a preference for natural therapies and a greater interest in alternative medicines. Traditional medicinal practice involving herbs is an integral part of many communities, and the World Health Organization (WHO) estimates that 80% of the world’s population relies on herbal medicine as a primary source of healthcare. Strategic marketing by manufacturers of herbal medicines has expanded product visibility, and the continuous introduction of new herbal products into the market has led to public health issues and safety concerns.

CHALLENGES
All medicines must be safe and of suitable quality, yet a single herb plant may contain hundreds of natural constituents. Such complexity means that the control of raw herbal materials and finished herbal products is more involved than for conventional pharmaceuticals. A substantial proportion of the global drug market, herbal medicines require pharmacovigilance and safety monitoring. The WHO recommends national quality specifications and standards related to the manufacturing, import, and marketing of herbal materials; however, in most countries, herbal medicines arrive on the market without mandatory safety or toxicological evaluations and without evidence of quality and efficacy. The common misconception that natural products are nontoxic and devoid of adverse effects leads to improper use and unrestrained intake, along with the risk of severe poisoning and acute health problems. Herbal medicinal products have been implicated in cases of poisoning, with certain compounds capable of reacting with cellular macromolecules including DNA and inducing cellular toxicity and/or genotoxicity. 

SAFETY AND TOXICITY
The safety of traditional and herbal medicines is paramount to national health authorities and the general public, yet:

• There is limited knowledge of potential adverse reactions.
• Many herbal preparations remain untested and their use unmonitored.
• The safest and most effective therapies have not been identified, and rational use has not been promoted.
• Traditional health practitioners may not be certified or licensed.

Possible causes of adverse events resulting from the consumption of herbal medicines include
mistaken use of the wrong plant species, misidentification of medicinal plants, adulteration of herbal products with undeclared medicines, mislabeling of herbal medicinal products, contamination with toxic or hazardous substances, overdose, and misuse of herbal medicines by healthcare providers or consumers – including concomitant administration with other medicines. Predictably, adverse event analysis with herbal medicines is more complex than with conventional pharmaceuticals.

Evaluation of product safety is further complicated by geographical origin of the plant material, processing technique, route of administration, and compatibility with other medicines.

PROPERTIES OF SPECIFIC HERBS    

Aristolochic acids and Aristolochia species. After findings of potential nephrotoxicity and carcinogenicity of aristolochic acids, studies confirmed their genotoxic activity. Aristolochic acid-related DNA adducts have been found in the renal tissues of patients; these mutagenic adducts are usually poorly repaired and capable of persisting for years in DNA. All plants in the genus Aristolochia contain aristolochic acids and are banned in Europe and the United States. Intake of slimming pills containing the Chinese herb Aristolochia fangchi has been linked to Aristolochic acid nephropathy and the development of subacute interstitial fibrosis of the kidneys and urothelial malignancies.
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The tubers and roots of the Aconitum species have been used medicinally for centuries in herbal preparations for stroke, heart failure, diabetes, rheumatic fever, painful joints, gastroenteritis, edema, bronchial asthma, and other disorders. Aconitum carmichaeli and Aconitum kusnezoffii are used traditionally for pain relief.  The toxicity of these plants derives primarily from the presence of diester diterpene alkaloids. Severe cases of cardiotoxicity from consumption of aconitine-containing herbal preparations manifest as ventricular tachycardia and fibrillation and eventually death. Bradycardia and hypotension have also been observed. The toxicity of aconitine and related diterpene alkaloids can be denatured by special processing and in China only the processed (i.e., detoxified) tubers and roots of Aconitum can be administered orally. More than 70 techniques are applied to the processing of Aconitum roots in order to reduce levels of toxic alkaloids below a certain threshold; note that this principle is not accepted in Europe. 

