Acute, Reproductive Toxicity and Two‐generation Teratology Studies of a Standardized Quassinoid‐rich Extract of <i>Eurycoma longifolia</i> Jack in Sprague–Dawley Rats

Low, Bin-Seng; Das, P. K.; Chan, Kit‐Lam

doi:10.1002/ptr.5094

Cited by 15 publications

(14 citation statements)

References 25 publications

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“…The oral median lethal dose (LD 50 ) of a similar quassinoid-rich E . longifolia extract for female and male Sprague-Dawley rats was 1293 and > 2000 mg/kg, respectively [ 53 ]. In the same study, normal prostate histology with the absence of hyperplasia was also observed in tissues of rat fed chronically with the extract.…”

Section: Discussionmentioning

confidence: 99%

The In Vitro and In Vivo Anti-Cancer Activities of a Standardized Quassinoids Composition from Eurycoma longifolia on LNCaP Human Prostate Cancer Cells

et al. 2015

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Quassinoids are a group of diterpenoids found in plants from the Simaroubaceae family. They are also the major bioactive compounds found in Eurycoma longifolia which is commonly used as traditional medicine in South East Asia to treat various ailments including sexual dysfunction and infertility. These uses are attributed to its ability to improve testosterone level in men. Chronic consumption of E. longifolia extracts has been reported to increase testosterone level in men and animal model but its effect on prostate growth remains unknown. Therefore, the present study investigates the effects of a standardized total quassinoids composition (SQ40) containing 40% of the total quassinoids found in E. longifolia on LNCaP human prostate cancer cell line. SQ40 inhibited LNCaP cell growth at IC50 value of 5.97 μg/mL while the IC50 on RWPE-1 human prostate normal cells was 59.26 μg/mL. SQ40 also inhibited 5α-dihydrotestosterone-stimulated growth in LNCaP cells dose-dependently. The inhibitory effect of SQ40 in anchorage-independent growth of LNCaP cells was also demonstrated using soft agar assay. SQ40 suppressed LNCaP cell growth via G0/G1 phase arrest which was accompanied by the down-regulation of CDK4, CDK2, Cyclin D1 and Cyclin D3 and up-regulation of p21Waf1/Cip1 protein levels. SQ40 at higher concentrations or longer treatment duration can cause G2M growth arrest leading to apoptotic cell death as demonstrated by the detection of poly(ADP-ribose) polymerase cleavage in LNCaP cells. Moreover, SQ40 also inhibited androgen receptor translocation to nucleus which is important for the transactivation of its target gene, prostate-specific antigen (PSA) and resulted in a significant reduction of PSA secretion after the treatment. In addition, intraperitoneal injection of 5 and 10 mg/kg of SQ40 also significantly suppressed the LNCaP tumor growth on mouse xenograft model. Results from the present study suggest that the standardized total quassinoids composition from E. longifolia promotes anti-prostate cancer activities in LNCaP human prostate cancer cells.

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Section: Discussionmentioning

confidence: 99%

The In Vitro and In Vivo Anti-Cancer Activities of a Standardized Quassinoids Composition from Eurycoma longifolia on LNCaP Human Prostate Cancer Cells

et al. 2015

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“…Though EN (14.49 ± 0.26% w/w) was about two fold higher than EP (7.39 ± 0.17% w/w) in concentration from the original TAF2 extract, the AUC 0-24 and F abs data (Table 1B) showed a 3.3 fold higher increment of blood EN than EP concentrations produced by the formulated TAF2-SD. From the previously reported data, EN was relatively less polar than EP, since the latter developed a shorter retention time than EN in the reverse phase HPLC chromatogram [22], and a smaller R f value than EN on TLC of normal phase silica gel coated plates [23]. Furthermore, the structures of both quassinoids (Figure 1) are the same except the epoxide moiety in EP, whereas EN displayed a double bond at C-13 and C-21.…”

Section: Discussionmentioning

confidence: 77%

“…The reference quassinoid markers of eurycomanone (EN) and 13α(21)-epoxyeurycomanone (EP) were isolated and purified from the TAF2 extract following previously described protocol [22]. The spectroscopic data (UV, IR, MS and NMR) of the two quassinoids were similar to those previously reported [23]. The purity of the quassinoids was above 95% as determined by a Waters Delta Prep HPLC system equipped with a Waters 2996 photodiode array detector (PDA) and Empower 2 workstation (Waters, Milford, MA).…”

Section: Methodsmentioning

confidence: 76%

“…The isocratic mobile phase consisted of acetonitrile-water (1:9) passing through the column at a flow-rate of 0.9 mL min -1 . The detection was adjusted to 238 nm for quantitative analysis of reference markers EP and EN, and their plasma concentration [23], whereas the reference markers of theophylline and sulfapyridine in plasma were measured at 272 nm [28]. The chromatograms of the quassinoids were analyzed for peak height using EZChrom Elite Compact version 3.3.2 software (Scientific Software, Agilent Technologies).…”

