Suramin

{{Short description|Medical drug}} {{redirect|Germanin|the 1943 German drama film|Germanin (film)}} {{Use dmy dates|date=March 2024}} {{cs1 config|name-list-style=vanc|display-authors=6}} {{Drugbox | Verifiedfields = changed | Watchedfields = changed | verifiedrevid = 411355479 | image = Suramin 2D skeletal.svg | image_class = skin-invert-image | width = 360 | alt = | image2 = Suramin ball-and-stick 2H9T.png | image_class2 = bg-transparent | alt2 =

<!-- Clinical data --> | tradename = Antrypol, 309 Fourneau, Bayer 205, others | Drugs.com = {{drugs.com|mmx|suramin-sodium}} | pregnancy_category = | routes_of_administration = by injection only | ATC_prefix = P01 | ATC_suffix = CX02 | ATC_supplemental = {{ATCvet|P51|AE02}}

| legal_US =

<!-- Pharmacokinetic data --> | bioavailability = | metabolism = | excretion =

<!-- Identifiers --> | CAS_number_Ref = {{cascite|correct|CAS}} | CAS_number = 145-63-1 | PubChem = 5361 | IUPHAR_ligand = 1728 | DrugBank_Ref = {{drugbankcite|correct|drugbank}} | DrugBank = DB04786 | ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}} | ChemSpiderID = 5168 | UNII_Ref = {{fdacite|correct|FDA}} | UNII = 6032D45BEM | KEGG_Ref = {{keggcite|correct|kegg}} | KEGG = C07974 | ChEBI_Ref = {{ebicite|correct|EBI}} | ChEBI = 45906 | ChEMBL_Ref = {{ebicite|correct|EBI}} | ChEMBL = 265502 | NIAID_ChemDB = | PDB_ligand = SVR | synonyms =

<!-- Chemical data --> | IUPAC_name = 8,8'-<nowiki/>{Carbonylbis[imino-3,1-phenylenecarbonylimino(4-methyl-3,1-phenylene)carbonylimino]}di(1,3,5-naphthalenetrisulfonic acid) | C=51 | H=40 | N=6 | O=23 | S=6 | SMILES = O=C(Nc1cc(ccc1C)C(=O)Nc3c2c(cc(cc2c(cc3)S(=O)(=O)O)S(=O)(=O)O)S(=O)(=O)O)c8cccc(NC(=O)Nc7cc(C(=O)Nc6cc(C(=O)Nc5c4c(cc(cc4c(cc5)S(=O)(=O)O)S(=O)(=O)O)S(=O)(=O)O)ccc6C)ccc7)c8 | StdInChI_Ref = {{stdinchicite|correct|chemspider}} | StdInChI = 1S/C51H40N6O23S6/c1-25-9-11-29(49(60)54-37-13-15-41(83(69,70)71)35-21-33(81(63,64)65)23-43(45(35)37)85(75,76)77)19-39(25)56-47(58)27-5-3-7-31(17-27)52-51(62)53-32-8-4-6-28(18-32)48(59)57-40-20-30(12-10-26(40)2)50(61)55-38-14-16-42(84(72,73)74)36-22-34(82(66,67)68)24-44(46(36)38)86(78,79)80/h3-24H,1-2H3,(H,54,60)(H,55,61)(H,56,58)(H,57,59)(H2,52,53,62)(H,63,64,65)(H,66,67,68)(H,69,70,71)(H,72,73,74)(H,75,76,77)(H,78,79,80) | StdInChIKey_Ref = {{stdinchicite|correct|chemspider}} | StdInChIKey = FIAFUQMPZJWCLV-UHFFFAOYSA-N }}

<!-- Definition and symptoms --> '''Suramin''' is a medication used to treat African sleeping sickness and river blindness.<ref name="Drugs.com consumer">{{cite web | title=Suramin Injection Advanced Patient Information | website=Drugs.com | date=3 January 2020 | url=https://www.drugs.com/cons/suramin-injection.html | access-date=11 January 2020}}</ref><ref name=PMH2016/> It is the treatment of choice for sleeping sickness without central nervous system involvement.<ref name=CDC2016/> It is given by injection into a vein.<ref name=Zuc2002>{{cite book| vauthors = Zuckerman JN |title=Principles and Practice of Travel Medicine|date=2002|publisher=John Wiley & Sons|isbn=9780471490791|page=113|url=https://books.google.com/books?id=QLSsRQYRV-8C&pg=PA113|language=en|url-status=live|archive-url=https://web.archive.org/web/20161130191739/https://books.google.com/books?id=QLSsRQYRV-8C&pg=PA113|archive-date=30 November 2016}}</ref>