​Traditionally, Tussilago farfara or coltsfoot has been used for thousands of years to treat pulmonary complaints, acute and chronic coughs, bronchitis, laryngitis, and asthma. The polysaccharides are anti-inflammatory and immuno-stimulating, as well as demulcent, and the flavonoids have anti-inflammatory and antispasmodic actions. Tussilago farfara is generally regarded as nontoxic, although total alkaloids isolated from this plant have demonstrated hepatotoxicity. Recently, the effects of the pyrrolizidine alkaloids found in Tussilago farfara were reviewed and hepatic veno-occlusive disease and cirrhosis suggested as potential disease outcomes in humans. Restricted intake of pyrrolizidine-containing herbs is recommended.

There are reports on the efficacy of Garlic (Allium sativum) for management of hypertension and hypercholesterolemia. The main compound in the fresh plant is alliin, which on crushing undergoes enzymatic hydrolysis by alliinase to produce allicin. Due to the antiplatelet effects of garlic, care should be taken if given in combination with antiplatelet drugs and warfarin. Adverse effects associated with garlic extract include burning sensation in the gastrointestinal tract, nausea, diaphoresis, and lightheadedness. 

The active compounds of St. John’s wort (Hypericum perforatum) include hypericin, hyperforin, and melatonin. The plant has clinically well-established effects for mild depressive symptoms, although allergic reactions, headache, dizziness, restlessness, fatigue, gastrointestinal symptoms, and photosensitivity have been reported, as well as hyperesthesia and a syndrome of dyspnea and hyperventilation with mydriasis, nausea, palpitations, and tremors. Interaction of St. John’s wort with antidepressants and anticoagulants has been demonstrated and use is not recommended in pregnancy because of the herb’s uterotonic activity.

RECOMMENDATIONS
It is vital to inform and protect the public by identifying risks associated with herbal medicines, incorporating herbal products into pharmacovigilance systems, linking safety monitoring to the regulatory status of herbal medicines, promoting safe use through adequate labeling and appropriate patient information, advancing knowledge of traditional, complementary, alternative, and herbal medicines within national drug regulatory authorities, and standardizing definitions and categorizations of herbal medicinal plants on an international level. Herbal medicines must be assessed for safety, toxicity, efficacy, and quality.

Providers of medicines – physicians, nurses, and pharmacists – need training to understand how herbal medicines affect the health of their patients. Healthcare professionals and medical communicators (translators and writers) must inform the public. The right knowledge base is crucial. 

Citation: Ekor M (2014) The growing use of herbal medicines: issues relating to
adverse reactions and challenges in monitoring safety. Front. Pharmacol. 4:177. doi:
10.3389/fphar.2013.00177

​Conclusions
In the Annals of Internal Medicine study, Cucurma longa (turmeric) extract was more effective than placebo for knee pain but did not affect knee effusion–synovitis or cartilage composition. In the Chinese Journal of Tissue Engineering Research article, common femoral vein index (the primary observation indicator) in the tuina group was lower than in the control group, demonstrating that lower limb point pressure therapy at the Shu transporting points was able to reduce common femoral vein stasis after total knee arthroplasty, improving blood flow in the lower limbs after knee replacement and reducing the risk of thrombus formation. Other indicators, such as D-dimer value and pressure pain threshold, were also improved in the tuina group relative to the control group.

Active ingredients in herbs from traditional Chinese medicine have shown promising efficacy in rehabilitating and protecting the liver after injury from excess acetaminophen. 

Drug-induced liver injury
A significant number of cases of acute liver failure are caused by acetaminophen, also known as paracetamol. Acetaminophen is not toxic to the liver, but its reactive metabolite may cause liver injury. Excess quantities of acetaminophen can deplete the glutathione needed to convert the toxic metabolite NAPQI into a nontoxic metabolic product. Toxins generated during metabolization, mitochondrial dysfunction, inflammatory response, oxidative stress, the release of damage-associated molecular patterns (DAMPs), autophagy, endoplasmic reticulum stress, and microcirculatory dysfunction are among the mechanisms of injury.
 
