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Lack of the cytochrome P450 3A interaction of methanolic extract of Withania somnifera, Withaferin A, Withanolide A and Withanoside IV
Abstract
Aims: Withania somnifera is widely employed as a rejuvenator and expected to promote physical health and increase longevity. The aim of the present research work was to evaluate Cytochrome P450 3A (CYP3A) interaction of Withania somnifera. Materials and Methods: In vitro CYP3A interaction of methanolic extract of Withania somnifera (WS) and its principal phytoconstituents: Withaferin-A (WA), Withanolide-A (WL-A) and Withanoside-IV (WS-IV) were investigated in rat and human liver microsomes. In vivo CYP3A interaction potential was investigated by administering methanolic extract of WS orally at a dose of 500 mg/kg in female Wistar rats. Sildenafil citrate was used to index the activity of CYP3A. Results: IC 50 values of methanolic extract of Withania somnifera, WA, WL-A, WS-IV were found to be 200 μg/ml, >20 μM, >64 μM and >64 μM for CYP3A both in rats and humans, respectively. When sildenafil citrate was orally co-administered with methanolic extract of WS and compared with orally administered sildenafil citrate alone, the area under plasma concentration time (AUC) curve and C max did not significantly differ as compared to the group which received rifampicin orally (positive control). Conclusions: Results suggested that methanolic extract of WS, WA, WL-A, WS-IV showed no in vitro CYP3A inhibition in rats and humans. Methanolic extract of WS did not significantly alter the pharmacokinetics of sildenafil citrate in rats; indicating its safety when co-administered with other drugs that are substrates of CYP3A. Thus the results indicate the lesser likelihood of drug herb interactions when concomitantly administered with CYP3A substrates.
... Previous studies have reported the lack of significant interactions of Withania root extracts with CYP1A, 3A4 and 2D6 in vitro in human and rat liver microsomes (Savai et al., 2014) and CYP1A2 and 2C9 in HLM alone (Savai et al., 2015). Other studies demonstrated the methanolic extract and the pure molecules isolated from Withania such as Withaferin A, Withanolide A, and Withanoside IV to have no significant effect on CYP3A activity in the same liver microsomes (Varghese et al., 2013). In a study done in Bangladesh, Withania ethanolic extracts were found to inhibit CYP3A4 activity in rat liver microsomes with an IC 50 of 18.01 ng/ml (Sultana et al., 2018). ...
... CYP2B6 being highly inducible and polymorphic plays a critical role in the drug metabolism pathways and is being assessed more for clinically significant induction studies and risk assessments involving DDIs and HDIs (Hedrich et al., 2016). In this study, Withania extracts exhibited moderate induction effect on CYP3A4 mRNA expression (in comparison to the CC) and had no significant effect on CYP2B6 in HepG2 cells, in contrast to previous studies reporting the lack of significant interactions with CYP1A2, 2C19, 2C9, 2D6, 2E1 and 3A4 (Savai et al., 2014(Savai et al., , 2015Dey et al., 2015;Varghese et al., 2013). This could be attributed to the effect of a potential unidentified inducing phytomolecule or the synergistic effects of several phytochemicals within the extracts on CYP3A4 (Picking et al., 2018;Wang et al., 2014), modulating mRNA expression for higher protein levels. ...
... In previous studies, compounds from herbal extracts such as isopelletierine have been reported to modulate CYP1A2 and CYP3A4 activity (Yu et al., 2014;Hidaka et al., 2005). Pure molecules isolated from Withania (Withaferin-A, Withanolide-A, and Withanoside-IV) and crude methanolic extracts were previously reported of lacking significant interactive effect on the activity of CYP3A4, CYP1A and CYP2D6 in rat and human liver microsomes (IC 50 > 10 μM & > 100 μg/ml); crude methanolic extract of Withania administered orally in female Wistar rats did not alter the pharmacokinetics of sildenafil citrate (Varghese et al., 2013). This could be attributed to the dosage of the crude extract (oral dose of 500 mg/kg) as well as the negated inhibitory effects of a single purified molecule compared to the synergistic effects of multiple molecules in the extract. ...
Ethnopharmacological relevance
Withania somnifera (L.) Dunal (Solanaceae) is a traditional herb, used in African indigenous systems of medicine for the treatment of various diseases (including HIV/AIDS and tuberculosis). The relevance of clinically significant interactions of Withania with ARVs and anti-TB drugs needs to be investigated.
Aim of the study
This study evaluated the effects of its roots on cytochromes P450 (CYPs) 2B6, 3A4, and rifampicin metabolism pathway, using methanol, ethanol, aqueous, and ethyl acetate solvent extractions.
Materials and methods
The extracts were tested on human liver microsomes (HLM) for CYP inhibition, mRNA expression in HepG2 cells for CYP induction. Biochemical qualitative tests and LC-MS/MS methodology were used to determine active phytoconstituents.
Results
The methanolic and ethyl acetate extracts inhibited CYP2B6 with IC50s 79.16 and 57.96 μg/ml respectively, while none of the extracts had any effect on rifampicin metabolism or showed time-dependant inhibition (TDI). All extracts were moderate inducers of CYP3A4; the aqueous extract exhibited 38%-fold shift induction of CYP3A4 compared to the control. The methanolic extract had the lowest CTC50 (50% of cytotoxicity inhibition) (67.13±0.83 μg/ml). LC-MS/MS-PDA full scans were consistent with the presence of flavone salvigenin (m/z 327), alkaloid isopelletierine (m/z 133), steroidal lactone 2,3-dihydrowithaferin-A (m/z 472), and other withanolides including withaperuvin I (m/z 533), withaferin derivative (m/z 567), some of these compounds likely being responsible for the observed CYP2B6 inhibition and CYP3A4 induction. The putative gastrointestinal tract (GIT) concentration for the active extracts was 1800 μg/ml and the hepatic circulation concentrations were estimated at about 220 μg/ml and 13.5 μg/ml for the methanolic and ethyl acetate extracts, respectively. The extrapolated in vivo percentage of inhibition was at 85% for the methanolic extract against CYP2B6.
