nach oben

Drugs

Erschienen in:

01.03.2016 | Current Opinion

Managing Metastatic Castration-Resistant Prostate Cancer in the Pre-chemotherapy Setting: A Changing Approach in the Era of New Targeted Agents

verfasst von: Zafeiris Zafeiriou, Anuradha Jayaram, Adam Sharp, Johann S. de Bono

Erschienen in: Drugs | Ausgabe 4/2016

Einloggen, um Zugang zu erhalten

Abstract

In recent years, the therapeutic options for treating men with metastatic castration-resistant prostate cancer have increased substantially. The hormonal treatments abiraterone acetate and enzalutamide, the chemotherapeutics docetaxel and cabazitaxel, the radiopharmaceutical alpharadin and the immunotherapeutic Sipuleucel-T have entered the field. Additionally, corticosteroids, which are used extensively, have documented activity but no documented survival benefit. Physicians treating patients with metastatic prostate cancer immediately after castration resistance develops currently have at least four different options to choose from for the first treatment. These therapeutic choices and their several possible ways of sequential use have not yet been compared to each other head-to-head and may never be. Therefore, there is an unmet need to inform their use with prospective clinical data. Additionally, the new indications of docetaxel for hormone naïve prostate cancer is changing the landscape of prostate cancer treatment and questions the traditional classifications ‘pre-chemotherapy’ and ‘post-chemotherapy’. In this work we attempt to address these challenges in the treatment of metastatic castration-resistant prostate cancer with the focus mainly on the non-cytotoxic agents. We try to integrate available clinical and preclinical information to suggest optimal ways of treatment.

Nur mit Berechtigung zugänglich

Ferlay J, Soerjomataram I, Ervik M, Dikshit R, Eser S, Mathers C, et al. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer 2015;136(5):E359–E386. doi:10.1038/nature14406

Buzzoni C, Auvinen A, Roobol MJ, Carlsson S, Moss SM, Puliti D, de Koning HJ, Bangma CH, Denis LJ, Kwiatkowski M, et al. Metastatic prostate cancer incidence and prostate-specific antigen testing: new insights from the european randomized study of screening for prostate cancer. Eur Urol. 2015. doi:10.1016/j.eururo.2015.02.042.PubMed

Prostate Cancer Trialists’ Collaborative Group. Maximum androgen blockade in advanced prostate cancer: an overview of the randomised trials. Lancet 2000;355:1491–1498.

Crawford ED, Eisenberger MA, McLeod DG, Spaulding JT, Benson R, Dorr FA, Blumenstein BA, Davis MA, Goodman PJ. A controlled trial of leuprolide with and without flutamide in prostatic carcinoma. N Engl J Med. 1989;321:419–24.CrossRefPubMed

Ryan CJ, Smith MR, de Bono JS, Molina A, Logothetis CJ, de Souza P, Fizazi K, Mainwaring P, Piulats JM, Ng S, et al. Abiraterone in metastatic prostate cancer without previous chemotherapy. N Engl J Med. 2013;368:138–48.CrossRefPubMedPubMedCentral

Beer TM, Armstrong AJ, Rathkopf DE, Loriot Y, Sternberg CN, Higano CS, Iversen P, Bhattacharya S, Carles J, Chowdhury S, et al. Enzalutamide in metastatic prostate cancer before chemotherapy. N Engl J Med. 2014;371:424–33.CrossRefPubMedPubMedCentral

Robinson D, Van Allen EM, Wu Y-M, Schultz N, Lonigro RJ, Mosquera J-M, Montgomery B, Taplin M-E, Pritchard CC, Attard G, et al. Integrative clinical genomics of advanced prostate cancer. Cell. 2015;161:1215–28.CrossRefPubMed

Berry W, Dakhil S, Modiano M, Gregurich M, Asmar L. Phase III study of mitoxantrone plus low dose prednisone versus low dose prednisone alone in patients with asymptomatic hormone refractory prostate cancer. J Urol. 2002;168:2439–43.CrossRefPubMed

Tannock IF, Osoba D, Stockler MR, Ernst DS, Neville AJ, Moore MJ, Armitage GR, Wilson JJ, Venner PM, Coppin CM, et al. Chemotherapy with mitoxantrone plus prednisone or prednisone alone for symptomatic hormone-resistant prostate cancer: a Canadian randomized trial with palliative end points. J Clin Oncol. 1996;14:1756–64.PubMed

10.

