Suramin

Suramin is a medication used to treat African sleeping sickness and river blindness.<ref name="Drugs.com consumer">{{#invoke:citation/CS1|citation |CitationClass=web }}</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>Template:Cite book</ref>

Suramin causes a fair number of side effects.<ref name=Zuc2002/> Common side effects include nausea, vomiting, diarrhea, headache, skin tingling, and weakness.<ref name=PMH2016/> 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>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

Suramin was made at least as early as 1916.<ref>Template:Cite book</ref> It is on the World Health Organization's List of Essential Medicines.<ref name="WHO21st">Template:Cite book</ref> In the United States it can be acquired from the Centers for Disease Control (CDC).<ref name=CDC2016>{{#invoke:citation/CS1|citation |CitationClass=web }}</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>{{#invoke:citation/CS1|citation |CitationClass=web }}</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>{{#invoke:citation/CS1|citation |CitationClass=web }}</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>Template:Cite journal</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>{{#invoke:citation/CS1|citation |CitationClass=web }}</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>Template:Cite journal</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 Template: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.<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>Template:Cite book</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">Template:Cite book</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>Template:Cite journal</ref><ref>Template:Cite journal</ref> or starting with a urea and appending successive groups.<ref>Template:Cite journal</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>Template:Cite book</ref>Template:Rp<ref>Template:Cite journal</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">Template:Cite journal</ref> the P2 receptor,<ref name="pmid16968944">Template:Cite journal</ref><ref name="pmid11171941">Template:Cite journal</ref> and ryanodine receptors.<ref name="pmid16056233">Template:Cite journal</ref> Suramin is also an inhibitor of ABC-type<ref name="pmid10491158">Template:Cite journal</ref> and P-type<ref name="pmid4355468">Template:Cite journal</ref> ATPases, which acts competitively with ATP.

Suramin was studied as a possible treatment for prostate cancer in a clinical trial.<ref name="pmid15484217">Template:Cite journal</ref>

Suramin has been studied in a mouse model of autism and in a small phase I/II human trial.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref>Template:Cite journal</ref><ref>Template:Cite journal</ref><ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</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>Template:Cite journal</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>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

Further reading

• Template:Cite journal

External links

• Suramin sodium National Cancer Institute