Conclusions
The findings reported in this study suggest that W. somnifera extracts have the potential of causing clinically significant herb-drug interactions (HDI) as moderate inducer of CYP3A4 and inhibitor of CYP2B6 metabolism pathway (methanol and ethyl acetate extracts).
... However, there are conflicting results concerning the nature of those interactions. In vitro studies reported that Withania somnifera extracts may inhibit (Sultana and Sultan, 2018), induce (Kumar et al., 2021a), or reveal no significant impact on CYP3A4 (Savai et al., 2013, Savai et al., 2015. Further studies are required to understand the associations between CYP isoenzymes and Withania somnifera extracts, as well as the clinical relevance of these findings. ...
Aim: We aimed to systematically evaluate the prevalence and clinical characteristics of adverse events associated with the adaptogens and antidepressant drug interactions in a retrospective chart review.
Methodology: A total of 1,816 reports of adverse events were evaluated. Cases were included in the analysis if the pharmacoepidemiological analysis showed the presence of a high probability of a causal relationship between an adaptogen and antidepressant interaction and the occurrence of adverse events. The following data were extracted from the reports: age, sex, antidepressant, plant products containing adaptogens, other concomitant medications, and clinical consequences of the interactions and their possible mechanisms.
Results: Adaptogens were involved in 9% of adverse events associated with the concomitant use of antidepressants and other preparations. We identified 30 reports in which side effects presented a causal relationship with the use of antidepressants and adaptogens. Here, we present the list of adaptogens with the corresponding antidepressants and the side effects caused by their interactions: Withania somnifera : reboxetine (testicle pain and ejaculatory dysfunctions), sertraline (severe diarrhea), escitalopram (myalgia, epigastric pain, nausea, vomiting, restless legs syndrome, and severe cough), and paroxetine (generalized myalgia, ophthalmalgia, and ocular hypertension); Eleutherococcus senticosus : duloxetine (upper gastrointestinal bleeding), paroxetine (epistaxis), sertraline (vaginal hemorrhage), and agomelatine (irritability, agitation, headache, and dizziness); Schisandra chinensis : bupropion (arthralgia and thrombocytopenia), amitriptyline (delirium), and fluoxetine (dysuria); Tribulus terrestris : citalopram (generalized pruritus), escitalopram (galactorrhea), and trazodone (psoriasis relapse); Coptis chinensis : mianserin (arrhythmias), mirtazapine (edema of lower limbs and myalgia), and fluoxetine (gynecomastia); Cimicifuga racemosa : mianserin (restless legs syndrome), paroxetine (gynecomastia and mastalgia), and venlafaxine (hyponatremia); Bacopa monnieri : agomelatine (back pain and hyperhidrosis) and moclobemide (myocardial infarction); Gynostemma pentaphyllum : duloxetine (back pain); Cordyceps sinensis : sertraline (upper gastrointestinal bleeding); Lepidium meyenii : mianserin (restless legs syndrome); and Scutellaria baicalensis : bupropion (seizures).
Conclusion: Clinicians should monitor the adverse events associated with the concomitant use of adaptogens and antidepressant drugs in patients with mental disorders. Aggregation of side effects and pharmacokinetic interactions (inhibition of CYP and p-glycoprotein) between those medicines may result in clinically significant adverse events.
... Among the Ayurvedic Rasayana herbs, Ashwagandha has the highest rank (41)(42)(43)(44) and just as nourishing the roots helps the tree to rejuvenate, activating the reproductive organs helps to rejuvenate the body (45) . Withania somnifera is generally said to have powerful aphrodisiac, sedative, rejuvenating, and life-prolonging effects (46)(47) . It is also used as a common energy-enhancing tonic known as Medhya Rasayana (a nootropic herb) (48) . ...
Ashwagandha scientifically known as Withania somnifera described in Ayurveda as a powerful rejuvenating herbal medicine. Their roots are thick and whitish brown, the leaves are somewhat oval in shape, hairless, and small. Withania somnifera is pharmacology as an adaptogen, antibiotic, abortion, aphrodisiac, astringent, anti-inflammatory, obtrusive, diuretic, narcotic, sedative, tonic, etc. Ashwagandha has been found to provide strong antioxidant protection. It stimulates the activation of immune system cells such as lymphocytes and phagocytic cells. Withania somnifera (L.) Dunal has been used to treat all kinds of illnesses and human illnesses. Withania somnifera is an important medicinal plant that has been used in Ayurvedic and indigenous medicine for over 3000 years.
... However, several studies reported no significant inhibitory effects of W. somnifera extract on the CYP isoforms, which are associated with NAPQI generation from APAP (Savai et al., 2013;Varghese et al., 2014;Dey et al., 2015;Savai et al., 2015), indicating that it is less likely that WA exerts hepatoprotective effect towards APAP-induced liver injury by inhibiting CYP-mediated APAP metabolic activation. However, W. somnifera extract was found to exhibit inductive effects on CYP3A4 and CYP1A enzymes (Kumar et al., 2021). ...
Withaferin A (WA) is a natural steroidal compound used in Ayurvedic medicine in India and elsewhere. While WA was used as an anti-cancer reagent for decades, its role in the treatment of liver diseases has only recently been experimentally explored. Here, the effects of WA in the treatment of liver injury, systematic inflammation, and liver cancer are reviewed, and the toxicity and metabolism of WA as well as pharmacological potentials of other extracts from W. somnifera discussed. The pharmacokinetic behaviors of WA are summarized and pharmacokinetic insights into current progress and future opportunities are highlighted. Significance Statement This review outlines the current experimental progress of WA hepatoprotective activities and highlights gaps in the field. This work also discusses the pharmacokinetics of WA that can be used to guide future studies for the possible treatment of liver diseases with this compound.