Shamash J, Powles T, Sarker SJ, Protheroe A, Mithal N, Mills R, Beard R, Wilson P, Tranter N, O’Brien N, et al. A multi-centre randomised phase III trial of dexamethasone vs dexamethasone and diethylstilbestrol in castration-resistant prostate cancer: immediate vs deferred diethylstilbestrol. Br J Cancer. 2011;104:620–8.CrossRefPubMedPubMedCentral

11.

Hayward WG. The treatment of late relapse in prostatic carcinoma by cortisone. J Urol. 1953;69:152–6.PubMed

12.

Venkitaraman R, Lorente D, Murthy V, Thomas K, Parker L, Ahiabor R, Dearnaley D, Huddart R, De Bono J, Parker C. A randomised phase 2 trial of dexamethasone versus prednisolone in castration-resistant prostate cancer. Eur Urol. 2015;67:673–9.CrossRefPubMed

13.

De Bono JS, Logothetis CJ, Molina A, Fizazi K, North S, Chu L, Chi KN, Jones RJ, Goodman OB Jr, Saad F, et al. Abiraterone and increased survival in metastatic prostate cancer. N Engl J Med. 2011;364:1995–2005.CrossRefPubMedPubMedCentral

14.

Lorente D, Weatherstone K, Omlin A, Pezaro C, Ferraldeschi R, Parker C, Dearnaley D, Harland S, De Bono J, Attard G. Tumor responses after steroid switch of prednisolone (P) to dexamethasone (D) in castration-resistant prostate cancer (CRPC) patients (pts) on abiraterone acetate (AA). Eur J Cancer. 2013;49:2918.

15.

Arora VK, Schenkein E, Murali R, Subudhi SK, Wongvipat J, Balbas MD, Shah N, Cai L, Efstathiou E, Logothetis C, et al. Glucocorticoid receptor confers resistance to antiandrogens by bypassing androgen receptor blockade. Cell. 2013;155:1309–22.CrossRefPubMedPubMedCentral

16.

Zhao XY, Malloy PJ, Krishnan AV, Swami S, Navone NM, Peehl DM, Feldman D. Glucocorticoids can promote androgen-independent growth of prostate cancer cells through a mutated androgen receptor. Nat Med. 2000;6:703–6.CrossRefPubMed

17.

Scher HI, Kelly WK. Flutamide withdrawal syndrome: its impact on clinical trials in hormone-refractory prostate cancer. J Clin Oncol. 1993;11:1566–72.PubMed

18.

Tannock IF, de Wit R, Berry WR, Horti J, Pluzanska A, Chi KN, Oudard S, Théodore C, James ND, Turesson I, et al. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med. 2004;351:1502–12.CrossRefPubMed

19.

Kantoff PW, Higano CS, Shore ND, Berger ER, Small EJ, Penson DF, Redfern CH, Ferrari AC, Dreicer R, Sims RB, et al. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med. 2010;363:411–22.CrossRefPubMed

20.

De Bono JS, Oudard S, Ozguroglu M, Hansen S, Machiels J, Kocak I, Gravis G, Pompidou EG. Prednisone plus cabazitaxel or mitoxantrone for metastatic castration-resistant prostate cancer progressing after docetaxel treatment: a randomised open-label trial. Lancet. 2010;376:1147–54.CrossRef

21.

Holzbeierlein J, Lal P, LaTulippe E, Smith A, Satagopan J, Zhang L, Ryan C, Smith S, Scher H, Scardino P, et al. Gene expression analysis of human prostate carcinoma during hormonal therapy identifies androgen-responsive genes and mechanisms of therapy resistance. Am J Pathol. 2004;164:217–27.CrossRefPubMedPubMedCentral

22.

Visakorpi T, Hyytinen E, Koivisto P, Tanner M, Keinänen R, Palmberg C, Palotie A, Tammela T, Isola J, Kallioniemi OP. In vivo amplification of the androgen receptor gene and progression of human prostate cancer. Nat Genet. 1995;9:401–6.CrossRefPubMed

23.

Locke JA, Guns ES, Lubik AA, Adomat HH, Hendy SC, Wood CA, Ettinger SL, Gleave ME, Nelson CC. Androgen levels increase by intratumoral de novo steroidogenesis during progression of castration-resistant prostate cancer. Cancer Res. 2008;68:6407–15.CrossRefPubMed

24.

