Scientific Papers and Patents on Substances with Unproven Effects. Part 2

Sergei    V.   Jargin
doi:10.2174/1872211313666190819124752
Abstract

Several examples are discussed in this review, where substances without proven effects were proposed for practical use within the scope of evidence-based medicines. The following is discussed here: generalizations of the hormesis concept and its use in support of homeopathy; phytoestrogens and soy products potentially having feminizing effects; glycosaminoglycans for the treatment of osteoarthritis and possibilities of their replacement by diet modifications; flavonoids recommended for the treatment of chronic venous insufficiency and varicose veins; acetylcysteine as a mucolytic agent and its questionable efficiency especially by an oral intake; stem cells and cell therapies. In conclusion, placebo therapies can be beneficial and ethically justifiable but it is not a sufficient reason to publish biased information. Importantly, placebo must be devoid of adverse effects, otherwise, it is named pseudo-placebo. Therapeutic methods with unproven effects should be tested in high-quality research shielded from the funding bias. Some issues discussed in this review are not entirely clear, and the arguments provided here can initiate a constructive discussion.
Keywords: Placebo, hormesis, nutrition, phytoestrogens, soy, osteoarthritis, acetylcysteine.
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Graphical Abstract

[1] 
Jargin SV. Scientific papers and patents on substances with unproven effects. Recent Pat Drug Deliv Formul  2019; 13: 37-45.
[http://dx.doi.org/10.2174/1872211313666190307162041] [PMID:  30848224] 
[2] 
Mattson MP, Calabrese EJ. Hormesis A Revolution in Biology, Toxicology and Medicine. Springer New York 2010.
[3] 
Jargin SV. Hormesis and homeopathy: The artificial twins. J Intercult Ethnopharmacol  2015; 4(1): 74-7.
[http://dx.doi.org/10.5455/jice.20140929114417] [PMID:  26401389] 
[4] 
Calabrese EJ, Calabrese V, Giordano J. The role of hormesis in the functional performance and protection of neural systems. Brain Circ  2017; 3(1): 1-13.
[PMID:  30276298] 
[5] 
Jargin SV. Hormetic use of stress in gerontological interventions requires a cautious approach. Biogerontology  2016; 17(2): 417-20.
[http://dx.doi.org/10.1007/s10522-015-9630-8] [PMID:  26712317] 
[6] 
Calabrese EJ, Iavicoli I, Calabrese V. Hormesis: Its impact on medicine and health. Hum Exp Toxicol  2013; 32(2): 120-52.
[http://dx.doi.org/10.1177/0960327112455069] [PMID:  23060412] 
[7] 
Calabrese EJ, Iavicoli I, Calabrese V. Hormesis: Why it is important to biogerontologists. Biogerontology  2012; 13(3): 215-35.
[http://dx.doi.org/10.1007/s10522-012-9374-7] [PMID:  22270337] 
[8] 
Calabrese EJ. Hormesis: Principles and applications. Homeopathy  2015; 104(2): 69-82.
[http://dx.doi.org/10.1016/j.homp.2015.02.007] [PMID:  25869971] 
[9] 
Weihrauch TR. Placebo treatment is effective differently in different diseases- but is it also harmless? A brief synopsis. Sci Eng Ethics  2004; 10(1): 151-5.
[http://dx.doi.org/10.1007/s11948-004-0072-y] [PMID:  14986781] 
[10] 
Moffett JR. Miasmas, germs, homeopathy and hormesis: Commentary on the relationship between homeopathy and hormesis. Hum Exp Toxicol  2010; 29(7): 539-43.
[http://dx.doi.org/10.1177/0960327110369855] [PMID:  20558603] 
[11] 
Nebera SA. Homeopathic preparation for the treatment of myopia.  RU2203674C1 (2003)
[12] 
Ostreikovskii IE. Treatment method of acute pneumonia. RU2063224C1  (1996).
[13] 
Chernozubov IE.   The medications and method of tuberculosis
 treatment. RU2119338C1 (1996).
[14] 
Epshtein OI.  The medications and treatment method of pathological
  syndrome. RU2192888C1 (2002).
[15] 
Luchkin VA.   Method of treatment of degenerative - Dystrophic
  diseases of locomotor system. RU2015147929A (2016)
[16] 
Patisaul HB. Endocrine disruption by dietary phyto-oestrogens: Impact on dimorphic sexual systems and behaviours. Proc Nutr Soc  2017; 76(2): 130-44.
[http://dx.doi.org/10.1017/S0029665116000677] [PMID:  27389644] 
[17] 
Rietjens IMCM, Louisse J, Beekmann K. The potential health effects of dietary phytoestrogens. Br J Pharmacol  2017; 174(11): 1263-80.
[http://dx.doi.org/10.1111/bph.13622] [PMID:  27723080] 
[18] 
Gencel VB, Benjamin MM, Bahou SN, Khalil RA. Vascular effects of phytoestrogens and alternative menopausal hormone therapy in cardiovascular disease. Mini Rev Med Chem  2012; 12(2): 149-74.
[http://dx.doi.org/10.2174/138955712798995020] [PMID:  22070687] 
[19] 
Taku K, Melby MK, Kronenberg F, Kurzer MS, Messina M. Extracted or synthesized soybean isoflavones reduce menopausal hot flash frequency and severity: Systematic review and meta-analysis of randomized controlled trials. Menopause  2012; 19(7): 776-90.
[http://dx.doi.org/10.1097/gme.0b013e3182410159] [PMID:  22433977] 
[20] 
Baber R. Phytoestrogens and post reproductive health. Maturitas  2010; 66(4): 344-9.
[http://dx.doi.org/10.1016/j.maturitas.2010.03.023] [PMID:  20409653] 
[21] 
Gold EB, Leung K, Crawford SL, Huang MH, Waetjen LE, Greendale GA. Phytoestrogen and fiber intakes in relation to incident vasomotor symptoms: Results from the study of women’s health across the nation. Menopause  2013; 20(3): 305-14.
[PMID:  23435028] 
[22] 
Lethaby AE, Brown J, Marjoribanks J, Kronenberg F, Roberts H, Eden J. Phytoestrogens for vasomotor menopausal symptoms. Cochrane Database Syst Rev  2007; 4 CD001395 PMID: 17943751.
[23] 
Krebs EE, Ensrud KE, MacDonald R, Wilt TJ. Phytoestrogens for treatment of menopausal symptoms: A systematic review. Obstet Gynecol  2004; 104(4): 824-36.
[http://dx.doi.org/10.1097/01.AOG.0000140688.71638.d3] [PMID:  15458907] 
[24] 
Cheema D, Coomarasamy A, El-Toukhy T. Non-hormonal therapy of post-menopausal vasomotor symptoms: A structured evidence-based review. Arch Gynecol Obstet  2007; 276(5): 463-9.
[http://dx.doi.org/10.1007/s00404-007-0390-9] [PMID:  17593379] 
[25] 
Al-Azzawi F, Wahab M. Effectiveness of phytoestrogens in climacteric medicine. Ann N Y Acad Sci  2010; 1205: 262-7.
[http://dx.doi.org/10.1111/j.1749-6632.2010.05678.x] [PMID:  20840282] 
[26] 
Villaseca P. Non-estrogen conventional and phytochemical treatments for vasomotor symptoms: What needs to be known for practice. Climacteric  2012; 15(2): 115-24.
[http://dx.doi.org/10.3109/13697137.2011.624214] [PMID:  22148909] 
[27] 
Roberts H, Lethaby A. Phytoestrogens for menopausal vasomotor symptoms: A cochrane review summary. Maturitas  2014; 78(2): 79-81.
