Therapeutic Options for Homozygous Familial Hypercholesterolemia: The Role of Lomitapide

Author(s): Antonina Giammanco, Angelo B. Cefalù, Davide Noto, Maurizio R. Averna*

Journal Name: Current Medicinal Chemistry

Volume 27 , Issue 23 , 2020

  Journal Home
Translate in Chinese
Become EABM
Become Reviewer
Call for Editor


Background: Lomitapide (Juxtapid® in US and Lojuxta® in Europe) is the first developed inhibitor of the Microsomal Triglyceride Transfer Protein (MTP) approved as a novel drug for the management of Homozygous Familial Hypercholesterolemia (HoFH). It acts by binding directly and selectively to MTP thus decreasing the assembly and secretion of the apo-B containing lipoproteins both in the liver and in the intestine.

Aims: The present review aims at summarizing the recent knowledge on lomitapide in the management of HoFH.

Results: The efficacy and safety of lomitapide have been evaluated in several trials and it has been shown a reduction of the plasma levels of Low-Density Lipoprotein Cholesterol (LDL-C) by an average of more than 50%. Although the most common side effects are gastrointestinal and liver events, lomitapide presents generally with a good tolerability and satisfactory patients compliance. Recently, in Europe, to evaluate the long-term safety and efficacy of lomitapide, the LOWER registry ( Identifier: NCT02135705) has been established in order to acquire informations on HoFH lomitapidetreated patients from “real life” clinical practice.

Furthermore, the observation that lomitapide decreases triglyceride levels may be considered for patients affected by severe forms of hypertriglyceridemia who undergo recurrent episodes of pancreatitis and are poor responders to conventional treatment.

Conclusion: Lomitapide represents an innovative and efficacious drug for the treatment of HoFH. Longterm safety data, treatment of pediatric and pregnant HoFH patients and management of severe hypertriglyceridemia still require further investigations.

Keywords: HoFH, Lomitapide, LOWER Registry, MTP inhibition, MTP SNPs, Autosomal Dominant Hypercholesterolemia (ADH).

