Suramin is a

medication A medication (also called medicament, medicine, pharmaceutical drug, medicinal drug or simply drug) is a drug used to diagnose, cure, treat, or prevent disease. Drug therapy (pharmacotherapy) is an important part of the medical field and re ...

used to treat

African sleeping sickness African trypanosomiasis, also known as African sleeping sickness or simply sleeping sickness, is an insect-borne parasitic infection of humans and other animals. It is caused by the species '' Trypanosoma brucei''. Humans are infected by two ty ...

and river blindness. It is the treatment of choice for sleeping sickness without

central nervous system The central nervous system (CNS) is the part of the nervous system consisting primarily of the brain and spinal cord. The CNS is so named because the brain integrates the received information and coordinates and influences the activity of all par ...

involvement. It is given by

injection into a vein Intravenous therapy (abbreviated as IV therapy) is a medical technique that administers fluids, medications and nutrients directly into a person's vein. The intravenous route of administration is commonly used for rehydration or to provide nutrie ...

. Suramin causes a fair number of side effects. Common side effects include nausea, vomiting,

diarrhea Diarrhea, also spelled diarrhoea, is the condition of having at least three loose, liquid, or watery bowel movements each day. It often lasts for a few days and can result in dehydration due to fluid loss. Signs of dehydration often begin wi ...

, headache, skin tingling, and weakness. Sore palms of the hands and soles of the feet, trouble seeing,

fever Fever, also referred to as pyrexia, is defined as having a body temperature, temperature above the human body temperature, normal range due to an increase in the body's temperature Human body temperature#Fever, set point. There is not a single ...

, and abdominal pain may also occur. Severe side effects may include low blood pressure,

decreased level of consciousness An altered level of consciousness is any measure of arousal other than normal. Level of consciousness (LOC) is a measurement of a person's arousability and responsiveness to stimuli from the environment. A mildly depressed level of consciousne ...

, kidney problems, and low blood cell levels. It is unclear if it is safe when

breastfeeding Breastfeeding, or nursing, is the process by which human breast milk is fed to a child. Breast milk may be from the breast, or may be expressed by hand or pumped and fed to the infant. The World Health Organization (WHO) recommends that br ...

. Suramin was made at least as early as 1916. It is on the World Health Organization's List of Essential Medicines. In the United States it can be acquired from the Centers for Disease Control (CDC). In regions of the world where the disease is common suramin is provided for free by the

World Health Organization The World Health Organization (WHO) is a specialized agency of the United Nations responsible for international public health. The WHO Constitution states its main objective as "the attainment by all peoples of the highest possible level of h ...

(WHO).

Medical uses

Suramin is used for treatment of human sleeping sickness caused by trypanosomes. Specifically, it is used for treatment of first-stage African trypanosomiasis caused by ''

Trypanosoma brucei rhodesiense ''Trypanosoma brucei'' is a species of parasitic kinetoplastid belonging to the genus ''Trypanosoma'' that is present in sub-Saharan Africa. Unlike other protozoan parasites that normally infect blood and tissue cells, it is exclusively extrace ...

'' and ''

Trypanosoma brucei gambiense ''Trypanosoma brucei'' is a species of parasitic kinetoplastid belonging to the genus ''Trypanosoma'' that is present in sub-Saharan Africa. Unlike other protozoan parasites that normally infect blood and tissue cells, it is exclusively extracellu ...

'' without involvement of central nervous system. It is considered first-line treatment for ''

'', and second-line treatment for early-stage ''

'', where

pentamidine Pentamidine is an antimicrobial medication used to treat African trypanosomiasis, leishmaniasis, ''Balamuthia'' infections, babesiosis, and to prevent and treat pneumocystis pneumonia (PCP) in people with poor immune function. In African trypano ...

is recommended as first line. It has been used in the treatment of river blindness (onchocerciasis).

Pregnancy and breastfeeding

It is unknown whether it is safe for the baby when a woman takes it while breastfeeding.

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. Other skin reactions include skin rash, swelling and stinging sensation. Suramin can also cause loss of appetite and irritability. Suramin causes non-harmful changes in urine during use, specifically making the urine cloudy. It may exacerbate

kidney disease Kidney disease, or renal disease, technically referred to as nephropathy, is damage to or disease of a kidney. Nephritis is an inflammatory kidney disease and has several types according to the location of the inflammation. Inflammation can ...

. Less common side effects include extreme fatigue, ulcers in the mouth, and painful tender glands in the neck, armpits and groin. Suramin uncommonly affects the eyes causing watery eyes, swelling around the eyes, photophobia, and changes or loss of vision. Rare side effects include hypersensitivity reactions causing difficulty breathing. Other rare systemic effects include decreased blood pressure, fever, rapid heart rate, and convulsions. Other rare side effects include symptoms of liver dysfunction such as tenderness in upper abdomen, jaundice in eyes and skin, unusual bleeding or bruising. 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.

Pharmacokinetics

Suramin is not orally bioavailable and must be given intravenously. Intramuscular and subcutaneous administration could result in local tissue inflammation or necrosis . 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.

