Determination of withaferin A and withanolide A in mice plasma using high-performance liquid chromatography-tandem mass spectrometry: Application to pharmacokinetics after oral administration of Withania somnifera aqueous extract

Patil, Dada; Gautam, Manish; Mishra, Sanjay; Karupothula, Suresh; Gairola, Sunil; Jadhav, Suresh; Pawar, Shrikrishna; Patwardhan, Bhushan

doi:10.1016/j.jpba.2013.03.001

Cited by 81 publications

(58 citation statements)

References 19 publications

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“…4A). Consistently, and despite its short in vivo half-life (18), withaferin A induced a marked enhancement of the antitumor effects of Notch inhibition with DBZ in vivo in a mouse model of Notch1-induced T-ALL (10) (Fig. 4 B and C).…”

Section: Analysis Of Antileukemic Effects and Interaction With Notch1mentioning

confidence: 56%

Synergistic antileukemic therapies in NOTCH1 -induced T-ALL

Sánchez-Martín

Ambesi-Impiombato

Qin

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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TheNotch1gene is a major oncogenic driver and therapeutic target in T-cell acute lymphoblastic leukemia (T-ALL). However, inhibition of NOTCH signaling with γ-secretase inhibitors (GSIs) has shown limited antileukemic activity in clinical trials. Here we performed an expression-based virtual screening to identify highly active antileukemic drugs that synergize with NOTCH1 inhibition in T-ALL. Among these, withaferin A demonstrated the strongest cytotoxic and GSI-synergistic antileukemic effects in vitro and in vivo. Mechanistically, network perturbation analyses showed eIF2A-phosphorylation–mediated inhibition of protein translation as a critical mediator of the antileukemic effects of withaferin A and its interaction with NOTCH1 inhibition. Overall, these results support a role for anti-NOTCH1 therapies and protein translation inhibitor combinations in the treatment of T-ALL.

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Section: Analysis Of Antileukemic Effects and Interaction With Notch1mentioning

confidence: 56%

Synergistic antileukemic therapies in NOTCH1 -induced T-ALL

Sánchez-Martín

Ambesi-Impiombato

Qin

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…Till now, comprehensive PK and TD studies of pure active WA have not been reported. However, a PK study of aqueous extract of W. somnifera has been carried out (Patil et al, ). The extracts are complex mixtures of different phytochemicals and are known to affect the absorption, distribution, and elimination of each other (Chang, Zuo, Ho, & Chow, ; Li et al, ; Li et al, ).…”

Section: Introductionmentioning

confidence: 99%

Determination of permeability, plasma protein binding, blood partitioning, pharmacokinetics and tissue distribution of Withanolide A in rats: A neuroprotective steroidal lactone

Singh

Valicherla

Joshi

et al. 2018

Drug Development Research

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Preclinical Research & Development Withanolide A (WA), a steroidal lactone is a major bioactive constituent of Withania somnifera (L.) with remarkable neuropharmacological activity. In this study, we investigated the permeability, plasma protein binding (PPB), blood partitioning, intravenous (i.v.), and oral pharmacokinetics as well as i.v. tissue distribution (TD) of pure WA in a rat model. The PPB, RBCs partitioning, and permeability of WA were determined by Ultra Performance Liquid Chromatography (UPLC) method. However, the pharmacokinetics and TD of WA were evaluated by validated and sensitive liquid chromatography coupled mass spectrometry (LC‐ESI‐MS/MS) method. The PPB and permeability of WA were determined by equilibrium dialysis and parallel artificial membrane permeability assay method, respectively. The results demonstrated that WA has high PPB and passive permeability. Furthermore, WA was found to have fast equilibration between RBCs and plasma. Following i.v. (2 mg/kg) and per‐oral (25 mg/kg) administration of WA, the max concentration (Cmax) in plasma was found as 85.53 ± 6.54 and 48.04 ±5.78 ng/mL, respectively. The TD study results indicated that WA has a rapid and wide TD. The maximum concentration in various tissues was found in following order: Clung > Cliver > Ckidney ≈ Cspleen > Cheart > Cbrain. The preclinical in vitro, as well as pharmacokinetics and TD results, are anticipated to support the future preclinical and clinical application of WA.

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“…When we adapted the reported HPLC method (Agrawal et al, 2015; Patial and Gota, 2011; Patil et al, 2013) to UPLC using PDA-UV detector patterned, we reached a detection limit for WFA at 0.3 ng. This detection limit was substantially lower than the detection limit of 34 ng reported (Agrawal et al, 2015).…”

Section: Resultsmentioning

confidence: 99%

Development of a goat model for evaluation of withaferin A: Cervical implants for the treatment of cervical intraepithelial neoplasia

Sherwood

Aqil

Vadhanam

et al. 2017

Experimental and Molecular Pathology

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Cervical cancer is caused by human papillomavirus (HPV). The disease develops over many years through a series of precancerous lesions. Cervical cancer can be prevented by HPV-vaccination, screening and treatment of precancer before development of cervical cancer. The treatment of high-grade cervical dysplasia (CIN2+) has traditionally been by cervical conization. Surgical procedures are associated with increased risk of undesirable side effects including bleeding, infection, scarring (stenosis), infertility and complications in later pregnancies. An inexpensive, non-invasive method of delivering therapeutics locally will be favorable to treat precancerous cervical lesions without damaging healthy tissue. The feasibility and safety of a sustained, continuous drug-releasing cervical polymeric implant for use in clinical trials was studied using a large animal model. The goat (Capra hircus), non-pregnant adult female Boer goats (n=7), was chosen due to similarities in cervical dimensions to the human. Estrus was induced with progesterone CIDR® vaginal implants for 14 days followed by the administration of chorionic gonadotropins 48 hours prior to removal of the progesterone implants to relax the cervix to allow for the placement of the cervical implant. Cervical implants, containing 2% and 4% withaferin A (WFA), with 8 coats of blank polymer, provided sustained release for a long duration and were used for the animal study. The ‘mushroom’-shaped cervical polymeric implant, originally designed for women required redesigning to be accommodated within the goat cervix. The cervical implants were well tolerated by the animals with no obvious evidence of discomfort, systemic or local inflammation or toxicity. In addition, we developed a new method to analyze tissue WFA levels by solvent extractions and LS/MS-MS. WFA was found to be localized to the target and adjacent tissues with 12 – 16 ng WFA/g tissue, with essentially no detectable WFA in distant tissues. This study suggests that the goat is a good large animal model for the future development and evaluation of therapeutic efficacy of continuous local drug delivery by cervical polymeric implants to treat precancerous cervical lesions.

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Determination of withaferin A and withanolide A in mice plasma using high-performance liquid chromatography-tandem mass spectrometry: Application to pharmacokinetics after oral administration of Withania somnifera aqueous extract

Cited by 81 publications

References 19 publications

Synergistic antileukemic therapies in NOTCH1 -induced T-ALL

Synergistic antileukemic therapies in NOTCH1 -induced T-ALL

Determination of permeability, plasma protein binding, blood partitioning, pharmacokinetics and tissue distribution of Withanolide A in rats: A neuroprotective steroidal lactone

Development of a goat model for evaluation of withaferin A: Cervical implants for the treatment of cervical intraepithelial neoplasia

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