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General Description:

Nifurtimox, identified by CAS number 23256-30-6, is a notable compound with significant therapeutic applications. Chagas disease, caused by a parasite known as Trypanosoma cruzi (T.cruzi), is a vector-transmitted disease affecting animals and humans in the Americas. It is commonly known as American Trypanosomiasis. The CDC estimates that approximately 8 million people in Central America, South America, and Mexico are infected with T. cruzi, without symptoms. If Chagas disease is left untreated, life-threatening sequelae may result. Nifurtimox, developed by Bayer, is a nitrofuran antiprotozoal drug used in the treatment of Chagas disease. On August 6 2020, accelerated FDA approval was granted for its use in pediatric patients in response to promising results from phase III clinical trials. Continued approval will be contingent upon confirmatory data. A convenient feature of Bayer's formulation is the ability to divide the scored tablets manually without the need for pill-cutting devices.

Indications:

This drug is primarily indicated for: Nifurtimox is indicated in pediatric patients under 18 weighing at least 2.5 kg. Continued approval of this drug for this indication is dependent upon confirmatory clinical trial results. Its use in specific medical scenarios underscores its importance in the therapeutic landscape.

Metabolism:

Nifurtimox undergoes metabolic processing primarily in: Nifurtimox is largely metabolized via nitroreductase enzymes. Two major inactive metabolites have been identified: M-4 and M-6. The M-4 metabolite is a cysteine conjugate of nifurtimox, while M-6 is likely formed by hydrolytic cleavage of the hydrazone moiety of nifurtimox. Other minor metabolites have also been identified in human plasma. This metabolic pathway ensures efficient processing of the drug, helping to minimize potential toxicity and side effects.

Absorption:

The absorption characteristics of Nifurtimox are crucial for its therapeutic efficacy: The average AUC of nifurtimox is estimated between 1676-2670 μg∙h/L. One pharmacokinetic study of healthy volunteers revealed an AUC of 5430 ng∙ml^-1∙h. Cmax ranges between 425-568 μg/L (26–50%) after a single dose of 20 mg with food in adults. Tmax is 4 hours, ranging from 2 to 8 hours post-dose in the fed state. In a pharmacokinetic study of healthy volunteers, serum concentration was low, likely due to the first-pass effect. The drug's ability to rapidly penetrate into cells ensures quick onset of action.

Half-life:

The half-life of Nifurtimox is an important consideration for its dosing schedule: The elimination half-life of nifurtimox ranges from 2.4–3.6 hours. A pharmacokinetic study of healthy volunteers and patients with renal failure revealed respective mean half-lives of 2.95 h and 3.95 h. This determines the duration of action and helps in formulating effective dosing regimens.

Protein Binding:

Nifurtimox exhibits a strong affinity for binding with plasma proteins: The plasma protein binding of nifurtimox is approximately 42%. It is primarily bound to albumin. This property plays a key role in the drug's pharmacokinetics and distribution within the body.

Route of Elimination:

The elimination of Nifurtimox from the body primarily occurs through: In the fed state, 44% of the dose was mainly recovered in the urine as metabolites. Fecal and biliary excretion of nifurtimox have not been studied. Understanding this pathway is essential for assessing potential drug accumulation and toxicity risks.

Volume of Distribution:

Nifurtimox is distributed throughout the body with a volume of distribution of: Nifurtimox crosses the blood-brain barrier and the placenta. This metric indicates how extensively the drug permeates into body tissues.

Clearance:

The clearance rate of Nifurtimox is a critical factor in determining its safe and effective dosage: One pharmacokinetic study of nifurtimox revealed a clearance of 193.4 l∙h^-1. In patients without renal failure; clearance was 99.7 l∙h^-1. It reflects the efficiency with which the drug is removed from the systemic circulation.

Pharmacodynamics:

Nifurtimox exerts its therapeutic effects through: Nifurtimox exerts trypanosomal activity against Trypanosoma cruzi, treating Chagas disease. One study reports that nifurtimox and other benzofuran derivatives reduce parasite dehydrogenase activity. Results of a recent phase III clinical trial have shown that a significant number of pediatric patients with acute or chronic Chagas disease treated with nifurtimox were immunoglobulin G (IgG) antibody negative and demonstrated at least a 20% decrease in optical density on two IgG antibody tests for T. cruzi antigens. The drug's ability to modulate various physiological processes underscores its efficacy in treating specific conditions.

Mechanism of Action:

Nifurtimox functions by: The mechanism of action of nifurtimox has not been fully elucidated, however, is believed to occur by the activation of nitroreductase enzymes that produce reactive metabolites with a series of deleterious effects on Trypanosoma cruzi, the parasite causing Chagas disease. The antiprotozoal actions of nifurtimox occur both intracellularly and extracellularly. Inhibition of parasite dehydrogenase activity is another purported mode of action of nifurtimox that warrants further research. This mechanism highlights the drug's role in inhibiting or promoting specific biological pathways, contributing to its therapeutic effects.

Toxicity:

Classification:

Nifurtimox belongs to the class of organic compounds known as nitrofurans. These are compounds containing a furan ring which bears a nitro group, classified under the direct parent group Nitrofurans. This compound is a part of the Organic compounds, falling under the Organoheterocyclic compounds superclass, and categorized within the Furans class, specifically within the Nitrofurans subclass.

Categories:

Nifurtimox is categorized under the following therapeutic classes: Agents Against Leishmaniasis and Trypanosomiasis, Anti-Infective Agents, Antiparasitic Agents, Antiparasitic Products, Insecticides and Repellents, Antiprotozoals, BCRP/ABCG2 Substrates, Furans, Nitro Compounds, Nitrofuran Antiprotozoals, Nitrofuran Derivatives, Nitrofurans, Sulfur Compounds, Thiazines, Trypanocidal Agents. These classifications highlight the drug's diverse therapeutic applications and its importance in treating various conditions.

Experimental Properties:

Further physical and chemical characteristics of Nifurtimox include:

• Melting Point: 177-183
• Boiling Point: 550.3±50.0
• logP: -0.27
• logS: 0.158
• pKa: -1.01±0.40