... 凋亡 [16] 。 另外不同剂量的睡茄内酯 withaferin A 对人类黑色 素瘤细胞、人肾癌细胞( Caki) 和胰腺癌细胞 Pac-1、MiaPaCa 药物相互作用 睡茄根提取物( 甲醇、水醇和水) 以及 分离的 withaferin A、withanolide A、withanoside Ⅳ成分对大鼠 和人肝微粒体中 CYP3A4 和 CYP2D6 均无抑 制 作 用[45][46] 。 王悦等:睡茄---近年来国际上流行的一种药食两用植物 (120 mg·d -1 ) 和选择性 5-羟色胺再摄取抑制剂( SSRIs) 治疗 30 例强迫 症 患 者, 观 察 到 以 Y-BOCS ( 耶 鲁-布 朗 强 迫 症 量 ...
Withania somnifera, also known as Indian ginseng, is an important traditional medicine in the Ayurvedic medical system of India, which has a significant effect of adaptation. Modern studies have shown that the main chemical components of W. somnifera are withanolides, which have antioxidant, anti-tumor, enhancing immunity, cardiovascular protection, neuroprotection, anti-stress, anti-stress reaction and hypoglycemic activities. Studies on human, animal, mutagenesis, genotoxicity, reproductive toxicity and drug interaction showed that W. somnifera had good safety. Clinical trials have proved that W. somnifera is effective in treating a variety of human diseases. As a famous traditional medicine and modern dietary supplement, it has a high reputation and market in the international health product market, but in China, there is little scientific research, market development, product introduction and application. In this paper, the traditional application, chemical composition, pharmacological activity, safety evaluation and clinical study of the plant were introduced, so as to increase the understanding of the dual use of the plant, and to provide reference for the future introduction of the product, the service to the health of the Chinese people and the promotion of the "double cycle" of the trade of health products between China and the international community.
... It helps invigorate the body by rejuvenating the reproductive organs, just as a tree is invigorated by feeding the roots [16] . Withania somnifera is widely claimed to have potent aphrodisiac, sedative, rejuvenative, and life prolonging properties [17][18] . It is also used as a general energy-enhancing tonic known as Medhya Rasayana (nootropic herbs) [19] . ...
The use of ghee in suitable conditions with appropriate doses of desired preparations will render various benefits due to its potency to nullify toxins and toxic effects of drugs; and its capability to act as a media to dissolve and enhance the efficacy of the active principles in the drugs used. The Ayurvedic classics have mentioned Rasayana which is described as an herbal or metallic preparation that are health tonics to children, medicines to middle aged and rejuvenators to the elderly. Ashwagandha is used as Rasayana since the ancient time especially for children in the management of malnourishment. This paper details the practical approach in preparing Ashwagandha ghrita by incorporating the traditional knowledge along with the modern technology in drug manufacture. 1. Introduction Ghee, referred to as Ghrita in Ayurvedic science, is described as the best among lipids due to its quality of inheriting and enhancing potency of the drug it is enriched with. This property of ghee is deployed to use ghee as medicine where the lipids or fat property along with fat soluable chemical constituents of a particular drug are to be extracted for treatment [1-2]. It is used as media for the absorption of lipid soluble vitamins or other active principles in the food or medicine. Ghee stimulates biliary secretion and contraction of gall bladder, nourishes GI mucosa, lubricates it, enhances the absorption of fat-soluble vitamins and strengthens the colonic flora of useful microbes. Thus the usage of ghee in suitable conditions with appropriate doses of desired preparations will render various benefits due to its potency to nullify toxins and toxic effects of drugs; and its capability to act as a media to dissolve and enhance the efficacy of the active principles in the drugs used. The specific property of ghee to increase absorption, transportation and bio-availability of the drugs renders it suitable for use in treatment as medicine orally, by anorectal route and for external applications.
... It was found that two purified sesquiterpenes, zederone and germacrone, from Curcuma elata induced expression of CYP2B6 and CYP3A4 but not CYP1A2 mRNAs in human primary hepatocytes, thus providing some information on the safety of the Curcuma species [47]. Withania somnifera methanolic extract or pure molecules like Withaferin A, Withanolide A, or Withanoside IV did have some inhibitory activity of CYP3a only at very high dose (200 í µí¼g/mL) in human and rat liver microsome study and did not alter significantly the pharmacokinetics of sildenafil citrate in rats [48]. In an interesting observation, Rana et al. showed that Withania somnifera may have some CYP450 reductase, a paralog enzyme for withanolide biosyn- thesis [49]. ...
Ayurvedic plants are known for thousands of years to have anti-inflammatory and antiarthritic effect. We have recently shown that BV-9238, a proprietary formulation of Withania somnifera, Boswellia serrata, Zingiber officinale, and Curcuma longa, inhibits LPS-induced TNF-alpha and nitric oxide production from mouse macrophage and reduces inflammation in different animal models. To evaluate the safety parameters of BV-9238, we conducted a cytotoxicity study in RAW 264.7 cells (0.005-1 mg/mL) by MTT/formazan method, an acute single dose (2-10 g/kg bodyweight) toxicity study and a 180-day chronic study with 1 g and 2 g/kg bodyweight in Sprague Dawley rats. Some sedation, ptosis, and ataxia were observed for first 15-20 min in very high acute doses and hence not used for further chronic studies. At the end of 180 days, gross and histopathology, blood cell counts, liver and renal functions were all at normal levels. Further, a modest attempt was made to assess the effects of BV-9238 (0.5 µg/mL) on six major human cytochrome P450 enzymes and (3)H radioligand binding assay with human hERG receptors. BV-9238 did not show any significant inhibition of these enzymes at the tested dose. All these suggest that BV-9238 has potential as a safe and well tolerated anti-inflammatory formulation for future use.
... RLM were collected inhouse and protein concentration was determined [8] , while HLM was purchased from the authentic vendor. RLM and HLM were used for assessing the inhibition potential of aqueous, alcoholic and hydroalcoholic extract of T. arjuna (1-100 µg/ml) and AA and AG (1-50 µM) by estimating phenacetin-o-deethylation activity and the inhibition potential was compared with the positive control α-naphthoflavone (known CYP1A inhibitor in rats and humans). ...
