Trypanosoma

When mice infected with Trypanosoma cruzi Tulahuen strain or SGO-Z12 isolate are treated with benzidazole (100 mg/kg/day, p.o., 30 days), the results include a decrease in electrocardiographic alterations, fewer modifications in the affinity and density of cardiac receptors, and a few isolated areas of fibrosis in the heart[1].

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This study is a prospective cohort analysis (SaMi-Trop cohort) investigating the long-term clinical benefits of previous benznidazole treatment in patients with chronic Chagas disease (ChD). A total of 1,813 seropositive patients with abnormal electrocardiograms were included. Of these, 493 patients who self-reported receiving at least one course of benznidazole treatment were classified as the Treated Group (TrG). The remaining 1,320 patients who never received treatment formed the Control Group (CG). The average self-reported treatment duration was 90 days. Most patients (64%) started treatment within 30 days of serological diagnosis, and 83% reported being treated before the age of 40, indicating treatment likely occurred during earlier, less severe disease stages. Outcomes were assessed at a baseline visit and after a two-year follow-up period. [3]
The primary outcome was all-cause mortality after two years. Mortality was significantly lower in the TrG (2.8%, 14/493) compared to the CG (7.6%, 100/1320). After adjustment using genetic matching analysis, the odds ratio (OR) for death was 0.37 (95% CI: 0.21, 0.63), indicating a protective effect associated with prior benznidazole treatment. Kaplan-Meier survival analysis showed significantly better survival in the treated group (P = 0.001). [3]
Secondary outcomes assessed at baseline included parasitological and cardiac severity markers. Polymerase-chain-reaction (PCR) positivity for Trypanosoma cruzi DNA in blood was significantly lower in the TrG (16.6%, 82/493) than in the CG (36.4%, 481/1320), with an adjusted OR of 0.35 (95% CI: 0.27, 0.45). This indicates a long-lasting reduction in detectable parasitemia. [3]
Cardiac severity was assessed via electrocardiogram (ECG) abnormalities typical of Chagas cardiomyopathy and age-adjusted N-terminal pro-brain natriuretic peptide (NT-ProBNP) levels suggestive of heart failure. The prevalence of typical ECG abnormalities was lower in the TrG (48.4%) versus the CG (60.0%) (adjusted OR: 0.64; 95% CI: 0.52, 0.79). High age-adjusted NT-ProBNP levels were also less frequent in the TrG (6.1%) than in the CG (13.3%) (adjusted OR: 0.41; 95% CI: 0.28, 0.60). A composite outcome of both typical ECG abnormalities and high NT-ProBNP was significantly lower in the TrG (5.0%) compared to the CG (12.6%) (adjusted OR: 0.35; 95% CI: 0.23, 0.53). [3]

Animal Model: Mice infected with Trypanosoma cruzi Tulahuen strain or SGO-Z12[1]
Dosage: 100 mg/kg/day
Administration: Orally for 30 days
Result: reduced the number of changes in the affinity and density of cardiac receptors, reduced the number of isolated cardiac fibrosis regions, and decreased electrocardiographic alterations.

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Albino Swiss mice were infected by intraperitoneal injection with 50 trypomastigotes of Trypanosoma cruzi (Tulahuen strain or SGO-Z12 isolate).
Treatment was initiated in the chronic phase of infection, at 180 days post-infection. Benznidazole was administered orally at a dose of 100 mg/kg/day. The treatment duration was 30 consecutive days.
Parasitemia was monitored weekly via tail vein blood samples. Electrocardiographic studies were performed before infection, before treatment (180 days p.i.), and after treatment (215 and 350 days p.i.). Mice were monitored daily for survival. At the endpoint (350 days p.i.), hearts were collected for histopathological examination and β-receptor binding studies. [1]

Absorption, Distribution and Excretion
The bioavailability of bennidazole is 91.7%, with a time to peak concentration (Tmax) of 2.93 hours. The metabolites of bennidazole are primarily excreted in the urine. The apparent volume of distribution is 39.19 L. The apparent oral clearance is 2.04 L/h. Metabolites/Metabolites Bennidazole is metabolized in Trypanosoma cruzi by nitroreductases and cytochrome P450 enzymes. Biological Half-Life The elimination half-life is 13.27 hours.

Hepatotoxicity
Bennidazole treatment is associated with a significant proportion of elevated serum enzymes, occurring in at least 10% of patients. However, these abnormalities are usually mild, transient, and without other symptoms or jaundice. No clinically significant liver injury with jaundice due to benidazole has been reported in clinical trials. However, since benidazole was approved and widely used, several cases of eosinophilia and systemic symptoms (DRESS syndrome) with elevated serum enzymes associated with benidazole treatment have been reported, one of which was accompanied by jaundice. Furthermore, cases of immune-mediated hepatitis have been reported with other more commonly used nitroimidazole drugs, such as metronidazole and ornidazole, some of which were quite severe. Therefore, the clinical application of benidazole therapy is limited, but it appears to have the potential to cause symptomatic immune-mediated hepatitis with jaundice. Probability Score: D (Possibly a rare cause of clinically significant liver injury, often a component of drug-induced eosinophilia and systemic symptoms (DRESS) syndrome).

