Abstract
Aims: The aim of this study is to determine the potential adverse effects associated with the prolonged administration of Zingiber roseum rhizome extract.
Background: This study aimed to evaluate the sub-chronic toxicity of Z. roseum, commonly known as rosy ginger, using a mouse model. Z. roseum has been traditionally used for its medicinal properties; however, there is limited information regarding its potential toxic effects.
Objective: The objective of this study is to assess the safety profile of ZRR extract at various doses and conduct a detailed analysis of hematological, biochemical, and histological parameters regarding sub-chronic toxicity.
Methods: Mice were orally administered ZRR methanolic extract at doses of 300, 600, and 1200 mg/kg for 14 days as per the guidelines of ‘The Brazilian Agency of National Health Surveillance.’ Subchronic toxicity was conducted by monitoring multiple indicators, including changes in body weight, food and water consumption, blood profile (HB, RBC, WBC, and PLT), and biochemical markers (ALT, AST, ALP, TP, ALB, TC, TG, HDL, LDL, Creatinine, and Urea) and histopathological examination of the liver.
Results: Throughout the study, the mice showed normal behavior and appeared healthy. The administration of Z. roseum at all tested doses did not significantly affect body weight, food, and water intake, blood, biochemical markers, or liver. Z. roseum at these doses was safe, with no fatalities or harm.
Conclusion: Lastly, the sub-chronic administration of Z. roseum at doses of 300, 600, and 1200 mg/kg in a mice model did not elicit any toxic effects, indicating its potential safety as a therapeutic agent.
Graphical Abstract
[1]
Fennell CW, Lindsey KL, McGaw LJ, et al. Assessing African medicinal plants for efficacy and safety: Pharmacological screening and toxicology. J Ethnopharmacol 2004; 94(2-3): 205-17.
[http://dx.doi.org/10.1016/j.jep.2004.05.012] [PMID: 15325724]
[http://dx.doi.org/10.1016/j.jep.2004.05.012] [PMID: 15325724]
[2]
Jamshidi-Kia F, Lorigooini Z, Amini-Khoei H. Medicinal plants: Past history and future perspective. J Herbmed Pharmacol 2018; 7(1): 1-7.
[http://dx.doi.org/10.15171/jhp.2018.01]
[http://dx.doi.org/10.15171/jhp.2018.01]
[3]
Pal SK, Shukla Y. Herbal medicine: Current status and the future. Asian Pac J Cancer Prev 2003; 4(4): 281-8.
[PMID: 14728584]
[PMID: 14728584]
[4]
Ertekin V, Selimoğlu MA, Altinkaynak S. A combination of unusual presentations of Datura stramonium intoxication in a child: Rhabdomyolysis and fulminant hepatitius. J Emerg Med 2005; 28(2): 227-8.
[http://dx.doi.org/10.1016/j.jemermed.2004.11.006] [PMID: 15707824]
[http://dx.doi.org/10.1016/j.jemermed.2004.11.006] [PMID: 15707824]
[5]
Koduru S, Grierson DS, Afolayan AJ. Antimicrobial Activity of Solanum aculeastrum. Pharm Biol 2006; 44(4): 283-6.
[http://dx.doi.org/10.1080/13880200600714145]
[http://dx.doi.org/10.1080/13880200600714145]
[6]
Ekor M. The growing use of herbal medicines: Issues relating to adverse reactions and challenges in monitoring safety. Front Pharmacol 2014; 4: 177.
[http://dx.doi.org/10.3389/fphar.2013.00177] [PMID: 24454289]
[http://dx.doi.org/10.3389/fphar.2013.00177] [PMID: 24454289]
[7]
Ben-Arye E, Samuels N, Goldstein LH, et al. Potential risks associated with traditional herbal medicine use in cancer care: A study of Middle Eastern oncology health care professionals. Cancer 2016; 122(4): 598-610.
[http://dx.doi.org/10.1002/cncr.29796] [PMID: 26599199]
[http://dx.doi.org/10.1002/cncr.29796] [PMID: 26599199]
[8]
Hunter P. A toxic brew we cannot live without. EMBO Rep 2008; 9(1): 15-8.