[http://dx.doi.org/10.1016/j.maturitas.2014.04.004] [PMID:  24768128] 
[28] 
Sirtori CR, Arnoldi A, Johnson SK. Phytoestrogens: End of a tale? Ann Med  2005; 37(6): 423-38.
[http://dx.doi.org/10.1080/07853890510044586] [PMID:  16203615] 
[29] 
Davis SR. Phytoestrogen therapy for menopausal symptoms? BMJ  2001; 323(7309): 354-5.
[http://dx.doi.org/10.1136/bmj.323.7309.354] [PMID:  11509412] 
[30] 
Coxam V. Phyto-oestrogens and bone health. Proc Nutr Soc  2008; 67(2): 184-95.
[http://dx.doi.org/10.1017/S0029665108007027] [PMID:  18412992] 
[31] 
Ye CF, Pan YM, Zhou H. Regulation of vitamin D receptor and Genistein on bone metabolism in mouse osteoblasts and the molecular mechanism of osteoporosis. J Biol Regul Homeost Agents  2018; 32(3): 497-505.
[PMID:  29921374] 
[32] 
Lagari VS, Levis S. Phytoestrogens in the prevention of postmenopausal bone loss. J Clin Densitom  2013; 16(4): 445-9.
[http://dx.doi.org/10.1016/j.jocd.2013.08.011] [PMID:  24090647] 
[33] 
Arcoraci V, Atteritano M, Squadrito F, et al. Antiosteoporotic activity of genistein aglycone in postmenopausal women: Evidence from a post-hoc analysis of a multicenter randomized controlled trial. Nutrients  2017; 9(2): 1-7.
[http://dx.doi.org/10.3390/nu9020179] [PMID:  28241420] 
[34] 
Tit DM, Bungau S, Iovan C, et al. Effects of the hormone replacement therapy and of soy isoflavones on bone resorption in postmenopause. J Clin Med  2018; 7(10): 1-13.
[http://dx.doi.org/10.3390/jcm7100297] [PMID:  30248918] 
[35] 
This P, de Cremoux P, Leclercq G, Jacquot Y. A critical view of the effects of phytoestrogens on hot flashes and breast cancer risk. Maturitas  2011; 70(3): 222-6.
[http://dx.doi.org/10.1016/j.maturitas.2011.07.001] [PMID:  21813250] 
[36] 
Haimov-Kochman R, Brzezinski A, Hochner-Celnikier D. Herbal remedies for menopausal symptoms: Are we cautious enough? Eur J Contracept Reprod Health Care  2008; 13(2): 133-7.
[http://dx.doi.org/10.1080/13625180801920131] [PMID:  18465474] 
[37] 
Wilson S, Blaschek K, de Mejia E. Allergenic proteins in soybean: Processing and reduction of P34 allergenicity. Nutr Rev  2005; 63(2): 47-58.
[http://dx.doi.org/10.1111/j.1753-4887.2005.tb00121.x] [PMID:  15762088] 
[38] 
de Villiers TJ, Bagratee JS, Dalmeyer JP, Davey MR, Davis CP, Guidozzi F. South African Menopause Society Council revised consensus position statement on menopausal hormone therapy. S Afr Med J  2007; 97: 354-7.
[39] 
Leclercq G, de Cremoux P, This P, Jacquot Y. Lack of sufficient information on the specificity and selectivity of commercial phytoestrogens preparations for therapeutic purposes. Maturitas  2011; 68(1): 56-64.
[http://dx.doi.org/10.1016/j.maturitas.2010.10.003] [PMID:  21074339] 
[40] 
Usui T. Pharmaceutical prospects of phytoestrogens. Endocr J  2006; 53(1): 7-20.
[http://dx.doi.org/10.1507/endocrj.53.7] [PMID:  16543667] 
[41] 
Setchell KD, Clerici C. Equol: History, chemistry, and formation. J Nutr  2010; 40(7): 1355S-62S.
[http://dx.doi.org/10.3945/jn.109.119776] [PMID:  20519412] 
[42] 
Rizzo G, Baroni L. Soy, soy foods and their role in vegetarian diets. Nutrients  2018; 10(1): 1-51.
[http://dx.doi.org/10.3390/nu10010043] [PMID:  29304010] 
[43] 
van Duursen MBM. Modulation of estrogen synthesis and metabolism by phytoestrogens in vitro and the implications for women’s health. Toxicol Res (Camb)  2017; 6(6): 772-94.
[http://dx.doi.org/10.1039/C7TX00184C] [PMID:  30090542] 
[44] 
Czuczwar P, Paszkowski T, Lisiecki M, Woźniak S, Stępniak A. The safety and tolerance of phytotherapies in menopausal medicine - A review of the literature. Przegl Menopauz  2017; 16(1): 8-11.
[http://dx.doi.org/10.5114/pm.2017.67365] [PMID:  28546801] 
[45] 
Adgent MA, Daniels JL, Edwards LJ, Siega-Riz AM, Rogan WJ. Early-life soy exposure and gender-role play behavior in children. Environ Health Perspect  2011; 119(12): 1811-6.
[http://dx.doi.org/10.1289/ehp.1103579] [PMID:  21813368] 
[46] 
Martinez J, Lewi JE. An unusual case of gynecomastia associated with soy product consumption. Endocr Pract  2008; 14(4): 415-8.
[http://dx.doi.org/10.4158/EP.14.4.415] [PMID:  18558591] 
[47] 
Jacobsen BK, Jaceldo-Siegl K, Knutsen SF, Fan J, Oda K, Fraser GE. Soy isoflavone intake and the likelihood of ever becoming a mother: The adventist health study-2. Int J Womens Health  2014; 6: 377-84.
[http://dx.doi.org/10.2147/IJWH.S57137] [PMID:  24741329] 
[48] 
Adgent M, Daniels JL, Rogan WJ, et al. Early-life soy exposure and age at menarche. Paediatr Perinat Epidemiol  2012; 26(2): 163-75.
[http://dx.doi.org/10.1111/j.1365-3016.2011.01244.x] [PMID:  22324503] 
[49] 
Jefferson W, Williams CJ. Circulating levels of genistein in the neonate, apart from dose and route, predict future adverse female reproductive outcomes. Reprod Toxicol  2011; 31(3): 272-9.
[http://dx.doi.org/10.1016/j.reprotox.2010.10.001] [PMID:  20955782] 
[50] 
Testa I, Salvatori C, Di Cara G, et al. Soy-based infant formula: Are phyto-oestrogens still in doubt? Front Nutr  2018; 5: 110.
[http://dx.doi.org/10.3389/fnut.2018.00110] [PMID:  30533415] 
[51] 
Whitten PL, Lewis C, Russell E, Naftolin F. Potential adverse effects of phytoestrogens. J Nutr  1995; 125(3): 771S-6S.
[PMID:  7884563] 
[52] 
Hashem NM, Abo-Elsoud MA, Nour El-Din ANM, Kamel KI, Hassan GA. Prolonged exposure of dietary phytoestrogens on semen characteristics and reproductive performance of rabbit bucks. Domest Anim Endocrinol  2018; 64: 84-92.
[http://dx.doi.org/10.1016/j.domaniend.2018.03.003] [PMID:  29754011] 
[53] 
Dean M, Murphy BT, Burdette JE. Phytosteroids beyond estrogens: Regulators of reproductive and endocrine function in natural products. Mol Cell Endocrinol  2017; 442: 98-105.
[http://dx.doi.org/10.1016/j.mce.2016.12.013] [PMID:  27986590] 
[54] 
Yang J, Wen L, Jiang Y, Yang B. Natural estrogen receptor modulators and their heterologous biosynthesis. Trends Endocrinol Metab  2019; 30(1): 66-76.