Sjouke, B.; Hovingh, G.K.; Kastelein, J.J.P.; Stefanutti, C. Homozygous autosomal dominant hypercholesterolaemia: prevalence, diagnosis, and current and future treatment perspectives. Curr. Opin. Lipidol., 2015, 26(3), 200-209.
[] [PMID: 25950706]
Hartgers, M.L.; Ray, K.K.; Hovingh, G.K. New approaches in detection and treatment of familial hypercholesterolemia. Curr. Cardiol. Rep., 2015, 17(12), 109.
[] [PMID: 26482752]
Patel, R.S.; Scopelliti, E.M.; Savelloni, J. Therapeutic management of familial hypercholesterolemia: current and emerging drug therapies. Pharmacotherapy, 2015, 35(12), 1189-1203.
[] [PMID: 26684558]
Stefanutti, C.; Morozzi, C.; Di Giacomo, S.; Sovrano, B.; Mesce, D.; Grossi, A. Management of homozygous familial hypercholesterolemia in real-world clinical practice: A report of 7 Italian patients treated in Rome with lomitapide and lipoprotein apheresis. J. Clin. Lipidol., 2016, 10(4), 782-789.
[] [PMID: 27578108]
Pisciotta, L.; Priore Oliva, C.; Pes, G.M.; Di Scala, L.; Bellocchio, A.; Fresa, R.; Cantafora, A.; Arca, M.; Calandra, S.; Bertolini, S. Autosomal recessive hypercholesterolemia (ARH) and homozygous familial hypercholesterolemia (FH): a phenotypic comparison. Atherosclerosis, 2006, 188(2), 398-405.
[] [PMID: 16343504]
Nordestgaard, B.G.; Chapman, M.J.; Humphries, S.E.; Ginsberg, H.N.; Masana, L.; Descamps, O.S.; Wiklund, O.; Hegele, R.A.; Raal, F.J.; Defesche, J.C.; Wiegman, A.; Santos, R.D.; Watts, G.F.; Parhofer, K.G.; Hovingh, G.K.; Kovanen, P.T.; Boileau, C.; Averna, M.; Borén, J.; Bruckert, E.; Catapano, A.L.; Kuivenhoven, J.A.; Pajukanta, P.; Ray, K.; Stalenhoef, A.F.; Stroes, E.; Taskinen, M.R.; Tybjærg-Hansen, A. European Atherosclerosis Society Consensus Panel. Familial hypercholesterolaemia is underdiagnosed and undertreated in the general population: guidance for clinicians to prevent coronary heart disease: consensus statement of the European Atherosclerosis Society. Eur. Heart J., 2013, 34(45), 3478-90a.
[] [PMID: 23956253]
Cuchel, M.; Bruckert, E.; Ginsberg, H.N.; Raal, F.J.; Santos, R.D.; Hegele, R.A.; Kuivenhoven, J.A.; Nordestgaard, B.G.; Descamps, O.S.; Steinhagen-Thiessen, E.; Tybjærg-Hansen, A.; Watts, G.F.; Averna, M.; Boileau, C.; Borén, J.; Catapano, A.L.; Defesche, J.C.; Hovingh, G.K.; Humphries, S.E.; Kovanen, P.T.; Masana, L.; Pajukanta, P.; Parhofer, K.G.; Ray, K.K.; Stalenhoef, A.F.; Stroes, E.; Taskinen, M.R.; Wiegman, A.; Wiklund, O.; Chapman, M.J. European Atherosclerosis Society Consensus Panel on Familial Hypercholesterolaemia. Homozygous familial hypercholesterolaemia: new insights and guidance for clinicians to improve detection and clinical management. A position paper from the Consensus Panel on Familial Hypercholesterolaemia of the European Atherosclerosis Society. Eur. Heart J., 2014, 35(32), 2146-2157.
[] [PMID: 25053660]
Sjouke, B.; Kusters, D.M.; Kindt, I.; Besseling, J.; Defesche, J.C.; Sijbrands, E.J.; Roeters van Lennep, J.E.; Stalenhoef, A.F.; Wiegman, A.; de Graaf, J.; Fouchier, S.W.; Kastelein, J.J.; Hovingh, G.K. Homozygous autosomal dominant hypercholesterolaemia in the Netherlands: prevalence, genotype-phenotype relationship, and clinical outcome. Eur. Heart J., 2015, 36(9), 560-565.
[] [PMID: 24585268]
France, M. Homozygous familial hypercholesterolaemia: update on management. Paediatr. Int. Child Health, 2016, 36(4), 243-247.
[] [PMID: 27967828]
