Benznidazole is an antiparasitic medication used in the treatment of

Chagas disease Chagas disease, also known as American trypanosomiasis, is a tropical parasitic disease caused by ''Trypanosoma cruzi''. It is spread mostly by insects in the subfamily '' Triatominae'', known as "kissing bugs". The symptoms change over the co ...

. While it is highly effective in early disease this decreases in those who have long-term infection. It is the first-line treatment given its moderate side effects compared to

nifurtimox Nifurtimox, sold under the brand name Lampit, is a medication used to treat Chagas disease and sleeping sickness. For sleeping sickness it is used together with eflornithine in nifurtimox-eflornithine combination treatment. In Chagas disease ...

. It is taken by mouth. Side effects are fairly common. They include rash, numbness,

fever Fever, also referred to as pyrexia, is defined as having a temperature above the normal range due to an increase in the body's temperature set point. There is not a single agreed-upon upper limit for normal temperature with sources using val ...

muscle pain Myalgia (also called muscle pain and muscle ache in layman's terms) is the medical term for muscle pain. Myalgia is a symptom of many diseases. The most common cause of acute myalgia is the overuse of a muscle or group of muscles; another like ...

, loss of appetite, and trouble sleeping. Rare side effects include

bone marrow suppression Bone marrow suppression also known as myelotoxicity or myelosuppression, is the decrease in production of cells responsible for providing immunity ( leukocytes), carrying oxygen ( erythrocytes), and/or those responsible for normal blood clotting ...

which can lead to low blood cell levels. It is not recommended during

pregnancy Pregnancy is the time during which one or more offspring develops ( gestates) inside a woman's uterus (womb). A multiple pregnancy involves more than one offspring, such as with twins. Pregnancy usually occurs by sexual intercourse, but ...

or in people with severe liver or kidney disease. Benznidazole is in the

nitroimidazole 5-Nitroimidazole is an organic compound with the formula O2NC3H2N2H. The nitro group at position 5 on the imidazole ring is the most common positional isomer. The term nitroimidazole also refers to a class of antibiotics that share similar ch ...

family of medication and works by the production of

free radicals In chemistry, a radical, also known as a free radical, is an atom, molecule, or ion that has at least one unpaired valence electron. With some exceptions, these unpaired electrons make radicals highly chemically reactive. Many radicals spon ...

. Benznidazole came into medical use in 1971. It is on the

World Health Organization's List of Essential Medicines The WHO Model List of Essential Medicines (aka Essential Medicines List or EML), published by the World Health Organization (WHO), contains the medications considered to be most effective and safe to meet the most important needs in a health s ...

. As of 2012, Laboratório Farmacêutico do Estado de Pernambuco, a government run pharmaceutical company in Brazil was the only producer.

Medical uses

Benznidazole has a significant activity during the acute phase of Chagas disease, with a success rate of up to 80%. Its curative capabilities during the chronic phase are, however, limited. Some studies have found parasitologic cure (a complete elimination of ''T. cruzi'' from the body) in children during the early stage of the chronic phase, but overall failure rate in chronically infected individuals is typically above 80%. Some studies indicate treatment with benznidazole during the chronic phase, even if incapable of producing parasitologic cure because it reduces electrocardiographic changes and delays worsening of the clinical condition of the patient. Benznidazole has proven to be effective in the treatment of reactivated ''T. cruzi'' infections caused by

immunosuppression Immunosuppression is a reduction of the activation or efficacy of the immune system. Some portions of the immune system itself have immunosuppressive effects on other parts of the immune system, and immunosuppression may occur as an adverse reacti ...

, such as in people with

AIDS Human immunodeficiency virus infection and acquired immunodeficiency syndrome (HIV/AIDS) is a spectrum of conditions caused by infection with the human immunodeficiency virus (HIV), a retrovirus. Following initial infection an individual ma ...

or in those under immunosuppressive therapy related to organ transplants.