<!-- Side effects and mechanism --> Common side effects include nausea, vomiting, diarrhea, headache, skin tingling, and weakness.<ref name=PMH2016/><ref name=Zuc2002/> Sore palms of the hands and soles of the feet, trouble seeing, fever, and abdominal pain may also occur.<ref name=PMH2016/> Severe side effects may include low blood pressure, decreased level of consciousness, kidney problems, and low blood cell levels.<ref name=Zuc2002/> It is unclear if it is safe when breastfeeding.<ref name=PMH2016>{{cite web|title=Micromedex Detailed Drug Information for the Consumer: Suramin (Injection route)|url=https://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0045224/|publisher=PubMed Health|date=1 November 2016|url-status=dead|archive-url=https://web.archive.org/web/20170908214205/https://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0045224/|archive-date=8 September 2017}}</ref>

<!-- Society and culture --> Suramin was made at least as early as 1916.<ref>{{cite book| vauthors = Mehlhorn H |title=Encyclopedia of Parasitology: A-M |date=2008 |publisher=Springer Science & Business Media |isbn=9783540489948 |page=475 |url=https://books.google.com/books?id=Jpg1ysgVn-AC&pg=PA475 |language=en |url-status=live |archive-url= https://web.archive.org/web/20161130191806/https://books.google.com/books?id=Jpg1ysgVn-AC&pg=PA475|archive-date=30 November 2016}}</ref> It is on the World Health Organization's List of Essential Medicines.<ref name="WHO21st">{{cite book | vauthors = ((World Health Organization)) | title = World Health Organization model list of essential medicines: 21st list 2019 | year = 2019 | hdl = 10665/325771 | author-link = World Health Organization | publisher = World Health Organization | location = Geneva | id = WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO | hdl-access=free }}</ref> In the United States it can be acquired from the Centers for Disease Control (CDC).<ref name=CDC2016>{{cite web|title=Our Formulary Infectious Diseases Laboratories CDC|url=https://www.cdc.gov/laboratory/drugservice/formulary.html|website=www.cdc.gov|access-date=30 November 2016|date=22 September 2016|url-status=live|archive-url=https://web.archive.org/web/20161216173833/https://www.cdc.gov/laboratory/drugservice/formulary.html|archive-date=16 December 2016}}</ref> In regions of the world where the disease is common suramin is provided for free by the World Health Organization (WHO).<ref name=WHO2016>{{cite web|title=Trypanosomiasis, human African (sleeping sickness)|url=https://www.who.int/mediacentre/factsheets/fs259/en/|website=World Health Organization|access-date=7 December 2016|date=February 2016|url-status=live|archive-url=https://web.archive.org/web/20161204153318/http://www.who.int/mediacentre/factsheets/fs259/en/|archive-date=4 December 2016}}</ref>

==Medical uses== Suramin is used for treatment of human sleeping sickness caused by trypanosomes.<ref name="Drugs.com consumer"/> Specifically, it is used for treatment of first-stage African trypanosomiasis caused by ''Trypanosoma brucei rhodesiense'' and ''Trypanosoma brucei gambiense'' without involvement of central nervous system.<ref>{{Cite web|url=https://www.cdc.gov/laboratory/drugservice/formulary.html#tsuramin|title=CDC Infectious Diseases Laboratory: Our Formulary|website=CDC|access-date=8 November 2016|url-status=live|archive-url=https://web.archive.org/web/20161108135341/http://www.cdc.gov/laboratory/drugservice/formulary.html#tsuramin|archive-date=8 November 2016}}</ref><ref name=Kap2016/> It is considered first-line treatment for ''Trypanosoma brucei rhodesiense'', and second-line treatment for early-stage ''Trypanosoma brucei gambiense'', where pentamidine is recommended as first line.<ref name=Kap2016>{{cite journal | vauthors = Kappagoda S, Singh U, Blackburn BG | title = Antiparasitic therapy | journal = Mayo Clinic Proceedings | volume = 86 | issue = 6 | pages = 561–583 | date = June 2011 | pmid = 21628620 | pmc = 3104918 | doi = 10.4065/mcp.2011.0203 }}</ref>

