Potential of Using Vitamin D as an Adjuvant Treatment of Malignant Melanoma
Authors:
B. Bolerázska 1,2; E. Ďurovcová 1,2; M. Mareková 1
Authors place of work:
Ústav lekárskej a klinickej biochémie, LF UPJŠ v Košiciach, Slovenská republika
1; Oddelenie klinickej biochémie, Medirex, a. s., Košice, Slovenská republika
2
Published in the journal:
Klin Onkol 2017; 30(5): 327-336
Category:
Review
doi:
https://doi.org/10.14735/amko2017327
Summary
The incidence of malignant melanoma worldwide continues to grow despite the enormous advances in topical and systemic therapy. This increase is recorded regularly even in countries where, as a result of public health campaigns, dermatological examination and subsequent treatment have become more frequent. However, there have been reports of a stable or even decreasing mortality rate that seem to contradict the objective increase in its incidence. The well-known risk factors for malignant melanoma include sunburns and occasional sunbathing, whereas regular sunbathing is associated with a lower incidence. Besides DNA damage, exposure to the sun also results in the synthesis of vitamin D (cholecalciferol) in the skin, which contributes to over 90% of circulating Calcidiol (25 (OH) D) in serum. Current cultural norms (dressing, working indoors, avoiding sun exposure, and dietary choices) affect the serum vitamin D level, resulting in severely low serum levels of vitamin D in some sectors of today’s society. Emerging data suggests that mild, unprotected exposure to UV radiation or dietary supplementation with oral vitamin D can reduce cancer mortality. Supplementation with vitamin D or alternatively UV exposure may be regarded as an adjuvant for the treatment of many types of tumors (e. g. tumors of the colon, prostate, and breast). The effect of vitamin D on malignant melanoma may be due to its non-calcemic systemic effects. Additionally, vitamin D may have more pronounced effects locally in the skin because of the unique ability of keratinocytes to synthesize the active form of vitamin D.
Key words:
malignant melanoma – vitamin D – adjuvant treatment therapy – clinical oncology
The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study.
The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers.
Submitted:
7. 10. 2016
Accepted:
26. 7. 2017
Zdroje
1. Garbe C, Peris K, Hauschild A et al. Diagnosis and treatment of melanoma: European consensus-based interdisciplinary guideline. Eur J Cancer 2010; 46 (2): 270–283. doi: 10.1016/j.ejca.2009.10.032.
2. Tomíška M, Novotná Š, Klvačová L et al. Vitamin D during cancer treatment. Klin Onkol 2015; 28 (2): 99–104. doi: 10.14735/amko201599.
3. Jacobs ET, Kohler LN, Kunihiro AG et al. Vitamin D and Colorectal, Breast, and Prostate Cancers: A Review of the Epidemiological Evidence. J Cancer 2016; 7 (3): 232–240. doi: 10.7150/jca.13403.
4. Newton-Bishop JA, Beswick S, Randerson-Moor J et al. Serum 25-hydroxyvitamin D3 levels are associated with breslow thickness at presentation and survival from melanoma. J Clin Oncol 2009; 27 (32): 5439–5444. doi: 10.1200/JCO.2009.22.1135.
5. Wyatt C, Lucas RM, Hurst C et al. Vitamin D deficiency at melanoma diagnosis is associated with higher Breslow thickness. PLoS One 2015; 10 (5): e0126394. doi: 10.1371/journal.pone.0126394.
6. Slominski AT, Brozyna A, Jozwicki W et al. Vitamin D as an adjuvant in melanoma therapy. Melanoma Manag 2015; 2 (1): 1–4. doi: 10.2217/mmt.14.36.
7. Nelemans PJ, Groenendal H, Kiemeney LA et al. Effect of intermittent exposure to sunlight on melanoma risk among indoor workers and sun-sensitive individuals. Environ Health Perspect 1993; 101 (3): 252–255.
8. Gandini S, Raimondi S, Gnagnarella P et al. Vitamin D and skin cancer: a meta-analysis. Eur J Cancer 2009; 45 (4): 634–641. doi: 10.1016/j.ejca.2008.10.003.
9. Newton-Bishop JA, Chang, YM, Elliott F et al. Relationship between sun exposure and melanoma risk for tumours in different body sites in a large case-control study in a temperate climate. Eur J Cancer 2011; 47 (5): 732–741. doi: 10.1016/j.ejca.2010.10.008.