Terminalia arjuna Wight and Arn. (Combretaceae) is a tree having an extensive medicinal potential in cardiovascular disorders. Triterpenoids are mainly responsible for cardiovascular properties. Aqueous, hydroalcoholic and alcoholic extract of T. arjuna, arjunic acid and arjungenin were examined for their potential to inhibit CYP1A enzyme in rat and human liver microsomes. IC50 values of aqueous, hydroalcoholic and alcoholic extract of T. arjuna was found to be 11.4, 28.9 and 44.6 μg/ml in rat liver microsomes while 30.0, 29.7 and 39.0 μg/ml in human liver microsomes, respectively for CYP1A. However IC50 values of arjunic acid and arjungenin for both rat liver microsomes and human liver microsomes were found to be >50 μM. Arjunic acid and arjungenin did not show inhibition of CYP1A enzyme up to concentrations of 50 μM. These in vitro data indicate that Terminalia arjuna extracts contain constituents that can potently inhibit the activity of CYP1A, which could in turn lead to undesirable pharmacokinetic drug-herb interactions in vivo. Based on the in vitro data, interaction potential of the aqueous extract of Terminalia arjuna orally in rats was investigated. A probe substrate, phenacetin, was used to index the activity of CYP1A. In vivo pharmacokinetic study of coadministration of aqueous extract of Terminalia arjuna and phenacetin, revealed that the aqueous extract did not lead to any significant change in the pharmacokinetic parameters of phenacetin as compared with control group. Though there was no in vivo-in vitro correlation, drug interactions could arise with drugs having a narrow therapeutic range and extensively cleared by CYP1A enzyme, which could lead to undesirable side effects.
Ethnopharmacological relevance
Withania somnifera popularly known as Aswagandha or Indian Ginseng/Poison Gooseberry have thousands years of history of use in Indian traditional medicine. Besides, finding place root of the plant as Indian Ginseng, Ayurveda also uses root of this plant as general health tonic, adaptogenic, nootropic, immunomodulatoryetc. With its widespread and growing use, it becomes prudent to scientifically evaluate and document both the efficacy and safety of this plant in humans.
Aim of the study
Aswagnadha root is rapidly gaining popularity abroad for use as medicine. Current article attempts to primarily review the human efficacy and safety of Aswagandha generated through clinical trials.
Methods
A systematic search both for indexed and non-indexed literature was made for W. somnifera using various search engines and databases and the details of research articles pertaining to all clinical trials/human studies, animal studies addressing safety issues of CNS, CVS, general toxicity, mutagenicity, genotoxicity, reproductive safety and herb-drug interactions were reviewed and compiled comprehensively from full texts.
Results
A total of 69 (39 pre-clinical and 30 clinical) studies documenting efficacy and safety aspects were identified and the desired information of these studies is comprehensively presented in this review. Retrieved thirty(30) human studies demonstrated reasonable efficacy of root preparations in subclinical hypothyroidism (1), schizophrenia (3), chronic stress (2), insomnia (2), anxiety (1), memory and cognitive improvement (2), obsessive-compulsive disorder (1), rheumatoid arthritis (2), type-2 diabetes (2), male infertility (6), fertility promotion activity in females (1), adaptogenic (3), growth promoter in children (3) and chemotherapy adjuvant (1).
Reasonable safety of root preparations of Aswagandha has been established by these retrieved 30 human trials. No serious adverse events or any changes in haematological, biochemical or vital parameters were reported in these human studies. Only mild and mainly transient type adverse events of somnolence, epigastric pain/discomfort and loose stools were reported as most common (>5%); and giddiness, drowsiness, hallucinogenic, vertigo, nasal congestion (rhinitis), cough, cold, decreased appetite, nausea, constipation, dry mouth, hyperactivity, nocturnal cramps, blurring of vision, hyperacidity, skin rash and weight gain were reported as less common adverse events.
Pre-clinical chronic toxicity studies conducted up to 8 months also found root extracts to be safe. No mutagenicity or genotoxicity was reported for the root; only mild CNS depression and increase in thyroxine (T4) levels were reported with rootby some studies. Further, there was no in vitro and in vivo inhibition seen for CYP3A4 and CYP2D6, the two major hepatic drug metabolizing enzymes.
Conclusion
Root of the Ayurvedic drug W. somnifera (Aswagandha) appears a promising safe and effective traditional medicine for management of schizophrenia, chronic stress, insomnia, anxiety, memory/cognitive enhancement, obsessive-compulsive disorder, rheumatoid arthritis, type-2 diabetes and male infertility, and bears fertility promotion activity in females adaptogenic, growth promoter activity in children and as adjuvant for reduction of fatigue and improvement in quality of life among cancer patients undergoing chemotherapy. Properly designed, randomized-controlled, large-size, prospective trials with standardized preparations are needed to ascertain efficacy of Aswagandha root in previously studied and other new indications.
Several herbal drugs and allopathic medicines when co-administered can lead to severe herb-drug interactions. Hence, this study was undertaken in order to assess the in vitro inhibition potential of Withania somnifera and Centella asiatica with cytochrome P450 (CYP) 1A2 and 2C9 enzyme using human liver microsomes.
Inhibitory potential of crude extracts of both the medicinal plants along with their principal phytoconstituents were investigated using selective probe substrate technique. IC50, Ki values and mode of inhibition were determined.
The results of the study revealed that W. somnifera showed no significant interaction with both the isoforms of CYP. However, ethanolic extract of C. asiatica significantly inhibited both CYP1A2 (IC50 value - 42.23±3.65 μg/mL/Ki value - 14.93±4.59 μg/mL) and 2C9 enzyme (IC50 value - 48.41±4.64 μg/mL/Ki value - 23.89±3.14 μg/mL) in a competitive manner. The flavonoids, quercetin and kaempferol showed potent (IC50 values less than 10 μM) inhibition of CYP1A2 activity with no significant inhibition of CYP2C9 enzyme.
Thus, these findings of the study might be helpful for safe and effective use of C. asiatica in clinical practice. However, its in vivo interaction study in humans is still warranted.