[http://dx.doi.org/10.1016/j.tem.2018.11.002] [PMID:  30527917] 
[55] 
Beszterda M, Frański R. Endocrine disruptor compounds in environment: As a danger for children health. Pediatr Endocrinol Diabetes Metab  2018; 24(2): 88-95.
[http://dx.doi.org/10.18544/PEDM-24.02.0107] [PMID:  30300430] 
[56] 
Saayman BD. The use of alternative lipid emulsions in paediatric and neonatal parenteral nutrition. South Afr J Clin Nutr  2011; 24: S32-4.
[http://dx.doi.org/10.1080/16070658.2011.11734378] 
[57] 
Messina M. Soybean isoflavone exposure does not have feminizing effects on men: A critical examination of the clinical evidence. Fertil Steril  2010; 93(7): 2095-104.
[http://dx.doi.org/10.1016/j.fertnstert.2010.03.002] [PMID:  20378106] 
[58] 
Nikitina NA, Sobenin IA, Myasoedova VA, et al. Antiatherogenic effect of grape flavonoids in an ex vivo model. Bull Exp Biol Med  2006; 141(6): 712-5.
[http://dx.doi.org/10.1007/s10517-006-0260-7] [PMID:  17364057] 
[59] 
Orekhov AN, Sobenin IA, Revin VV, Bobryshev YV. Development of antiatherosclerotic drugs on the basis of natural products using cell model approach. Oxid Med Cell Longev  2015; 2015 463797
[http://dx.doi.org/10.1155/2015/463797] [PMID:  26347804] 
[60] 
Jargin SV. Phytoestrogens and other botanicals: On the problems of evidence-based evaluation. Recent Pat Cardiovasc Drug Discov  2013; 8(1): 67-71.
[http://dx.doi.org/10.2174/18722083113079990009] [PMID:  23514086] 
[61] 
Jargin SV. Development of antiatherosclerotic drugs on the basis of cell models: A comment. Int J Pharmacol Phytochem Ethnomed  2015; 1: 10-4.
[http://dx.doi.org/10.18052/www.scipress.com/IJPPE.1.10] 
[62] 
Kuznetsova IV, Kirpikov AS, Khovrina EA.  Method of treating
 benign hyperplastic processes of female reproductive system.
 RU2471485C1 (2013).
[63] 
Bruyère O, Cooper C, Pelletier JP, et al. A consensus statement on the European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis (ESCEO) algorithm for the management of knee osteoarthritis-From evidence-based medicine to the real-life setting. Semin Arthritis Rheum  2016; 45(4): S3-S11.
[http://dx.doi.org/10.1016/j.semarthrit.2015.11.010] [PMID:  26806188] 
[64] 
Jones IA, Togashi R, Wilson ML, Heckmann N, Vangsness CT. Intra-articular treatment options for knee osteoarthritis. Nat Rev Rheumatol  2019; 15(2): 77-90.
[http://dx.doi.org/10.1038/s41584-018-0123-4] [PMID:  30498258] 
[65] 
Vista ES, Lau CS. What about supplements for osteoarthritis? A critical and evidenced-based review. Int J Rheum Dis  2011; 14(2): 152-8.
[http://dx.doi.org/10.1111/j.1756-185X.2011.01619.x] [PMID:  21518314] 
[66] 
Wandel S, Jüni P, Tendal B, et al. Effects of glucosamine, chondroitin, or placebo in patients with osteoarthritis of hip or knee: Network meta-analysis. BMJ  2010; 341: c4675.
[http://dx.doi.org/10.1136/bmj.c4675] [PMID:  20847017] 
[67] 
Singh JA, Noorbaloochi S, MacDonald R, Maxwell LJ. Chondroitin for osteoarthritis. Cochrane Database Syst Rev  2015; 1 CD005614
[PMID:  25629804] 
[68] 
Vincent P. Intra-articular hyaluronic acid in the symptomatic treatment of knee osteoarthritis: A meta-analysis of single-injection products. Curr Ther Res Clin Exp  2019; 90: 39-51.
[http://dx.doi.org/10.1016/j.curtheres.2019.02.003] [PMID:  31289603] 
[69] 
Wehling P, Evans C, Wehling J, Maixner W. Effectiveness of intra-articular therapies in osteoarthritis: A literature review. Ther Adv Musculoskelet Dis  2017; 9(8): 183-96.
[http://dx.doi.org/10.1177/1759720X17712695] [PMID:  28835778] 
[70] 
Zhang B, Thayaparan A, Horner N, Bedi A, Alolabi B, Khan M. Outcomes of hyaluronic acid injections for glenohumeral osteoarthritis: A systematic review and meta-analysis. J Shoulder Elbow Surg  2019; 28(3): 596-606.
[http://dx.doi.org/10.1016/j.jse.2018.09.011] [PMID:  30502030] 
[71] 
Zhu X, Sang L, Wu D, Rong J, Jiang L. Effectiveness and safety of glucosamine and chondroitin for the treatment of osteoarthritis: A meta-analysis of randomized controlled trials. J Orthop Surg Res  2018; 13(1): 170.
[http://dx.doi.org/10.1186/s13018-018-0871-5] [PMID:  29980200] 
[72] 
Simental-Mendía M, Sánchez-García A, Vilchez-Cavazos F, Acosta-Olivo CA, Peña-Martínez VM, Simental-Mendía LE. Effect of glucosamine and chondroitin sulfate in symptomatic knee osteoarthritis: A systematic review and meta-analysis of randomized placebo-controlled trials. Rheumatol Int  2018; 38(8): 1413-28.
[http://dx.doi.org/10.1007/s00296-018-4077-2] [PMID:  29947998] 
[73] 
Black C, Clar C, Henderson R, MacEachern C, McNamee P, Quayyum Z. The clinical effectiveness of glucosamine and chondroitin supplements in lowing or arresting progression of osteoarthritis of the knee: A systematic review and economic evaluation  Health echnol Assess (Rockv) 2009; 13: 1-148.
[74] 
Volpi N. Quality of different chondroitin sulfate preparations in relation to their therapeutic activity. J Pharm Pharmacol  2009; 61(10): 1271-80.
[http://dx.doi.org/10.1211/jpp.61.10.0002] [PMID:  19814858] 
[75] 
Arrich J, Piribauer F, Mad P, Schmid D, Klaushofer K, Müllner M. Intra-articular hyaluronic acid for the treatment of osteoarthritis of the knee: Systematic review and meta-analysis. CMAJ  2005; 172(8): 1039-43.
[http://dx.doi.org/10.1503/cmaj.1041203] [PMID:  15824412] 
[76] 
Rutjes AW, Jüni P, da Costa BR, Trelle S, Nüesch E, Reichenbach S. Viscosupplementation for osteoarthritis of the knee: A systematic review and meta-analysis. Ann Intern Med  2012; 157(3): 180-91.
[http://dx.doi.org/10.7326/0003-4819-157-3-201208070-00473] [PMID:  22868835] 
[77] 
Nguyen C, Lefèvre-Colau MM, Poiraudeau S, Rannou F. Evidence and recommendations for use of intra-articular injections for knee osteoarthritis. Ann Phys Rehabil Med  2016; 59(3): 184-9.
[http://dx.doi.org/10.1016/j.rehab.2016.02.008] [PMID:  27103055] 
[78] 
Witteveen AG, Hofstad CJ, Kerkhoffs GM. Hyaluronic acid and other conservative treatment options for osteoarthritis of the ankle. Cochrane Database Syst Rev  2015; 10 CD010643
[http://dx.doi.org/10.1002/14651858.CD010643.pub2] [PMID:  26475434] 
[79] 
Lohmander LS, Dalén N, Englund G, et al. Hyaluronan multicentre trial group. Intra-articular hyaluronan injections in the treatment of osteoarthritis of the knee: A randomised, double blind, placebo controlled multicentre trial. Ann Rheum Dis  1996; 55(7): 424-31.