It has been used in the treatment of river blindness (onchocerciasis).<ref name=PMH2016/>

===Pregnancy and breastfeeding=== It is unknown whether it is safe for the baby when a woman takes it while breastfeeding.<ref name=PMH2016/>

==Adverse reactions== The most frequent adverse reactions are nausea, vomiting, diarrhea, abdominal pain, and a feeling of general discomfort. It is also common to experience various sensations in the skin, from crawling or tingling sensations, tenderness of palms and the soles, and numbness of hands, arm, legs or feet.<ref name=drugs/> Other skin reactions include skin rash, swelling and stinging sensation.<ref name=drugs>{{Cite web|url=https://www.drugs.com/cons/suramin-injection.html|title=Suramin Injection Advanced Patient Information - Drugs.com|access-date=8 November 2016|url-status=live|archive-url=https://web.archive.org/web/20161108195804/https://www.drugs.com/cons/suramin-injection.html|archive-date=8 November 2016}}</ref> Suramin can also cause loss of appetite and irritability.<ref name=drugs/> Suramin causes non-harmful changes in urine during use, specifically making the urine cloudy.<ref name=drugs/> It may exacerbate kidney disease.<ref name=GoodmanGilman12/>

Less common side effects include extreme fatigue, ulcers in the mouth, and painful tender glands in the neck, armpits and groin.<ref name=drugs/> Suramin uncommonly affects the eyes causing watery eyes, swelling around the eyes, photophobia, and changes or loss of vision.<ref name=drugs/>

Rare side effects include hypersensitivity reactions causing difficulty breathing. Other rare systemic effects include decreased blood pressure, fever, rapid heart rate, and convulsions.<ref name=drugs/> Other rare side effects include symptoms of liver dysfunction such as tenderness in upper abdomen, jaundice in eyes and skin, unusual bleeding or bruising.<ref name=drugs/>

Suramin has been applied clinically to HIV/AIDS patients resulting in a significant number of fatal occurrences and as a result the application of this molecule was abandoned for this condition.<ref>{{cite journal | vauthors = Kaplan LD, Wolfe PR, Volberding PA, Feorino P, Levy JA, Abrams DI, Kiprov D, Wong R, Kaufman L, Gottlieb MS | title = Lack of response to suramin in patients with AIDS and AIDS-related complex | journal = The American Journal of Medicine | volume = 82 | issue = 3 Spec No | pages = 615–620 | date = March 1987 | pmid = 3548350 | doi = 10.1016/0002-9343(87)90108-2 }}</ref>

== Pharmacology ==

=== Pharmacokinetics === Suramin is not orally bioavailable and must be given intravenously. Intramuscular and subcutaneous administration could result in local tissue inflammation or necrosis {{Citation needed|date=November 2022}}. Suramin is approximately 99-98% protein bound in the serum and has a half-life of 41–78 days average of 50 days; however, the pharmacokinetics of suramin can vary substantially between individual patients. Suramin does not distribute well into cerebral spinal fluid and its concentration in the tissues is equivalently lower than its concentration in the plasma. Suramin is not extensively metabolized and about 80% is eliminated via the kidneys.<ref name=GoodmanGilman12/>

=== Mechanism of action === The mechanism of action for suramin is unclear, but it is thought that parasites are able to selectively uptake suramin via receptor-mediated endocytosis of drug that is bound to low-density lipoproteins and, to a lesser extent, other serum proteins.<ref name=GoodmanGilman12/> Once inside parasites, suramin combines with proteins, especially trypanosomal glycolytic enzymes, to inhibit energy metabolism.<ref>{{cite book| vauthors = Moore TA | veditors = Kasper DL |display-editors=etal |title=Harrison's Principles of Internal Medicine|date=2015|publisher=McGraw-Hill|isbn=9780071802161|edition=19th|chapter=246e: Agents Used to Treat Parasitic Infections}}</ref>

