Miltefosine

Miltefosine is an alkylphosphocholine drug with demonstrated activity against various parasite species and cancer cells . It is the only oral drug approved for the treatment of Leishmaniasis and American Trypanosomiasis (Chagas disease) .

Target of Action

This compound’s primary targets are the Leishmania parasites and neoplastic cells . It has a broad-spectrum anti-parasitic effect, primarily disrupting the intracellular Ca2+ homeostasis of the parasites while sparing the human hosts .

Mode of Action

This compound interacts with its targets primarily through two mechanisms :

• Apoptosis : this compound induces apoptosis-like cell death in its targets .
• Disturbance of lipid-dependent cell signaling pathways : this compound interferes with the functioning of several enzymes involved in phospholipid metabolism .

Biochemical Pathways

This compound affects the unique giant mitochondria and the acidocalcisomes of parasites, both of which are involved in Ca2+ regulation . It inhibits phosphatidylcholine biosynthesis in mammalian cells, primarily via the Kennedy CDP–Choline pathway, by blocking phosphocholine citidyltransferase . In Trypanosoma cruzi, this compound inhibits the Greenberg (transmethylation) pathway by acting on phosphatidylethanolamine N methyl-transferase .

Pharmacokinetics

This compound is characterized by slow absorption and elimination, leading to long initial (approximately 7 days) and terminal (approximately 30 days) half-lives . It is not a substrate of cytochrome P450 metabolic enzymes and only 0.2% of the administered dose is eliminated in the urine at day 23 of a 28-day treatment regimen . The absorption of this compound is concentration-dependent, with passive paracellular diffusion applicable to the concentration below 20.4 μg/mL .

Result of Action

This compound exhibits broad-spectrum anti-parasitic effects primarily by disrupting the intracellular Ca2+ homeostasis of the parasites . It also positively affects the host’s immune system . The drug interferes with biosynthesis of phospholipids and metabolism of alkyl-lipids . It is known to cause cell shrinkage, nuclear DNA condensation, and DNA fragmentation resulting in apoptosis-like cell death in L. donovani .

Action Environment

It is known that the drug’s therapeutic effect extends beyond its impact on the parasite to also positively affect the host’s immune system . These findings suggest a complex interplay between drug susceptibility, neutrophil activation, and Leishmania survival .

Biochemical Properties

Miltefosine plays a significant role in biochemical reactions. It interacts with various enzymes, proteins, and other biomolecules. The compound is metabolized mainly by phospholipase D, releasing choline, choline-containing metabolites, and hexadecanol . These metabolites are all endogenous and are likely used for the biosynthesis of acetylcholine, cell membranes, and long-chain fatty acids .

Cellular Effects

This compound has profound effects on various types of cells and cellular processes. It influences cell function, including impacts on cell signaling pathways, gene expression, and cellular metabolism . It has been found to affect the unique giant mitochondria and the acidocalcisomes of parasites, both of which are involved in Ca 2+ regulation .

Molecular Mechanism

The molecular mechanism of action of this compound involves its binding interactions with biomolecules, enzyme inhibition or activation, and changes in gene expression . In addition to its inhibitory effects on phosphatidylcholine synthesis and cytochrome c oxidase, this compound has been found to affect the unique giant mitochondria and the acidocalcisomes of parasites .

Dosage Effects in Animal Models

The effects of this compound vary with different dosages in animal models . This includes any threshold effects observed in these studies, as well as any toxic or adverse effects at high doses .

Metabolic Pathways

This compound is involved in several metabolic pathways. It interacts with enzymes or cofactors, and it can also affect metabolic flux or metabolite levels .

Transport and Distribution

This compound is transported and distributed within cells and tissues . This includes any transporters or binding proteins that it interacts with, as well as any effects on its localization or accumulation .

Subcellular Localization

This could include any targeting signals or post-translational modifications that direct it to specific compartments or organelles .

Voies de synthèse et conditions de réaction

La miltéfosine peut être synthétisée par un processus en plusieurs étapes. Une méthode courante implique la réaction de l'alcool cétylique avec la triéthylamine et l'oxyde de trichlorure de phosphore dans le tétrahydrofurane. Ceci est suivi de l'addition de diméthyléthanolamine et de triéthylamine pour obtenir le phosphamide de cétyle .

Méthodes de production industrielle

La production industrielle de la miltéfosine implique généralement une synthèse à grande échelle utilisant des réactions chimiques similaires à celles décrites ci-dessus. Le processus est optimisé pour un rendement élevé et une pureté élevée, garantissant que le produit final répond aux normes pharmaceutiques .