Section: Preparation Of the Lipid-based Solid Dispersion Taf2-sdmentioning

confidence: 99%

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Investigating the Double-Peak Phenomenon in Oral Pharmacokinetics of Eurycoma longifolia quassinoids in Lipid-Based Solid Dispersion

Ebrahimi¹,

Nak²,

Chan³

2015

Journal of Bioequivalence Studies

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13α(21)-Epoxyeurycomanone (EP) and eurycomanone (EN), the polar quassinoids of Eurycoma longifolia extract (TAF2) formulated as a lipid-based solid dispersion (TAF2-SD) to increase sperm count for oligospermic infertility, displayed improvement of oral pharmacokinetics and bioavailability in rats over the non-formulated TAF2 extract. The plasma concentration-time curves of the quassinoids in both preparations displayed double-peak phenomenon, similarly observed in BCS Class 3 drugs that are highly hydrophilic and of low phospholipid membrane permeability, which therefore prompted investigation of the contributing factors. The results following the oral co-administration of TAF2-SD with the gastrointestinal transit markers indicated that less than 50% w/w of EP and EN were absorbed in the rat small intestine prior to 2.5 h, the gastric emptying time of 50% w/w theophylline marker absorption. More than 70% w/w of the quassinoids were absorbed in the colon after 8 h, the detection of 50% w/w sulfapyridine, the hydrolyzed metabolite of sulfasalazine marker. The non-formulated TAF2 extract at 0.028 ppm and its major quassinoid, EN at 0.005 ppm reduced acetylcholine-and histamine-induced contractions of the guinea pig ileum, suggesting that the muscle relaxant effect contributed to the delay in gastric-emptying and absorption in the intestine. In conclusion, the formulated quassinoids improved the oral bioavailability without changing the double-peak pharmacokinetic profile, and reduced gut motility causing delayed gastric emptying and intestinal absorption.

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“…Fertility was estimated in adult male Wistar rats according to the method of Pandey et al 14 24 h after 28 days MEPA, each male was placed in a separate cage with two virgin untreated female of the same strain. They are left together for 7 days, and during this period, one estrous cycle should have elapsed as described by Low et al 15 Following positive identification of mating, female were placed to individual cages. Positive mating was confirmed by the presence of a copulatory plug or the presence of sperm in the vaginal smears.…”

Section: Examination Of Male Fertilitymentioning

confidence: 99%

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2018

IJPSR

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The present study was aimed to evaluate the effects of repeated administration of methanolic leaf extract of Pterospermum acerifolium Linn. Willd. (MEPA) on the reproductive system of male and female Wistar albino rats and its developmental effects on subsequent generation. MEPA was administered to Wistar albino rats by gavage for 28 days repeatedly at doses of 250, 500 and 1000 mg/kg body weight, in accordance to OECD guidelines 414 (developmental study) and 416 (reproductive study). Male fertility was estimated by sperm count. Biochemical evaluations included estimation of glycogen content, superoxide dismutase activity and ascorbic acid. Body weight and food intake behavior was also monitored regularly. MEPA treated male and female rats were allowed to mate. After mating females were observed for signs of parturition and allowed to give birth to the F1 generation. The pups were clinically observed. At the dose levels tested MEPA does not significantly (p<0.01) alter sperm count of male rats. Female reproductive system tolerates MEPA well. Normal gestational period was observed. Normal birth rates of F1 pups showed absence of developmental toxicity of MEPA. The no observed effect level (NOEL) for maternal and development toxicity was 1000 mg/kg/bw/d, the highest dose evaluated (p<0.01). MEPA does not cause male or female toxicity in Wistar albino rats upon 28 day repeated oral administration upon repeated MEPA administration upto 1000 mg/kg/bw/d. INTRODUCTION: An herb is a plant or plant part used for its scent, flavor, or therapeutic properties. Herbal medicines are one type of dietary supplement. They are sold as tablets, capsules, powders, teas, extracts, and fresh or dried plants.

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Acute, Reproductive Toxicity and Two‐generation Teratology Studies of a Standardized Quassinoid‐rich Extract of Eurycoma longifolia Jack in Sprague–Dawley Rats

Cited by 15 publications

References 25 publications

The In Vitro and In Vivo Anti-Cancer Activities of a Standardized Quassinoids Composition from Eurycoma longifolia on LNCaP Human Prostate Cancer Cells

The In Vitro and In Vivo Anti-Cancer Activities of a Standardized Quassinoids Composition from Eurycoma longifolia on LNCaP Human Prostate Cancer Cells

Investigating the Double-Peak Phenomenon in Oral Pharmacokinetics of Eurycoma longifolia quassinoids in Lipid-Based Solid Dispersion

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