Children

Benznidazole can be used in children, with the same 5–7 mg/kg per day weight-based dosing regimen that is used to treat adult infections. A formulation for children up to two years of age is available. It was added to the WHO Essential Medicines List for Children in 2013. Children are found to be at a lower risk of adverse events compared to adults, possibly due to increased hepatic clearance of the drug. The most prevalent adverse effects in children were found to be gastrointestinal, dermatologic, and neurologic in nature. However, the incidence of severe dermatologic and neurologic adverse events is lower in the pediatric population compared to adults. It use for Chagas in children was approved by the FDA in the US in 2017.

Pregnant women

Studies in animals have shown that benznidazole can cross the placenta. Due to its potential for teratogenicity, use of benznidazole in pregnancy is not recommended.

Side effects

Side effects tend to be common and occur more frequently with increased age. The most common adverse reactions associated with benznidazole are allergic dermatitis and peripheral neuropathy. It is reported that up to 30% of people will experience dermatitis when starting treatment. Benznidazole may cause photosensitization of the skin, resulting in rashes. Rashes usually appear within the first 2 weeks of treatment and resolve over time. In rare instances, skin hypersensitivity can result in exfoliative skin eruptions, edema, and fever.

Peripheral neuropathy Peripheral neuropathy, often shortened to neuropathy, is a general term describing disease affecting the peripheral nerves, meaning nerves beyond the brain and spinal cord. Damage to peripheral nerves may impair sensation, movement, gland, or or ...

may occur later on in the treatment course and is dose dependent. It is not permanent, but takes time to resolve. Other adverse reactions include anorexia, weight loss, nausea, vomiting, insomnia, and dysguesia, and bone marrow suppression. Gastrointestinal symptoms usually occur during the initial stages of treatment and resolves over time. Bone marrow suppression has been linked to the cumulative dose exposure.

Contraindications

Benznidazole should not be used in people with severe liver and/or kidney disease. Pregnant women should not use benznidazole because it can cross the placenta and cause

teratogenicity Teratology is the study of abnormalities of physiological development in organisms during their life span. It is a sub-discipline in medical genetics which focuses on the classification of congenital abnormalities in dysmorphology. The related ...

Pharmacology

Mechanism of action

Benznidazole is a

antiparasitic with good activity against acute infection with ''Trypanosoma cruzi,'' commonly referred to as Chagas disease''.'' Like other nitroimidazoles, benznidazole's main mechanism of action is to generate radical species which can damage the parasite's DNA or cellular machinery. The mechanism by which nitroimidazoles do this seems to depend on whether or not oxygen is present. This is particularly relevant in the case of ''

Trypanosoma ''Trypanosoma'' is a genus of kinetoplastids (class Trypanosomatidae), a monophyletic group of unicellular parasitic flagellate protozoa. Trypanosoma is part of the phylum Sarcomastigophora. The name is derived from the Greek ''trypano-'' (b ...

'' species, which are considered

facultative anaerobes A facultative anaerobic organism is an organism that makes ATP by aerobic respiration if oxygen is present, but is capable of switching to fermentation if oxygen is absent. Some examples of facultatively anaerobic bacteria are ''Staphylococcus' ...

. Under anaerobic conditions, the

nitro Nitro may refer to: Chemistry *Nitrogen, a chemical element and a gas except at very low temperatures, with which many compounds are formed: **Nitro compound, an organic compound containing one or more nitro functional groups, -NO2 **Nitroalkene, ...

group of nitroimidazoles is believed to be reduced by the pyruvate:ferredoxin oxidoreductase complex to create a reactive nitro radical species. The nitro radical can then either engage in other redox reactions directly or spontaneously give rise to a

nitrite The nitrite ion has the chemical formula . Nitrite (mostly sodium nitrite) is widely used throughout chemical and pharmaceutical industries. The nitrite anion is a pervasive intermediate in the nitrogen cycle in nature. The name nitrite also ...

ion and

imidazole Imidazole (ImH) is an organic compound with the formula C3N2H4. It is a white or colourless solid that is soluble in water, producing a mildly alkaline solution. In chemistry, it is an aromatic heterocycle, classified as a diazole, and has non ...