[http://dx.doi.org/10.1136/ard.55.7.424] [PMID:  8774159] 
[80] 
Brandt KD, Smith GN, Simon LS. Intraarticular injection of hyaluronan as treatment for knee osteoarthritis: What is the evidence? Arthritis Rheum  2000; 43(6): 1192-203.
[http://dx.doi.org/10.1002/1529-0131(200006)43:6<1192:AID-ANR2>3.0.CO;2-L] [PMID:  10857778] 
[81] 
Machado RC, Capela S, Rocha FAC. Polysaccharides as viscosupplementation agents: Structural molecular characteristics but not rheology appear crucial to the therapeutic response. Front Med (Lausanne)  2017; 4: 82.
[http://dx.doi.org/10.3389/fmed.2017.00082] [PMID:  28674692] 
[82] 
Uebelhart D. Clinical review of chondroitin sulfate in osteoarthritis. Osteoarthritis Cartilage  2008; 16(Suppl. 3): S19-21.
[http://dx.doi.org/10.1016/j.joca.2008.06.006] [PMID:  18674931] 
[83] 
Leighton R, Fitzpatrick J, Smith H, Crandall D, Flannery CR, Conrozier T. Systematic clinical evidence review of NASHA (Durolane hyaluronic acid) for the treatment of knee osteoarthritis. Open Access Rheumatol  2018; 10: 43-54.
[http://dx.doi.org/10.2147/OARRR.S162127] [PMID:  29849470] 
[84] 
Kulikov VG, Shusharin AG, Makhotin AA, Shevela AI.  Method of treating coxarthrosis. RU2396961C1 ( 2010).
[85] 
Migliore A, Anichini S. Intra-articular therapy in hip osteoarthritis. Clin Cases Miner Bone Metab  2017; 14(2): 179-81.
[http://dx.doi.org/10.11138/ccmbm/2017.14.1.179] [PMID:  29263729] 
[86] 
Maheu E, Bannuru RR, Herrero-Beaumont G, Allali F, Bard H, Migliore A. Why we should definitely include intra-articular hyaluronic acid as a therapeutic option in the management of knee osteoarthritis: Results of an extensive critical literature review. Semin Arthritis Rheum  2019; 48(4): 563-72.
[http://dx.doi.org/10.1016/j.semarthrit.2018.06.002] [PMID:  30072113] 
[87] 
Altman R, Hackel J, Niazi F, Shaw P, Nicholls M. Efficacy and safety of repeated courses of hyaluronic acid injections for knee osteoarthritis: A systematic review. Semin Arthritis Rheum  2018; 48(2): 168-75.
[http://dx.doi.org/10.1016/j.semarthrit.2018.01.009] [PMID:  29496227] 
[88] 
Xing D, Wang B, Liu Q, et al. Intra-articular hyaluronic acid in treating knee osteoarthritis: A PRISMA-compliant systematic review of overlapping meta-analysis. Sci Rep  2016; 6: 32790.
[http://dx.doi.org/10.1038/srep32790] [PMID:  27616273] 
[89] 
Jargin SV. Supplementation of glycosaminoglycans and their precursors in osteoarthritis versus diet modification. Int J Rheum Dis  2012; 15(3): e45-6.
[http://dx.doi.org/10.1111/j.1756-185X.2012.01707.x] [PMID:  22709499] 
[90] 
Tikhonov VP, Sidliarov DP, Zaveshchevskaia TL.   Agent for
 care of peripheral joints and backbone area. RU2376011C1 (2009)
[91] 
Bhathal A, Spryszak M, Louizos C, Frankel G. Glucosamine and chondroitin use in canines for osteoarthritis: A review. Open Vet J  2017; 7(1): 36-49.
[http://dx.doi.org/10.4314/ovj.v7i1.6] [PMID:  28331832] 
[92] 
Mansilha A, Sousa J. Pathophysiological mechanisms of chronic venous disease and implications for venoactive drug therapy. Int J Mol Sci  2018; 19(6): 1-21.
[http://dx.doi.org/10.3390/ijms19061669] [PMID:  29874834] 
[93] 
Katsenis K. Micronized Purified Flavonoid Fraction (MPFF): A review of its pharmacological effects, therapeutic efficacy and benefits in the management of chronic venous insufficiency. Curr Vasc Pharmacol  2005; 3(1): 1-9.
[http://dx.doi.org/10.2174/1570161052773870] [PMID:  15641940] 
[94] 
Danielsson G, Jungbeck C, Peterson K, Norgren L. A randomised controlled trial of micronised purified flavonoid fraction vs placebo in patients with chronic venous disease. Eur J Vasc Endovasc Surg  2002; 23(1): 73-6.
[http://dx.doi.org/10.1053/ejvs.2001.1531] [PMID:  11748952] 
[95] 
Bush R, Comerota A, Meissner M, Raffetto JD, Hahn SR, Freeman K. Recommendations for the medical management of chronic venous disease: The role of Micronized Purified Flavanoid Fraction (MPFF). Phlebology  2017; 32(1): 3-19.
[http://dx.doi.org/10.1177/0268355517692221] [PMID:  28211296] 
[96] 
Martinez-Zapata MJ, Vernooij RW, Uriona TSM, et al. Phlebotonics for venous insufficiency. Cochrane Database Syst Rev  2016; 4(4) CD003229
[PMID:  27048768] 
[97] 
Kharkevich DA. The principles of action and use of phlebotropic agents. Klin Med (Mosk)  2004; 82(11): 4-10.
[PMID:  15656390] 
[98] 
Bevan JA. Some bases of differences in vascular response to sympathetic activity. Circ Res  1979; 45(2): 161-71.
[http://dx.doi.org/10.1161/01.RES.45.2.161] [PMID:  36236] 
[99] 
Nicolaides AN. Cardiovascular disease educational and research trust european society of vascular surgery the international angiology scientific activity congress organization international union of angiology union internationale de phlebologie at the abbaye des vaux de cernay. investigation of chronic venous insufficiency: A consensus statement (France, March 5-9, 1997). Circulation  2000; 102(20): E126-63.
[http://dx.doi.org/10.1161/01.CIR.102.20.e126] [PMID:  11076834] 
[100] 
Perrin M, Ramelet AA. Pharmacological treatment of primary chronic venous disease: Rationale, results and unanswered questions. Eur J Vasc Endovasc Surg  2011; 41(1): 117-25.
[http://dx.doi.org/10.1016/j.ejvs.2010.09.025] [PMID:  21126890] 
[101] 
Duarte J, Pérez-Vizcaíno F, Zarzuelo A, Jiménez J, Tamargo J. Vasodilator effects of quercetin in isolated rat vascular smooth muscle. Eur J Pharmacol  1993; 239(1-3): 1-7.
[http://dx.doi.org/10.1016/0014-2999(93)90968-N] [PMID:  8223884] 
[102] 
Schmitt M, Blackman DJ, Middleton GW, Cockcroft JR, Frenneaux MP. Assessment of venous capacitance. Radionuclide plethysmography: Methodology and research applications. Br J Clin Pharmacol  2002; 54(6): 565-76.
[http://dx.doi.org/10.1046/j.1365-2125.2002.t01-7-01689.x] [PMID:  12492602] 
[103] 
Aellig WH. Clinical pharmacology, physiology and pathophysiology of superficial veins-2. Br J Clin Pharmacol  1994; 38(4): 289-305.
[http://dx.doi.org/10.1111/j.1365-2125.1994.tb04357.x] [PMID:  7833218] 
[104] 
Ivanov IS, Sidekhmenova AV, Nosarev AV, Tyukavkina NA, Plotnikov MB. Effect of dihydroquercetin on the tone of isolated rat veins. Bull Exp Biol Med  2013; 155(1): 65-6.