[http://dx.doi.org/10.1038/sj.embor.7401148] [PMID: 18174893]
[http://dx.doi.org/10.1038/sj.embor.7401148] [PMID: 18174893]
[9]
Amanat M, Gautam S, Chalotra R, et al. Zingiber roseum Roscoe. (Zingiberaceae): Current and future perspective. Pharmacol Res Mod Chin Med 2023; 2023: 100258.
[10]
Prakash O, Pant AK, Mathela CS. Linalool-Rich Essential Oil from the Rhizomes of Zingiber roseum Rosc. J Essent Oil Res 2006; 18(6): 638-9.
[http://dx.doi.org/10.1080/10412905.2006.9699190]
[http://dx.doi.org/10.1080/10412905.2006.9699190]
[11]
Amanat M, Daula ASU, Singh R. Acute toxicity assessment of methanolic extract of Zingiber roseum (Roscoe.) Rhizome in Swiss Albino mice. Pharmacol. Res. Zhongguo Xiandai Zhongyao 2023; 7: 100244.
[12]
Mahawer SK, Kumar R, Prakash O, et al. A comprehensive review on phytochemistry, ethnopharmacology, and pharmacological properties of Zingiber roseum (Roxb.) roscoe. Curr Top Med Chem 2023; 23(11): 931-42.
[http://dx.doi.org/10.2174/1568026623666230126143635] [PMID: 36703584]
[http://dx.doi.org/10.2174/1568026623666230126143635] [PMID: 36703584]
[13]
Al-Amin M, Siddiqui MA, Ruma SA, Eltayeb NM, Sultana GNN. Antimicrobial activity of the crude extract, fractions and isolation of zerumbone from the rhizomes of Zingiber roseum. Journal of Research in Pharmacy 2019; 23(3): 559-66.
[http://dx.doi.org/10.12991/jrp.2019.163]
[http://dx.doi.org/10.12991/jrp.2019.163]
[14]
Amanat M, Reza MS, Shuvo MSR, et al. Zingiber roseum Rosc. rhizome: A rich source of hepatoprotective polyphenols. Biomed Pharmacother 2021; 139: 111673.
[http://dx.doi.org/10.1016/j.biopha.2021.111673] [PMID: 33965729]
[http://dx.doi.org/10.1016/j.biopha.2021.111673] [PMID: 33965729]
[15]
Puupponen-Pimiä R, Nohynek L, Meier C, et al. Antimicrobial properties of phenolic compounds from berries. J Appl Microbiol 2001; 90(4): 494-507.
[http://dx.doi.org/10.1046/j.1365-2672.2001.01271.x] [PMID: 11309059]
[http://dx.doi.org/10.1046/j.1365-2672.2001.01271.x] [PMID: 11309059]
[16]
Jeevan Ram A, Bhakshu LM, Venkata Raju RR. In vitro antimicrobial activity of certain medicinal plants from Eastern Ghats, India, used for skin diseases. J Ethnopharmacol 2004; 90(2-3): 353-7.
[http://dx.doi.org/10.1016/j.jep.2003.10.013] [PMID: 15013201]
[http://dx.doi.org/10.1016/j.jep.2003.10.013] [PMID: 15013201]
[17]
Nayak S, Jena AK, Mittal DK, Joshi DJ. GC–MS analysis of phytoconstituents of some wild Zingiberaceae plants methanolic rhizome extracts. J Appl Microbiol 2014; 2(1): 1-5.
[18]
Amanat M, Shahid-Ud-Daula A J. Anthelmintic activity of Mansoa alliacea against Pheretima posthuma: In vitro and In silico approach. Thai J Pharmaceut Sci 2020; 44(3): 186-96.
[19]
Mohammadpour R, Dobrovolskaia MA, Cheney DL, Greish KF, Ghandehari H. Subchronic and chronic toxicity evaluation of inorganic nanoparticles for delivery applications. Adv Drug Deliv Rev 2019; 144: 112-32.
