Mercaptopurine

Last updated

Mercaptopurine
Mercaptopurine.svg
Mercaptopurin ball-and-stick.png
Clinical data
Trade names Purinethol, Purixan, others
Other names6-mercaptopurine (6-MP)
AHFS/Drugs.com Monograph
MedlinePlus a682653
License data
Routes of
administration 		By mouth
ATC code
Legal status
Legal status
  • EU:Rx-only [1]
  • In general: ℞ (Prescription only)
Pharmacokinetic data
Bioavailability 5 to 37%
Metabolism xanthine oxidase
Elimination half-life 60 to 120 min., longer for its active metabolites
Excretion kidney
Identifiers
  • 3,7-dihydropurine-6-thione
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.000.035 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C5H4N4S
Molar mass 152.18 g·mol−1
3D model (JSmol)
  • S=c1nc[nH]c2nc[nH]c12
  • InChI=1S/C5H4N4S/c10-5-3-4(7-1-6-3)8-2-9-5/h1-2H,(H2,6,7,8,9,10) Yes check.svgY
  • Key:GLVAUDGFNGKCSF-UHFFFAOYSA-N Yes check.svgY
   (verify)

Mercaptopurine (6-MP), sold under the brand name Purinethol among others, is a medication used for cancer and autoimmune diseases. [2] Specifically it is used to treat acute lymphocytic leukemia (ALL), acute promyelocytic leukemia (APL), Crohn's disease, and ulcerative colitis. [2] [3] For acute lymphocytic leukemia it is generally used with methotrexate. [2] It is taken orally. [2]

Contents

Common side effects include bone marrow suppression, liver toxicity, vomiting, and loss of appetite. [2] Other serious side effects include an increased risk of future cancer and pancreatitis. [2] Those with a genetic deficiency in thiopurine S-methyltransferase are at higher risk of side effects. [2] Use in pregnancy may harm the baby. [2] Mercaptopurine is in the thiopurine and antimetabolite family of medications. [4] [3]

Mercaptopurine was approved for medical use in the United States in 1953. [2] It is on the World Health Organization's List of Essential Medicines. [5]

Medical uses

It is used to treat acute lymphocytic leukemia, Crohn's disease, and ulcerative colitis. [6]

Side effects

Some of the adverse reactions of taking mercaptopurine may include diarrhea, nausea, vomiting, loss of appetite, fatigue, stomach/abdominal pain, weakness, skin rash, darkening of the skin, and hair loss. Serious adverse reactions include mouth sores, fever, sore throat, easy bruising or bleeding, pinpoint red spots on the skin, yellowing of eyes or skin, dark urine, and painful or difficult urination. Other more serious side effects include black or tarry stools (melena), bloody stools, and bloody urine. Treatment is discontinued in up to 30% of patients due these effects but therapeutic drug monitoring of the biologically active metabolites, i.e. thiopurine nucleotides can help to optimize the efficacy and safety. Clinically, most hospitals resort to on-exchange LC-MS (liquid chromatography - mass spectrometry) but the newly developed approach of porous graphitic carbon based chromatography hyphenated with mass spectrometry appears superior with respect to patient care in this respect. [7]

Symptoms of allergic reaction to mercaptopurine include rash, itching, swelling, dizziness, trouble breathing, and inflammation of the pancreas.

In some cases, mercaptopurine may suppress the production of blood cells, both white blood cells and red blood cells. It may be toxic to bone marrow. Quarterly blood counts are necessary for people on mercaptopurine. People should stop taking the medication at least temporarily while considering alternate treatment if there is an unexplained, abnormally large drop in white blood cell count, or any other blood count.

Toxicity of mercaptopurine can be linked to genetic polymorphisms in thiopurine S-methyltransferase (TPMT), nudix hydrolase 15 (NUDT15), [8] [9] and inosine triphosphate pyrophosphatase (ITPA). People with specific allele variants will require dose adjustments, especially for those with homozygous variant genotypes. Large differences of TPMT and NUDT15 among ethnicities in terms of variant allele frequency should be taken into consideration in clinical practice. [10] Caucasian people with a variant allele of the ITPA gene, experience higher rates of febrile neuropenia than people of other ethnic groups, due to differences in allelic frequencies among ethnicities. [11]

Precautions

Mercaptopurine can lower the body's ability to fight off infection. Those taking it should get permission from a doctor to receive immunizations and vaccinations. It is also recommended that, while on the drug, one should avoid those having recently received oral polio vaccine.