Withania somnifera is commonly used as a rejuvenator, whereas Centella asiatica is well known for its anxiolytic and nootropic effects. The present study aims at investigating the effect of crude extracts and principal phytoconstituents of both the medicinal plants with CYP3A4 and CYP2D6 enzyme activity in human liver microsomes (HLM). Phytoconstituents were quantified in the crude extracts of both the medicinal plants using reverse phase HPLC. Crude extracts and phytoconstituents of W. somnifera showed no significant interaction with both CYP3A4 and CYP2D6 enzymes in HLM. Of the crude extracts of C. asiatica screened in vitro, methanolic extract showed potent noncompetitive inhibition of only CYP3A4 enzyme (Ki-64.36 ± 1.82 µg/mL), whereas ethanol solution extract showed potent noncompetitive inhibition of only CYP2D6 enzyme (Ki-36.3 ± 0.44 µg/mL). The flavonoids, quercetin, and kaempferol showed potent (IC50 values less than 100 μM) inhibition of CYP3A4 activity, whereas quercetin alone showed potent inhibition of CYP2D6 activity in HLM. Because methanolic extract of C. asiatica showed a relatively high percentage content of quercetin and kaempferol than ethanol solution extract, the inhibitory effect of methanolic extract on CYP3A4 enzyme activity could be attributed to the flavonoids. Thus, co-administration of the alcoholic extracts of C. asiatica with drugs that are substrates of CYP3A4 and CYP2D6 enzymes may lead to undesirable herb-drug interactions in humans. Copyright © 2015 John Wiley & Sons, Ltd.
Copyright © 2015 John Wiley & Sons, Ltd.
Ayurveda is a Sanskrit word, which means "the scripture for longevity". It represents an ancient system of traditional medicine prevalent in India and in several other south Asian countries. It is based on a holistic view of treatment which is believed to cure human diseases through establishment of equilibrium in the different elements of human life, the body, the mind, the intellect and the soul [1].
Withania somnifera, commonly known as Ashwagandha, is an important medicinal plant that has been used in Ayurvedic and indigenous medicine for over 3,000 years. In view of its varied therapeutic potential, it has also been the subject of considerable modern scientific attention. The major chemical constituents of the Withania genus, the withanolides, are a group of naturally occurring C 28 -steroidal lactone triterpenoids built on an intact or rearranged ergostane framework, in which C-22 and C-26 are appropriately oxidized to form a six-membered lactone ring. In recent years, numerous pharmacological investigations have been carried out into the components of W. somnifera extracts. We present here an overview of the chemical structures of triterpenoid components and their biological activity, focusing on two novel activities, tumor inhibition and antiangiogenic properties of withaferin A and the effects of withanolide A on Alzheimer's disease. The most recent attempts in biotechnological production of withanolides are also discussed.
Despite the lack of sufficient information on the safety of herbal products, their use as alternative and/or complementary medicine is globally popular. There is also an increasing interest in medicinal herbs as precursor for pharmacological actives. Of serious concern is the concurrent consumption of herbal products and conventional drugs. Herb–drug interaction (HDI) is the single most important clinical consequence of this practice. Using a structured assessment procedure, the evidence of HDI presents with varying degree of clinical significance. While the potential for HDI for a number of herbal products is inferred from non-human studies, certain HDIs are well established through human studies and documented case reports. Various mechanisms of pharmacokinetic HDI have been identified and include the alteration in the gastrointestinal functions with consequent effects on drug absorption; induction and inhibition of metabolic enzymes and transport proteins; and alteration of renal excretion of drugs and their metabolites. Due to the intrinsic pharmacologic properties of phytochemicals, pharmacodynamic HDIs are also known to occur. The effects could be synergistic, additive, and/or antagonistic. Poor reporting on the part of patients and the inability to promptly identify HDI by health providers are identified as major factors limiting the extensive compilation of clinically relevant HDIs. A general overview and the significance of pharmacokinetic and pharmacodynamic HDI are provided, detailing basic mechanism, and nature of evidence available. An increased level of awareness of HDI is necessary among health professionals and drug discovery scientists. With the increasing number of plant-sourced pharmacological actives, the potential for HDI should always be assessed in the non-clinical safety assessment phase of drug development process. More clinically relevant research is also required in this area as current information on HDI is insufficient for clinical applications.
Background
Anxiety is a serious personal health condition and represents a substantial burden to overall quality of life. Additionally anxiety disorders represent a significant cost to the health care system as well as employers through benefits coverage and days missed due to incapacity. This study sought to explore the effectiveness of naturopathic care on anxiety symptoms using a randomized trial.Methods
Employees with moderate to severe anxiety of longer than 6 weeks duration were randomized based on age and gender to receive naturopathic care (NC) (n = 41) or standardized psychotherapy intervention (PT) (n = 40) over a period of 12 weeks. Blinding of investigators and participants during randomization and allocation was maintained. Participants in the NC group received dietary counseling, deep breathing relaxation techniques, a standard multi-vitamin, and the herbal medicine, ashwagandha (Withania somnifera) (300 mg b.i.d. standardized to 1.5% with anolides, prepared from root). The PT intervention received psychotherapy, and matched deep breathing relaxation techniques, and placebo. The primary outcome measure was the Beck Anxiety Inventory (BAI) and secondary outcome measures included the Short Form 36 (SF-36), Fatigue Symptom Inventory (FSI), and Measure Yourself Medical Outcomes Profile (MY-MOP) to measure anxiety, mental health, and quality of life respectively. Participants were blinded to the placebo-controlled intervention.ResultsSeventy-five participants (93%) were followed for 8 or more weeks on the trial. Final BAI scores decreased by 56.5% (p
Rat, mouse, rabbit, and guinea pig liver microsomes were prepared, using the calcium-aggregation method. The mean specific spectral cytochrome P450 content obtained for rat, mouse, rabbit, and guinea pig liver microsomes were 0.547, 0.394, 0.677, and 0.378 nmol cytochrome P450/mg protein, respectively. All the microsomal samples showed the ability to biotransform p-nitrophenol to p-nitrocatechol. The mean rate of formation of p-nitrocatechol by rat, mouse, rabbit, and guinea pig liver microsomes was 0.272, 0.247, 0.497 and 0.424 nmole/min/nmole cytochrome 450, respectively. This method circumvents the need of an ultracentrifuge for isolation of microsomes, by the conventional differential centrifugation method.