10. Bataille V, de Vries E. Melanoma – part 1: epidemiology, risk factors, and prevention. BMJ 2008; 337: a2249. doi: 10.1136/bmj.a2249.
11. Brożyna AA, Jozwicki W, Janjetovic Z et al. Expression of vitamin D receptor decreases during progression of pigmented skin lessions. Hum Pathol 2011; 42 (5): 618–631. doi: 10.1016/j.humpath.2010.09.014.
12. MacLennand R, Kelly JW, Rivers JK et al. The Eastern Australian Childhood Naevus Study: site differences in density and size of melanocytic nevi in relation to latitude and phenotype. J Am Acad Dermatol 2003; 48: 367–375. doi: 10.1067/mjd.2003.30.
13. Larue L, de Vuyst F, Delmas V. Modeling melanoblast development. Cell Mol Life Sci 2013; 70 (6): 1067–1079. doi: 10.1007/s00018-012-1112-4.
14. Bulliard JD, De Weck D, Fisch T et al. Detailed distribution of melanoma and sunlight exposure: aetiological patterns from a Swiss series. Ann Oncol 2007; 18: 789–794. doi: 10.1093/annonc/mdl490.
15. Joosse A, de Vries E, Eckel R et al. Gender differences in melanoma survival: female patients have a decreased risk of metastasis. J Invest Dermatol 2011; 131 (3): 719–726. doi: 10.1038/jid.2010.354.
16. O’Hara C, Birch J, McCabe M et al. Gender differences in survival among teenagers and young adults with CNS tumours. Cancer Outcomes Conference. [online]. Available from: www.ncin.org.uk/conference.
17. Lehmann B, Rudolph T, Pietzsch J et al. Conversion of vitamin D3 to 1alpha, 25-dihydroxyvitamin D3 in human skin equivalents. Exp Dermatol 2000; 9 (2): 97–103.
18. Morris HA, Anderson PH. Autocrine and paracrine actions of vitamin D. Clin Biochem Rev 2010; 31 (4): 129–138.
19. Seifert M, Rech M, Meineke V et al. Differential biological effects of 1,25-dihydroxyvitamin D3 on melanoma cell lines in vitro. J Steroid Biochem Mol Biol 2004; 89–90 (1–5): 375–379. doi: 10.1016/j.jsbmb.2004.03.002.
20. Colston K, Colston MJ, Feldman D. 1,25-dihydroxyvita-min D3 and malignant melanoma: the presence of receptors and inhibition of cell growth in culture. Endocrinology 1981; 108 (3): 1083–1086. doi: 10.1210/endo-108-3-1083.
21. Norman AW. Minireview: vitamin D receptor: new assignments for an already busy receptor. Endocrinology 2006; 147: 5542–5448. doi: 10.1210/en.2006-0946.
22. Brozyna A, Zbytek B, Granese J et al. Mechanism of UV-related carcinogenesis and its contribution to nevi/melanoma. Expert Rev Dermatol 2007; 2 (4): 451–469.
23. Haussler MR, Jurutka PW, Mizwicki M et al. Vitamin D receptor (VDR) -mediated actions of 1α,25 (OH) 2vitamin D3: Genomic and non-genomic mechanisms. Best Pract Res Clin Endocrinol Metab 2011; 25: 543–559. doi: 10.1016/j.beem.2011.05.010.
24. Szyszka P, Zmijewski MA, Slominski AT. New vitamin D analogs as potential therapeutics in melanoma. Expert Rev Anticancer Ther 2012; 12 (5): 585–599. doi: 10.1586/era.12.40.
25. Holick MF. Vitamin D deficiency. N Engl J Med 2007; 357 (3): 266–281. doi: 10.1056/NEJMra070553.
26. Jensen SS, Madsen MW, Lukas J et al. Inhibitory effects of 1alpha, 25-dihydroxyvitamin D (3) on the G (1) -S phase-controlling machinery. Mol Endocrinol 2001; 15: 1370–1380. doi: 10.1210/mend.15.8.0673.
27. Jiang F, Li P, Fornace AJ Jr et al. G2/M arrest by 1,25-di-hydroxyvitamin D3 in ovarian cancer cells mediated through the induction of GADD45 via an exonic enhancer. J Biol Chem 2003; 278 (48): 48030–48040. doi: 10.1074/jbc.M308430200.