This drug was formerly not recommended during pregnancy and early evidence indicated pregnant women on the drug (or the related azathioprine) showed a seven-fold incidence of fetal abnormalities as well as a 20-fold increase in miscarriage. [12] There were also anecdotal reports linking mercaptopurine with spontaneous abortion, leading to the US FDA rating both AZA and mercaptopurine as category D drugs. However, Davis et al. 1999 found mercaptopurine, compared to methotrexate, was ineffective as a single-agent abortifacient; every woman in the mercaptopurine arm of the study had fetal cardiac activity at follow-up (two weeks later) and was given a suction abortion. [13] A more recent, larger study, however, performed by the Cancers et Surrisque Associe aux Maladies inflamatoires intestinales En France (CESAME) indicated an overall rate of congenital malformations not significantly greater than the general population in France. [14] The European Crohn's and Colitis Organisation (ECCO) concluded in a consensus paper in 2010 that while AZA and mercaptopurine have an FDA rating of D, new research in both animals and humans indicates that "thiopurines are safe and well tolerated during pregnancy." [15]

Mercaptopurine causes changes to chromosomes in animals and humans, though a study in 1990 [16] found, "while the carcinogenic potential of 6-MP cannot be precluded, it can be only very weak or marginal." Another study in 1999 [17] noted an increased risk of developing leukemia when taking large doses of 6-MP with other cytotoxic drugs.

Drug interactions

Allopurinol inhibits xanthine oxidase, the enzyme that breaks down mercaptopurine. Those taking allopurinol (often used to prevent gout) are at risk for mercaptopurine toxicity. The dose should be reduced or allopurinol should be discontinued. Several published studies have demonstrated that the use of allopurinol in combination with low dose 6-MP helps reduce 6-MP levels, which are toxic to liver tissue, whilst increasing the therapeutic levels of 6-MP for some inflammatory conditions.

Mechanisms of action

Official information from the package insert for purinethol: [18]

6-MP ribonucleotide inhibits purine nucleotide synthesis and metabolism by inhibiting an enzyme called phosphoribosyl pyrophosphate amidotransferase (PRPP amidotransferase). Since this enzyme is the rate limiting factor for purine synthesis, [21] this alters the synthesis and function of RNA and DNA.[ citation needed ] Mercaptopurine interferes with nucleotide interconversion and glycoprotein synthesis.

Pharmacogenetics

The enzyme thiopurine S-methyltransferase (TPMT) is responsible, in part, for the inactivation of 6-mercaptopurine. TPMT catalyzes the methylation of 6-mercaptopurine into the inactive metabolite 6-methylmercaptopurine – this methylation prevents mercaptopurine from further conversion into active, cytotoxic thioguanine nucleotide (TGN) metabolites. [22] [23] [24] Certain genetic variations within the TPMT gene can lead to decreased or absent TPMT enzyme activity, and individuals who are homozygous or heterozygous for these types of genetic variations may have increased levels of TGN metabolites and an increased risk of severe bone marrow suppression (myelosuppression) when receiving mercaptopurine. [25] In many ethnicities, TPMT polymorphisms that result in decreased or absent TPMT activity occur with a frequency of approximately 5%, meaning that about 0.25% of people are homozygous for these variants. [25] [26] However, an assay of TPMT activity in red blood cells or a TPMT genetic test can identify people with reduced TPMT activity, allowing for the adjustment of mercaptopurine dose or avoidance of the drug entirely. [25] [27] The FDA-approved drug label for mercaptopurine recommends testing for TPMT activity to identify people at risk for myelotoxicity. [28] [29] Testing for TPMT activity is an example of pharmacogenetics being translated into routine clinical care. [30]

History

6-MP was discovered by Nobel Prize–winning scientists Gertrude B. Elion and George H. Hitchings at Burroughs Wellcome in Tuckahoe, New York, [31] and was clinically developed in collaboration with investigators at Memorial Hospital (now Memorial Sloan Kettering Cancer Center in New York City). [32] The collaboration was initiated by Cornelius P. Rhoads, who had run chemical weapons programs for the US Army and had been involved in the work that led to the discovery that nitrogen mustards could potentially be used as cancer drugs, and had become the director of Memorial in 1948. [32]

Related Research Articles

<span class="mw-page-title-main">Allopurinol</span> Medication

Allopurinol is a medication used to decrease high blood uric acid levels. It is specifically used to prevent gout, prevent specific types of kidney stones and for the high uric acid levels that can occur with chemotherapy. It is taken orally or intravenously.