[http://dx.doi.org/10.1016/j.addr.2019.07.006] [PMID: 31295521]
[http://dx.doi.org/10.1016/j.addr.2019.07.006] [PMID: 31295521]
[20]
Yuan G, Dai S, Yin Z, et al. Toxicological assessment of combined lead and cadmium: Acute and sub-chronic toxicity study in rats. Food Chem Toxicol 2014; 65: 260-8.
[http://dx.doi.org/10.1016/j.fct.2013.12.041] [PMID: 24394482]
[http://dx.doi.org/10.1016/j.fct.2013.12.041] [PMID: 24394482]
[21]
Sheng Y, Qi X, Liu Y, et al. Subchronic toxicity study in vivo and allergenicity study in vitro for genetically modified rice that expresses pharmaceutical protein (human serum albumin). Food Chem Toxicol 2014; 72: 242-6.
[http://dx.doi.org/10.1016/j.fct.2014.07.030] [PMID: 25086369]
[http://dx.doi.org/10.1016/j.fct.2014.07.030] [PMID: 25086369]
[22]
Umer S, Andualem G, Getnet F, Alemayehu H, Tekewe A, Kebede NJ. Antidiarrheal and antibacterial activities of hydroalcoholic extracts of Salvia schimperi benth from Ethiopia. Int J Pharmacogn 2015; 2: 290-5.
[23]
Desta GT, Adela Alemu M, Tsegaw A, Belete TM, Adugna BY. Antidiarrheal effect of 80% methanol extract and fractions of Clerodendrum myricoides (hochst.) vatke (lamiaceae) leaf in swiss albino mice. Evid Based Complement Alternat Med 2021; 2021: 1-10.
[http://dx.doi.org/10.1155/2021/9369173] [PMID: 34712351]
[http://dx.doi.org/10.1155/2021/9369173] [PMID: 34712351]
[24]
Dikbas N, Kotan R, Dadasoglu F, Sahin F. Control of Aspergillus flavus with essential oil and methanol extract of Satureja hortensis. Int J Food Microbiol 2008; 124(2): 179-82.
[http://dx.doi.org/10.1016/j.ijfoodmicro.2008.03.034] [PMID: 18455819]
[http://dx.doi.org/10.1016/j.ijfoodmicro.2008.03.034] [PMID: 18455819]
[25]
Sengul M, Ercisli S, Yildiz H, Gungor N, Kavaz A, Çetin B. Antioxidant, antimicrobial activity and total phenolic content within the aerial parts of Artemisia absinthum, Artemisia santonicum and Saponaria officinalis. Iran J Pharm Res 2011; 10(1): 49-56.
[PMID: 24363680]
[PMID: 24363680]
[26]
Tariq KA, Chishti MZ, Ahmad F, Shawl AS. Anthelmintic activity of extracts of Artemisia absinthium against ovine nematodes. Vet Parasitol 2009; 160(1-2): 83-8.
[http://dx.doi.org/10.1016/j.vetpar.2008.10.084] [PMID: 19070963]
[http://dx.doi.org/10.1016/j.vetpar.2008.10.084] [PMID: 19070963]
[27]
Muthukumar T, Prabu P, Ghosh K, Sastry TP, Biointerfaces SB. Fish scale collagen sponge incorporated with Macrotyloma uniflorum plant extract as a possible wound/burn dressing material. Colloids Surf B Biointerfaces 2014; 113: 207-12.
[http://dx.doi.org/10.1016/j.colsurfb.2013.09.019] [PMID: 24096157]
[http://dx.doi.org/10.1016/j.colsurfb.2013.09.019] [PMID: 24096157]
[28]
Hadisoewignyo L, Soeliono I, Hartono S B, Hestianah E P, Mahanani S R. Hepatoprotective effects of curcumin-mesoporous silica nanoparticles on CCl4-induced hepatotoxicity wistar rats. Indonesian J Pharm 2019; 30(2): 114-21.
[29]
Kurniawan A, Wibawa T H A, Iswahyudi I, Daruwati I J. Pharmacokinetics interaction and biodistribution of 5 fluorouracil with radiopharmaceuticals 99mTc glutathione for cancer diagnostic in mice cancer model. Indonesian J Pharm 2019; 30(2): 91-7.