Montgomery RB, Mostaghel EA, Vessella R, Hess DL, Kalhorn TF, Higano CS, True LD, Nelson PS. Maintenance of intratumoral androgens in metastatic prostate cancer: a mechanism for castration-resistant tumor growth. Cancer Res. 2008;68:4447–54.CrossRefPubMedPubMedCentral

25.

Taplin ME, Bubley GJ, Shuster TD, Frantz ME, Spooner AE, Ogata GK, Keer HN, Balk SP. Mutation of the androgen-receptor gene in metastatic androgen-independent prostate cancer. N Engl J Med. 1995;332:1393–8.CrossRefPubMed

26.

Guo Z, Yang X, Sun F, Jiang R, Linn DE, Chen H, Chen H, Kong X, Melamed J, Tepper CG, et al. A novel androgen receptor splice variant is up-regulated during prostate cancer progression and promotes androgen depletion-resistant growth. Cancer Res. 2009;69:2305–13.CrossRefPubMedPubMedCentral

27.

Parker C, Nilsson S, Heinrich D, Helle SI, O’Sullivan JM, Fosså SD, Chodacki A, Wiechno P, Logue J, Seke M, et al. Alpha emitter radium-223 and survival in metastatic prostate cancer. N Engl J Med. 2013;369:213–23.CrossRefPubMed

28.

Rowlands MG, Barrie SE, Chan F, Houghton J, Jarman M, McCague R, Potter GA. Esters of 3-pyridylacetic acid that combine potent inhibition of 17 alpha-hydroxylase/C17,20-lyase (cytochrome P45017 alpha) with resistance to esterase hydrolysis. J Med Chem. 1995;38:4191–7.CrossRefPubMed

29.

Chan FC, Potter GA, Barrie SE, Haynes BP, Rowlands MG, Houghton J, Jarman M. 3- and 4-pyridylalkyl adamantanecarboxylates: inhibitors of human cytochrome P450(17 alpha) (17 alpha-hydroxylase/C17,20-lyase). Potential nonsteroidal agents for the treatment of prostatic cancer. J Med Chem. 1996;39:3319–23.CrossRefPubMed

30.

Li Z, Bishop AC, Alyamani M, Garcia JA, Dreicer R, Bunch D, et al. Conversion of abiraterone to D4A drives anti-tumour activity in prostate cancer. Nature. 2015;523(7560):347–351. doi:10.1038/nature14406.

31.

Tran C, Ouk S, Clegg NJ, Chen Y, Watson PA, Arora V, Wongvipat J, Smith-Jones PM, Yoo D, Kwon A, et al. Development of a second-generation antiandrogen for treatment of advanced prostate cancer. Science. 2009;324:787–90.CrossRefPubMedPubMedCentral

32.

Scher HI, Fizazi K, Saad F, Taplin M-E, Sternberg CN, Miller K, de Wit R, Mulders P, Chi KN, Shore ND, et al. Increased survival with enzalutamide in prostate cancer after chemotherapy. N Engl J Med. 2012;367:1187–97.CrossRefPubMed

33.

Scher HI, Fizazi K, Saad F, Chi KN, Taplin M-E, Sternberg CN, Armstrong AJA. Association of baseline corticosteroid with outcomes in a multivariate analysis of the phase 3 affirm study of enzalutamide (ENZA), an androgen receptor signaling inhibitor (ARSI). Esmo. 2012;12:abs 2887.

34.

Fizazi K, Scher HI, Molina A, Logothetis CJ, Chi KN, Jones RJ, Staffurth JN, North S, Vogelzang NJ, Saad F, et al. Abiraterone acetate for treatment of metastatic castration-resistant prostate cancer: final overall survival analysis of the COU-AA-301 randomised, double-blind, placebo-controlled phase 3 study. Lancet Oncol. 2012;13:983–92.CrossRefPubMed

35.

Ryan CJ, Smith MR, Fizazi K, Saad F, Mulders PFA, Sternberg CN, Miller K, Logothetis CJ, Shore ND, Small EJ, et al. Abiraterone acetate plus prednisone versus placebo plus prednisone in chemotherapy-naive men with metastatic castration-resistant prostate cancer (COU-AA-302): final overall survival analysis of a randomised, double-blind, placebo-controlled phase 3 study. Lancet Oncol. 2015;16:152–60.CrossRefPubMed

36.