Limits of pharmacologic drugs 
The chief pharmacologic agent used for the clinical treatment of acetaminophen-induced liver injury is N-acetylcysteine (NAC), but NAC has limited treatment results and its administration is time-sensitive. For optimal results, NAC is administered approximately one hour after oral acetaminophen.
 
Protective effects of traditional Chinese medicine
A number of active ingredients discovered in Chinese herbs suppress liver toxicity. These compounds vary in how they benefit liver injury: they may alleviate liver disease, mitigate damage to liver tissue, reduce the degree of liver injury, and prevent or ameliorate side effects by suppressing the pathways and mechanisms of liver injury. These active ingredients are fast acting, with notable efficacy and few toxic side effects, and include polyphenol compounds, flavonoid compounds, saponins, organic acids, terpenoid compounds, phenylpropanoids, polysaccharides, and alkaloids. 

Polyphenol compounds
Polyphenol compounds are widely present in traditional Chinese herbal remedies. Polyphenols  can affect the production of biomarkers associated with oxidative stress, a major cause of hepatotoxicity induced by acetaminophen overdose. In the research of Hasanein (2017), rosmarinic acid (found in basil, rosemary, and lemon balm) produced remarkable hepatoprotective effects by inhibiting CYP2E1 activity in the liver and lipid peroxidation.
 
Flavonoid compounds 
The protective effects of flavonoid compounds include the effects of ginseng anthocyanins on acetaminophen-induced hepatotoxicity (Qi 2017) and hyperoside which can hinder the formation of toxic intermediates and boost acetaminophen detoxification in the liver (Xie 2016). Fu (2018)  discovered that α-mangostin notably suppressed acetaminophen-induced oxidative stress; α-mangostin, a xanthone derivative found in the pericarp of mangosteen fruit, also reduced  inflammatory response through the anti-inflammatory mechanism mediated by the NF-κB and mitogen-activated protein kinase (MAPK) signaling pathways. Lu (2018) demonstrated that licochalcone A isolated from the root of Glycyrrhiza glabra had a protective effect on acetaminophen-induced liver injury through the Nrf2-mediated oxidative stress defense mechanism.
 
Saponins
Xu (2017) discovered that the antioxidant, anti-apoptotic, and anti-inflammatory actions of saponins (ginsenosides) had a protective effect on acetaminophen-induced liver injury in mice. Hu (2017) found that ginsenoside Rk1 pretreatment of acetaminophen-induced liver injury in mice significantly lowered levels of the lipid peroxidation product MDA. By increasing Bcl-2 and reducing Bax protein expression, ginsenoside Rk1 impeded activation of the apoptosis pathway. In Ning (2018), ginsenoside Rg1 prevented acetaminophen-induced liver injury through in vivo and in vitro activation of the Nrf2 signaling pathway. Leng (2018) proved that Platycodon grandiflorum saponins had pronounced protective effects on acetaminophen-induced liver injury through the NF-κB and AMPK/PI3K/Akt signaling pathways.

Organic acids 
In Heidari (2016), taurine effectively relieved acetaminophen-induced liver injury and its complications in mice. Jiang (2017) established that, by reducing thiobarbituric acid reactive substances (TBARS) which form as a byproduct of lipid peroxidation and reducing iNOS, COX-2, TNF-2, IL-12, and IL-6, the acids from Potentilla chinensis inhibited inflammation and oxidative stress to alleviate acetaminophen-induced liver injury. Cha (2018) discovered that p-coumaric acid (an abundant isomer of hydroxycinnamic acid widely found in fruits and vegetables) suppressed acetaminophen-induced hepatocyte apoptosis by modulating the MAPK signaling axis in a reactive oxygen species (ROS)-dependent manner and by alleviating response and inflammation from ROS-mediated DNA damage . 

