It has been used in the treatment of river blindness (onchocerciasis).[2]
Pregnancy and breastfeeding
It is unknown whether it is safe for the baby when a woman takes it while breastfeeding.[2]
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.[10] Other skin reactions include skin rash, swelling and stinging sensation.[10] Suramin can also cause loss of appetite and irritability.[10] Suramin causes non-harmful changes in urine during use, specifically making the urine cloudy.[10] It may exacerbate kidney disease.[11]
Less common side effects include extreme fatigue, ulcers in the mouth, and painful tender glands in the neck, armpits and groin.[10] Suramin uncommonly affects the eyes causing watery eyes, swelling around the eyes, photophobia, and changes or loss of vision.[10]
Rare side effects include hypersensitivity reactions causing difficulty breathing. Other rare systemic effects include decreased blood pressure, fever, rapid heart rate, and convulsions.[10] Other rare side effects include symptoms of liver dysfunction such as tenderness in upper abdomen, jaundice in eyes and skin, unusual bleeding or bruising.[10]
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.[12]
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]. 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.[11]
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.[11] Once inside parasites, suramin combines with proteins, especially trypanosomal glycolytic enzymes, to inhibit energy metabolism.[13]
Chemistry
The molecular formula of suramin is C51H40N6O23S6. It is a symmetricmolecule 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 naphthalenemoieties – plus four amidefunctional groups (in addition to the urea) and six sulfonic acid groups. When given as a medication, it is usually delivered as the sodium sulfonatesalt as this formulation is water-soluble, though it does deteriorate rapidly in air.[11]
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[14][15] or starting with a urea and appending successive groups.[16]
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 nameGermanin. 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.[17]: 378–379 [18]
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,[19] the P2 receptor,[20][21] and ryanodine receptors.[22] Suramin is also an inhibitor of ABC-type[23] and P-type[24] ATPases, which acts competitively with ATP.
Suramin was studied as a possible treatment for prostate cancer in a clinical trial.[25]
Suramin has been studied in a mouse model of autism and in a small phase I/II human trial.[26][27][28][29] 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.[30]
^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.
^ abcdPhillips MA, Stanley Jr SL (2011). "Chapter 50: Chemotherapy of Protozoal Infections: Amebiasis, Giardiasis, Trichomoniasis, Trypanosomiasis, Leishmaniasis, and Other Protozoal Infections". In Brunton LL, Chabner BA, Knollmann BC (eds.). Goodman and Gilman's The Pharmacological Basis of Therapeutics (12th ed.). McGraw Hill. pp. 1437–1438. ISBN9780071769396.
^Kaplan LD, Wolfe PR, Volberding PA, Feorino P, Levy JA, Abrams DI, et al. (March 1987). "Lack of response to suramin in patients with AIDS and AIDS-related complex". The American Journal of Medicine. 82 (3 Spec No): 615–620. doi:10.1016/0002-9343(87)90108-2. PMID3548350.
^Moore TA (2015). "246e: Agents Used to Treat Parasitic Infections". In Kasper DL, et al. (eds.). Harrison's Principles of Internal Medicine (19th ed.). McGraw-Hil. ISBN9780071802161.
^Kassack MU, Braun K, Ganso M, Ullmann H, Nickel P, Böing B, et al. (April 2004). "Structure-activity relationships of analogues of NF449 confirm NF449 as the most potent and selective known P2X1 receptor antagonist". European Journal of Medicinal Chemistry. 39 (4): 345–357. doi:10.1016/j.ejmech.2004.01.007. PMID15072843.
^Ullmann H, Meis S, Hongwiset D, Marzian C, Wiese M, Nickel P, et al. (November 2005). "Synthesis and structure-activity relationships of suramin-derived P2Y11 receptor antagonists with nanomolar potency". Journal of Medicinal Chemistry. 48 (22): 7040–7048. doi:10.1021/jm050301p. PMID16250663.
^McGeary RP, Bennett AJ, Tran QB, Prins J, Ross BP (2009). "An 'inside-out' approach to suramin analogues". Tetrahedron. 65 (20): 3990–3997. doi:10.1016/j.tet.2009.03.033.
^Sneader W (2005). Drug Discovery: A History. John Wiley & Sons. ISBN9780471899792.
^Fourneau E, Théfouël VJ, Vallée J (1924). "Sur une nouvelle série de médicaments trypanocides". Comptes Rendus des Séances de l'Académie des Sciences. 178: 675.
^Buxbaum E (October 1999). "Co-operative binding sites for transported substrates in the multiple drug resistance transporter Mdr1". European Journal of Biochemistry. 265 (1): 64–70. doi:10.1046/j.1432-1327.1999.00644.x. PMID10491158.
^Fortes PA, Ellory JC, Lew VL (August 1973). "Suramin: a potent ATPase inhibitor which acts on the inside surface of the sodium pump". Biochimica et Biophysica Acta (BBA) - Biomembranes. 318 (2): 262–72. doi:10.1016/0005-2736(73)90119-3. PMID4355468.