==Chemistry== The molecular formula of suramin is C₅₁H₄₀N₆O₂₃S₆. It is a symmetric molecule in the center of which lies a urea (NH–CO–NH) functional group. Suramin contains six aromatic systems – four benzene rings, sandwiched by a pair of naphthalene moieties – plus four amide functional groups (in addition to the urea) and six sulfonic acid groups. When given as a medication, it is usually delivered as the sodium sulfonate salt as this formulation is water-soluble, though it does deteriorate rapidly in air.<ref name="GoodmanGilman12">{{cite book| vauthors = Phillips MA, Stanley Jr SL |title=Goodman and Gilman's The Pharmacological Basis of Therapeutics. |date=2011|publisher=McGraw Hill|isbn=9780071769396| veditors = Brunton LL, Chabner BA, Knollmann BC |edition=12th|pages=1437–1438|chapter=Chapter 50: Chemotherapy of Protozoal Infections: Amebiasis, Giardiasis, Trichomoniasis, Trypanosomiasis, Leishmaniasis, and Other Protozoal Infections|author-link=Margaret A. Phillips }}</ref>

The synthesis of suramin itself and structural analogs is by successive formation of the amide bonds from their corresponding amine (aniline) and carboxyl (as acyl chloride) components. Various routes to these compounds have been developed, including starting from separate naphthalene structures and building towards an eventual unification by formation of the urea<ref>{{cite journal | vauthors = Kassack MU, Braun K, Ganso M, Ullmann H, Nickel P, Böing B, Müller G, Lambrecht G | title = Structure-activity relationships of analogues of NF449 confirm NF449 as the most potent and selective known P2X1 receptor antagonist | journal = European Journal of Medicinal Chemistry | volume = 39 | issue = 4 | pages = 345–357 | date = April 2004 | pmid = 15072843 | doi = 10.1016/j.ejmech.2004.01.007 }}</ref><ref>{{cite journal | vauthors = Ullmann H, Meis S, Hongwiset D, Marzian C, Wiese M, Nickel P, Communi D, Boeynaems JM, Wolf C, Hausmann R, Schmalzing G, Kassack MU | title = Synthesis and structure-activity relationships of suramin-derived P2Y11 receptor antagonists with nanomolar potency | journal = Journal of Medicinal Chemistry | volume = 48 | issue = 22 | pages = 7040–7048 | date = November 2005 | pmid = 16250663 | doi = 10.1021/jm050301p }}</ref> or starting with a urea and appending successive groups.<ref>{{cite journal |title= An 'inside-out' approach to suramin analogues | vauthors = McGeary RP, Bennett AJ, Tran QB, Prins J, Ross BP |journal= Tetrahedron |year= 2009 |volume= 65 |issue= 20 |pages= 3990–3997 |doi= 10.1016/j.tet.2009.03.033 }}</ref>

==History== Suramin was first made by the chemists Oskar Dressel, Richard Kothe and Bernhard Heymann at Bayer AG laboratories in Elberfeld, after research on a series of urea-like compounds. The drug is still sold by Bayer under the brand name '''Germanin'''. The chemical structure of suramin was kept secret by Bayer for commercial and strategic reasons, but it was elucidated and published in 1924 by Ernest Fourneau and his team at the Pasteur Institute.<ref>{{cite book | vauthors = Sneader W |title=Drug Discovery: A History |publisher=John Wiley & Sons |year=2005 |isbn=9780471899792}}</ref>{{rp|378–379}}<ref>{{cite journal | vauthors = Fourneau E, Théfouël VJ, Vallée J | year = 1924 | title = Sur une nouvelle série de médicaments trypanocides | journal = Comptes Rendus des Séances de l'Académie des Sciences | volume = 178 | page = 675 }}</ref>