Types de réactions

La miltéfosine subit diverses réactions chimiques, notamment l'oxydation, la réduction et la substitution. Ces réactions sont essentielles pour son métabolisme et son activité biologique .

Réactifs et conditions courants

Les réactifs courants utilisés dans les réactions impliquant la miltéfosine comprennent les oxydants, les réducteurs et divers solvants. Les conditions de ces réactions sont soigneusement contrôlées pour assurer les résultats souhaités .

Principaux produits formés

Les principaux produits formés à partir des réactions de la miltéfosine dépendent des réactifs et des conditions spécifiques utilisés. Par exemple, les réactions d'oxydation peuvent produire différents métabolites qui contribuent à ses effets thérapeutiques .

Applications de la recherche scientifique

La miltéfosine a un large éventail d'applications de recherche scientifique :

Chimie : La miltéfosine est étudiée pour ses propriétés chimiques uniques et son potentiel en tant que composé modèle pour le développement de nouveaux médicaments.

Biologie : Les chercheurs étudient ses effets sur les processus cellulaires et son potentiel en tant qu'outil pour l'étude des membranes cellulaires.

Médecine : La miltéfosine est utilisée pour traiter la leishmaniose et les infections par des amibes libres. .

Industrie : Les propriétés antimicrobiennes du composé en font un candidat pour une utilisation dans diverses applications industrielles, y compris le traitement de l'eau et l'assainissement.

Mécanisme d'action

La miltéfosine exerce ses effets en perturbant les membranes intracellulaires des parasites, ce qui conduit à la mort cellulaire. Elle inhibe la synthèse de la phosphatidylcholine et affecte l'homéostasie du calcium intracellulaire, ce qui est crucial pour la survie des parasites . Le médicament cible également la cytochrome c oxydase et d'autres enzymes essentielles, contribuant ainsi à son activité antiparasitaire .

Miltefosine is an alkylphosphocholine drug with activity against some pathogenic bacteria and fungi, various parasite species, and cancer cells . It is the first oral drug and remains the only one available for treating visceral leishmaniasis (VL) and cutaneous leishmaniasis (CL) . this compound was initially developed as an anticancer agent in the 1990s and was registered in India in 2002 for treating visceral leishmaniasis .

Pharmacology of this compound

This compound has demonstrated activity against neoplastic cells and Leishmania parasites, primarily due to its effects on apoptosis and disturbance of lipid-dependent cell signalling pathways . While several potential antileishmanial mechanisms of action have been proposed, none has been definitively identified . this compound inhibits cytochrome-c oxidase within the mitochondria, which leads to mitochondrial dysfunction and apoptosis-like cell death . The antineoplastic mechanisms of action are related to antileishmanial targets, including inhibition of phosphatidylcholine biosynthesis and inhibition of Akt (protein kinase B), a crucial protein within the PI3K/Akt/mTOR intracellular signalling pathway that regulates the cell cycle .

Indications

This compound is indicated for treating mucosal leishmaniasis (caused by Leishmania braziliensis), cutaneous leishmaniasis (caused by L. braziliensis, L. guyanensis, and L. panamensis), and visceral leishmaniasis (caused by L. donovani) . L. donovani is the most susceptible to this compound, while L. major is the least susceptible among Leishmania species . this compound is also used off-label to treat free-living amoebae (FLA) infections . Animal studies suggest it may be effective against metronidazole-resistant strains of Trichonomas vaginalis, Trypanosome cruzi (responsible for Chagas' disease), and may have broad-spectrum antifungal activity .

Clinical Trials and Efficacy

This compound has demonstrated high cure rates for visceral leishmaniasis in clinical trials performed in India, with 94%–97% cure rates using regimens of 2.5 mg/kg/day for 28 days . Clinical trials in India involving children under 12 years of age have shown 83%–94% cure rates . A trial in Bangladesh, including adults and children, achieved 85% cure rates .

Adverse Effects

The standard 28-day this compound monotherapy regimen is well-tolerated, though it has some side effects, such as mild gastrointestinal issues . Common adverse events include nausea/vomiting (97%) and lack of appetite (54%) . Clinical management or dose reduction was required in a third of cases . Most laboratory abnormalities, including elevated creatinine and aminotransferases, were mild and normalized after treatment .

Leishmaniasis Treatment

This compound is the only recognized oral agent with the potential to treat leishmaniasis . It has demonstrated very good cure rates for visceral leishmaniasis in India, Nepal, and Bangladesh . However, there have been reports of high rates of clinical failures recently . In East Africa, it has moderate efficacy for VL, while data from Mediterranean countries and Latin America are scarce .