<span class="mw-page-title-main">Azathioprine</span> Immunosuppressive medication

Azathioprine, sold under the brand name Imuran, among others, is an immunosuppressive medication. It is used for the treatment of rheumatoid arthritis, granulomatosis with polyangiitis, Crohn's disease, ulcerative colitis, and systemic lupus erythematosus; and in kidney transplants to prevent rejection. It is listed by the International Agency for Research on Cancer as a group 1 human carcinogen. It is taken by mouth or injected into a vein.

<span class="mw-page-title-main">Cytarabine</span> Chemical compound (chemotherapy medication)

Cytarabine, also known as cytosine arabinoside (ara-C), is a chemotherapy medication used to treat acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL), chronic myelogenous leukemia (CML), and non-Hodgkin's lymphoma. It is given by injection into a vein, under the skin, or into the cerebrospinal fluid. There is a liposomal formulation for which there is tentative evidence of better outcomes in lymphoma involving the meninges.

Fluorouracil, sold under the brand name Adrucil among others, is a cytotoxic chemotherapy medication used to treat cancer. By intravenous injection it is used for treatment of colorectal cancer, oesophageal cancer, stomach cancer, pancreatic cancer, breast cancer, and cervical cancer. As a cream it is used for actinic keratosis, basal cell carcinoma, and skin warts.

<span class="mw-page-title-main">Antimetabolite</span> Chemical that inhibits the use of a metabolite

An antimetabolite is a chemical that inhibits the use of a metabolite, which is another chemical that is part of normal metabolism. Such substances are often similar in structure to the metabolite that they interfere with, such as the antifolates that interfere with the use of folic acid; thus, competitive inhibition can occur, and the presence of antimetabolites can have toxic effects on cells, such as halting cell growth and cell division, so these compounds are used in chemotherapy for cancer.

<span class="mw-page-title-main">History of cancer chemotherapy</span>

The era of cancer chemotherapy began in the 1940s with the first use of nitrogen mustards and folic acid antagonist drugs. The targeted therapy revolution has arrived, but many of the principles and limitations of chemotherapy discovered by the early researchers still apply.

<span class="mw-page-title-main">Azacitidine</span> Chemical compound

Azacitidine, sold under the brand name Vidaza among others, is a medication used for the treatment of myelodysplastic syndrome, myeloid leukemia, and juvenile myelomonocytic leukemia. It is a chemical analog of cytidine, a nucleoside in DNA and RNA. Azacitidine and its deoxy derivative, decitabine were first synthesized in Czechoslovakia as potential chemotherapeutic agents for cancer.

<span class="mw-page-title-main">Cladribine</span> Pharmaceutical drug

Cladribine, sold under the brand name Leustatin, among others, is a medication used to treat hairy cell leukemia and B-cell chronic lymphocytic leukemia. Cladribine, sold under the brand name Mavenclad, is used for the treatment of adults with highly active forms of relapsing-remitting multiple sclerosis.

<span class="mw-page-title-main">Thiopurine methyltransferase</span>

Thiopurine methyltransferase or thiopurine S-methyltransferase (TPMT) is an enzyme that in humans is encoded by the TPMT gene. A pseudogene for this locus is located on chromosome 18q.

<span class="mw-page-title-main">Tioguanine</span> Chemical compound

Tioguanine, also known as thioguanine or 6-thioguanine (6-TG) or tabloid is a medication used to treat acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL), and chronic myeloid leukemia (CML). Long-term use is not recommended. It is given by mouth.

Purine metabolism refers to the metabolic pathways to synthesize and break down purines that are present in many organisms.