==Research== It is also used as a research reagent to inhibit the activation of heterotrimeric G proteins in a variety of GPCRs with varying potency. It prevents the association of heteromeric G proteins and therefore the receptors guanine exchange functionality (GEF). With this blockade the GDP will not release from the Gα subunit so it can not be replaced by a GTP and become activated. This has the effect of blocking downstream G protein mediated signaling of various GPCR proteins including rhodopsin, the A1 adenosine receptor, the D2 receptor,<ref name="pmid8700151">{{cite journal | vauthors = Beindl W, Mitterauer T, Hohenegger M, Ijzerman AP, Nanoff C, Freissmuth M | title = Inhibition of receptor/G protein coupling by suramin analogues | journal = Molecular Pharmacology | volume = 50 | issue = 2 | pages = 415–423 | date = August 1996 | doi = 10.1016/S0026-895X(25)09262-4 | pmid = 8700151 | url = http://molpharm.aspetjournals.org/content/50/2/415.long | url-status = live | archive-url = https://web.archive.org/web/20170908214204/http://molpharm.aspetjournals.org/content/50/2/415.long | archive-date = 8 September 2017 | url-access = subscription }}</ref> the P2 receptor,<ref name="pmid16968944">{{cite journal | vauthors = Abbracchio MP, Burnstock G, Boeynaems JM, Barnard EA, Boyer JL, Kennedy C, Knight GE, Fumagalli M, Gachet C, Jacobson KA, Weisman GA | title = International Union of Pharmacology LVIII: update on the P2Y G protein-coupled nucleotide receptors: from molecular mechanisms and pathophysiology to therapy | journal = Pharmacological Reviews | volume = 58 | issue = 3 | pages = 281–341 | date = September 2006 | pmid = 16968944 | pmc = 3471216 | doi = 10.1124/pr.58.3.3 }}</ref><ref name="pmid11171941">{{cite journal | vauthors = Khakh BS, Burnstock G, Kennedy C, King BF, North RA, Séguéla P, Voigt M, Humphrey PP | title = International union of pharmacology. XXIV. Current status of the nomenclature and properties of P2X receptors and their subunits | journal = Pharmacological Reviews | volume = 53 | issue = 1 | pages = 107–118 | date = March 2001 | doi = 10.1016/S0031-6997(24)01482-0 | pmid = 11171941 | url = http://pharmrev.aspetjournals.org/content/53/1/107/tab-figures-data | url-status = live | archive-url = https://web.archive.org/web/20161118164555/http://pharmrev.aspetjournals.org/content/53/1/107/tab-figures-data | archive-date = 18 November 2016 | url-access = subscription }}</ref> and ryanodine receptors.<ref name="pmid16056233">{{cite journal | vauthors = Wolner I, Kassack MU, Ullmann H, Karel A, Hohenegger M | title = Use-dependent inhibition of the skeletal muscle ryanodine receptor by the suramin analogue NF676 | journal = British Journal of Pharmacology | volume = 146 | issue = 4 | pages = 525–533 | date = October 2005 | pmid = 16056233 | pmc = 1751178 | doi = 10.1038/sj.bjp.0706359 }}</ref> Suramin is also an inhibitor of ABC-type<ref name="pmid10491158">{{cite journal | vauthors = Buxbaum E | title = Co-operative binding sites for transported substrates in the multiple drug resistance transporter Mdr1 | journal = European Journal of Biochemistry | volume = 265 | issue = 1 | pages = 64–70 | date = October 1999 | pmid = 10491158 | doi = 10.1046/j.1432-1327.1999.00644.x }}</ref> and P-type<ref name="pmid4355468">{{cite journal | vauthors = Fortes PA, Ellory JC, Lew VL | title = Suramin: a potent ATPase inhibitor which acts on the inside surface of the sodium pump | journal = Biochimica et Biophysica Acta (BBA) - Biomembranes | volume = 318 | issue = 2 | pages = 262–72 | date = August 1973 | pmid = 4355468 | doi = 10.1016/0005-2736(73)90119-3 }}</ref> ATPases, which acts competitively with ATP.

Suramin was studied as a possible treatment for prostate cancer in a clinical trial.<ref name="pmid15484217">{{cite journal | vauthors = Ahles TA, Herndon JE, Small EJ, Vogelzang NJ, Kornblith AB, Ratain MJ, Stadler W, Palchak D, Marshall ME, Wilding G, Petrylak D, Holland JC | title = Quality of life impact of three different doses of suramin in patients with metastatic hormone-refractory prostate carcinoma: results of Intergroup O159/Cancer and Leukemia Group B 9480 | journal = Cancer | volume = 101 | issue = 10 | pages = 2202–2208 | date = November 2004 | pmid = 15484217 | doi = 10.1002/cncr.20655 | s2cid = 29107328 | doi-access = free }}</ref>