28. Blutt SE, McDonnell TJ, Polek TC et al. Calcitriol-induced apoptosis in LNCaP cells is blocked by overexpression of Bcl-2. Endocrinology 2000; 141 (1): 10–17. doi: 10.1210/endo.141.1.7289.
29. Bikle DD. Vitamin D metabolism, mechanism of action, and clinical applications. Chem Biol 2014; 21 (3): 319–329. doi: 10.1016/j.chembiol.2013.12.016.
30. Høyer–Hansen M, Bastholm L, Mathiasen IS et al. Vitamin D analog EB1089 triggers dramatic lysosomal changes and Beclin 1-mediated autophagic cell death. Cell Death Differ 2005; 12 (10): 1297–1309. doi: 10.1038/sj.cdd.4401651.
31. James SY, Mackay AG, Colston KW. Effects of 1,25 dihydroxyvitamin D3 and its analogues on induction of apoptosis in breast cancer cells. J Steroid Biochem Mol Biol 1996; 58 (4): 395–401. doi: 10.1016/0960-0760 (96) 00048-9.
32. Diaz GD, Paraskeva C, Thomas MG et al. Apoptosis is induced by the active metabolite of vitamin D3 and its analogue EB1089 in colorectal adenoma and carcinoma cells: possible implications for prevention and therapy. Cancer Res 2000; 60 (8): 2304–2312.
33. Kumagai T, Shih LY, Hughes SV et al. 19-Nor-l,25 (OH) 2D2 (a novel, noncalcemic vitamin D analogue), combined with arsenic trioxide, has potent antitumor activity against myeloid leukemia. Cancer Res 2005; 65 (6): 2488–2497. doi: 10.1158/0008-5472.CAN-04-2800.
34. Fridman JS, Lowe SW. Control of apoptosis by p53. Oncogene 2003; 22 (56): 9030–9040. doi: 10.1038/sj.onc.1207116.
35. Chakraborti CK. Vitamin D as a promising anticancer agent. Indian J Pharmacol 2011; 43 (2): 113–120. doi: 10.4103/0253-7613.77335.
36. Gupta R, Dixon KM, Deo SS et al. Photoprotection by 1,25 dihydroxyvitamin D3 is associated with an increase in p53 and a decreasein nitric oxide products. J Invest Dermatol 2007; 127 (3): 707–715. doi: 10.1038/sj.jid.5700597.
37. Kundu JK, Surh YJ. Inflammation: gearing the journey to cancer. Mutat Res 2008; 659 (1–2): 15–30. doi: 10.1016/j.mrrev.2008.03.002.
38. Mantell DJ, Owens PE, Bundred NJ et al. 1 alpha, 25-dihydroxyvitamin D (3) inhibits angiogenesis in vitro and in vivo. Circ Res 2000; 87 (3): 214–220. doi: 10.1161/01.RES.87.3.214.
39. Ben-Shoshan M, Amir S, Dang DT et al. 1 alpha, 25-dihydroxyvitamin D3 (calcitriol) inhibits hypoxia-inducible factor-1/vascular endothelial growth factor pathway in human cancer cells. Mol Cancer Ther 2007; 6 (4): 1433–1439. doi: 10.1158/1535-7163.MCT-06-0677.
40. Moreno J, Krishnan AV, Swami S et al. Regulation of prostaglandin metabolism by calcitriol attenuates growth stimulation in prostate cancer cells. Cancer Res 2005; 65 (17): 7917–7925. doi: 10.1158/0008-5472.CAN-05-1435.
41. Mantovani A, Allavena P, Sica A et al. Cancer-related inflammation. Nature 2008; 454 (7203): 436–444. doi: 0.1038/nature07205.
42. Hoesel B, Schmid JA. The complexity of NF-κB signaling in inflammation and cancer. Mol Cancer 2013; 12: 86. doi: 10.1186/1476-4598-12-86.
43. Cohen-Lahav M, Shany S, Tobvin D et al. Vitamin D decreases NFkappaB activity by increasing IkappaBalpha levels. Nephrol Dial Transplant 2006; 21 (4): 889–897. doi: 10.1093/ndt/gfi254.
44. Madonna G, Ullman CD, Gentilcore G et al. NF-κB as potential target in the treatment of melanoma. J Transl Med 2012; 10: 53. doi: 10.1186/1479-5876-10-53.
45. Villanueva J, Herlyn M. Melanoma and the tumor microenvironment. Curr Oncol Rep 2008; 10 (5): 439–446.
46. Kodet O, Lacina L, Krejčí E et al. Melanoma cells influence the differentiation pattern of human epidermal keratinocytes. Mol Cancer 2015; 14: 1. doi: 10.1186/1476-4598-14-1.