<span class="mw-page-title-main">Thiopurine</span> Class of chemical compounds

The thiopurine drugs are purine antimetabolites widely used in the treatment of acute lymphoblastic leukemia, autoimmune disorders, and organ transplant recipients.

<span class="mw-page-title-main">Antifolate</span> Class of antimetabolite medications

Antifolates are a class of antimetabolite medications that antagonise (that is, block) the actions of folic acid (vitamin B9). Folic acid's primary function in the body is as a cofactor to various methyltransferases involved in serine, methionine, thymidine and purine biosynthesis. Consequently, antifolates inhibit cell division, DNA/RNA synthesis and repair and protein synthesis. Some such as proguanil, pyrimethamine and trimethoprim selectively inhibit folate's actions in microbial organisms such as bacteria, protozoa and fungi. The majority of antifolates work by inhibiting dihydrofolate reductase (DHFR).

<span class="mw-page-title-main">Axitinib</span> Chemical compound

Axitinib, sold under the brand name Inlyta, is a small molecule tyrosine kinase inhibitor developed by Pfizer. It has been shown to significantly inhibit growth of breast cancer in animal (xenograft) models and has shown partial responses in clinical trials with renal cell carcinoma (RCC) and several other tumour types.

Purine analogues are antimetabolites that mimic the structure of metabolic purines.

The molecular formula C5H4N4S (molar mass : 152.18 g/mol) may refer to :

VAMP regimen or VAMP chemotherapy is a four-drug combination chemotherapy regimen, used today in the treatment of Hodgkin lymphoma. It was one of the earliest combination chemotherapy regimens, originally developed as a treatment for childhood leukemia by a group of researchers at the National Cancer Institute led by Emil Frei and Emil Freireich. The first clinical trial of VAMP began in 1961. Because it was the first time that four chemotherapeutic agents were used at once, the trial was highly controversial at its time. Although new combination chemotherapy regimens have replaced the use of VAMP in the treatment of childhood leukemia, VAMP is considered an important precursor to modern treatments, confirming the effectiveness of combination chemotherapy and leading to the use of combination chemotherapy regimens to treat other types of cancer.

<span class="mw-page-title-main">NUDT15</span>

Nudix hydrolase 15 is a protein that in humans is encoded by the NUDT15 gene.

<span class="mw-page-title-main">Cancer pharmacogenomics</span>

Cancer pharmacogenomics is the study of how variances in the genome influences an individual’s response to different cancer drug treatments. It is a subset of the broader field of pharmacogenomics, which is the area of study aimed at understanding how genetic variants influence drug efficacy and toxicity.

Howard L. McLeod is an American pharmacogeneticist and implementation scientist specialized in precision medicine.