Bertolini, S.; Pisciotta, L.; Rabacchi, C.; Cefalù, A.B.; Noto, D.; Fasano, T.; Signori, A.; Fresa, R.; Averna, M.; Calandra, S. Spectrum of mutations and phenotypic expression in patients with autosomal dominant hypercholesterolemia identified in Italy. Atherosclerosis, 2013, 227(2), 342-348.
[] [PMID: 23375686]
Blom, D.J.; Fayad, Z.A.; Kastelein, J.J.; Larrey, D.; Makris, L.; Schwamlein, C.; Bloeden, L.; Underberg, J. LOWER investigators. LOWER, a registry of lomitapide-treated patients with homozygous familial hypercholesterolemia: Rationale and design. J. Clin. Lipidol., 2016, 10(2), 273-282.
[] [PMID: 27055957]
Panno, M.D.; Cefalù, A.B.; Averna, M.R. Lomitapide: a novel drug for homozygous familial hypercholesterolemia. Clin. Lipidol., 2014, 9, 19-32.
Davis, K.A.; Miyares, M.A. Lomitapide: A novel agent for the treatment of homozygous familial hypercholesterolemia. Am. J. Health Syst. Pharm., 2014, 71(12), 1001-1008.
[] [PMID: 24865757]
Rader, D.J.; Kastelein, J.J. Lomitapide and mipomersen: two first-in-class drugs for reducing low-density lipoprotein cholesterol in patients with homozygous familial hypercholesterolemia. Circulation, 2014, 129(9), 1022-1032.
[] [PMID: 24589695]
Averna, M.; Cefalù, A.B.; Stefanutti, C.; Di Giacomo, S.; Sirtori, C.R.; Vigna, G. Individual analysis of patients with HoFH participating in a phase 3 trial with lomitapide: The Italian cohort. Nutr. Metab. Cardiovasc. Dis., 2016, 26(1), 36-44.
[] [PMID: 26723464]
Farnier, M.; Bruckert, E. Severe familial hypercholesterolaemia: current and future management. Arch. Cardiovasc. Dis., 2012, 105(12), 656-665.
[] [PMID: 23199621]
Sanchez, A.P.; Cunard, R.; Ward, D.M. The selective therapeutic apheresis procedures. J. Clin. Apher., 2013, 28(1), 20-29.
[] [PMID: 23420592]
Thompson, G.R.; Miller, J.P.; Breslow, J.L. Improved survival of patients with homozygous familial hypercholesterolaemia treated with plasma exchange. Br. Med. J. (Clin. Res. Ed.), 1985, 291(6510), 1671-1673.
[] [PMID: 3935235]
Catapano, A.L.; Graham, I.; De Backer, G.; Wiklund, O.; Chapman, M.J.; Drexel, H.; Hoes, A.W.; Jennings, C.S.; Landmesser, U.; Pedersen, T.R.; Reiner, Ž.; Riccardi, G.; Taskinen, M.R.; Tokgozoglu, L.; Verschuren, W.M.M.; Vlachopoulos, C.; Wood, D.A.; Zamorano, J.L.; Cooney, M.T. ESC Scientific Document Group. 2016 ESC/EAS guidelines for the management of dyslipidaemias. Eur. Heart J., 2016, 37(39), 2999-3058.
[] [PMID: 27567407]
Robinson, J.G. Management of familial hypercholesterolemia: a review of the recommendations from the national lipid association expert panel on familial hypercholesterolemia. J. Manag. Care Pharm., 2013, 19(2), 139-149.
[] [PMID: 23461430]
Watts, G.F.; Gidding, S.; Wierzbicki, A.S.; Toth, P.P.; Alonso, R.; Brown, W.V.; Bruckert, E.; Defesche, J.; Lin, K.K.; Livingston, M.; Mata, P.; Parhofer, K.G.; Raal, F.J.; Santos, R.D.; Sijbrands, E.J.; Simpson, W.G.; Sullivan, D.R.; Susekov, A.V.; Tomlinson, B.; Wiegman, A.; Yamashita, S.; Kastelein, J.J.; International, F.H. Integrated guidance on the care of familial hypercholesterolemia from the International FH Foundation. J. Clin. Lipidol., 2014, 8(2), 148-172.
[] [PMID: 24636175]
Maron, D.J.; Fazio, S.; Linton, M.F. Current perspectives on statins. Circulation, 2000, 101(2), 207-213.
[] [PMID: 10637210]
Thompson, G.R.; Barbir, M.; Davies, D.; Dobral, P.; Gesinde, M.; Livingston, M.; Mandry, P.; Marais, A.D.; Matthews, S.; Neuwirth, C.; Pottle, A.; le Roux, C.; Scullard, D.; Tyler, C.; Watkins, S. Efficacy criteria and cholesterol targets for LDL apheresis. Atherosclerosis, 2010, 208(2), 317-321.
[] [PMID: 19589528]