[http://dx.doi.org/10.1007/s10517-013-2080-x] [PMID:  23667873] 
[105] 
Savineau JP, Marthan R. Diosmin-induced increase in sensitivity to Ca2+ of the smooth muscle contractile apparatus in the rat isolated femoral vein. Br J Pharmacol  1994; 111(4): 978-80.
[http://dx.doi.org/10.1111/j.1476-5381.1994.tb14838.x] [PMID:  8032624] 
[106] 
Testai L, Calderone V. Nutraceutical value of citrus flavanones and their implications in cardiovascular disease. Nutrients  2017; 9(5): 502.
[http://dx.doi.org/10.3390/nu9050502] [PMID:  28509871] 
[107] 
Takumi H, Nakamura H, Simizu T, et al. Bioavailability of orally administered water-dispersible hesperetin and its effect on peripheral vasodilatation in human subjects: Implication of endothelial functions of plasma conjugated metabolites. Food Funct  2012; 3(4): 389-98.
[http://dx.doi.org/10.1039/c2fo10224b] [PMID:  22307524] 
[108] 
Scallon C, Bell-Syer SE, Aziz Z. Flavonoids for treating venous leg ulcers. Cochrane Database Syst Rev  2013; 5 CD006477
[PMID:  23728661] 
[109] 
Aziz Z, Tang WL, Chong NJ, Tho LY. A systematic review of the efficacy and tolerability of hydroxyethylrutosides for improvement of the signs and symptoms of chronic venous insufficiency. J Clin Pharm Ther  2015; 40(2): 177-85.
[http://dx.doi.org/10.1111/jcpt.12247] [PMID:  25630350] 
[110] 
Kakkos SK, Nicolaides AN. Efficacy of micronized purified flavonoid fraction (Daflon®) on improving individual symptoms, signs and quality of life in patients with chronic venous disease: A systematic review and meta-analysis of randomized double-blind placebo-controlled trials. Int Angiol  2018; 37(2): 143-54.
[PMID:  29385792] 
[111] 
Geroulakos G, Nicolaides AN. Controlled studies of Daflon 500 mg in chronic venous insufficiency. Angiology  1994; 45(6 Pt 2): 549-53.
[PMID:  8203786] 
[112] 
Duchene MP, Amiel M, Barbe R. Evaluation of the clinical pharmacological activity of a phlebotonic agent. Application to the study of Daflon 500 mg. Int Angiol  1988; 7(2): 25-32.
[PMID:  3053940] 
[113] 
Allaert FA. Meta-analysis of the impact of the principal venoactive drugs agents on malleolar venous edema. Int Angiol  2012; 31(4): 310-5.
[PMID:  22801396] 
[114] 
Rabe E, Agus GB, Roztocil K. Analysis of the effects of micronized purified flavonoid fraction versus placebo on symptoms and quality of life in patients suffering from chronic venous disease: From a prospective randomized trial. Int Angiol  2015; 34(5): 428-36.
[PMID:  25972136] 
[115] 
Giorgio M. Oxidative stress and the unfulfilled promises of antioxidant agents. Ecancermedicalscience  2015; 9: 556.
[http://dx.doi.org/10.3332/ecancer.2015.556] [PMID:  26284120] 
[116] 
Jargin SV. On the use of carnosine and antioxidants: A letter from Russia. J Intercult Ethnopharmacol  2016; 5(3): 317-9.
[http://dx.doi.org/10.5455/jice.20160409010229] [PMID:  27366359] 
[117] 
Abu Raihan SM. Effect of plant flavonoids on mosquito larvae. Nat Univ J Sci  2014; 1: 27-30.
[118] 
Goszcz K, Deakin SJ, Duthie GG, et al. Antioxidants in cardiovascular therapy: Panacea or false hope? Front Cardiovasc Med  2015; 2: 29.
[http://dx.doi.org/10.3389/fcvm.2015.00029] [PMID:  26664900] 
[119] 
Duda-Chodak A. The inhibitory effect of polyphenols on human gut microbiota. J Physiol Pharmacol  2012; 63(5): 497-503.
[PMID:  23211303] 
[120] 
Lichota A, Gwozdzinski L, Gwozdzinski K. Therapeutic potential of natural compounds in inflammation and chronic venous insufficiency. Eur J Med Chem  2019; 176: 68-91.
[http://dx.doi.org/10.1016/j.ejmech.2019.04.075] [PMID:  31096120] 
[121] 
Gattuso G, Barreca D, Gargiulli C, Leuzzi U, Caristi C. Flavonoid composition of Citrus juices. Molecules  2007; 12(8): 1641-73.
[http://dx.doi.org/10.3390/12081641] [PMID:  17960080] 
[122] 
Jargin SV. Grapefruit: Some perspectives in pharmacology and nutrition. J Intercult Ethnopharmacol  2017; 6(3): 339-41.
[http://dx.doi.org/10.5455/jice.20170511061624] [PMID:  28894634] 
[123] 
Sathe NA, Krishnaswami S, Andrews J, Ficzere C, McPheeters ML. Pharmacologic agents that promote airway clearance in hospitalized subjects: A systematic review. Respir Care  2015; 60(7): 1061-70.
[http://dx.doi.org/10.4187/respcare.04086] [PMID:  25944943] 
[124] 
Rogers DF. Mucoactive agents for airway mucus hypersecretory diseases. Respir Care  2007; 52(9): 1176-93.
[PMID:  17716385] 
[125] 
Otu A, Langridge P, Denning DW. Nebulised N-acetylcysteine for unresponsive bronchial obstruction in allergic brochopulmonary aspergillosis: A case series and review of the literature. J Fungi (Basel)  2018; 4(4): 1-13.
[http://dx.doi.org/10.3390/jof4040117] [PMID:  30326585] 
[126] 
Konrad F, Schoenberg MH, Wiedmann H, Kilian J, Georgieff M. The application of n-acetylcysteine as an antioxidant and mucolytic in mechanical ventilation in intensive care patients. A prospective, randomized, placebo-controlled, double-blind study. Anaesthesist  1995; 44(9): 651-8.
[http://dx.doi.org/10.1007/s001010050200] [PMID:  7485927] 
[127] 
Cazzola M, Calzetta L, Page C, et al. Influence of N-acetylcysteine on chronic bronchitis or COPD exacerbations: A meta-analysis. Eur Respir Rev  2015; 24(137): 451-61.
[http://dx.doi.org/10.1183/16000617.00002215] [PMID:  26324807] 
[128] 
Decramer M, Rutten-van Mölken M, Dekhuijzen PN, et al. Effects of N-acetylcysteine on outcomes in chronic obstructive pulmonary disease (Bronchitis Randomized on NAC Cost-Utility Study, BRONCUS): A randomised placebo-controlled trial. Lancet  2005; 365(9470): 1552-60.
[http://dx.doi.org/10.1016/S0140-6736(05)66456-2] [PMID:  15866309] 
[129] 
Rubin BK. Aerosol medications for treatment of mucus clearance disorders. Respir Care  2015; 60(6): 825-9.
[http://dx.doi.org/10.4187/respcare.04087] [PMID:  26070577] 
[130] 
Tam J, Nash EF, Ratjen F, Tullis E, Stephenson A. Nebulized and oral thiol derivatives for pulmonary disease in cystic fibrosis. Cochrane Database Syst Rev  2013; 7 CD007168
[http://dx.doi.org/10.1002/14651858.CD007168.pub3] [PMID:  23852992] 
[131] 
Black PN, Morgan-Day A, McMillan TE, Poole PJ, Young RP. Randomised, controlled trial of N-acetylcysteine for treatment of acute exacerbations of chronic obstructive pulmonary disease. ISRCTN21676344 BMC Pulm Med  2004; 4: 13.
