Miltefosin

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) . Miltefosine was initially developed as an anticancer agent in the 1990s and was registered in India in 2002 for treating visceral leishmaniasis .

Pharmacology of Miltefosine

Miltefosine 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 . Miltefosine 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

Miltefosine 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 miltefosine, while L. major is the least susceptible among Leishmania species . Miltefosine 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

Miltefosine 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 miltefosine 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

Miltefosine 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 miltefosine may be an effective and safe oral medication for treating Old World cutaneous leishmaniasis caused by L. major .
• Primary Amoebic Meningoencephalitis (PAM): Miltefosine 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

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

Miltefosine’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

Miltefosine interacts with its targets primarily through two mechanisms :

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

Biochemical Pathways

Miltefosine 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, miltefosine inhibits the Greenberg (transmethylation) pathway by acting on phosphatidylethanolamine N methyl-transferase .

Pharmacokinetics

Miltefosine 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 miltefosine is concentration-dependent, with passive paracellular diffusion applicable to the concentration below 20.4 μg/mL .

Result of Action

Miltefosine 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

Miltefosine 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 Miltefosine 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, miltefosine has been found to affect the unique giant mitochondria and the acidocalcisomes of parasites .

Dosage Effects in Animal Models

The effects of Miltefosine 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

Miltefosine 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

Miltefosine 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 .

Synthesewege und Reaktionsbedingungen

Miltefosin kann durch einen mehrstufigen Prozess synthetisiert werden. Eine gängige Methode beinhaltet die Reaktion von Cetylalkohol mit Triethylamin und Trichlorphosphinoxid in Tetrahydrofuran. Anschließend wird Dimethylethanolamin und Triethylamin zugegeben, um Cetylphosphoramid zu erhalten .

Industrielle Produktionsmethoden

Die industrielle Produktion von this compound beinhaltet typischerweise die großtechnische Synthese unter Verwendung ähnlicher chemischer Reaktionen wie oben beschrieben. Der Prozess ist auf hohe Ausbeute und Reinheit optimiert, um sicherzustellen, dass das Endprodukt pharmazeutische Standards erfüllt .

Arten von Reaktionen

Miltefosin unterliegt verschiedenen chemischen Reaktionen, darunter Oxidation, Reduktion und Substitution. Diese Reaktionen sind für seinen Stoffwechsel und seine biologische Aktivität unerlässlich .

Häufige Reagenzien und Bedingungen

Häufige Reagenzien, die bei den Reaktionen mit this compound verwendet werden, sind Oxidationsmittel, Reduktionsmittel und verschiedene Lösungsmittel. Die Bedingungen für diese Reaktionen werden sorgfältig kontrolliert, um die gewünschten Ergebnisse zu erzielen .

Hauptprodukte, die gebildet werden

Die Hauptprodukte, die aus den Reaktionen von this compound gebildet werden, hängen von den verwendeten Reagenzien und Bedingungen ab. Beispielsweise können Oxidationsreaktionen verschiedene Metaboliten produzieren, die zu seinen therapeutischen Wirkungen beitragen .

Wissenschaftliche Forschungsanwendungen

This compound hat eine breite Palette wissenschaftlicher Forschungsanwendungen:

Chemie: This compound wird auf seine einzigartigen chemischen Eigenschaften und sein Potenzial als Modellverbindung für die Entwicklung neuer Medikamente untersucht.

Biologie: Forscher untersuchen seine Auswirkungen auf zelluläre Prozesse und sein Potenzial als Werkzeug zur Untersuchung von Zellmembranen.

Medizin: this compound wird zur Behandlung von Leishmaniose und Infektionen mit frei lebenden Amöben eingesetzt. .

Industrie: Die antimikrobiellen Eigenschaften der Verbindung machen sie zu einem Kandidaten für den Einsatz in verschiedenen industriellen Anwendungen, einschließlich Wasseraufbereitung und Hygiene.

Wirkmechanismus

This compound übt seine Wirkungen aus, indem es die intrazellulären Membranen von Parasiten stört, was zum Zelltod führt. Es hemmt die Synthese von Phosphatidylcholin und beeinflusst die intrazelluläre Calciumhomöostase, die für das Überleben von Parasiten entscheidend ist . Das Medikament zielt auch auf Cytochrom-c-Oxidase und andere essentielle Enzyme ab, was zu seiner antiparasitären Aktivität beiträgt .

Miltefosin gehört zur Klasse der Alkylphosphorcholinkomponenten. Ähnliche Verbindungen umfassen Hexadecylphosphorcholin und andere Alkylglycerophosphocholine. Diese Verbindungen teilen strukturelle Ähnlichkeiten, unterscheiden sich jedoch in ihrer Alkylkettenlänge und ihrer Rückgratstruktur . Die einzigartige Kombination von Eigenschaften von this compound macht es besonders wirksam gegen Leishmaniose und andere parasitäre Infektionen .

Liste ähnlicher Verbindungen

• Hexadecylphosphorcholin
• Alkylglycerophosphocholine
• Etherlipide

This compound zeichnet sich durch seine orale Bioverfügbarkeit und seine Breitbandaktivität aus, was es zu einem wertvollen Werkzeug im Kampf gegen parasitäre Krankheiten macht .

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.

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

• Disruption of Lipid Metabolism : Miltefosine 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 : Miltefosine 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

Miltefosine 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 miltefosine, 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 miltefosine. 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 miltefosine 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 miltefosine over time .

Case Study 2: Cutaneous Leishmaniasis

In a cohort treated for cutaneous leishmaniasis, miltefosine 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 miltefosine poses a significant challenge. Studies have shown that parasites isolated from relapsed patients exhibited more than two-fold tolerance to miltefosine 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