radical instead. The initial reduction takes place because nitroimidazoles are better

electron acceptor An electron acceptor is a chemical entity that accepts electrons transferred to it from another compound. It is an oxidizing agent that, by virtue of its accepting electrons, is itself reduced in the process. Electron acceptors are sometimes mista ...

s for

ferredoxin Ferredoxins (from Latin ''ferrum'': iron + redox, often abbreviated "fd") are iron–sulfur proteins that mediate electron transfer in a range of metabolic reactions. The term "ferredoxin" was coined by D.C. Wharton of the DuPont Co. and applied t ...

than the natural substrates. In mammals, the principal mediators of electron transport are NAD+/NADH and NADP+/NADPH, which have a more positive

reduction potential Redox potential (also known as oxidation / reduction potential, ''ORP'', ''pe'', ''E_'', or E_) is a measure of the tendency of a chemical species to acquire electrons from or lose electrons to an electrode and thereby be reduced or oxidised respe ...

and so will not reduce nitroimidazoles to the radical form. This limits the spectrum of activity of nitroimidazoles so that host cells and DNA are not also damaged. This mechanism has been well-established for 5-nitroimidazoles such as

metronidazole Metronidazole, sold under the brand name Flagyl among others, is an antibiotic and antiprotozoal medication. It is used either alone or with other antibiotics to treat pelvic inflammatory disease, endocarditis, and bacterial vaginosis. It is ...

, but it is unclear if the same mechanism can be expanded to 2-nitroimidazoles (including benznidazole). In the presence of oxygen, by contrast, any radical nitro compounds produced will be rapidly oxidized by

molecular oxygen There are several known allotropes of oxygen. The most familiar is molecular oxygen (O2), present at significant levels in Earth's atmosphere and also known as dioxygen or triplet oxygen. Another is the highly reactive ozone (O3). Others are ...

, yielding the original nitroimidazole compound and a

superoxide In chemistry, a superoxide is a compound that contains the superoxide ion, which has the chemical formula . The systematic name of the anion is dioxide(1−). The reactive oxygen ion superoxide is particularly important as the product of t ...

anion in a process known as " futile cycling". In these cases, the generation of superoxide is believed to give rise to other

reactive oxygen species In chemistry, reactive oxygen species (ROS) are highly reactive chemicals formed from diatomic oxygen (). Examples of ROS include peroxides, superoxide, hydroxyl radical, singlet oxygen, and alpha-oxygen. The reduction of molecular oxygen () p ...

. The degree of

toxicity Toxicity is the degree to which a chemical substance or a particular mixture of substances can damage an organism. Toxicity can refer to the effect on a whole organism, such as an animal, bacterium, or plant, as well as the effect on a subs ...

mutagen In genetics, a mutagen is a physical or chemical agent that permanently changes genetic material, usually DNA, in an organism and thus increases the frequency of mutations above the natural background level. As many mutations can cause cancer i ...

icity produced by these oxygen radicals depends on cells' ability to detoxify superoxide radicals and other reactive oxygen species. In mammals, these radicals can be converted safely to

hydrogen peroxide Hydrogen peroxide is a chemical compound with the formula . In its pure form, it is a very pale blue liquid that is slightly more viscous than water. It is used as an oxidizer, bleaching agent, and antiseptic, usually as a dilute solution (3 ...

, meaning benznidazole has very limited direct toxicity to human cells. In ''Trypanosoma'' species, however, there is a reduced capacity to detoxify these radicals, which results in damage to the parasite's cellular machinery.

Pharmacokinetics

Oral The word oral may refer to: Relating to the mouth * Relating to the mouth, the first portion of the alimentary canal that primarily receives food and liquid ** Oral administration of medicines ** Oral examination (also known as an oral exam or or ...

benznidazole has a

bioavailability In pharmacology, bioavailability is a subcategory of absorption and is the fraction (%) of an administered drug that reaches the systemic circulation. By definition, when a medication is administered intravenously, its bioavailability is 100%. Ho ...

of 92%, with a peak concentration time of 3–4 hours after administration. 5% of the parent drug is excreted unchanged in the

urine Urine is a liquid by-product of metabolism in humans and in many other animals. Urine flows from the kidneys through the ureters to the urinary bladder. Urination results in urine being excreted from the body through the urethra. Cellul ...