Chemistry

The molecular formula of suramin is C₅₁H₄₀N₆O₂₃S₆. It is a symmetric

molecule A molecule is a group of two or more atoms held together by attractive forces known as chemical bonds; depending on context, the term may or may not include ions which satisfy this criterion. In quantum physics, organic chemistry, and bioch ...

in the center of which lies a

urea Urea, also known as carbamide, is an organic compound with chemical formula . This amide has two amino groups (–) joined by a carbonyl functional group (–C(=O)–). It is thus the simplest amide of carbamic acid. Urea serves an important r ...

(NH–CO–NH) functional group. Suramin contains six aromatic systems – four benzene rings, sandwiched by a pair of

naphthalene Naphthalene is an organic compound with formula . It is the simplest polycyclic aromatic hydrocarbon, and is a white crystalline solid with a characteristic odor that is detectable at concentrations as low as 0.08 ppm by mass. As an aromati ...

moieties – plus four

amide In organic chemistry, an amide, also known as an organic amide or a carboxamide, is a compound with the general formula , where R, R', and R″ represent organic groups or hydrogen atoms. The amide group is called a peptide bond when it is ...

functional group In organic chemistry, a functional group is a substituent or moiety in a molecule that causes the molecule's characteristic chemical reactions. The same functional group will undergo the same or similar chemical reactions regardless of the rest ...

s (in addition to the urea) and six

sulfonic acid In organic chemistry, sulfonic acid (or sulphonic acid) refers to a member of the class of organosulfur compounds with the general formula , where R is an organic alkyl or aryl group and the group a sulfonyl hydroxide. As a substituent, it is kn ...

groups. When given as a medication, it is usually delivered as the sodium sulfonate

salt Salt is a mineral composed primarily of sodium chloride (NaCl), a chemical compound belonging to the larger class of salts; salt in the form of a natural crystalline mineral is known as rock salt or halite. Salt is present in vast quantitie ...

as this formulation is water-soluble, though it does deteriorate rapidly in air. The

synthesis Synthesis or synthesize may refer to: Science Chemistry and biochemistry *Chemical synthesis, the execution of chemical reactions to form a more complex molecule from chemical precursors ** Organic synthesis, the chemical synthesis of organ ...

of suramin itself and structural analogs is by successive formation of the amide bonds from their corresponding

amine In chemistry, amines (, ) are compounds and functional groups that contain a basic nitrogen atom with a lone pair. Amines are formally derivatives of ammonia (), wherein one or more hydrogen atoms have been replaced by a substituen ...

(

aniline Aniline is an organic compound with the formula C6 H5 NH2. Consisting of a phenyl group attached to an amino group, aniline is the simplest aromatic amine In organic chemistry, an aromatic amine is an organic compound consisting of an aroma ...

) and carboxyl (as

acyl chloride In organic chemistry, an acyl chloride (or acid chloride) is an organic compound with the functional group . Their formula is usually written , where R is a side chain. They are reactive derivatives of carboxylic acids (). A specific example o ...

) 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 or starting with a urea and appending successive groups.

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. Once inside parasites, suramin combines with proteins, especially trypanosomal

glycolytic Glycolysis is the metabolic pathway that converts glucose () into pyruvate (). The free energy released in this process is used to form the high-energy molecules adenosine triphosphate (ATP) and reduced nicotinamide adenine dinucleotide (NADH ...

enzymes, to inhibit energy metabolism.

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 Ernest Fourneau (4 October 1872 – 5 August 1949) was a French pharmacist graduated in Pharmacy 1898 for the Paris university specialist in medicinal chemical and pharmacology who played a major role in the discovery of synthetic local anesthetic ...

and his team at the

Pasteur Institute The Pasteur Institute (french: Institut Pasteur) is a French non-profit private foundation dedicated to the study of biology, micro-organisms, diseases, and vaccines. It is named after Louis Pasteur, who invented pasteurization and vaccines f ...

Research

It is also used as a research

reagent In chemistry, a reagent ( ) or analytical reagent is a substance or compound added to a system to cause a chemical reaction, or test if one occurs. The terms ''reactant'' and ''reagent'' are often used interchangeably, but reactant specifies a ...

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 Rhodopsin, also known as visual purple, is a protein encoded by the RHO gene and a G-protein-coupled receptor (GPCR). It is the opsin of the rod cells in the retina and a light-sensitive receptor protein that triggers visual phototransduction ...

, the A1 adenosine receptor, the D2 receptor, the P2 receptor, and

ryanodine receptor Ryanodine receptors (RyR for short) form a class of intracellular calcium channels in various forms of excitable animal tissue like muscles and neurons. There are three major isoforms of the ryanodine receptor, which are found in different tissu ...

s. Suramin was studied as a possible treatment for

prostate cancer Prostate cancer is cancer of the prostate. Prostate cancer is the second most common cancerous tumor worldwide and is the fifth leading cause of cancer-related mortality among men. The prostate is a gland in the male reproductive system that sur ...

in a clinical trial. Suramin has been studied in a mouse model of

autism The autism spectrum, often referred to as just autism or in the context of a professional diagnosis autism spectrum disorder (ASD) or autism spectrum condition (ASC), is a neurodevelopmental condition (or conditions) characterized by difficulti ...

and in a small phase I/II human trial.

References

External links

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Suramin sodium
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