[30]
Araújo MCPM, Barcellos NMS, Vieira PMA, et al. Acute and sub chronic toxicity study of aqueous extract from the leaves and branches of Campomanesia velutina (Cambess) O. Berg. J Ethnopharmacol 2017; 201: 17-25.
[http://dx.doi.org/10.1016/j.jep.2017.02.043] [PMID: 28254483]
[http://dx.doi.org/10.1016/j.jep.2017.02.043] [PMID: 28254483]
[31]
Mohamed EAH, Lim CP, Ebrika OS, Asmawi MZ, Sadikun A, Yam MF. Toxicity evaluation of a standardised 50% ethanol extract of Orthosiphon stamineus. J Ethnopharmacol 2011; 133(2): 358-63.
[http://dx.doi.org/10.1016/j.jep.2010.10.008] [PMID: 20937371]
[http://dx.doi.org/10.1016/j.jep.2010.10.008] [PMID: 20937371]
[32]
Saleem U, Amin S, Ahmad B, Azeem H, Anwar F, Mary S. Acute oral toxicity evaluation of aqueous ethanolic extract of Saccharum munja Roxb. roots in albino mice as per OECD 425 TG. Toxicol Rep 2017; 4: 580-5.
[http://dx.doi.org/10.1016/j.toxrep.2017.10.005] [PMID: 29152463]
[http://dx.doi.org/10.1016/j.toxrep.2017.10.005] [PMID: 29152463]
[33]
McManus JFA, Mowry RW. Staining methods: Histologic and histochemical. 1960. Available From: http://hdl.handle.net/123456789/1642
[34]
Giacomelli MG, Husvogt L, Vardeh H, et al. Virtual hematoxylin and eosin transillumination microscopy using epi-fluorescence imaging. PLoS One 2016; 11(8): e0159337.
[http://dx.doi.org/10.1371/journal.pone.0159337] [PMID: 27500636]
[http://dx.doi.org/10.1371/journal.pone.0159337] [PMID: 27500636]
[35]
Ridtitid W, Sae-wong C, Reanmongkol W, Wongnawa M. Antinociceptive activity of the methanolic extract of Kaempferia galanga Linn. in experimental animals. J Ethnopharmacol 2008; 118(2): 225-30.
[http://dx.doi.org/10.1016/j.jep.2008.04.002] [PMID: 18486374]
[http://dx.doi.org/10.1016/j.jep.2008.04.002] [PMID: 18486374]
[36]
Hotwani K, Baliga S, Sharma K. Phytodentistry: Use of medicinal plants. J Complement Integr Med 2014; 11(4): 233-51.
[PMID: 25153610]
[PMID: 25153610]
[37]
Bhardwaj S, Verma R, Gupta J. Challenges and future prospects of herbal medicine. Int J Res Med Health Sci 2018; 1(1): 12-5.
[38]
Hussain K, Majeed MT, Ismail Z, Sadikun A, Ibrahim P. Traditional and complementary medicines: Quality assessment strategies and safe usage. South Med Rev 2009; 2(1): 19-23.
[PMID: 23093874]
[PMID: 23093874]
[39]
Tungmunnithum D, Thongboonyou A, Pholboon A, Yangsabai A. Flavonoids and other phenolic compounds from medicinal plants for pharmaceutical and medical aspects: An overview. Medicines (Basel) 2018; 5(3): 93.
[http://dx.doi.org/10.3390/medicines5030093] [PMID: 30149600]
[http://dx.doi.org/10.3390/medicines5030093] [PMID: 30149600]
[40]
Amanat M, Tawhid M, Shahid-Ud-Daula A. Anthelmintic activity of Zingiber roseum rhizomes against Pheretima posthuma: In vitro and in silico approach. Int J Scientific Res Chem 2022; 7(1): 1-15.
[41]
Kabera JN, Semana E, Mussa AR, He XJ. Plant secondary metabolites: Biosynthesis, classification, function and pharmacological properties. J Pharm Pharmacol 2014; 2(7): 377-92.