To investigate the impact of Withania somnifera roots on semen profile, oxidative biomarkers, and reproductive hormone levels of infertile men.
Prospective study.
Departments of Biochemistry and Urology, Chhatrapati Shahuji Maharaj Medical University, Lucknow, India.
Seventy-five normal healthy fertile men (control subjects) and 75 men undergoing infertility screening.
High-performance liquid chromatography assay procedure for quantization of vitamin A and E in seminal plasma. Biochemical parameters in seminal plasma were estimated by standard spectrophotometric procedures. Estimation of T, LH, FSH, and PRL in blood serum by RIA methods.
Before and after the treatment, seminal plasma biochemical parameters, antioxidant vitamins, and serum T, LH, FSH, and PRL levels were measured.
Withania somnifera inhibited lipid peroxidation and protein carbonyl content and improved sperm count and motility. Treatment of infertile men recovered the seminal plasma levels of antioxidant enzymes and vitamins A, C, and E and corrected fructose. Moreover, treatment also significantly increased serum T and LH and reduced the levels of FSH and PRL.
The treatment with W. somnifera effectively reduced oxidative stress, as assessed by decreased levels of various oxidants and improved level of diverse antioxidants. Moreover, the levels of T, LH, FSH and PRL, good indicators of semen quality, were also reversed in infertile subjects after treatment with the herbal preparation.
A lot of medicinal plants, traditionally used for thousands of years, are present in a group of herbal preparations of the Indian traditional health care system (Ayurveda) named Rasayana proposed for their interesting antioxidant activities. Among the medicinal plants used in ayurvedic Rasayana for their therapeutic action, some of these have been throughly investigated. In the present paper seven plants (Emblica officinalis L., Curcuma longa L., Mangifera indica L., Momordica charantia L., Santalum album L., Swertia chirata Buch-Ham, Withania somnifera (L.) Dunal) are viewed for their historical, etymological, morphological, phytochemical and pharmacological aspects. The plants described contain antioxidant principles, that can explain and justify their use in traditional medicine in the past as well as the present. In order to identify the plants with antioxidant activity in Ayurveda, a formulation of some rasayanas with well defined antioxidant properties has been examinated. For this purpose, we have considered Sharma's work on the preparation MAK4, MAK5, MA631, MA 471, MA Raja's Cup, MA Student Rasayana, MA Ladies Rasayana.
The objective of this paper is to review the literature regarding Withania somnifera (ashwagandha, WS) a commonly used herb in Ayurvedic medicine. Specifically, the literature was reviewed for articles pertaining to chemical properties, therapeutic benefits, and toxicity.
This review is in a narrative format and consists of all publications relevant to ashwagandha that were identified by the authors through a systematic search of major computerized medical databases; no statistical pooling of results or evaluation of the quality of the studies was performed due to the widely different methods employed by each study.
Studies indicate ashwagandha possesses anti-inflammatory, antitumor, antistress, antioxidant, immunomodulatory, hemopoietic, and rejuvenating properties. It also appears to exert a positive influence on the endocrine, cardiopulmonary, and central nervous systems. The mechanisms of action for these properties are not fully understood. Toxicity studies reveal that ashwagandha appears to be a safe compound.
Preliminary studies have found various constituents of ashwagandha exhibit a variety of therapeutic effects with little or no associated toxicity. These results are very encouraging and indicate this herb should be studied more extensively to confirm these results and reveal other potential therapeutic effects. Clinical trials using ashwagandha for a variety of conditions should also be conducted.
Although recent research has shown that many people in the United States use complementary and alternative medical (CAM) therapies, little is known about time trends in use.
To present data on time trends in CAM therapy use in the United States over the past half-century.
Nationally representative telephone survey of 2055 respondents that obtained information on current use, lifetime use, and age at first use for 20 CAM therapies.
The 48 contiguous U.S. states.
Household residents 18 years of age and older.
Retrospective self-reports of age at first use for each of 20 CAM therapies.
Previously reported analyses of these data showed that more than one third of the U.S. population was currently using CAM therapy in the year of the interview (1997). Subsequent analyses of lifetime use and age at onset showed that 67.6% of respondents had used at least one CAM therapy in their lifetime. Lifetime use steadily increased with age across three age cohorts: Approximately 3 of every 10 respondents in the pre-baby boom cohort, 5 of 10 in the baby boom cohort, and 7 of 10 in the post-baby boom cohort reported using some type of CAM therapy by age 33 years. Of respondents who ever used a CAM therapy, nearly half continued to use many years later. A wide range of individual CAM therapies increased in use over time, and the growth was similar across all major sociodemographic sectors of the study sample.
Use of CAM therapies by a large proportion of the study sample is the result of a secular trend that began at least a half century ago. This trend suggests a continuing demand for CAM therapies that will affect health care delivery for the foreseeable future.
To evaluate the inhibition of CYP3A4 activity in human liver microsomes by flavonoids, furanocoumarins and related compounds and investigate possibly more important and potential inhibitors of CYP3A4 in grapefruit juice.
The effects of various flavonoids and furanocoumarin derivatives on CYP3A4 activity in two human liver microsomal samples was determined using quinine as a substrate. All flavonoids and furanocoumarin derivatives were dissolved in DMSO. In all cases, inhibition activities were compared with activities in control incubations containing 0.2% (v/v) DMSO.