[http://dx.doi.org/10.1186/1471-2466-4-13] [PMID:  15581425] 
[132] 
Rubin BK. Mucolytics, expectorants, and mucokinetic medications. Respir Care  2007; 52(7): 859-65.
[PMID:  17594730] 
[133] 
Tarrant BJ, Maitre CL, Romero L, et al. Mucoactive agents for adults with acute lung conditions: A systematic review. Heart Lung  2019; 48(2): 141-7.
[http://dx.doi.org/10.1016/j.hrtlng.2018.09.010] [PMID:  30409442] 
[134] 
Tarrant BJ, Le Maitre C, Romero L, et al. Mucoactive agents for chronic, non-cystic fibrosis lung disease: A systematic review and meta-analysis. Respirology  2017; 22(6): 1084-92.
[http://dx.doi.org/10.1111/resp.13047] [PMID:  28397992] 
[135] 
Ehre C, Rushton ZL, Wang B, et al. An improved inhaled mucolytic to treat airway muco-obstructive diseases. Am J Respir Crit Care Med  2019; 199(2): 171-80.
[http://dx.doi.org/10.1164/rccm.201802-0245OC] [PMID:  30212240] 
[136] 
Poole PJ, Black PN. Oral mucolytic drugs for exacerbations of chronic obstructive pulmonary disease: Systematic review. BMJ  2001; 322(7297): 1271-4.
[http://dx.doi.org/10.1136/bmj.322.7297.1271] [PMID:  11375228] 
[137] 
Gerrits CM, Herings RM, Leufkens HG, Lammers JW. N-acetylcysteine reduces the risk of re-hospitalisation among patients with chronic obstructive pulmonary disease. Eur Respir J  2003; 21(5): 795-8.
[http://dx.doi.org/10.1183/09031936.03.00063402] [PMID:  12765423] 
[138] 
Ernst P, Suissa S. N-acetylcysteine is unlikely to reduce hospitalisation for chronic obstructive pulmonary disease. Eur Respir J  2003; 22(5): 865.
[http://dx.doi.org/10.1183/09031936.03.00063403] [PMID:  14621098] 
[139] 
Sun T, Liu J, Zhao W. Zhao de W. Efficacy of N-acetylcysteine in idiopathic pulmonary fibrosis: A systematic review and meta-analysis. Medicine (Baltimore)  2016; 95(19) e3629
[http://dx.doi.org/10.1097/MD.0000000000003629] [PMID:  27175674] 
[140] 
Bridgeman MM, Marsden M, MacNee W, Flenley DC, Ryle AP. Cysteine and glutathione concentrations in plasma and bronchoalveolar lavage fluid after treatment with N-acetylcysteine. Thorax  1991; 46(1): 39-42.
[http://dx.doi.org/10.1136/thx.46.1.39] [PMID:  1871695] 
[141] 
Cotgreave IA, Eklund A, Larsson K, Moldéus PW. No penetration of orally administered N-acetylcysteine into bronchoalveolar lavage fluid. Eur J Respir Dis  1987; 70(2): 73-7.
[PMID:  3817074] 
[142] 
Rodenstein D, DeCoster A, Gazzaniga A. Pharmacokinetics of oral acetylcysteine: Absorption, binding and metabolism in patients with respiratory disorders. Clin Pharmacokinet  1978; 3(3): 247-54.
[http://dx.doi.org/10.2165/00003088-197803030-00005] [PMID:  657688] 
[143] 
Millar AB, Pavia D, Agnew JE, Lopez-Vidriero MT, Lauque D, Clarke SW. Effect of oral N-acetylcysteine on mucus clearance. Br J Dis Chest  1985; 79(3): 262-6.
[http://dx.doi.org/10.1016/0007-0971(85)90046-4] [PMID:  3893512] 
[144] 
Holdiness MR. Clinical pharmacokinetics of N-acetylcysteine. Clin Pharmacokinet  1991; 20(2): 123-34.
[http://dx.doi.org/10.2165/00003088-199120020-00004] [PMID:  2029805] 
[145] 
Pintucci JP, Corno S, Garotta M. Biofilms and infections of the upper respiratory tract. Eur Rev Med Pharmacol Sci  2010; 14(8): 683-90.
[PMID:  20707288] 
[146] 
Dinicola S, De Grazia S, Carlomagno G, Pintucci JP. N-acetylcysteine as powerful molecule to destroy bacterial biofilms. A systematic review. Eur Rev Med Pharmacol Sci  2014; 18(19): 2942-8.
[PMID:  25339490] 
[147] 
Smith A, Buchinsky FJ, Post JC. Eradicating chronic ear, nose, and throat infections: A systematically conducted literature review of advances in biofilm treatment. Otolaryngol Head Neck Surg  2011; 144(3): 338-47.
[http://dx.doi.org/10.1177/0194599810391620] [PMID:  21493193] 
[148] 
Bulut F, Meric F, Yorgancilar E, et al. Effects of N-acetyl-cysteine and acetylsalicylic acid on the tonsil bacterial biofilm tissues by light and electron microscopy. Eur Rev Med Pharmacol Sci  2014; 18(23): 3720-5.
[PMID:  25535147] 
[149] 
Blasi F, Page C, Rossolini GM, et al. The effect of N-acetylcysteine on biofilms: Implications for the treatment of respiratory tract infections. Respir Med  2016; 117: 190-7.
[http://dx.doi.org/10.1016/j.rmed.2016.06.015] [PMID:  27492531] 
[150] 
Moon JH, Choi YS, Lee HW, Heo JS, Chang SW, Lee JY. Antibacterial effects of N-acetylcysteine against endodontic pathogens. J Microbiol  2016; 54(4): 322-9.
[http://dx.doi.org/10.1007/s12275-016-5534-9] [PMID:  27033208] 
[151] 
Onger ME, Gocer H, Emir D, Kaplan S. N-acetylcysteine eradicates Pseudomonas aeruginosa biofilms in bone cement. Scanning  2016; 38(6): 766-70.
[http://dx.doi.org/10.1002/sca.21326] [PMID:  27186786] 
[152] 
Pei Y, Liu H, Yang Y, et al. Biological activities and potential oral applications of N-acetylcysteine: progress and prospects. Oxid Med Cell Longev  2018; 2018 2835787
[http://dx.doi.org/10.1155/2018/2835787] [PMID:  29849877] 
[153] 
Livingstone CR, Andrews MA, Jenkins SM, Marriott C. Model systems for the evaluation of mucolytic drugs: Acetylcysteine and S-carboxymethylcysteine. J Pharm Pharmacol  1990; 42(2): 73-8.
[http://dx.doi.org/10.1111/j.2042-7158.1990.tb05357.x] [PMID:  1972405] 
[154] 
Johnson K, McEvoy CE, Naqvi S, et al. High-dose oral N-acetylcysteine fails to improve respiratory health status in patients with chronic obstructive pulmonary disease and chronic bronchitis: A randomized, placebo-controlled trial. Int J Chron Obstruct Pulmon Dis  2016; 11: 799-807.
[PMID:  27143871] 
[155] 
Zheng JP, Wen FQ, Bai CX, et al. PANTHEON study group. Twice daily N-acetylcysteine 600 mg for exacerbations of chronic obstructive pulmonary disease (PANTHEON): A randomised, double-blind placebo-controlled trial. Lancet Respir Med  2014; 2(3): 187-94.
[http://dx.doi.org/10.1016/S2213-2600(13)70286-8] [PMID:  24621680] 
[156] 
Ziment I. Acetylcysteine: A drug that is much more than a mucokinetic. Biomed Pharmacother  1988; 42(8): 513-9.
