Nifurtimox 120mg tablets

This article reviews the trypanocidal therapy for chronic Chagas disease, emphasizing its indications, efficacy, limitations, and future perspectives. The etiological treatment is based on the use of benznidazole and nifurtimox, both of which were developed over five decades ago. These drugs are most effective in the acute phase, but are also recommended for children, adolescents, and adults aged <50 years without severe organ damage, and women of childbearing age to prevent congenital transmission. Adherence to treatment is limited by adverse drug reactions, which affect approximately half of the patients, leading to treatment discontinuation in approximately 30% of cases. The cure criteria included parasitological, serological, and clinical responses that required long-term follow-up. Clinical trials and systematic reviews have shown heterogeneous results that are influenced by age, clinical stage, and geographical region. Recent public policies supported by non-governmental organizations and academic networks have expanded access to diagnosis and treatment, although structural and informational barriers persist. New therapeutic strategies include shortened benznidazole regimens, drug repositioning, and combination therapies aimed at reducing adverse drug reactions and improving efficacy. Novel molecules with distinct mechanisms and vaccines with therapeutic and preventive potentials are under investigation. Despite these advances, the challenge remains in translating these innovations into concrete benefits for affected populations, particularly in the most vulnerable regions.

Abstract licence: CC BY

Nifurtimox has been used for over 50 years to treat patients with Chagas disease, a potentially life-threatening neglected tropical disease caused by the protozoan parasite Trypanosoma cruzi. Without effective antitrypanosomal treatment, the infection can persist and progress to a chronic, often debilitating, clinical form. Migration and urbanization, as well as the shifting distribution of the parasite's insect vector, have contributed to the emergence of Chagas disease as a global health threat. Administration of nifurtimox involves adjusting the dose for age and body weight. Particularly for children, this often requires the previously available 120 mg tablet to be divided manually, which could be problematic. To address this challenge, a new formulation tablet of nifurtimox was developed. Available in two dose strengths, 30 mg and 120 mg, the new formulation tablets contain a functional score line to facilitate accurate division. In addition, the formulation now allows rapid and easy dispersion in water to form a slurry for use by patients with difficulty swallowing tablets. These features enable more accurate body-weight-based and age-appropriate dosing and administration, which should prove beneficial for younger patients, including newborns and babies with a body weight ≥2.5 kg. Development of the new formulation nifurtimox tablets was guided by substantially updating pharmacological and clinical knowledge of the drug to meet current standards and regulatory requirements. This was achieved by conducting a substantial array of additional non-clinical and clinical studies to better understand and characterize clinically relevant aspects of nifurtimox pharmacokinetics. The efficacy and safety of the new tablet in children with Chagas disease was subsequently demonstrated in a large prospective randomized clinical trial with prolonged follow-up. In the present paper, we review key findings that contributed to the successful clinical development of the new formulation nifurtimox tablet, the availability of which redefines the treatment of young patients with Chagas disease.

Abstract licence: CC BY

Chagas disease or American Trypanosomiasis, caused by the parasite Trypanosoma cruzi, is an endemic neglected infection found in 21 countries across Latin America. To date, nifurtimox is one of the only two drugs approved to treat Chagas disease but exhibits serious concerns related to its low aqueous solubility and erratic bioavailability. Thus, the aim of this work was to evaluate whether the formation of complexes with βcyclodextrin and sulfobutylether-β-cyclodextrin would improve drug solubility and dissolution rate. Drug-cyclodextrin interactions in solid-state were analyzed by differential scanning calorimetry, X-ray diffractometry, infrared spectroscopy, and nuclear magnetic resonance. The systems were characterized in solution by means of phase solubility, dissolution, and kinetic studies. Phase solubility study showed an AL-type diagram indicating the formation of inclusion complex in a 1:1 M ratio. The drug dissolution rate from sulfobutylether-β-cyclodextrin complexes was faster than that of the β-cyclodextrin complexes. The modification of the endothermic peak of nifurtimox revealed the presence of interactions between the drug and CDs. The crystalline character of the drug was greatly diminished after complexation with sulfobutylether-β-cyclodextrin. Microscopy evaluation revealed the formation of new structures of the solid particles, which suggest strong interactions between the drug and the carriers. The 1H and 13C nuclear magnetic resonance confirmed that the drug was included in the carriers. The selected nifurtimox complex stored at 25 °C and 40 °C during 6 months showed a remarkable stability in terms of drug dissolution and crystallinity.

Abstract licence: CC BY-NC-ND