The results showed that the inhibition of quinine 3-hydroxylation (CYP3A4 activity) by bergapten (67%), and quercetin (55%) was greater than naringenin (39%) and naringin (6%), at the same inhibitor concentration of 100 M. The results also demonstrated that the furan ring in the furanocoumarins enhanced the inhibitory effect on CYP3A4 activity. Flavonoids with more phenolic hydroxyl (-OH) groups produced stronger inhibition than those with less hydroxyl groups. Of all the chemicals studied, bergapten (5-methoxypsoralen) with the lowest IC50 value (19-36 microM) was the most potent CYP3A4 inhibitor.
These results suggest that more than one component present in grapefruit juice may contribute to the inhibitory effect on CYP3A4. Bergapten appears to be a potent inhibitor of CYP3A4, and may therefore be primarily responsible for the effect of grapefruit juice on CYP3A4 activity.
Sildenafil citrate, marketed as Viagra, for the treatment of erectile dysfunction, has a proven record of safety in humans as predicted by the results of extensive pharmacological and toxicological testing in animals and in vitro, and confirmed by pharmacokinetic exposure data. The aim of this paper is to review succinctly the main findings resulting from these experiments. Daily doses of sildenafil, within and far beyond the human therapeutic range, were given to dogs and rodents for up to 1 and 2 y, respectively. Plasma analyses were conducted to determine the exposure to sildenafil. We found species-specific effects in dogs (Beagle pain syndrome), mice (marked intestinal dilatation) and rats (adaptive reversible hepatocellular hypertrophy associated with secondary thyroid hypertrophy). All these effects in rodents and dogs have no relevance to humans. Morphometric thickness measurements of the retinal layers carried out in response to clinical observations of visual disturbances in humans indicated no difference between treated and control rats and dogs after up to 24 months of treatment. There was no evidence of histopathologic damage to any structures of the visual pathway. Sildenafil had no effects on fertility, no teratogenic potential, was not genotoxic and has no carcinogenic potential. In rats and dogs, safety ratios were 40:1 and 28:1, respectively, in terms of exposure over 24 h (AUC24 h) and 19:1 and 8:1, respectively, in terms of peak plasma concentration (Cmax). These safety ratios illustrate the separation between exposure to sildenafil of animals at large nontoxic doses and the much smaller human therapeutic exposure. This profile highlights the very low risk of human toxicity for sildenafil. The favourable results of the nonclinical safety evaluation of sildenafil in established animal models have been confirmed by many years of clinical experience during the development and marketing of sildenafil.
This study investigated the effect of Withania somnifera Dunal (WS) root extract and diazepam in social isolation induced behavior such as anxiety and depression in rats. Rats were isolated for 6 weeks and the assessment of changed behavior were done on elevated plus maze (EPM) and forced swim test (FST). Isolation reared rats spent less time into the open arms on EPM and significantly increased immobility time in FST compared to group housed rats. WS (100, 200 or 500 mg/kg, oral) and diazepam (1 or 2 mg/kg, ip) dose dependently increased the time spent and entries into the open arms on EPM test and showed the anxiolytic activity. Subeffective dose of WS (50 mg/kg, oral) potentiated the anxiolytic action of diazepam (0.5, 1 or 2 mg/kg, ip). WS (100, 200 or 500 mg/kg, oral) also reduced the immobility time in FST, thus showed antidepressant effect in both group housed and social isolates. The investigations support the use of WS as a mood stabilizer in socially isolation behavior in Ayurveda.
The expression of cytochrome P450 is regulated by both endogenous factors and xenobiotics including chemical drugs and natural medicines. Induction on cytochrome P450 can reduce the therapeutic efficacy from drugs inactivated by this enzyme system, but may increase the efficacy or lead to intoxication for prodrugs. Shexiang Baoxin Pill (SBP) is a traditional Chinese medicine widely used for the treatment of angina pectoris and myocardial infarction in China and other oriental countries. To assess the potential of SBP to alter the activity and expression of cytochrome P450 3A (CYP3A) extensively involved in drug metabolism, we investigated the enzyme-inducing effects of SBP in HepG2 cells and in rats. The results showed that treatment with SBP increased the enzyme activity, mRNA levels and protein expression of CYP3A4 in a concentration-dependent manner in HepG2 cells. Moreover, treatment with SBP enhanced the activities and mRNA expressions of CYP3A1 and CYP3A2 ex vivo in rats. Furthermore, we utilized HepG2 cell line to identify individual components in SBP as potential inducers of CYP3A4. It was found that bufalin, cinobufagin, and resibufogenin were novel CYP3A4 inducers. Among them, bufalin and cinobufagin significantly promoted the CYP3A4 enzyme activity, mRNA and protein levels, with the maximal induction challenging or exceeding that of the induction by rifampicin, indicating that they might play a critical role in CYP3A4 enzyme-inducing effects of SBP. In addition, the metabolic studies with specific inhibitors of CYP isoforms suggested that the three CYP3A4 inducers in SBP are also the substrates for the enzyme. Overall, our results show that SBP contains constituents that can potently induce CYP3A and suggest that this traditional Chinese medicine should be examined clinically for potential drug metabolic interactions.
'Triphala' is one of the age-old, most commonly used polyherbal preparation from Ayurveda as Rasayana drug.
This study was aimed at evaluating the effect of 'Triphala' on drug modulating enzymes to assess its safety through its potential to interact with co-administered drugs.
The cytochrome P450 inhibitory effect of 'triphala' formulation was investigated on rat liver microsomes using CYP450-CO complex assay and on individual isoform such as CYP3A4 and 2D6 using fluorescence screening. RP-HPLC method was developed to standardize 'triphala' and its individual components using gallic acid as analytical marker compound.
RP-HPLC analysis demonstrated the presence of gallic acid (4.30±2.09 mg/g) in the formulation. The formulation showed 23% inhibition of the rat liver microsomes through CYP450-CO complex assay which is comparatively less when compared with the individual components. Further, the effect of standardized formulation dissolved in ethanol showed CYP3A4 and CYP2D6 inhibitory activity at the IC(50) values of 119.65±1.91 μg/ml and 105.03±0.98 μg/ml respectively. Gallic acid was also found to inhibit both the isoforms at the IC(50) values of 87.24±1.11 μg/ml and 92.03±0.38 μg/ml respectively.