[42]
Hussein RA, El-Anssary A. Plants secondary metabolites: The key drivers of the pharmacological actions of medicinal plants. Herb Med 2019; 1(3)
[http://dx.doi.org/10.5772/intechopen.76139]
[http://dx.doi.org/10.5772/intechopen.76139]
[43]
Elshafie HS, Camele I, Mohamed AA. A Comprehensive review on the biological, agricultural and pharmaceutical properties of secondary metabolites based-plant origin. Int J Mol Sci 2023; 24(4): 3266.
[http://dx.doi.org/10.3390/ijms24043266] [PMID: 36834673]
[http://dx.doi.org/10.3390/ijms24043266] [PMID: 36834673]
[44]
Epifano F, Genovese S, Menghini L, Curini M. Chemistry and pharmacology of oxyprenylated secondary plant metabolites. Phytochemistry 2007; 68(7): 939-53.
[http://dx.doi.org/10.1016/j.phytochem.2007.01.019] [PMID: 17343885]
[http://dx.doi.org/10.1016/j.phytochem.2007.01.019] [PMID: 17343885]
[46]
Bull RJ, Reckhow DA, Li X, Humpage AR, Joll C, Hrudey SE. Potential carcinogenic hazards of non-regulated disinfection by-products: Haloquinones, halo-cyclopentene and cyclohexene derivatives, N-halamines, halonitriles, and heterocyclic amines. Toxicology 2011; 286(1-3): 1-19.
[http://dx.doi.org/10.1016/j.tox.2011.05.004] [PMID: 21605618]
[http://dx.doi.org/10.1016/j.tox.2011.05.004] [PMID: 21605618]
[47]
Matejczyk M, Świsłocka R, Golonko A, Lewandowski W, Hawrylik E. Cytotoxic, genotoxic and antimicrobial activity of caffeic and rosmarinic acids and their lithium, sodium and potassium salts as potential anticancer compounds. Adv Med Sci 2018; 63(1): 14-21.
[http://dx.doi.org/10.1016/j.advms.2017.07.003] [PMID: 28818744]
[http://dx.doi.org/10.1016/j.advms.2017.07.003] [PMID: 28818744]
[48]
Nieva Moreno MI, Zampini IC, Ordóñez RM, Jaime GS, Vattuone MA, Isla MI. Evaluation of the cytotoxicity, genotoxicity, mutagenicity, and antimutagenicity of propolis from Tucuman, Argentina. J Agric Food Chem 2005; 53(23): 8957-62.
[http://dx.doi.org/10.1021/jf0513359] [PMID: 16277388]
[http://dx.doi.org/10.1021/jf0513359] [PMID: 16277388]
[49]
Ahmadi A, Gandomi H, Derakhshandeh A, Misaghi A, Noori N. Phytochemical composition and In vitro safety evaluation of Ziziphora clinopodioides Lam. ethanolic extract: Cytotoxicity, genotoxicity and mutagenicity assessment. J Ethnopharmacol 2021; 266: 113428.
[http://dx.doi.org/10.1016/j.jep.2020.113428] [PMID: 33011368]
[http://dx.doi.org/10.1016/j.jep.2020.113428] [PMID: 33011368]
[50]
Rasool N, Omer MO, Javeed A, et al. Phytochemical properties and in-vitro cytotoxicity, genotoxicity and mutagenicity assessment of ethanolic and aqueous extracts of Argyrolobium roseum (Camb.). Int J Food Prop 2023; 26(1): 1457-69.
[http://dx.doi.org/10.1080/10942912.2023.2219859]
[http://dx.doi.org/10.1080/10942912.2023.2219859]
[51]
Walum E, Nilsson M, Clemedson C, Ekwall B. The MEIC program and its implications for the prediction of acute human systemic toxicity. Altern Methods Toxicol 1995; 11: 275-82.
[52]
Shanks N, Greek R, Greek J. Are animal models predictive for humans? Philos Ethics Humanit Med 2009; 4(1): 2.
