Leishmaniasis
In the same year as the discovery of the anticancer property, miltefosine was reported by S. L. Croft and his team at the London School of Hygiene and Tropical Medicine as having antileishmanial effect as well. The compound was effective against Leishmania donovani amastigotes in cultured mouse peritoneal macrophages at a dose of 12.8 mg/kg/day in a five-day course. However, priority was given to the development of the compound for cutaneous metastases of breast cancer. In 1992 a new research was reported in which the compound was highly effective in mouse against different life cycle stages of different Leishmania species, and in fact, more potent than the conventional sodium stibogluconate therapy by a factor of more than 600. Results of the first clinical trial in humans were reported from Indian patients with chronic leishmaniasis with high degree of success and safety. This promising development promulgated a unique public–private partnership collaboration between ASTA Medica (later Zentaris GmbH), the World Health Organization (WHO) Special Programme for Research and Training in Tropical Diseases, and the Government of India. Eventually, several successful Phase II and III trials led to the approval of miltefosine in 2002 as the first and only oral drug for leishmaniasis. Naegleria fowleri and Acanthamoeba
In 2013, the US Centers for Disease Control and Prevention recommended miltefosine for the treatment of free-living amoeba infections such as granulomatous amoebic encephalitis and primary amoebic meningoencephalitis, two fatal protozoal diseases. Historically, only four survivors have been recorded out of 138 confirmed infections in North America.
Overdose
Single doses up to 500 times the recommended dose, as well as multiple doses up to 150 times the recommended dose for ten days, resulted in an increase of the mentioned side effects. Theses side effects were mild to moderate. Interactions
As naldemedine is mainly metabolized by the liver enzyme CYP3A4, inhibitors of this enzyme can increase its concentrations in the body and thus its potential for side effects. Examples include itraconazole (which increased naldemedine exposure 2.9-fold in a study), ketoconazole, clarithromycin and grapefruit juice. Conversely, CYP3A4 inducers such as rifampicin and St Johns wort decrease naldemedine concentrations; with rifampicin, the reduction was 83% in a study.Strong inhibitors of the pump P-glycoprotein such as ciclosporin may increase naldemedine concentrations in the blood plasma. Pharmacology
Mechanism of action
Naldemedine is a derivative of naltrexone and, like this substance, blocks opioid receptors of the types μ (mu), δ (delta) and κ (kappa). While naltrexone is able to cross the blood–brain barrier and can therefore be used to treat opioid dependence, the large hydrophilic side chain of naldemedine and its affinity to P-glycoprotein result in negligible concentrations in the central nervous system when recommended doses are applied. Instead, it acts mainly on μ-receptors in the gastrointestinal tract, where it counteracts the constipation inducing effects of opioid drugs. Pharmacokinetics
After oral intake, naldemedine has an absolute bioavailability in the range of 20% to 56% and reaches highest blood plasma levels after 0.75 hours when taken without food and 2.5 hours when taken with a high-fat meal.