47. Reichrath J, Rech M, Moeini M et al. In vitro comparison of the vitamin D endocrine system in 1,25 (OH) 2D3-responsive and -resistant melanoma cells. Cancer Biol Ther 2007; 6 (1): 48–55.
48. Osborne JE, Hutchinson PE. Vitamin D and systemic cancer: is this relevant to malignant melanoma? Br J Dermatol 2002; 147 (2): 197–213. doi: 10.1046/j.1365-2133.2002.04960.x.
49. Eisman JA, Barkla DH, Tutton PJ. Suppression of in vivo growth of human cancer solid tumor xenografts by 1,25-dihydroxyvitamin D3. Cancer Res 1987; 47 (1): 21–25.
50. Pawlowska E, Wysokinski D, Blasiak J. Nucleotide Excision Repair and Vitamin D-Relevance for Skin Cancer Therapy. Int J Mol Sci 2016; 17 (4): 372. doi: 10.3390/ijms17040372.
51. Dixon KM, Deo SS, Wong G et al. Skin cancer prevention: a possible role of 1,25dihydroxyvitamin D3 and its analogs. J Steroid Biochem Mol Biol 2005; 97 (1–2): 137–143. doi: 10.1016/j.jsbmb.2005.06.006.
52. Bataille V, Grulich A, Sasieni P et al. The association between naevi and melanoma in populations with different sun exposure: a joint case-control study of melanoma in the UK and Australia. Br J Cancer 1998; 77 (3): 505–510.
53. Erdei E, Torres SM. A new understanding in the epidemiology of melanoma. Expert Rev Anticancer Ther 2010; 10 (11): 1811–1823. doi: 10.1586/era.10.170.
54. Garbe C, Leiter U. Melanoma epidemiology and trends. Clin Dermatol 2009; 27: 3–9. doi: 10.1016/j.clindermatol.2008.09.001.
55. Welch HG, Black WC. Overdiagnosis in cancer. J Natl Cancer Inst 2010; 102 (9): 605–613. doi: 10.1093/jnci/djq099.
56. Bleyer A, Welch HG. Effectof three decades of screening mammography on breast-cancer incidence. N Engl J Med 2012; 367 (21): 1998–2005. doi: 10.1056/NEJMoa1206809.
57. Esserman L, Shieh Y, Thompson I. Rethinking Screening for Breast Cancer and Prostate Cancer JAMA 2009; 302 (15): 1685–1692. doi: 10.1001/jama.2009. 1498.
58. Godar DE, Landry RJ, Lucas AD: Increases UVA exposures and decreases cutaneous Vitamin D (3) may be responsible for the increasing incidence of melanoma. Med Hypotheses 2009; 72 (4): 434–443. doi: 10.1016/j.mehy.2008.09.056.
59. Berwick M, Armstrong BK, Ben-Porat L et al. Sun exposure and mortality from melanoma. J Natl Cancer Inst 2005; 97 (3): 195–199. doi: 10.1093/jnci/dji019.
60. Field S, Newton-Bishop JA. Melanoma and vitamin D. Mol Oncol 2011; 5 (2): 197–214. doi: 10.1016/j.molonc.2011.01.007.
61. Mason RS, Sequeira VB, Dixon KM et al. Photoprotection by 1 alpha,25-dihydroxyvitamin D and analogs: further studies on mechanisms andimplications for UV-damage. J Steroid Biochem Mol Biol 2010; 121 (1–2): 164–168. doi: 10.1016/j.jsbmb.2010.03.082.
62. Damian DL, Kim YJ, Dixon KM et al. Topical calcitriol protects from UV-induced genetic damage but sup-presses cutaneous immunity in humans. Exp Dermatol 2010; 19 (8): e23–e30. doi: 10.1111/j.1600-0625.2009. 00955.x.
63. Bishop DT, Demenais F, Iles MM et al. Genome-wide association study identifies three loci associated with melanoma risk. Nat Genet 2009; 41 (8): 920–925. doi: 10.1038/ng.411.
64. Downing, A, Yu XQ, Newton-Bishop JA et al. Trends in prognostic factors and survival from cutaneous melanoma in Yorkshire, UK and New South Wales, Australia between 1993 and 2003. Int J Cancer 2008; 123 (4): 861–866. doi: 10.1002/ijc.23495.