[http://dx.doi.org/10.1186/1747-5341-4-2]
[http://dx.doi.org/10.1186/1747-5341-4-2]
[53]
Asare GA, Gyan B, Bugyei K, et al. Toxicity potentials of the nutraceutical Moringa oleifera at supra-supplementation levels. J Ethnopharmacol 2012; 139(1): 265-72.
[http://dx.doi.org/10.1016/j.jep.2011.11.009] [PMID: 22101359]
[http://dx.doi.org/10.1016/j.jep.2011.11.009] [PMID: 22101359]
[54]
Magdeburg A, Stalter D, Oehlmann J. Whole effluent toxicity assessment at a wastewater treatment plant upgraded with a full-scale post-ozonation using aquatic key species. Chemosphere 2012; 88(8): 1008-14.
[http://dx.doi.org/10.1016/j.chemosphere.2012.04.017] [PMID: 22560180]
[http://dx.doi.org/10.1016/j.chemosphere.2012.04.017] [PMID: 22560180]
[55]
Gatsing D, Aliyu R, Kuiate JR, et al. Toxicological evaluation of the aqueous extract of Allium sativum bulbs on laboratory mice and rats. Cameroon J Exp Biol 2005; 1(1): 39-45.
[57]
Waring JF, Ciurlionis R, Jolly RA, Heindel M, Ulrich RG. Microarray analysis of hepatotoxins in vitro reveals a correlation between gene expression profiles and mechanisms of toxicity. Toxicol Lett 2001; 120(1-3): 359-68.
[http://dx.doi.org/10.1016/S0378-4274(01)00267-3] [PMID: 11323195]
[http://dx.doi.org/10.1016/S0378-4274(01)00267-3] [PMID: 11323195]
[58]
Ashafa A, Yakubu M, Grierson D, Afolayan AJ. Toxicological evaluation of the aqueous extract of Felicia muricata Thunb. leaves in Wistar rats. Afr J Biotechnol 2009; 8(6): 949-54.
[59]
Auletta CS. Acute, subchronic, and chronic toxicology.Handbook of Toxicology. Amsterdam: Elsevier 1995; pp. 51-162.
[60]
Bale SS, Moore L, Yarmush M, Jindal R. Emerging In vitro liver technologies for drug metabolism and inter-organ interactions. Tissue Eng Part B Rev 2016; 22(5): 383-94.
[http://dx.doi.org/10.1089/ten.teb.2016.0031] [PMID: 27049038]
[http://dx.doi.org/10.1089/ten.teb.2016.0031] [PMID: 27049038]
[61]
Rajan SAP, Aleman J, Wan M, et al. Probing prodrug metabolism and reciprocal toxicity with an integrated and humanized multi-tissue organ-on-a-chip platform. Acta Biomater 2020; 106: 124-35.
[http://dx.doi.org/10.1016/j.actbio.2020.02.015] [PMID: 32068138]
[http://dx.doi.org/10.1016/j.actbio.2020.02.015] [PMID: 32068138]
[62]
Cho Y-E. Increased liver-specific proteins in circulating extracellular vesicles as potential biomarkers for drug-and alcohol-induced liver injury. PLoS One 2017; 12(2): e0172463.
[http://dx.doi.org/10.1371/journal.pone.0172463] [PMID: 28225807]
[http://dx.doi.org/10.1371/journal.pone.0172463] [PMID: 28225807]
[63]
Palanivel M, Rajkapoor B, Kumar RS, Einstein JW. Hepatoprotective and antioxidant effect of Pisonia aculeata L. against CCl4-induced hepatic damage in rats. Sci Pharm 2008; 76(2): 203-15.
[http://dx.doi.org/10.3797/scipharm.0803-16]
[http://dx.doi.org/10.3797/scipharm.0803-16]
[64]
Wu C-T, Deng J-S, Huang W-C, Shieh P-C, Chung M-I, Huang G J. Salvianolic acid C against acetaminophen-induced acute liver injury by attenuating inflammation, oxidative stress, and apoptosis through inhibition of the Keap1/Nrf2/HO-1 signaling. Oxid Med Cell Longev 2019; 2019: 9056845.