Mabuchi, H.; Koizumi, J.; Shimizu, M.; Kajinami, K.; Miyamoto, S.; Ueda, K.; Takegoshi, T. Hokuriku-FH-LDL-Apheresis Study Group. Long-term efficacy of low-density lipoprotein apheresis on coronary heart disease in familial hypercholesterolemia. Am. J. Cardiol., 1998, 82(12), 1489-1495.
[] [PMID: 9874053]
Stefanutti, C.; Blom, D.J.; Averna, M.R.; Meagher, E.A.; Theron, Hd.; Marais, A.D.; Hegele, R.A.; Sirtori, C.R.; Shah, P.K.; Gaudet, D.; Vigna, G.B.; Sachais, B.S.; Di Giacomo, S.; du Plessis, A.M.; Bloedon, L.T.; Balser, J.; Rader, D.J.; Cuchel, M. Phase 3 HoFH Lomitapide Study Investigators. The lipid-lowering effects of lomitapide are unaffected by adjunctive apheresis in patients with homozygous familial hypercholesterolaemia - a post-hoc analysis of a Phase 3, single-arm, open-label trial. Atherosclerosis, 2015, 240(2), 408-414.
[] [PMID: 25897792]
Thompson, G.R. Managing homozygous familial hypercholesterolaemia from cradle to grave. Atheroscler. Suppl., 2015, 18, 16-20.
[] [PMID: 25936299]
Schuff-Werner, P.; Fenger, S.; Kohlschein, P. Role of lipid apheresis in changing times. Clin. Res. Cardiol. Suppl., 2012, 7, 7-14.
[] [PMID: 22911176]
Thompson, G.R. HEART-UK LDL Apheresis Working Group. Recommendations for the use of LDL apheresis. Atherosclerosis, 2008, 198(2), 247-255.
[] [PMID: 18371971]
Seidah, N.G.; Benjannet, S.; Wickham, L.; Marcinkiewicz, J.; Jasmin, S.B.; Stifani, S.; Basak, A.; Prat, A.; Chretien, M. The secretory proprotein convertase neural apoptosis-regulated convertase 1 (NARC-1): liver regeneration and neuronal differentiation. Proc. Natl. Acad. Sci. USA, 2003, 100(3), 928-933.
[] [PMID: 12552133]
Fasano, T.; Cefalù, A.B.; Di Leo, E.; Noto, D.; Pollaccia, D.; Bocchi, L.; Valenti, V.; Bonardi, R.; Guardamagna, O.; Averna, M.; Tarugi, P. A novel loss of function mutation of PCSK9 gene in white subjects with low-plasma low-density lipoprotein cholesterol. Arterioscler. Thromb. Vasc. Biol., 2007, 27(3), 677-681.
[] [PMID: 17170371]
Cohen, J.C.; Boerwinkle, E.; Mosley, T.H., Jr; Hobbs, H.H. Sequence variations in PCSK9, low LDL, and protection against coronary heart disease. N. Engl. J. Med., 2006, 354(12), 1264-1272.
[] [PMID: 16554528]
Noto, D.; Giammanco, A.; Barbagallo, C.M.; Cefalù, A.B.; Averna, M.R. Anti-PCSK9 treatment: Is ultra-low LDL always good? Cardiovasc. Res., 2018, 114(12), 1595-1604.
[] [PMID: 29931148]
Abifadel, M.; Varret, M.; Rabès, J.P.; Allard, D.; Ouguerram, K.; Devillers, M.; Cruaud, C.; Benjannet, S.; Wickham, L.; Erlich, D.; Derré, A.; Villéger, L.; Farnier, M.; Beucler, I.; Bruckert, E.; Chambaz, J.; Chanu, B.; Lecerf, J.M.; Luc, G.; Moulin, P.; Weissenbach, J.; Prat, A.; Krempf, M.; Junien, C.; Seidah, N.G.; Boileau, C. Mutations in PCSK9 cause autosomal dominant hypercholesterolemia. Nat. Genet., 2003, 34(2), 154-156.
[] [PMID: 12730697]
Robinson, J.G.; Farnier, M.; Krempf, M.; Bergeron, J.; Luc, G.; Averna, M.; Stroes, E.S.; Langslet, G.; Raal, F.J.; El Shahawy, M.; Koren, M.J.; Lepor, N.E.; Lorenzato, C.; Pordy, R.; Chaudhari, U.; Kastelein, J.J. ODYSSEY LONG TERM Investigators. Efficacy and safety of alirocumab in reducing lipids and cardiovascular events. N. Engl. J. Med., 2015, 372(16), 1489-1499.
[] [PMID: 25773378]
Sabatine, M.S.; Giugliano, R.P.; Wiviott, S.D.; Raal, F.J.; Blom, D.J.; Robinson, J.; Ballantyne, C.M.; Somaratne, R.; Legg, J.; Wasserman, S.M.; Scott, R.; Koren, M.J.; Stein, E.A. Open-Label Study of Long-Term Evaluation against LDL Cholesterol (OSLER) Investigators. Efficacy and safety of evolocumab in reducing lipids and cardiovascular events. N. Engl. J. Med., 2015, 372(16), 1500-1509.