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Effects during pregnancy and lactation
◉ Overview of use during lactation
Benznidazole is excreted into breast milk at doses far below the therapeutic dose for infants. Because the amount of benznidazole in breast milk is low and it is safe for direct administration to infants, it is safe for breastfeeding women to use.
◉ Effects on breastfed infants
Ten women with chronic Chagas disease received benznidazole at a median oral dose of 5.65 mg/kg twice daily for 30 days. Median infant age: Ten women with chronic Chagas disease received benznidazole at a median oral dose of 5.65 mg/kg twice daily for 30 days. The median infant age was 5.2 months (range 20 days to 13 months). Five infants were exclusively breastfed, and the remaining infants were partially breastfed. No adverse reactions related to benznidazole were observed in any of the infants.
A postpartum woman diagnosed with Chagas disease began treatment with benitroazole one month postpartum at a dose of 5 mg/kg once daily for 30 days. She continued to breastfeed her infant (feeding extent not specified). The authors reported no adverse reactions in the infant.
◉ Effects on lactation and breast milk
As of the revision date, no relevant published information was found.

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In this specific study, benitroazole was well tolerated at the dose and dosing regimen used (100 mg/kg/day, orally, for 30 days).

[1]. Int J Antimicrob Agents. 2007 Jun;29(6):733-7.

[2]. Biomedica. 2009 Sep;29(3):448-55.

[3]. PLoS Negl Trop Dis.2018 Nov 1;12(11):e0006814.

Benznidazole is a monocarboxylic acid amide, formed by the condensation of the carboxyl group of (2-nitroimidazole-1-yl)acetic acid with the aromatic amino group of benzylamine. It is used to treat Chagas disease. It is an antiprobiotic. Benznidazole belongs to the imidazole class of compounds, is a C-nitro compound, and is also a monocarboxylic acid amide. Benznidazole is a prescription antiprobiotic drug approved by the U.S. Food and Drug Administration (FDA) for the treatment of Chagas disease caused by Trypanosoma cruzi infection. Benznidazole has been approved by the U.S. Food and Drug Administration (FDA) for use in children aged 2 to 12 years. Chagas disease is an opportunistic infection of HIV. On August 29, 2017, the FDA granted accelerated approval to Benznidazole for the treatment of Chagas disease in children aged 2 to 12 years. It was the first drug approved in the United States for the treatment of Chagas disease. Benznidazole is an oral broad-spectrum antibacterial drug used to treat Chagas disease (American trypanosomiasis). Benznidazole is a nitroimidazole drug, similar to metronidazole. During treatment, up to 10% of patients experience elevated serum enzymes, but no clinically significant cases of acute liver injury have been found. Benznidazole has been reported to exist in Xenorhabdus nematophila, and relevant data are available. Benznidazole is a nitroimidazole derivative with antiprotozoal activity. Its mechanism of action is through interfering with parasite protein biosynthesis, affecting cytokine production, and stimulating host phagocytosis. (NCI)

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Drug Indications
For the treatment of Chagas disease in children aged 2-12 years.

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Mechanism of Action
Benznidazole is believed to be reduced in Trypanosoma cruzi by nitroreductases to various electrophilic metabolites. These metabolites may bind to proteins, lipids, DNA, and RNA, thereby damaging these macromolecules. Studies have found that benitroazole can increase trypanosome mortality through interferon-γ, and the increase in interferon-γ may be due to inflammation caused by macromolecular damage. Research has also shown that the DNA in parasites affected by benitroazole undergoes extensive unpacking, accompanied by overexpression of DNA repair proteins, supporting the view that DNA damage is one of the drug's mechanisms of action.
Pharmacodynamics

Bennitroazole is a trypanolytic agent that kills Trypanosoma cruzi, the pathogen of Chagas disease.
Bennitroazole
is an antiparasitic drug used to treat Chagas disease (American trypanosomiasis) caused by Trypanosoma cruzi.
In Brazil, the recommended treatment regimen for benitroazole is 300 mg daily for 60 consecutive days. [3]
This study concluded that prior treatment with benitroazole in patients with chronic Chagas disease, especially when initiated early in the disease and at a younger age (e.g., before age 40), significantly reduced parasitemia, decreased the prevalence of markers of severe cardiomyopathy, and reduced all-cause mortality during a two-year follow-up period.
These results suggest that early use of benitroazole in Chagas disease may improve clinical and parasitological outcomes and support consideration of treatment in patients without advanced cardiomyopathy, particularly those under 50 years of age. [3]

C12H12N4O3

260.25

260.091

C, 55.38; H, 4.65; N, 21.53; O, 18.44

22994-85-0

31593

Off-white to light yellow solid powder

1.35g/cm3

189-192ºC(lit.)

1.643

2.021

1

4

4

19

325

0

O=C(C([H])([H])N1C([H])=C([H])N=C1[N+](=O)[O-])N([H])C([H])([H])C1C([H])=C([H])C([H])=C([H])C=1[H]

CULUWZNBISUWAS-UHFFFAOYSA-N

InChI=1S/C12H12N4O3/c17-11(14-8-10-4-2-1-3-5-10)9-15-7-6-13-12(15)16(18)19/h1-7H,8-9H2,(H,14,17)

2-Nitro-N-(phenylmethyl)-1H-imidazole-1-acetamide

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : 50~52 mg/mL ( 192.12~199.8 mM )
Ethanol : ~5 mg/mL

Solubility in Formulation 1: ≥ 2.08 mg/mL (7.99 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.08 mg/mL (7.99 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 2.08 mg/mL (7.99 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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Solubility in Formulation 4: 10% DMSO+40% PEG300+5% Tween-80+45% Saline: ≥ 2.08 mg/mL (7.99 mM)

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 (Please use freshly prepared in vivo formulations for optimal results.)