65. de Luca HF. Evolution of our understanding of vitamin D. Nutr Rev 2008; 66 (10 Suppl 2), 73–87. doi: 10.1111/j.1753-4887.2008.00105.x.
66. Webb AR, DeCosta BR, Holick MF. Sunlight regulates the cutaneous production of vitamin D3 by causing its photodegradation. J Clin Endocrinol Metab 1989; 68 (5): 882–887. doi: 10.1210/jcem-68-5-882.
67. Tang JY, Fu T, Lau C et al. Vitamin D in cutaneous carcinogenesis: part II. J Am Acad Dermatol 2012; 67 (5): 817.e1–e11; quiz 827–828. doi: 10.1016/j.jaad.2012.07.022.
68. Nürnberg B, Gräber S, Gärtner B et al. Reduced serum 25-hydroxyvitamin D levels in stage IV melanoma patients. Anticancer Res 2009; 29 (9): 3669–3674.
69. Gandini S, Francesco F, Johanson H et al. Why vitamin D for cancer patients? Ecancermedicalscience 2009; 3: 160. doi: 10.3332/ecancer.2009.160.
70. Gorham ED, Garland CF, Garland FC, et al. Vitamin D and prevention of colorectal cancer. J Steroid Biochem Mol Biol 2005; 97 (1–2): 179–194. doi: 10.1016/j.jsbmb.2005.06.018.
71. Bischoff-Ferrari HA, Giovannucci E, Willett WC et al. Estimation of optimal serum concentrations of 25-hydroxyvitamin D for multiple health outcomes. Am J Clin Nutr 2006; 84 (1): 18–28.
72. Coyne health care. Vitamin D: A New Intervention for Melanoma? [online]. Available from: https: //coynehealthcare.co.za/vitamin-d-a-new-intervention-for-melanoma/.
73. Flynn A, Hirvonen T, Mensink GB et al. Intake of selected nutrients from foods, from fortification and from supplements in various European countries. Food Nutr Res 2009; 53. doi: 10.3402/fnr.v53i0.2038.
74. Balvers MG, Brouwer-Brolsma EM, Endenburg S et al. Recommended intakes of vitamin D to optimise health, associated circulating 25-hydroxyvitamin D concentrations, and dosing regimens to treat deficiency: workshop report and overview of current literature. J Nutr Sci 2015; 4: e23. doi: 10.1017/jns.2015.10.
75. Bade B, Zdebik A, Wagenpfeil S et al. Low serum 25-hydroxyvitamin D concentrations are associated with increased risk for melanoma and unfavourable prognosis. PloS One 2014; 9: e112863. doi: 10.1371/journal.pone.0112863.
76. Timerman D, McEnery-Stonelake M, Joyce CJ et al. Vitamin D deficiency is associated with a worse prognosis in metastatic melanoma, Oncotarget 2017; 8 (4): 6873–6882. doi: 10.18632/oncotarget.14316.
77. Saiag P, Aegerter P, Vitoux D et al. Prognostic Value of 25-hydroxyvitamin D3 Levels at Diagnosis and During Follow-up in Melanoma Patients. J Natl Cancer Inst 2015: 107 (12). djv264. doi: 10.1093/jnci/djv264.
78. Saw RP, Armstrong BK, Mason RS et al. Adjuvant therapy with high dose vitamin D following primary treatment of melanoma at high risk of recurrence: a placebo controlled randomised phase II trial (ANZMTG 02.09 Mel-D). BMC Cancer 2014; 14: 780. doi: 10.1186/1471-2407-14-780.
79. Heaney RP, Davies KM, Chen TC et al. Human serum 25-hydroxycholecalciferol response to extended oral dosing with cholecalciferol. Am J Clin Nutr 2003; 77 (1): 204–210.
80. Sambrook P. Vitamin D and fractures: quo vadis? Lancet 2005; 365 (9471): 1599–1600. doi: 10.1016/S0140-6736 (05) 66385-4.
81. Adams JS, Lee G. Gains in bone mineral density with resolution of vitamin D intoxication. Ann Intern Med 1997; 127 (3): 203–206. doi: 10.7326/0003-4819-127-3-199708010-00004.
82. Koutkia P, Chen TC, Holick MF. Vitamin D intoxication associated with an over-the-counter supplement. N Engl J Med 2001; 345 (1): 66–67. doi: 10.1056/NEJM200107053450114.