[] [PMID: 25773607]
Stein, E.A.; Honarpour, N.; Wasserman, S.M.; Xu, F.; Scott, R.; Raal, F.J. Effect of the proprotein convertase subtilisin/kexin 9 monoclonal antibody, AMG 145, in homozygous familial hypercholesterolemia. Circulation, 2013, 128(19), 2113-2120.
[] [PMID: 24014831]
Raal, F.J.; Hovingh, G.K.; Blom, D.; Santos, R.D.; Harada-Shiba, M.; Bruckert, E.; Couture, P.; Soran, H.; Watts, G.F.; Kurtz, C.; Honarpour, N.; Tang, L.; Kasichayanula, S.; Wasserman, S.M.; Stein, E.A. Long-term treatment with evolocumab added to conventional drug therapy, with or without apheresis, in patients with homozygous familial hypercholesterolaemia: an interim subset analysis of the open-label TAUSSIG study. Lancet Diabetes Endocrinol., 2017, 5(4), 280-290.
[] [PMID: 28215937]
Guerin, M. Reverse cholesterol transport in familial hypercholesterolemia. Curr. Opin. Lipidol., 2012, 23(4), 377-385.
[] [PMID: 22510809]
Ballantyne, C.M.; Shah, S.; Kher, U.; Hunter, J.A.; Gill, G.G.; Cressman, M.D.; Ashraf, T.B.; Johnson-Levonas, A.O.; Mitchel, Y.B. Lipid-modifying efficacy and tolerability of anacetrapib added to ongoing statin therapy in patients with hypercholesterolemia or Low high-density lipoprotein cholesterol. Am. J. Cardiol., 2017, 119(3), 388-396.
[] [PMID: 27956003]
Gouni-Berthold, I.; Berthold, H.K. Mipomersen and lomitapide: Two new drugs for the treatment of homozygous familial hypercholesterolemia. Atheroscler. Suppl., 2015, 18, 28-34.
[] [PMID: 25936301]
Hussain, M.M.; Rava, P.; Walsh, M.; Rana, M.; Iqbal, J. Multiple functions of microsomal triglyceride transfer protein. Nutr. Metab. (Lond.), 2012, 9, 14.
[] [PMID: 22353470]
Goldberg, A.C. Emerging low-density lipoprotein therapies: Microsomal triglyceride transfer protein inhibitors. J. Clin. Lipidol., 2013, 7(3)(Suppl.), S16-S20.
[] [PMID: 23642324]
Gordon, D.A.; Jamil, H. Progress towards understanding the role of microsomal triglyceride transfer protein in apolipoprotein-B lipoprotein assembly. Biochim. Biophys. Acta, 2000, 1486(1), 72-83.
[] [PMID: 10856714]
Vuorio, A.; Tikkanen, M.J.; Kovanen, P.T. Inhibition of hepatic microsomal triglyceride transfer protein - a novel therapeutic option for treatment of homozygous familial hypercholesterolemia. Vasc. Health Risk Manag., 2014, 10, 263-270.
[] [PMID: 24851052]
Haghpassand, M.; Wilder, D.; Moberly, J.B. Inhibition of apolipoprotein B and triglyceride secretion in human hepatoma cells (HepG2). J. Lipid Res., 1996, 37(7), 1468-1480.
[PMID: 8827519]
Cuchel, M.; Meagher, E.A.; du Toit Theron, H.; Blom, D.J.; Marais, A.D.; Hegele, R.A.; Averna, M.R.; Sirtori, C.R.; Shah, P.K.; Gaudet, D.; Stefanutti, C.; Vigna, G.B.; Du Plessis, A.M.; Propert, K.J.; Sasiela, W.J.; Bloedon, L.T.; Rader, D.J. Phase 3 HoFH Lomitapide Study investigators. Efficacy and safety of a microsomal triglyceride transfer protein inhibitor in patients with homozygous familial hypercholesterolaemia: a single-arm, open-label, phase 3 study. Lancet, 2013, 381(9860), 40-46.
[] [PMID: 23122768]
Blom, D.J.; Averna, M.R.; Meagher, E.A.; du Toit Theron, H.; Sirtori, C.R.; Hegele, R.A.; Shah, P.K.; Gaudet, D.; Stefanutti, C.; Vigna, G.B.; Larrey, D.; Bloedon, L.T.; Foulds, P.; Rader, D.J.; Cuchel, M. Long-term efficacy and safety of the microsomal triglyceride transfer protein inhibitor lomitapide in patients with homozygous familial hypercholesterolemia. Circulation, 2017, 136(3), 332-335.