References

  1. ↑ "Xaluprine EPAR". European Medicines Agency. 30 April 2009. Retrieved 25 June 2024.
  2. 1 2 3 4 5 6 7 8 9 "Mercaptopurine". The American Society of Health-System Pharmacists. Archived from the original on 20 December 2016. Retrieved 8 December 2016.
  3. 1 2 British national formulary : BNF 69 (69 ed.). British Medical Association. 2015. p. 590. ISBN   9780857111562.
  4. ↑ Sahasranaman S, Howard D, Roy S (August 2008). "Clinical pharmacology and pharmacogenetics of thiopurines". European Journal of Clinical Pharmacology. 64 (8): 753–67. doi:10.1007/s00228-008-0478-6. PMID   18506437. S2CID   27475772.
  5. ↑ World Health Organization (2019). World Health Organization model list of essential medicines: 21st list 2019. Geneva: World Health Organization. hdl: 10665/325771 . WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO.
  6. ↑ "Mercaptopurine". The American Society of Health-System Pharmacists. Archived from the original on 6 September 2015. Retrieved 28 August 2015.
  7. ↑ Pecher D, Zelinkova Z, Lucenicova J, Peppelenbosch M, Dokupilova S, Mikusova V, et al. (November 2020). "Porous graphitic carbon based chromatography hyphenated with mass spectrometry: A new strategy for profiling thiopurine nucleotides in patients with inflammatory bowel diseases". Analytica Chimica Acta. 1137 (1137): 64–73. Bibcode:2020AcAC.1137...64P. doi:10.1016/j.aca.2020.08.064. PMID   33153610. S2CID   225287631.
  8. ↑ Yang JJ, Landier W, Yang W, Liu C, Hageman L, Cheng C, et al. (April 2015). "Inherited NUDT15 variant is a genetic determinant of mercaptopurine intolerance in children with acute lymphoblastic leukemia". Journal of Clinical Oncology. 33 (11): 1235–42. doi:10.1200/jco.2014.59.4671. PMC   4375304 . PMID   25624441.{{cite journal}}: CS1 maint: overridden setting (link)
  9. ↑ Moriyama T, Nishii R, Perez-Andreu V, Yang W, Klussmann FA, Zhao X, et al. (April 2016). "NUDT15 polymorphisms alter thiopurine metabolism and hematopoietic toxicity". Nature Genetics. 48 (4): 367–73. doi:10.1038/ng.3508. PMC   5029084 . PMID   26878724.{{cite journal}}: CS1 maint: overridden setting (link)
  10. ↑ Yin D, Xia X, Zhang J, Zhang S, Liao F, Zhang G, et al. (February 2017). "Impact of NUDT15 polymorphisms on thiopurines-induced myelotoxicity and thiopurines tolerance dose". Oncotarget. 8 (8): 13575–13585. doi:10.18632/oncotarget.14594. PMC   5355121 . PMID   28088792.{{cite journal}}: CS1 maint: overridden setting (link)
  11. ↑ Esses SI, Morley TP (February 1983). "Spinal arachnoiditis". The Canadian Journal of Neurological Sciences. 10 (1): 2–10. doi: 10.1017/s0317167100044486 . PMID   6404543.
  12. ↑ Nørgård B, Pedersen L, Fonager K, Rasmussen SN, Sørensen HT (March 2003). "Azathioprine, mercaptopurine and birth outcome: a population-based cohort study". Alimentary Pharmacology & Therapeutics. 17 (6): 827–34. doi: 10.1046/j.1365-2036.2003.01537.x . PMID   12641505. S2CID   25314258.
  13. ↑ Davis AR, Miller L, Tamimi H, Gown A (June 1999). "Methotrexate compared with mercaptopurine for early induced abortion". Obstetrics and Gynecology. 93 (6): 904–9. doi:10.1016/S0029-7844(98)00569-9. PMID   10362152. Archived from the original on 19 June 2006.
  14. ↑ Coelho J, Beaugerie L, Colombel JF, Hébuterne X, Lerebours E, Lémann M, et al. (February 2011). "Pregnancy outcome in patients with inflammatory bowel disease treated with thiopurines: cohort from the CESAME Study". Gut. 60 (2): 198–203. doi:10.1136/gut.2010.222893. PMID   21115547. S2CID   25614617.{{cite journal}}: CS1 maint: overridden setting (link)
  15. ↑ Van Assche G, Dignass A, Reinisch W, van der Woude CJ, Sturm A, De Vos M, et al. (February 2010). "The second European evidence-based Consensus on the diagnosis and management of Crohn's disease: Special situations". Journal of Crohn's & Colitis. 4 (1): 63–101. doi: 10.1016/j.crohns.2009.09.009 . PMID   21122490.{{cite journal}}: CS1 maint: overridden setting (link)
