Visceral Leishmaniasis: Alternative Treatments

1. Amphotericin B was isolated in 1956 from Streptomyces nodosus from the Orinoco valley in Venezuela. It is a polyene and has a fairly complex structure with a hydrophilic and a lipophilic component. The name of the compound is derived from its amphipatic character: Greek: “amphi” = two-sided. The recommended dose of amphotericin B [Fungizone®] is 0.5-1 mg/kg/day IV, to be given over 6 hours; total dose max. 1-3 g. This drug is mainly used for the treatment of deep mycoses, though it is also active against Leishmania. It is a rather toxic medicament. Shivering, fever, nausea, vomiting, headache, anaemia, phlebitis at the site of the infusion, cardiotoxicity, kidney failure, hypokalamia and hypomagnesaemia are frequent side effects. Side effects occurring shortly after administration can be reduced by cortisone IV or meperidine (pethidine), a morphine analogue. Administration of 500-1,000 ml physiological isotonic saline solution before starting the IV-drip reduces the risk of nephrotoxicity. Amphotericin B is not eliminated via haemodialysis. The toxicity of the drug is reduced by pharmacological complexing with lipids prior to the administration. The drugs are then concentrated in the reticuloendothelial system and not in the kidneys so that a higher daily dose per kg of bodyweight can be administered and treatment time shortened (e.g. to 5 days). In 1990 AmBisome® was developed as a first-choice drug. Several lipid formulations of amphotericin B are now available. They differ from each other in the type of phospholipid and the ratio of lipid to amphotericin B. In the last few years good results have been obtained with these lipid formulations. If these results are confirmed and the drug (AmBisome®, Amphotec®, Abelcet®) is made available at a reasonable price, this will greatly simplify therapy. The efficacy of heated amphotericin B (70°C for 20 minutes) is being studied. Heating might reduce the toxicity and enhance the efficacy.

Formulations of Amphotericin B

• Fungizone®: Amphotericin B deoxycholate. Contains no lipids.

• Emulsification of Fungizone® in Intralipid 20%: little reduction of toxicity

• AmBisome®: L-AmB: incorporation in liposomes (vesicles).

• Abelcet®: ABLC or Amphotericin B Lipid Complex. Microscopically small ribbon-like membranes formed by complexing with phospholipids.

• Amphotec®: ABCD (= Amphocil®) Amphotericin B Colloidal Dispersion: AmB-cholesteryl sulphate forms disc-shaped structures.

  
  

1. Pentamidine isethionate (4 mg/kg every 48 hours IM for 4 months). Pentamidine (Pentacarinat®) should not be confused with Pentostam® (pentavalent antimony). The parasites are located intracellularly in phagolysosomial vesicles in phagocytic cells. These cells can ingest small carrier molecules. When pentamidine is bound to nanoparticles the intracellular concentration of the active compound increases greatly. One carrier that is being studied is polymethacrylate. The amine groups of pentamidine are ionically bound to the acid groups of the carrier. This binding is pH-dependent. In the acidic phagolysosome a substantial proportion of pentamidine is released and kills the parasite. By increasing the bioavailability of the drug in this way it should be possible to make these new formulations more effective and less toxic.

   
   

2. Combination therapy with gamma-interferon (100-400 g/m² body area /day IM for 10-30 days) was described with initially good results but its exact value in treatment has not been determined yet. Where does this idea of using gamma-interferon come from? The immunological defence against Leishmania parasites is strongly dependent on the proper functioning of the reticuloendothelial system and is Th1-dependent. Gamma-interferon (INF) has the property of activating monocytes, which is essential for the defence against these parasites. Kala azar is associated with a specific anergy against the parasite, resulting in non-activated monocytes and macrophyes. By giving INF, one tries to activate these cells. This is the rationale for considering therapy INF in some patients. Activation of monocytes can be checked in vitro. After activation certain molecules show increased expression (FcR-1, HLA-DR, etc). If the receptor for INF is deficient or defective, the activation status of monocytes is influenced very little if at all after addition of exogenous INF. When INF production itself is deficient, the INF-dependent function are also deficient even if normally functioning receptors are present on monocytes.

   
   

3. High-dose allopurinol (Zyloric®), e.g. 3 x 7 mg/kg/day (that is, 20 mg/kg/day), for 4-12 weeks gave encouraging results.

   
   

4. Injectable aminosidine (paromomycine) is now being studied. It is an aminoglycoside antibiotic. The recommended dose is 16 mg/kg/day for 21 days. However, we have very little experience with this compound and it is difficult to obtain.

   
   

5. Terbinafine (Lamisil®) is an antimycotic drug that is being evaluated.

   
   

6. Miltefosine (Miltex®). Miltefosine or hexadecylphosphocholine is a lecithin analogue (= phosphatidyl-choline analogue). In the molecule phosphatidylcholine is bound to a carbohydrate component via an ether bridge instead of an ester. Miltefosine interferes with certain cellular signal cascades and with membrane synthesis, though its precise mode of action is still unknown. It was initially developed as an antineoplastic agent. Topical use in for example cutaneous metastases in breast cancer is being studied. In the 1990s it was also discovered that in vitro and in animal models it was active against Leishmania parasites. These organisms contain many ether lipids in the cell membrane. The main advantage of the compound is that it can be given orally, in contrast to the injectable antimony derivatives and amphotericin B. The molecule is fairly easy to produce and this should eventually bring down the price, which is very important in third world countries. The price in the West is quite high. The daily dose will amount to 100-150 mg (adults), and for children the guide dose is expected to be 2.5 mg/kg/day. It should be given for 4 weeks. The cure rate, according to preliminary studies, is excellent (97%). Dose-dependent gastrointestinal discomfort often occurs and reversible hepato- and nephrotoxicity sometimes occurs. It is teratogenic and so cannot be given to pregnant women or women who want to conceive in 6 months after treatment. How quickly resistance to miltefosine will develop when used as mono-therapy in the field is not yet clear.

   
   

7. Pamidronate, a bisphosphonate drug typically used in the treatment of osteoporosis, is effective against experimental cutaneous leishmaniasis. Several bisphosphonates have significant activity against Leishmania donovani in vitro, and several are potent inhibitors of bone resorption and in clinical use for the treatment of osteoporosis and Paget’s disease. Action on bone is based on binding of bisphosphonate moiety to the bone mineral and inhibition of the osteoclast’s enzyme FPPS (farnesyl pyro-phosphate synthase). Expressed FPPS is also potently inhibited by bisphosphonates in the trypanosomatid parasite Trypanosoma cruzi, in which FPPS is postulated to be the major target of bisphosphonates. It is possible that currently approved clinical regimens of the drug are not high enough to cure human cutaneous leishmaniasis. Pamidronate could be a useful lead compound in the synthesis of new drugs against this disease.

Category: Medicine Notes