Loriot Y, Miller K, Sternberg CN, Fizazi K, De Bono JS, Chowdhury S, Higano CS, Noonberg S, Holmstrom S, Mansbach H, et al. Effect of enzalutamide on health-related quality of life, pain, and skeletal-related events in asymptomatic and minimally symptomatic, chemotherapy-naive patients with metastatic castration-resistant prostate cancer (PREVAIL): results from a randomised, p. Lancet Oncol. 2015;16:509–21.CrossRefPubMed

37.

Logothetis CJ, Basch E, Molina A, Fizazi K, North SA, Chi KN, Jones RJ, Goodman OB, Mainwaring PN, Sternberg CN, et al. Effect of abiraterone acetate and prednisone compared with placebo and prednisone on pain control and skeletal-related events in patients with metastatic castration-resistant prostate cancer: exploratory analysis of data from the COU-AA-301 randomised tri. Lancet Oncol. 2012;13:1210–7.CrossRefPubMed

38.

Halabi S, Lin C-Y, Kelly WK, Fizazi KS, Moul JW, Kaplan EB, Morris MJ, Small EJ. Updated prognostic model for predicting overall survival in first-line chemotherapy for patients with metastatic castration-resistant prostate cancer. J Clin Oncol. 2014;32:671–7.CrossRefPubMedPubMedCentral

39.

Goodman OB, Flaig TW, Molina A, Mulders PFA, Fizazi K, Suttmann H, Li J, Kheoh T, de Bono JS, Scher HI. Exploratory analysis of the visceral disease subgroup in a phase III study of abiraterone acetate in metastatic castration-resistant prostate cancer. Prostate Cancer Prostatic Dis. 2014;17:34–9.CrossRefPubMedPubMedCentral

40.

Berthold DR, Pond GR, Soban F, de Wit R, Eisenberger M, Tannock IF. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer: Updated survival in the TAX 327 study. J Clin Oncol. 2008;26:242–5.CrossRefPubMed

41.

Berthold DR, Pond GR, Roessner M, de Wit R, Eisenberger M, Tannock AIF. Tannock AIF. Treatment of hormone-refractory prostate cancer with docetaxel or mitoxantrone: relationships between prostate-specific antigen, pain, and quality of life response and survival in the TAX-327 study. Clin Cancer Res. 2008;14:2763–7.CrossRefPubMed

42.

Sweeney CJ, Chen Y-H, Carducci M, Liu G, Jarrard DF, Eisenberger M, Wong Y-N, Hahn N, Kohli M, Cooney MM, et al. Chemohormonal therapy in metastatic hormone-sensitive prostate cancer. N Engl J Med. 2015;373:737–46.CrossRefPubMedPubMedCentral

43.

James ND, Sydes MR, Mason MD, Clarke NW, Dearnaley DP, Spears MR, Millman R, Parker C, Ritchie AWS, Russell JM, Staffurth J, Jones RJ, Tolan SP, John Wagstaf SI. Docetaxel and/or zoledronic acid for hormone-naïve prostate cancer: first overall survival results from STAMPEDE (NCT00268476). ASCO Annu. Meet. 2015 [no volume].

44.

Gravis G, Fizazi K, Joly F, Oudard S, Priou F, Esterni B, Latorzeff I, Delva R, Krakowski I, Laguerre B, et al. Androgen-deprivation therapy alone or with docetaxel in non-castrate metastatic prostate cancer (GETUG-AFU 15): a randomised, open-label, phase 3 trial. Lancet Oncol. 2013;14:149–58.CrossRefPubMed

45.

Zafeiriou Z, Ferraldeschi R, Omlin A, Pezaro C, Mukherji D, Lorente D, Altavilla A, Sideris S, Rescigno P, Mateo J, et al. Sequencing of docetaxel and abiraterone acetate for metastatic castration resistant prostate cancer. Ann Oncol. 2014;25:iv255–iv279(54). doi:10.1093/annonc/mdu336.

46.

Maughan BL, Xhou XC, Suzman DL, Nadal R, Bassi S, Schweizer MT, Antonarakis ES. Optimal sequencing of docetaxel and abiraterone in men with metastatic castration-resistant prostate cancer. Prostate. 2015;75:1814–20.CrossRefPubMed

47.