Suramin has been studied in a mouse model of autism and in a small phase I/II human trial.<ref>{{cite web | url = https://health.ucsd.edu/news/releases/Pages/2017-05-26-century-old-drug-potential-new-approach-to-autism.aspx | vauthors = LaFee S, Buschman H | title = Researchers Studying Century-Old Drug in Potential New Approach to Autism. | publisher = UC San Diego Health | date = 26 May 2017 | archive-url = https://web.archive.org/web/20170601054246/https://health.ucsd.edu/news/releases/Pages/2017-05-26-century-old-drug-potential-new-approach-to-autism.aspx | archive-date= 1 June 2017 }}</ref><ref>{{cite journal | vauthors = Naviaux JC, Schuchbauer MA, Li K, Wang L, Risbrough VB, Powell SB, Naviaux RK | title = Reversal of autism-like behaviors and metabolism in adult mice with single-dose antipurinergic therapy | journal = Translational Psychiatry | volume = 4 | issue = 6 | pages = e400 | date = June 2014 | pmid = 24937094 | pmc = 4080315 | doi = 10.1038/tp.2014.33 }}</ref><ref>{{cite journal | vauthors = Naviaux RK, Curtis B, Li K, Naviaux JC, Bright AT, Reiner GE, Westerfield M, Goh S, Alaynick WA, Wang L, Capparelli EV, Adams C, Sun J, Jain S, He F, Arellano DA, Mash LE, Chukoskie L, Lincoln A, Townsend J | title = Low-dose suramin in autism spectrum disorder: a small, phase I/II, randomized clinical trial | journal = Annals of Clinical and Translational Neurology | volume = 4 | issue = 7 | pages = 491–505 | date = July 2017 | pmid = 28695149 | pmc = 5497533 | doi = 10.1002/acn3.424 }}</ref><ref>{{Cite web|title=Q and A - Suramin and Autism |url=https://health.ucsd.edu/news/topics/Suramin-Autism/Pages/Q-and-A.aspx|access-date=27 July 2021|website=UC Health - UC San Diego|language=en-US}}</ref> Secondary outcomes showed improvements in language, social interaction, and decreased restricted or repetitive behaviors.The safety and activity of low‐dose suramin showed promise as a novel approach to treatment of ASD in this small study. Results from a randomized clinical study found no statistically significant effects of suramin (in either 10mg or 20mg doses) versus placebo on boys with moderate to severe autism spectrum disorder.<ref>{{cite journal | vauthors = Hough D, Mao AR, Aman M, Lozano R, Smith-Hicks C, Martinez-Cerdeno V, Derby M, Rome Z, Malan N, Findling RL | title = Randomized clinical trial of low dose suramin intravenous infusions for treatment of autism spectrum disorder | journal = Annals of General Psychiatry | volume = 22 | issue = 1 | article-number = 45 | date = November 2023 | pmid = 37932739 | pmc = 10626700 | doi = 10.1186/s12991-023-00477-8 | doi-access = free }}</ref>

Suramin is a reversible and competitive protein tyrosine phosphatase (PTPases) inhibitor, also is the potent inhibitor of sirtuins, purified topoisomerase II and SARS-CoV-2 RNA-dependent RNA polymerase (RdRp).<ref>{{cite web | title = Suramin sodium salt | url = https://www.selleckchem.com/products/suramin-sodium-salt.html | work = Selleck Chemicals }}</ref>

== References == {{Citation style|date=May 2017}} {{Reflist}}

== Further reading == {{refbegin}} * {{cite journal | vauthors = Zhang YL, Keng YF, Zhao Y, Wu L, Zhang ZY | title = Suramin is an active site-directed, reversible, and tight-binding inhibitor of protein-tyrosine phosphatases | journal = The Journal of Biological Chemistry | volume = 273 | issue = 20 | pages = 12281–12287 | date = May 1998 | pmid = 9575179 | doi = 10.1074/jbc.273.20.12281 | doi-access = free }} {{refend}}

== External links == * [http://www.cancer.gov/Templates/drugdictionary.aspx?CdrID=40052 Suramin sodium] National Cancer Institute

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