, which implies that clearance of benznidazole is mainly through metabolism by the liver. Its

elimination half-life Biological half-life (also known as elimination half-life, pharmacologic half-life) is the time taken for concentration of a biological substance (such as a medication) to decrease from its maximum concentration ( Cmax) to half of Cmax in the b ...

is 10.5-13.6 hours.

Interactions

Benznidazole and other nitroimidazoles have been shown to decrease the rate of clearance of

5-fluorouracil Fluorouracil (5-FU), 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, panc ...

(including 5-fluorouracil produced from its

prodrug A prodrug is a medication or compound that, after intake, is metabolized (i.e., converted within the body) into a pharmacologically active drug. Instead of administering a drug directly, a corresponding prodrug can be used to improve how the dru ...

capecitabine Capecitabine, sold under the brand name Xeloda among others, is a chemotherapy medication used to treat breast cancer, gastric cancer and colorectal cancer. For breast cancer it is often used together with docetaxel. It is taken by mouth. Com ...

, doxifluridine, and

tegafur Tegafur is a chemotherapeutic prodrug of 5-fluorouracil (5-FU) used in the treatment of cancers. It is a component of the combination drug tegafur/uracil. When metabolised, it becomes 5-FU. It was patented in 1967 and approved for medical use in ...

). While co-administration of any of these drugs with benznidazole is not

contraindicated In medicine, a contraindication is a condition that serves as a reason not to take a certain medical treatment due to the harm that it would cause the patient. Contraindication is the opposite of indication, which is a reason to use a certain tre ...

, monitoring for 5-fluorouracil

is recommended in the event they are used together. The

GLP-1 receptor agonist Glucagon-like peptide-1 receptor agonists, also known as GLP-1 receptor agonists (GLP-1-RA) or incretin mimetics, are agonists of the GLP-1 receptor. This class of medications is used for the treatment of type 2 diabetes Some drugs are also appr ...

lixisenatide may slow down the

absorption Absorption may refer to: Chemistry and biology *Absorption (biology), digestion **Absorption (small intestine) *Absorption (chemistry), diffusion of particles of gas or liquid into liquid or solid materials *Absorption (skin), a route by which s ...

and activity of benznidazole, presumably due to delayed

gastric emptying Gastrointestinal physiology is the branch of human physiology that addresses the physical function of the gastrointestinal (GI) tract. The function of the GI tract is to process ingested food by mechanical and chemical means, extract nutrients and ...

. Because nitroimidazoles can kill ''

Vibrio cholerae ''Vibrio cholerae'' is a species of Gram-negative, facultative anaerobe and comma-shaped bacteria. The bacteria naturally live in brackish or saltwater where they attach themselves easily to the chitin-containing shells of crabs, shrimps, and oth ...

'' cells, use is not recommended within 14 days of receiving a live

cholera Cholera is an infection of the small intestine by some strains of the bacterium '' Vibrio cholerae''. Symptoms may range from none, to mild, to severe. The classic symptom is large amounts of watery diarrhea that lasts a few days. Vomiting an ...

vaccine A vaccine is a biological preparation that provides active acquired immunity to a particular infectious or malignant disease. The safety and effectiveness of vaccines has been widely studied and verified.

.Product Information: VAXCHORA(TM) oral suspension, cholera vaccine live oral suspension. PaxVax Inc (per manufacturer), Redwood City, CA, 2016. Alcohol consumption can cause a

disulfiram Disulfiram is a medication used to support the treatment of chronic alcoholism by producing an acute sensitivity to ethanol (drinking alcohol). Disulfiram works by inhibiting the enzyme acetaldehyde dehydrogenase, causing many of the effects o ...

like reaction with benznidazole.

References

External links

* {{Portal bar, Medicine Antiprotozoal agents Chagas disease Disulfiram-like drugs Nitroimidazoles Carboxamides World Health Organization essential medicines Wikipedia medicine articles ready to translate