Brasso K, Thomsen FB, Schrader AJ, Schmid SC, Lorente D, Retz M, Merseburger AS, von Klot CA, Boegemann M, de Bono J. Enzalutamide antitumour activity against metastatic castration-resistant prostate cancer previously treated with docetaxel and abiraterone: a multicentre analysis. Eur Urol. 2015(2);68:317–24.CrossRefPubMed

48.

Antonarakis ES, Lu C, Wang H, Luber B, Nakazawa M, Roeser JC, et al. AR-V7 and resistance to enzalutamide and abiraterone in prostate cancer. N Engl J Med. 2014;371(11):1028–38.

49.

Richards J, Lim AC, Hay CW, Taylor AE, Wingate A, Nowakowska K, Pezaro C, Carreira S, Goodall J, Arlt W, et al. Interactions of abiraterone, eplerenone, and prednisolone with wild-type and mutant androgen receptor: a rationale for increasing abiraterone exposure or combining with MDV3100. Cancer Res. 2012;72:2176–82.CrossRefPubMedPubMedCentral

50.

Montgomery B, Cheng HH, Drechsler J, Mostaghel EA. Glucocorticoids and prostate cancer treatment: friend or foe?. Asian J Androl. 16:354–8.

51.

Ryan CJ, Smith MR, Fong L, Rosenberg JE, Kantoff P, Raynaud F, Martins V, Lee G, Kheoh T, Kim J, et al. Clinical trial of the CYP17 inhibitor abiraterone acetate demonstrating clinical activity in patients with castration-resistant prostate cancer who received prior ketoconazole therapy. J Clin Oncol. 2010;28:1481–8.CrossRefPubMedPubMedCentral

52.

Attard G, Reid AHM, Yap TA, Raynaud F, Dowsett M, Settatree S, Barrett M, Parker C, Martins V, Folkerd E, et al. Phase I clinical trial of a selective inhibitor of CYP17, abiraterone acetate, confirms that castration-resistant prostate cancer commonly remains hormone driven. J Clin Oncol. 2008;26:4563–71.

53.

Scher HI, Beer TM, Higano CS, Anand A, Taplin M-E, Efstathiou E, Rathkopf D, Shelkey J, Yu EY, Alumkal J, et al. Antitumour activity of MDV3100 in castration-resistant prostate cancer: a phase 1–2 study. Lancet (London, England). 2010;375:1437–46.

54.

Crona DJ, Whang YE. Posterior reversible encephalopathy syndrome induced by enzalutamide in a patient with castration-resistant prostate cancer. Invest New Drugs. 2015;33:751–4.CrossRefPubMed

55.

Bruland ØS, Nilsson S, Fisher DR, Larsen RH. High-linear energy transfer irradiation targeted to skeletal metastases by the alpha-emitter 223Ra: adjuvant or alternative to conventional modalities? Clin Cancer Res. 2006;12:6250s–7s.CrossRefPubMed

56.

Henriksen G, Breistøl K, Bruland ØS, Fodstad Ø, Larsen RH. Significant antitumor effect from bone-seeking, α-particle-emitting 223Ra demonstrated in an experimental skeletal metastases model. Cancer Res. 2002;62:3120–5.PubMed

57.

Liepe K. Alpharadin, a 223Ra-based alpha-particle-emitting pharmaceutical for the treatment of bone metastases in patients with cancer. Curr Opin Investig Drugs. 2009;10:1346–58.PubMed

58.

Hoskin P, Sartor O, Sullivan JM. Efficacy and safety of radium-223 dichloride in patients with castration-resistant prostate cancer and symptomatic bone metastases, with or without previous docetaxel use: a prespecified subgroup analysis from the randomised, double-blind, phase 3 ALSY. Lancet Oncol. 2014;15:1397–406.CrossRefPubMed

59.

Higano CS, Small EJ, Schellhammer P, Yasothan U, Gubernick S, Kirkpatrick P, Kantoff PW. Sipuleucel-T. Nat Rev Drug Discov. 2010;9:513–4.CrossRefPubMed

60.

Halabi S, Armstrong AJ, Sartor O, Bono J De, Kaplan E, Lin C, Solomon NC, Small EJ. Prostate-specific antigen changes as surrogate for overall survival in men with metastatic castration-resistant prostate cancer treated with second-line chemotherapy. J Clin Oncol. 2013;31:3944–3950.CrossRefPubMedPubMedCentral

61.