Good evidence of efficacy has been documented in Old World cutaneous leishmaniasis . Different cure rates among New World CL have been obtained depending on the geographical areas and species involved . Appropriate regimens for New World mucocutaneous leishmaniasis need to be established, although longer treatment duration seems to confer better results .

Case Studies

• Cutaneous Leishmaniasis: A study showed that this compound may be an effective and safe oral medication for treating Old World cutaneous leishmaniasis caused by L. major .
• Primary Amoebic Meningoencephalitis (PAM): this compound has been used in cases of PAM, with some reports of successful outcomes . In one report, a man with no comorbidities presented with fever, headache, and generalized weakness and was diagnosed with PAM within 24 hours. The CDC guideline was implemented on the first day. On day three, he developed diabetes insipidus (DI) and died four days later with cardiac arrest .
• Vitiligo: Autologous non-cultured basal-enriched epidermal cell suspension transplantation with some modifications is an effective, simple, and safe method for treating stable vitiligo .

Tables

Resistance

La miltéfosine appartient à la classe des composés alkylphosphocholine. Des composés similaires comprennent l'hexadécylphosphocholine et d'autres alkylglycérophosphocholines. Ces composés présentent des similitudes structurelles mais diffèrent par la longueur de leur chaîne alkyle et la structure de leur squelette . La combinaison unique de propriétés de la miltéfosine la rend particulièrement efficace contre la leishmaniose et d'autres infections parasitaires .

Liste des composés similaires

• Hexadécylphosphocholine
• Alkylglycérophosphocholines
• Lipides éther

La miltéfosine se distingue par sa biodisponibilité orale et son activité à large spectre, ce qui en fait un outil précieux dans la lutte contre les maladies parasitaires .

Miltefosine is a phospholipid analog primarily used in the treatment of leishmaniasis, a parasitic disease caused by protozoa of the genus Leishmania. This compound has gained attention due to its unique mechanism of action, efficacy, and the emergence of resistance in some cases. The following sections will detail its biological activity, mechanisms, clinical efficacy, and implications for future treatments.

This compound's biological activity is multifaceted, impacting both the parasite and the host's immune system. Key aspects include:

• Disruption of Lipid Metabolism : this compound inhibits phosphatidylcholine synthesis, crucial for maintaining cellular membrane integrity in parasites. This disruption leads to cell death in Leishmania species .
• Calcium Homeostasis : The drug significantly affects calcium ion regulation within the parasites. It activates specific calcium channels that increase intracellular calcium levels, disrupting mitochondrial function and leading to apoptosis .
• Immune Modulation : this compound has been shown to upregulate immune markers such as CD16 and CD86 on monocytes while downregulating CD14. This modulation may enhance the host's immune response against Leishmania infections .

Clinical Efficacy

This compound is the first oral medication approved for treating leishmaniasis. Its efficacy has been documented across various studies:

• Visceral Leishmaniasis (VL) : Initial studies reported cure rates of approximately 94% during early trials. However, recent data indicate a decline in efficacy, with cure rates dropping to around 90% over a decade of use .
• Post Kala-Azar Dermal Leishmaniasis (PKDL) : In a study involving 86 patients treated with this compound, 85% achieved clinical cure after 18 months, although relapse rates were notably higher in patients with greater pre-treatment parasite loads .
• Cutaneous Leishmaniasis : A case series demonstrated an overall cure rate of 77% among various Leishmania species treated with this compound. Adverse effects included nausea and vomiting, which were common but manageable .

Case Study 1: Efficacy in PKDL

A five-year study on PKDL patients showed that this compound treatment resulted in an initial cure rate of 78%. However, follow-up revealed a significant relapse rate linked to higher parasite loads at baseline. The study underscores the importance of monitoring parasite susceptibility to this compound over time .

Case Study 2: Cutaneous Leishmaniasis

In a cohort treated for cutaneous leishmaniasis, this compound resulted in an 80% complete response rate. The treatment was well-tolerated overall, although some patients experienced significant side effects requiring dose adjustments .

Resistance Concerns

The emergence of resistance to this compound poses a significant challenge. Studies have shown that parasites isolated from relapsed patients exhibited more than two-fold tolerance to this compound compared to pre-treatment isolates. This highlights the necessity for combination therapies to mitigate resistance risks and improve treatment outcomes .

Summary Table of Efficacy Data