  16. ↑ Maekawa A, Nagaoka T, Onodera H, Matsushima Y, Todate A, Shibutani M, et al. (May 1990). "Two-year carcinogenicity study of 6-mercaptopurine in F344 rats". Journal of Cancer Research and Clinical Oncology. 116 (3): 245–50. doi:10.1007/BF01612898. PMID   2370249. S2CID   21675626.{{cite journal}}: CS1 maint: overridden setting (link)
  17. ↑ Bo J, Schrøder H, Kristinsson J, Madsen B, Szumlanski C, Weinshilboum R, et al. (September 1999). "Possible carcinogenic effect of 6-mercaptopurine on bone marrow stem cells: relation to thiopurine metabolism". Cancer. 86 (6): 1080–6. doi: 10.1002/(SICI)1097-0142(19990915)86:6<1080::AID-CNCR26>3.0.CO;2-5 . PMID   10491537. S2CID   45441636.{{cite journal}}: CS1 maint: overridden setting (link)
  18. ↑ "PURINETHOL (mercaptopurine) tablet [Gate Pharmaceuticals]" (PDF). DailyMed. Gate Pharmaceuticals. August 2012. Archived from the original on 1 January 2014. Retrieved 31 December 2013.
  19. ↑ "Chemotherapy".
  20. ↑ Nielsen OH, Vainer B, Rask-Madsen J. Review article: the treatment of inflammatory bowel disease with 6-mercaptopurine or azathioprine. Aliment Pharmacol Ther. 2001 Nov;15(11):1699-708. doi: 10.1046/j.1365-2036.2001.01102.x. PMID 11683683.
  21. ↑ Hansen, Barbara. "Purine and Pyrimidine Metabolism." USMLE STEP 1 Biochemistry and Medical Genetics Lecture Notes. 2010 ed. N.p.: Kaplan, 2010. 288-90. Print.
  22. ↑ Zaza G, Cheok M, Krynetskaia N, Thorn C, Stocco G, Hebert JM, et al. (September 2010). "Thiopurine pathway". Pharmacogenetics and Genomics. 20 (9): 573–4. doi:10.1097/FPC.0b013e328334338f. PMC   3098750 . PMID   19952870.{{cite journal}}: CS1 maint: overridden setting (link)
  23. ↑ Stocco G, Pelin M, Franca R, De Iudicibus S, Cuzzoni E, Favretto D, et al. (April 2014). "Pharmacogenetics of azathioprine in inflammatory bowel disease: a role for glutathione-S-transferase?". World Journal of Gastroenterology. 20 (13): 3534–41. doi: 10.3748/wjg.v20.i13.3534 . PMC   3974520 . PMID   24707136.{{cite journal}}: CS1 maint: overridden setting (link)
  24. ↑ Fujita K, Sasaki Y (August 2007). "Pharmacogenomics in drug-metabolizing enzymes catalyzing anticancer drugs for personalized cancer chemotherapy". Current Drug Metabolism. 8 (6): 554–62. doi:10.2174/138920007781368890. PMID   17691917. Archived from the original on 12 January 2013.{{cite journal}}: CS1 maint: unfit URL (link)
  25. 1 2 3 Relling MV, Gardner EE, Sandborn WJ, Schmiegelow K, Pui CH, Yee SW, et al. (March 2011). "Clinical Pharmacogenetics Implementation Consortium guidelines for thiopurine methyltransferase genotype and thiopurine dosing". Clinical Pharmacology and Therapeutics. 89 (3): 387–91. doi:10.1038/clpt.2010.320. PMC   3098761 . PMID   21270794.{{cite journal}}: CS1 maint: overridden setting (link)
  26. ↑ Mutschler E, Schäfer-Korting M (2001). Arzneimittelwirkungen (in German) (8th ed.). Stuttgart: Wissenschaftliche Verlagsgesellschaft. pp. 107, 936. ISBN   978-3-8047-1763-3.
  27. ↑ Payne K, Newman W, Fargher E, Tricker K, Bruce IN, Ollier WE (May 2007). "TPMT testing in rheumatology: any better than routine monitoring?". Rheumatology. 46 (5): 727–9. doi: 10.1093/rheumatology/kel427 . PMID   17255139.
  28. ↑ "Label: Mercaptopurine – mercaptopurine tablet". Archived from the original on 6 October 2015. Retrieved 11 March 2015.
  29. ↑ "Purixan suspension". DailyMed. 9 April 2019. Retrieved 9 April 2020.
  30. ↑ Wang L, Pelleymounter L, Weinshilboum R, Johnson JA, Hebert JM, Altman RB, et al. (June 2010). "Very important pharmacogene summary: thiopurine S-methyltransferase". Pharmacogenetics and Genomics. 20 (6): 401–5. doi:10.1097/FPC.0b013e3283352860. PMC   3086840 . PMID   20154640.
  31. ↑ Bouton K (29 January 1989). "The Nobel Pair". The New York Times Magazine. Archived from the original on 7 October 2016.
  32. 1 2 Mukherjee S (2010). The Emperor of All Maladies: A Biography of Cancer. New York: Scribner. pp. 91–92. ISBN   978-1439170915.

Further reading

This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.