[] [PMID: 28716835]
D’Erasmo, L.; Cefalù, A.B.; Noto, D.; Giammanco, A.; Averna, M.; Pintus, P.; Medde, P.; Vigna, G.B.; Sirtori, C.; Calabresi, L.; Pavanello, C.; Bucci, M.; Sabbà, C.; Suppressa, P.; Natale, F.; Calabrò, P.; Sampietro, T.; Bigazzi, F.; Sbrana, F.; Bonomo, K.; Sileo, F.; Arca, M. Efficacy of lomitapide in the treatment of familial homozygous hypercholesterolemia: results of a real-world clinical experience in Italy. Adv. Ther., 2017, 34(5), 1200-1210.
[] [PMID: 28432645]
Harada-Shiba, M.; Ikewaki, K.; Nohara, A.; Otsubo, Y.; Yanagi, K.; Yoshida, M.; Chang, Q.; Foulds, P. Efficacy and safety of lomitapide in japanese patients with homozygous familial hypercholesterolemia. J. Atheroscler. Thromb., 2017, 24(4), 402-411.
[] [PMID: 28154305]
Aegerion Pharmaceuticals Juxtapid Prescribing Information, 2015.Available at:.
Berberich, A.J.; Hegele, R.A. Lomitapide for the treatment of hypercholesterolemia. Expert Opin. Pharmacother., 2017, 18(12), 1261-1268.
[] [PMID: 28598687]
Cuchel, M.; Blom, D.J.; Averna, M.R. Clinical experience of lomitapide therapy in patients with homozygous familial hypercholesterolaemia. Atheroscler. Suppl., 2014, 15(2), 33-45.
[] [PMID: 25257075]
Won, J.I.; Zhang, J.; Tecson, K.M.; McCullough, P.A. Balancing low-density lipoprotein cholesterol reduction and hepatotoxicity with lomitapide mesylate and mipomersen in patients with homozygous familial hypercholesterolemia. Rev. Cardiovasc. Med., 2017, 18(1), 21-28.
[PMID: 28509890]
Sacks, F.M.; Stanesa, M.; Hegele, R.A. Progression to hepatitis and fibrosis secondary to lomitapide use--reply. JAMA Intern. Med., 2014, 174(9), 1522-1523.
[] [PMID: 25178869]
Brown, W.V.; Bramlet, D.A.; Ross, J.L.; Underberg, J.A. JCL roundtable: Risk evaluation and mitigation strategy. J. Clin. Lipidol., 2016, 10(6), 1288-1296.
[] [PMID: 27919344]
France, M.; Rees, A.; Datta, D.; Thompson, G.; Capps, N.; Ferns, G.; Ramaswami, U.; Seed, M.; Neely, D.; Cramb, R.; Shoulders, C.; Barbir, M.; Pottle, A.; Eatough, R.; Martin, S.; Bayly, G.; Simpson, B.; Halcox, J.; Edwards, R.; Main, L.; Payne, J.; Soran, H. for HEART UK Medical Scientific and Research Committee. HEART UK statement on the management of homozygous familial hypercholesterolaemia in the United Kingdom. Atherosclerosis, 2016, 255, 128-139.
[] [PMID: 27839699]
Roeters van Lennep, J.; Averna, M.; Alonso, R. Treating homozygous familial hypercholesterolemia in a real-world setting: Experiences with lomitapide. J. Clin. Lipidol., 2015, 9(4), 607-617.
[] [PMID: 26228681]
Leipold, R.; Raal, F.; Ishak, J.; Hovingh, K.; Phillips, H. The effect of lomitapide on cardiovascular outcome measures in homozygous familial hypercholesterolemia: a modeling analysis., Eur. J. Prev. Cardiol,. 2017, 01-8.
Brahm, A.J.; Hegele, R.A. Lomitapide for the treatment of hypertriglyceridemia. Expert Opin. Investig. Drugs, 2016, 25(12), 1457-1463.
[] [PMID: 27785928]
Brahm, A.J.; Hegele, R.A. Lomitapide for the treatment of hypertriglyceridemia. Drug Evaluation, 2016, 25(12), 1457-1463.
Kolovou, G.D.; Kolovou, V.; Papadopoulou, A.; Watts, G.F.J. MTP Gene variants and response to lomitapide in patients with homozygous familial hypercholesterolemia. J. Atheroscler. Thromb., 2016, 23(7), 878-883.
[] [PMID: 27170061]

Rights & PermissionsPrintExport Cite as

Article Details

Year: 2020
Published on: 21 January, 2019
Page: [3773 - 3783]
Pages: 11
DOI: 10.2174/0929867326666190121120735
Price: $65

Article Metrics

PDF: 33