Terpenoid compounds  
In Uchida (2017), compounds in the essential oil of Cymbopogon citratus (lemongrass) hindered neutrophil migration and antioxidant activity in mice with acetaminophen-induced liver injury, thus relieving hepatotoxicity. The research of Zhang (2017) proved that by inhibiting the TNF-α-mediated JNK signaling pathway and the phosphorylation ERK and P38 pathways, pretreatment with astaxanthin (natural sources include shrimp, algae, yeast, and salmon) reduced hepatocellular necrosis, blocked the formation of ROS, prevented oxidative stress, and diminished cellular apoptosis, protecting the liver and alleviating drug-induced liver injury. In Yoshioka  (2017), kamebakaurin (isolated from Rabdosia excisa) improved hepatotoxicity from acetaminophen overdose by inhibiting lipid peroxidation and inflammatory response in mice. 

Phenylpropanoids 
Fructus schisandrae (schisandra fruit) is widely used for liver protection in traditional Chinese medicine and the research of Jiang (2015) proved that lignan components in Fructus schisandrae ameliorated acetaminophen-induced liver injury by inhibiting acetaminophen's CYP-mediated biologic and metabolic pathways. Furthermore, in Jiang (2016) schisandrin B increased liver detoxification and antioxidation by activating the Nrf2/ARE pathway and regulating the Nrf2 target gene, reflecting its hepatoprotective effects. Yan (2018) demonstrated that, by activating sustained autophagy, glycycoumarin relieved acetaminophen-induced oxidative stress and thus prevented liver injury. 

Polysaccharides 
Lin (2018) found that polysaccharides of Dendrobium officinale played a hepatoprotective role by lowering oxidative stress and activating the Nrf2-Keap1 signaling pathway. And in Zhao (2018) the anti-inflammatory effects of polysaccharides of Coreopsis tinctoria regulated the expression of apoptosis-related proteins such as Bax and Bcl-2 to prevent acetaminophen-induced hepatotoxicity. Wu (2018) proved that polysaccharides of Poria cocos played a protective role against acetaminophen-induced liver injury in mice and their molecular mechanism was associated with suppression of the hepatocellular inflammatory response and apoptosis. 

Alkaloids
Li (2014) discovered hepatoprotective effects of berberine on liver fibrosis via activation of AMP-activated protein kinase; and Zhao (2018) found that berberine had pronounced prophylactic effects on acetaminophen-induced hepatotoxicity by inhibiting oxidative stress, hepatocellular necrosis, and inflammatory response. In Park (2016), the alkaloids of Aconitum carmichaelii  protected the organism against acetaminophen-induced injury by suppressing mitochondrial dysfunction and defending liver cells, although the herb is toxic when taken in excess. In 2018, a trial by Bian confirmed that ligustrazine (an alkaloid isolated from Ligusticum wallichii) improved acetaminophen-induced liver injury in mice by regulating the NF-κF and MAPK signal transduction pathways. 

Other compounds  
In Wangkheirakpam (2018), Auricularia delicata demonstrated antimicrobial, antioxidant, and protective effects on acetaminophen-induced liver injury in rats. In Guo (2018), Rhizoma pinelliae  extract regulated bile acid transporter protein in mice with acetaminophen-induced liver injury. By activating Nrf2 and inhibiting NF-κB signal transduction, Garcinia cambogia extract played a protective role in acetaminophen-induced liver injury in mice (Ibrahim 2018). The antioxidant, anti-inflammatory, and anti-apoptotic actions of tannic acid demonstrated significant hepatoprotective effects on acetaminophen-induced hepatotoxicity in the work of Zhang (2017).  

Acetaminophen is a leading cause of drug-induced liver injury and recent research findings indicate that the use of active ingredients from traditional Chinese medicinal herbs might ameliorate such injury. Research on mechanisms of liver injury and the means by which such compounds protect against and alleviate injury holds promise for future antidotes to drug-induced liver injury.