[65]
Manjunatha BK, Vidya SM, Dhiman P, Pallavi R, Mankani KL. Hepatoprotective activity of Leucas hirta against CCl4 induced hepatic damage in rats. Indian J Exp Biol 2005; 43(8): 722-7.
[PMID: 16121714]
[PMID: 16121714]
[66]
Limdi JK, Hyde GM. Evaluation of abnormal liver function tests. Postgrad Med J 2003; 79(932): 307-12.
[http://dx.doi.org/10.1136/pmj.79.932.307] [PMID: 12840117]
[http://dx.doi.org/10.1136/pmj.79.932.307] [PMID: 12840117]
[67]
Patwardhan RV, Smith OJ, Farmelant MH. Serum transaminase levels and cholescintigraphic abnormalities in acute biliary tract obstruction. Arch Intern Med 1987; 147(7): 1249-53.
[http://dx.doi.org/10.1001/archinte.1987.00370070063010] [PMID: 3300588]
[http://dx.doi.org/10.1001/archinte.1987.00370070063010] [PMID: 3300588]
[68]
Wang J, Bo X, Li M, et al. Prediction efficacy for clinical outcome of prognostic nutritional index in patients with resectable biliary tract cancer depends on sex and obstructive jaundice status. Ann Surg Oncol 2021; 28(1): 430-8.
[http://dx.doi.org/10.1245/s10434-020-08728-8] [PMID: 32548755]
[http://dx.doi.org/10.1245/s10434-020-08728-8] [PMID: 32548755]
[69]
Khanna S, Mitra S, Lakhera PC, Khandelwal S. N -acetylcysteine effectively mitigates cadmium-induced oxidative damage and cell death in Leydig cells in vitro. Drug Chem Toxicol 2016; 39(1): 74-80.
[http://dx.doi.org/10.3109/01480545.2015.1028068] [PMID: 25885549]
[http://dx.doi.org/10.3109/01480545.2015.1028068] [PMID: 25885549]
[70]
Travlos GS, Morris RW, Elwell MR, Duke A, Rosenblum S, Thompson MB. Frequency and relationships of clinical chemistry and liver and kidney histopathology findings in 13-week toxicity studies in rats. Toxicology 1996; 107(1): 17-29.
[http://dx.doi.org/10.1016/0300-483X(95)03197-N] [PMID: 8597028]
[http://dx.doi.org/10.1016/0300-483X(95)03197-N] [PMID: 8597028]
[71]
Gowda S, Desai PB, Kulkarni SS, Hull VV, Math AA, Vernekar SN. Markers of renal function tests. N Am J Med Sci 2010; 2(4): 170-3.
[PMID: 22624135]
[PMID: 22624135]
[72]
Rosner MH, Bolton WK. Renal function testing. Am J Kidney Dis 2006; 47(1): 174-83.
[http://dx.doi.org/10.1053/j.ajkd.2005.08.038] [PMID: 16377400]
[http://dx.doi.org/10.1053/j.ajkd.2005.08.038] [PMID: 16377400]
[73]
Jain N, Sharma P, Sharma N, Joshi SC. Haemato-biochemical profile following sub acute toxicity of malathon in male albino rats. Pharmacologyonline 2009; 2: 500-6.
[74]
Li M, Jia Z, Hu Z, Zhang R, Shen T. Experimental study on the hemostatic activity of the Tibetan medicinal herbLamiophlomis rotata. Phytother Res 2008; 22(6): 759-65.
[http://dx.doi.org/10.1002/ptr.2359] [PMID: 18446844]
[http://dx.doi.org/10.1002/ptr.2359] [PMID: 18446844]
[75]
Hemalatha T, Ahino Mary D, Saravana Ganthi A. Acute and sub-acute toxicity study of Trema orientalis (L.) Bl. methanol extract in rats. J Drug Deliv Ther 2019; 9(1-s): 307-11.
[http://dx.doi.org/10.22270/jddt.v9i1-s.2353]
[http://dx.doi.org/10.22270/jddt.v9i1-s.2353]