[PMID:  3066412] 
[157] 
Tse HN, Tseng CZ. Update on the pathological processes, molecular biology, and clinical utility of N-acetylcysteine in chronic obstructive pulmonary disease. Int J Chron Obstruct Pulmon Dis  2014; 9: 825-36.
[http://dx.doi.org/10.2147/COPD.S51057] [PMID:  25125976] 
[158] 
Calzetta L, Matera MG, Rogliani P, Cazzola M. Multifaceted activity of N-acetyl-l-cysteine in chronic obstructive pulmonary disease. Expert Rev Respir Med  2018; 12(8): 693-708.
[http://dx.doi.org/10.1080/17476348.2018.1495562] [PMID:  29972340] 
[159] 
Lau A, Kennedy BK, Kirkland JL, Tullius SG. Mixing old and young: Enhancing rejuvenation and accelerating aging. J Clin Invest  2019; 129(1): 4-11.
[http://dx.doi.org/10.1172/JCI123946] [PMID:  30601138] 
[160] 
Neves J, Sousa-Victor P, Jasper H. Rejuvenating strategies for stem cell-based therapies in aging. Cell Stem Cell  2017; 20(2): 161-75.
[http://dx.doi.org/10.1016/j.stem.2017.01.008] [PMID:  28157498] 
[161] 
Zakrzewski W, Dobrzyński M, Szymonowicz M, Rybak Z. Stem cells: Past, present, and future. Stem Cell Res Ther  2019; 10(1): 68.
[http://dx.doi.org/10.1186/s13287-019-1165-5] [PMID:  30808416] 
[162] 
Blum B, Benvenisty N. The tumorigenicity of diploid and aneuploid human pluripotent stem cells. Cell Cycle  2009; 8(23): 3822-30.
[http://dx.doi.org/10.4161/cc.8.23.10067] [PMID:  19887907] 
[163] 
Mancuso P, Raman S, Glynn A, Barry F, Murphy JM. Mesenchymal stem cell therapy for osteoarthritis: The critical role of the cell secretome. Front Bioeng Biotechnol  2019; 7: 9.
[http://dx.doi.org/10.3389/fbioe.2019.00009] [PMID:  30761298] 
[164] 
Castro-Viñuelas R, Sanjurjo-Rodríguez C, Piñeiro-Ramil M, et al. Induced pluripotent stem cells for cartilage repair: Current status and future perspectives. Eur Cell Mater  2018; 36: 96-109.
[http://dx.doi.org/10.22203/eCM.v036a08] [PMID:  30204229] 
[165] 
Rashid H, Kwoh CK. Should platelet-rich plasma or stem cell therapy be used to treat osteoarthritis? Rheum Dis Clin North Am  2019; 45(3): 417-38.
[http://dx.doi.org/10.1016/j.rdc.2019.04.010] [PMID:  31277753] 
[166] 
Harrell CR, Markovic BS, Fellabaum C, Arsenijevic A, Volarevic V. Mesenchymal stem cell-based therapy of osteoarthritis: Current knowledge and future perspectives. Biomed Pharmacother  2019; 109: 2318-26.
[http://dx.doi.org/10.1016/j.biopha.2018.11.099] [PMID:  30551490] 
[167] 
Wang AT, Feng Y, Jia HH, Zhao M, Yu H. Application of mesenchymal stem cell therapy for the treatment of osteoarthritis of the knee: A concise review. World J Stem Cells  2019; 11(4): 222-35.
[http://dx.doi.org/10.4252/wjsc.v11.i4.222] [PMID:  31110603] 
[168] 
Berardis S, Dwisthi SP, Najimi M, Sokal EM. Use of mesenchymal stem cells to treat liver fibrosis: Current situation and future prospects. World J Gastroenterol  2015; 21(3): 742-58.
[http://dx.doi.org/10.3748/wjg.v21.i3.742] [PMID:  25624709] 
[169] 
Kwak KA, Cho HJ, Yang JY, Park YS. Current perspectives regarding stem cell-based therapy for liver cirrhosis. Can J Gastroenterol Hepatol  2018; 2018 4197857
[http://dx.doi.org/10.1155/2018/4197857] [PMID:  29670867] 
[170] 
Guo Y, Chen B, Chen LJ, Zhang CF, Xiang C. Current status and future prospects of mesenchymal stem cell therapy for liver fibrosis. J Zhejiang Univ Sci B  2016; 17(11): 831-41.
[http://dx.doi.org/10.1631/jzus.B1600101] [PMID:  27819130] 
[171] 
Marsh SE, Blurton-Jones M. Neural stem cell therapy for neurodegenerative disorders: The role of neurotrophic support. Neurochem Int  2017; 106: 94-100.
[http://dx.doi.org/10.1016/j.neuint.2017.02.006] [PMID:  28219641] 
[172] 
Walker PA, Shah SK, Harting MT, Cox CS. Progenitor cell therapies for traumatic brain injury: Barriers and opportunities in translation. Dis Model Mech  2009; 2(1-2): 23-38.
[http://dx.doi.org/10.1242/dmm.001198] [PMID:  19132123] 
[173] 
Fleifel D, Rahmoon MA, AlOkda A, Nasr M, Elserafy M, El-Khamisy SF. Recent advances in stem cells therapy: A focus on cancer, Parkinson’s and Alzheimer’s. J Genet Eng Biotechnol  2018; 16(2): 427-32.
[http://dx.doi.org/10.1016/j.jgeb.2018.09.002] [PMID:  30733756] 
[174] 
Scudellari M. How iPS cells changed the world. Nature  2016; 534(7607): 310-2.
[http://dx.doi.org/10.1038/534310a] [PMID:  27306170] 
[175] 
Tartaglione AM, Popoli P, Calamandrei G. Regenerative medicine in Huntington’s disease: Strengths and weaknesses of preclinical studies. Neurosci Biobehav Rev  2017; 77: 32-47.
[http://dx.doi.org/10.1016/j.neubiorev.2017.02.017] [PMID:  28223129] 
[176] 
Duncan T, Valenzuela M. Alzheimer’s disease, dementia, and stem cell therapy. Stem Cell Res Ther  2017; 8(1): 111.
[http://dx.doi.org/10.1186/s13287-017-0567-5] [PMID:  28494803] 
[177] 
Bardelli S, Moccetti M. Stem and progenitor cells in human cardiopulmonary development and regeneration. Stem Cells Int  2017; 2017 2653142
[http://dx.doi.org/10.1155/2017/2653142] [PMID:  29075297] 
[178] 
Fisher SA, Zhang H, Doree C, Mathur A, Martin-Rendon E. Stem cell treatment for acute myocardial infarction. Cochrane Database Syst Rev  2015; 9 CD006536
[http://dx.doi.org/10.1002/14651858.CD006536.pub4] [PMID:  26419913] 
[179] 
Fisher SA, Doree C, Mathur A, Taggart DP, Martin-Rendon E. Stem cell therapy for chronic ischaemic heart disease and congestive heart failure. Cochrane Database Syst Rev  2016; 12 CD007888
[http://dx.doi.org/10.1002/14651858.CD007888.pub3] [PMID:  28012165] 
[180] 
Tang JN, Cores J, Huang K, et al. Concise review: Is cardiac cell therapy dead? Embarrassing trial outcomes and new directions for the future. Stem Cells Transl Med  2018; 7(4): 354-9.
[http://dx.doi.org/10.1002/sctm.17-0196] [PMID:  29468830] 
[181] 
Yanamandala M, Zhu W, Garry DJ, et al. Overcoming the roadblocks to cardiac cell therapy using tissue engineering. J Am Coll Cardiol  2017; 70(6): 766-75.