Various concentrations of the formulation and its individual components showed significantly less inhibitory activity (p<0.001) on individual isoforms when compared with the positive control. Assessment on the in vitro effect of 'triphala' on drug modulating enzymes has important implications for predicting the likelihood of herb-drug interactions if these are administered concomitantly.
Antioxidant activity of active principles of Withania somnifera, consisting of equimolar concentrations of sitoindosides VII-X and withaferin A, was investigated for their effects on rat brain frontal cortical and striatal concentrations of superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPX). Results were compared with effects induced by deprenyl, an agent with well documented antioxidant activity. Active glycowithanolides of W. somnifera (WSG) (10 and 20 mg/kg, i.p.), administered once daily for 21 days, induced a dose-related increase in SOD, CAT and GPX activity in frontal cortex and striatum, which was statistically significant on days 14 and 21, except with the lower dose of WSG on GPX activity, where the effect was evident only on day 21. The data were comparable to those induced by deprenyl (2 mg/kg/day, i.p.) with respect to SOD, CAT and GPX activities, which were evident by day 14. These findings are consistent with the therapeutic use of W. somnifera as an Ayurvedic rasayana and medhyarasayana. Antioxidant effect of active principles of W. somnifera may explain, at least in part, the reported antistress, immunomodulatory, cognition-facilitating, anti-inflammatory and anti-aging effects produced by them in experimental animals, and in clinical situations.
Commercially available St. John's wort (Hypericum perforatum) extracts, preparations that are used in the treatment of depression, were examined for the potential to inhibit human cytochrome P450 (CYP) enzyme activities, specifically CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. Crude extracts demonstrated inhibition of each of these five enzymes, with CYP2D6, CYP2C9, and CYP3A4 being more sensitive than CYP1A2 and CYP2C19. Extracts were fractionated by HPLC, and each of the fractions was tested for inhibition of these five CYPs to identify individual constituents with inhibitory activity. Several fractions were shown to possess inhibitory activity, including the fractions containing hyperforin (the putative active antidepressant constituent), I3,II8-biapigenin, and hypericin. Hyperforin and I3,II8-biapigenin were isolated from the extract, and inhibition constants for the five CYP activities were measured. In addition, three other constituents, hypericin, quercetin, and chlorogenic acid, were tested for inhibitory activity toward the CYP enzymes. The flavonoid compound I3,II8-biapigenin was shown to be a potent, competitive inhibitor of CYP3A4, CYP2C9, and CYP1A2 activities with K(i) values of 0.038, 0.32, and 0.95 microM, respectively. Hyperforin was a potent noncompetitive inhibitor of CYP2D6 activity (K(i) = 1.5 microM) and competitive inhibitor of CYP2C9 and CYP3A4 activities (K(i) = 1.8 and 0.48 microM, respectively). Hypericin also demonstrated potent inhibition of several CYP activities. These in vitro data indicate that St. John's wort preparations contain constituents that can potently inhibit the activities of major human drug-metabolizing enzymes and suggest that these preparations should be examined for potential pharmacokinetic drug interactions in vivo.
The antioxidant activity of Withania somnifera (WS) glycowithanolides was assessed in chronic footshock stress induced changes in rat brain frontal cortex and striatum. The stress procedure, given once daily for 21 days, induced an increase in superoxide dismutase (SOD) and lipid peroxidation (LPO) activity, with concomitant decrease in catalase (CAT) and glutathione peroxidase (GPX) activities in both the brain regions. WS glycowithanolides (WSG), administered orally 1 h prior to the stress procedure for 21 days, in the doses of 10, 20 and 50 mg/kg, induced a dose-related reversal of the stress effects. Thus, WSG tended to normalise the augmented SOD and LPO activities and enhanced the activities of CAT and GPX. The results indicate that, at least part of chronic stress-induced pathology may be due to oxidative stress, which is mitigated by WSG, lending support to the clinical use of the plant as an antistress adaptogen.
Comparative study of the antiulcer and antisecretory activity of Asparagus racemosus Willd (Shatawari) and Withania somnifera Dunal (Ashwagandha) root extract with a standard drug, ranitidine, in various models of gastric ulcer in rats is presented. Ulcer was induced by the indomethacin (NSAID) and swim (restraint) stress treatment. Results demonstrated that A. racemosus as well as W. somnifera methanolic extract (100 mg/kg BW/day p.o.) given orally for 15 days significantly reduced the ulcer index, volume of gastric secretion, free acidity, and total acidity. A significant increase in the total carbohydrate and total carbohydrate/protein ratio was also observed. Study also indicated an increase in antioxidant defense, that is, enzymes superoxide dismutase, catalase, and ascorbic acid, increased significantly, whereas a significant decrease in lipid peroxidation was observed. A. racemosus was more effective in reducing gastric ulcer in indomethacin-treated gastric ulcerative rats, whereas W. somnifera was effective in stress-induced gastric ulcer. Results obtained for both herbal drugs were comparable to those of the standard drug ranitidine.
Withania somnifera is classified in Ayurveda, the ancient Indian system of medicine, as a rasayana, a group of plant-derived drugs which promote physical and mental health, augment resistance of the body against disease and diverse adverse environmental factors, revitalize the body in debilitated conditions and increase longevity. We investigated the effects of Withania somnifera on copper-induced lipid peroxidation and antioxidant enzymes in aging spinal cord of Wistar rats. The activity of glutathione peroxidase (GPx) decreased significantly in the spinal cord from adult to aged mice. Treatment with Withania somnifera successfully attenuated GPx activity and inhibited lipid peroxidation in a dose dependent manner. Withania somnifera inhibited both the lipid peroxidation and protein oxidative modification induced by copper. These effects were similar to those of superoxide dismutase and mannitol. The results indicate the therapeutic potential of Withania somnifera in aging and copper-induced pathophysiological conditions.
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Conflict of Interest: None declared
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Source of Support: Department of Biotechnology, New Delhi, India.
Conflict of Interest: None declared.
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