Kwak JJ, Tirumani SH, Van den Abbeele AD, Koo PJ, Jacene HA. Cancer immunotherapy: imaging assessment of novel treatment response patterns and immune-related adverse events. RadioGraphics. 2015;35:424–37.CrossRefPubMed

62.

Huber ML, Haynes L, Parker C, Iversen P. Interdisciplinary critique of sipuleucel-T as immunotherapy in castration-resistant prostate cancer. J Natl Cancer Inst. 2012;104:273–9.CrossRefPubMedPubMedCentral

63.

Clegg NJ, Wongvipat J, Joseph JD, Tran C, Ouk S, Dilhas A, Chen Y, Grillot K, Bischoff ED, Cai L, et al. ARN-509: a novel antiandrogen for prostate cancer treatment. Cancer Res. 2012;72:1494–503.CrossRefPubMedPubMedCentral

64.

Schrader AJ, et al. Enzalutamide in castration-resistant prostate cancer patients progressing after docetaxel and abiraterone. Eur urol 2014;65(1):30–6.

65.

Bianchini D, et al. Antitumour activity of enzalutamide (MDV3100) in patients with metastatic castration-resistant prostate cancer (CRPC) pre-treated with docetaxel and abiraterone. Eur J cancer 2014;50(1):78–84.

66.

Thomsen FB, et al. Enzalutamide treatment in patients with metastatic castration-resistant prostate cancer progressing after chemotherapy and abiraterone acetate. Scand J urol 2014;48(3):268–75.

67.

Badrising S, et al. Clinical activity and tolerability of enzalutamide (MDV3100) in patients with metastatic, castration-resistant prostate cancer who progress after docetaxel and abiraterone treatment. Cancer 2014;120(7):968–75.

68.

Azad AA, et al. Efficacy of enzalutamide following abiraterone acetate in chemotherapy-naive metastatic castration-resistant prostate cancer patients. Eur urol 2015;67(1):23–9.

69.

Suzman DL, et al. Clinical activity of enzalutamide versus docetaxel in men with castration-resistant prostate cancer progressing after abiraterone. Prostate 2014;74(13):1278–1285.

70.

Cheng HH, et al. Activity of enzalutamide in men with metastatic castration-resistant prostate cancer is affected by prior treatment with abiraterone and/or docetaxel. Prostate Cancer Prostatic Dis 2015;18:122–127.

71.

Noonan KL, et al. Clinical activity of abiraterone acetate in patients with metastatic castration-resistant prostate cancer progressing after enzalutamide. Ann Oncol 2013;24(7):1802–7.

72.

Loriot Y, Bianchini D, Ileana E, et al. 2013. Antitumour activity of abiraterone acetate against metastatic castration-resistant prostate cancer progressing after docetaxel and enzalutamide (MDV3100). Ann Oncol 2013;24:1807–1812.

73.

Schmid SC, et al. Enzalutamide after docetaxel and abiraterone therapy in metastatic castration-resistant prostate cancer. Adv Ther 2014;31(2):234–41.

Titel: Managing Metastatic Castration-Resistant Prostate Cancer in the Pre-chemotherapy Setting: A Changing Approach in the Era of New Targeted Agents
verfasst von: Zafeiris Zafeiriou
Anuradha Jayaram
Adam Sharp
Johann S. de Bono
Publikationsdatum: 01.03.2016
Verlag: Springer International Publishing
Erschienen in: Drugs / Ausgabe 4/2016
Print ISSN: 0012-6667
Elektronische ISSN: 1179-1950
DOI: https://doi.org/10.1007/s40265-015-0530-7

Springer Medizin

Abstract

Bitte loggen Sie sich ein, um Zugang zu diesem Inhalt zu erhalten

Weitere Artikel der Ausgabe 4/2016

Dichlorphenamide: A Review in Primary Periodic Paralyses

Lesinurad: First Global Approval

Therapeutic Strategies for the Treatment of Severe Cushing’s Syndrome

Management of Neuropsychiatric Systemic Lupus Erythematosus: Current Approaches and Future Perspectives

Liposomal Amphotericin B (AmBisome®): A Review of the Pharmacokinetics, Pharmacodynamics, Clinical Experience and Future Directions

Pharmacotherapy for Fragile X Syndrome: Progress to Date