83. Hathcock JN, Shao A, Vieth R et al. Risk assessment for vitamin D. Am J Clin Nutr 2007; 85 (1): 6–18.
84. Bacon CJ, Gamble GD, Horne AM et al. High-dose oral vitamin D3 supplementation in the elderly. Osteoporos Int 2009; 20 (8): 1407–1415. doi: 10.1007/s00198-008-0814-9.
85. Plum LA, Prahl JM, Ma X et al. Biologically active noncalcemic analogs of 1alpha, 25dihydroxyvitamin D with an abbreviated side chain containing no hydroxyl. Proc Natl Acad Sci U S A 2004; 101 (18): 6900–6904. doi: 10.1073/pnas.0401656101.
86. Holick MF, Garabedian M, Schnoes HK et al. Relationship of 25-hydroxyvitamin D3 side chain structure to biological activity. J Biol Chem 1975; 250 (1): 226–230.
87. Zmijewski MA, Li W, Chen J et al. Synthesis and photochemical transformation of 3β,21-dihydroxypregna-5,7-dien-20-one to novel secosteroids that show anti-melanoma activity. Steroids 2011; 76 (1–2): 193–203. doi: 10.1016/j.steroids.2010.10.009.
88. ClinicalTrials.gov. MelaViD: A Trial on Vitamin D Supplementation for Resected Stage II Melanoma Patients. [online]. Available from: https: //clinicaltrials.gov/ct2/show/NCT01264874.
89. ClinicalTrials.gov. Vitamin D Supplementation in Cutaneous Malignant Melanoma Outcome (ViDMe). [online]. Available from: https: //clinicaltrials.gov/ct2/show/NCT01748448.
90. Szyszka P, Zmijewski MA, Slominski AT. New vitamin D analogs as potential therapeutics in melanoma. Expert Rev Anticancer Ther 2012; 12 (5): 585–599. doi: 10.1586/era.12.40.
91. Slominski AT, Brozyna A, Jozwicki W et al. Vitamin D as an adjuvant in melanoma therapy. Melanoma Manag 2015; 2 (1): 1–4. doi: 10.2217/mmt.14.36.
92. Sondak VK, McIver B, Kanetsky PA. Vitamin D and Melanoma: What Do We Tell Our Patients? J Clin Oncol 2016; 34 (15): 1713–1714. doi: 10.1200/JCO.2016.66.5240.
93. Kubešová Matějovská H, Tůmová J, Polcarová V et al. Vitamin D – remarks of known and overwiev of new facts. Vnitr Lek 2012; 58 (3): 196–201.
94. Vidailhet M, Mallet E, Bocquet A et al. Vitamin D: still a topical matter in children and adolescents. A position paper by the Committee on Nutrition of the French Society of Paediatrics. Arch Pediatr 2012; 19 (3): 316–328. doi: 10.1016/j.arcped.2011.12.015.
95. Erdei E, Torres SM. A new understanding in the epidemiology of melanoma. Expert Rev Anticancer Ther 2010; 10 (11): 1811–1823. doi: 10.1586/era.10.170.
96. 99. EUCAN/WHO. Malignant melanoma of skin: Estimated incidence, mortality and prevalence of both sexes. [online]. Available from: http: //eco.iarc.fr/eucan/Cancer.aspx?Cancer=20.
Štítky
Paediatric clinical oncology Surgery Clinical oncologyČlánok vyšiel v časopise
Clinical Oncology
2017 Číslo 5
- Spasmolytic Effect of Metamizole
- Metamizole at a Glance and in Practice – Effective Non-Opioid Analgesic for All Ages
- Metamizole in perioperative treatment in children under 14 years – results of a questionnaire survey from practice
- Current Insights into the Antispasmodic and Analgesic Effects of Metamizole on the Gastrointestinal Tract
- Obstacle Called Vasospasm: Which Solution Is Most Effective in Microsurgery and How to Pharmacologically Assist It?
Najčítanejšie v tomto čísle
- Controversy in the Postoperative Treatment of Low-grade Gliomas
- The Role of Chemotherapy in the Treatment of Low-grade Gliomas
- Isocitrate Dehydrogenase Mutations are Better Prognostic Marker than O6-methylguanine-DNA Methyltransferase Promoter Methylation in Glioblastomas – a Retrospective, Single-centre Molecular Genetics Study of Gliomas
- Treatment Refusal in Pediatric Oncology