[http://dx.doi.org/10.1016/j.jacc.2017.06.012] [PMID:  28774384] 
[182] 
Bareeqa SB, Bibi F, Ahmed SI, Samar SS. Advancement in stem cell therapy for ischemic myocardial cell: A systematic review. Int J Hematol Oncol Stem Cell Res  2018; 12(4): 282-90.
[http://dx.doi.org/10.18502/ijhoscr.v12i4.106] [PMID:  30774828] 
[183] 
Wernly B, Mirna M, Rezar R, et al. Regenerative cardiovascular therapies: Stem cells and beyond. Int J Mol Sci  2019; 20(6) E1420
[http://dx.doi.org/10.3390/ijms20061420] [PMID:  30901815] 
[184] 
Toyserkani NM, Jørgensen MG, Tabatabaeifar S, Jensen CH, Sheikh SP, Sørensen JA. Concise review: A safety assessment of adipose-derived cell therapy in clinical trials: A systematic review of reported adverse events. Stem Cells Transl Med  2017; 6(9): 1786-94.
[http://dx.doi.org/10.1002/sctm.17-0031] [PMID:  28722289] 
[185] 
A futile cycle in cell therapy. Nat Biotechnol  2017; 35(4): 291.
[http://dx.doi.org/10.1038/nbt.3857] [PMID:  28398319] 
[186] 
Comella K, Parcero J, Bansal H, et al. Effects of the intramyocardial implantation of stromal vascular fraction in patients with chronic ischemic cardiomyopathy. J Transl Med  2016; 14(1): 158.
[http://dx.doi.org/10.1186/s12967-016-0918-5] [PMID:  27255774] 
[187] 
van den Akker F, de Jager SC, Sluijter JP. Mesenchymal stem cell therapy for cardiac inflammation: Immunomodulatory properties and the influence of toll-like receptors. Mediators Inflamm  2013; 2013 181020
[http://dx.doi.org/10.1155/2013/181020] [PMID:  24391353] 
[188] 
Jeong H, Yim HW, Park HJ, et al. Mesenchymal stem cell therapy for ischemic heart disease: Systematic review and meta-analysis. Int J Stem Cells  2018; 11(1): 1-12.
[http://dx.doi.org/10.15283/ijsc17061] [PMID:  29482311] 
[189] 
Ullah M, Sun Z. Stem cells and anti-aging genes: Double-edged sword-do the same job of life extension. Stem Cell Res Ther  2018; 9(1): 3.
[http://dx.doi.org/10.1186/s13287-017-0746-4] [PMID:  29321045] 
[190] 
Terzic A, Behfar A. Posology for regenerative therapy. Circ Res  2017; 121(11): 1213-5.
[http://dx.doi.org/10.1161/CIRCRESAHA.117.312074] [PMID:  29122941] 
[191] 
Tasso R, Pennesi G. When stem cells meet immunoregulation. Int Immunopharmacol  2009; 9(5): 596-8.
[http://dx.doi.org/10.1016/j.intimp.2009.01.014] [PMID:  19539568] 
[192] 
Suncion VY, Ghersin E, Fishman JE, et al. Does transendocardial injection of mesenchymal stem cells improve myocardial function locally or globally?: An analysis from the Percutaneous Stem Cell Injection Delivery Effects on Neomyogenesis (POSEIDON) randomized trial. Circ Res  2014; 114(8): 1292-301.
[http://dx.doi.org/10.1161/CIRCRESAHA.114.302854] [PMID:  24449819] 
[193] 
Kirillov AM, Fatkhudinov TK, Dyachkov AV, Koroteev AV, Goldshtein DV, Bochkov NP. Transplantation of allogenic cells in the therapy of patients with dilated cardiomyopathy. Bull Exp Biol Med  2007; 144(4): 635-9.
[http://dx.doi.org/10.1007/s10517-007-0392-4] [PMID:  18642728] 
[194] 
Schoenhard JA, Hatzopoulos AK. Stem cell therapy: Pieces of the puzzle. J Cardiovasc Transl Res  2010; 3(1): 49-60.
[http://dx.doi.org/10.1007/s12265-009-9148-z] [PMID:  20119487] 
[195] 
Bilgimol JC, Ragupathi S, Vengadassalapathy L, et al. Stem cells: An eventual treatment option for heart diseases. World J Stem Cells  2015; 7(8): 1118-26.
[http://dx.doi.org/10.4252/wjsc.v7.i8.1118] [PMID:  26435771] 
[196] 
Jargin SV. Scientific misconduct and related topics. Am J Exp Clin Res  2017; 4(1): 197-201.
[197] 
Jargin SV. Invasive procedures with questionable indications. Ann Med Surg (Lond)  2014; 3(4): 126-9.
[http://dx.doi.org/10.1016/j.amsu.2014.06.003] [PMID:  25568799] 
[198] 
Shomina EA, Yarygin NV, Yarygin KN. Unproven stem-cell therapy ban. Nature  2018; 454: 923.
[199] 
Rossbauer M. Unproven stem-cell therapy ban. Nature  2008; 454(7207): 923.
[http://dx.doi.org/10.1038/454923a] [PMID:  18719550] 
[200] 
Qiu J. China clamps down on controversial therapies. Lancet  2009; 373(9678): 1834-5.
[http://dx.doi.org/10.1016/S0140-6736(09)61007-2] [PMID:  19504665] 
[201] 
Foddy B. A duty to deceive: Placebos in clinical practice. Am J Bioeth  2009; 9(12): 4-12.
[http://dx.doi.org/10.1080/15265160903318350] [PMID:  20013484] 
[202] 
Hróbjartsson A. Clinical placebo interventions are unethical, unnecessary, and unprofessional. J Clin Ethics  2008; 19(1): 66-9.
[PMID:  18552056] 
[203] 
Linde K, Fässler M, Meissner K. Placebo interventions, placebo effects and clinical practice. Philos Trans R Soc Lond B Biol Sci  2011; 366(1572): 1905-12.
[http://dx.doi.org/10.1098/rstb.2010.0383] [PMID:  21576148] 
[204] 
Jargin SV. Urological concern after nuclear accidents. Urol Ann  2018; 10(3): 240-2.
[http://dx.doi.org/10.4103/0974-7796.236525] [PMID:  30089979] 
[205] 
Jargin SV. Renal biopsy research with implications for therapy of glomerulonephritis. Curr Drug Ther  2012; 7(4): 263-7.
[http://dx.doi.org/10.2174/157488512804999055] 
[206] 
Smith R. Research misconduct: The poisoning of the well. J R Soc Med  2006; 99(5): 232-7.
[http://dx.doi.org/10.1177/014107680609900514] [PMID:  16672756] 
[207] 
Jargin SV. Pathology in the former Soviet Union: Scientific misconduct and related phenomena. Dermatol Pract Concept  2011; 1(1): 75-81.
[http://dx.doi.org/10.5826/dpc.0101a16] [PMID:  24396725] 
[208] 
Jargin SV. Discussion of Evaluation of cholesterol-lowering and antioxidant properties of sugar cane policosanols in hamsters and humans. Appl Physiol Nutr Metab  2009; 34(1): 75.
[http://dx.doi.org/10.1139/H08-141] [PMID:  19234588] 
[209] 
Jargin SV. Calf hemodialysate hypothesis: Nutritive value plus placebo effect. Med Hypotheses  2017; 109: 95-6.
[http://dx.doi.org/10.1016/j.mehy.2017.09.029] [PMID:  29150305] 
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DOI https://dx.doi.org/10.2174/1872211313666190819124752	Print ISSN 1872-2113
Publisher Name Bentham Science Publisher	Online ISSN 2212-4039
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