Trypanosomiasis: Treatment, drugs that penetrate into the brain

• DFMO (Eflornitine, Ornidyl®). Di-fluoro-methyl-ornithine or DFMO was first used for trypanosomiasis in 1985. It is very water soluble. This substance penetrates quite well into the cerebrospinal fluid. An IV treatment for 2 weeks should be sufficient. This used to be followed by 4 weeks of oral administration, though the additional benefit of this is probably limited. Oral administration is an alternative (second choice) if no venous route of administration is possible. Oral ingestion frequently causes osmotic diarrhoea. The drug is expensive and if supplies are limited it is best reserved for melarsoprol-resistant cases. Unfortunately it is active only against T. b. gambiense. The dosage regimen is 100 mg/kg/6 hours IV x 2 weeks via physiological fluid infusion. This requires a large quantity of product per patient (about 1/3 kg per person). Concentrations in cerebrospinal fluid in children seem to be lower than in adults. Children possibly require a higher dose. [ Note: topical eflornitine is also being studied as a depilatory product in cosmetics.]

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• Melarsoprol (Arsobal®) was developed in 1949. This trivalent arsenic compound is insoluble in water or alcohol. It is therefore dissolved in propyleneglycol. This solvent is highly irritant to tissues. It causes phlebitis and chemical cellulitis when administered paravenously. Melaroprol is available in ready to use vials (3.6% solution). This may only be given by very slow IV infusion. The syringe must be perfectly dry, as otherwise flocculation occurs. Melarsoprol penetrates into the cerebrospinal fluid to only a very limited extent. It can nevertheless be used in late stage disease. Melarsoprol as such is quickly eliminated from the plasma. It also has a significant trypanocidal activity (measured via bioassay) in plasma and cerebrospinal fluid for up to several days after administration, although melarsoprol can then no longer be detected with HPLC (high performance liquid chromatography). The molecule is probably transformed into biologically active metabolites such as melarsene oxide, etc. The pharmacokinetic properties are not sufficiently known. Toxicity results in encephalitis. This manifests itself as a sudden violent neurological deterioration at the end of the first series or during the second series of injections. The higher the number of lymphocytes in the cerebrospinal fluid, the greater the risk of very severe neurological complications (fatality-rate approximately 50%). An (auto?)-immune reaction, rather than a direct toxic effect, is possibly involved here. It is therefore best to administer prednisolone before using melarsoprol. Another toxic effect of melarsoprol is polyneuropathy (analogous to heavy metal intoxication). This results in diminished sensitivity and/or paraesthesias in hands and feet. In this case melarsoprol should if possible be stopped and vitamin B (e.g. thiamine) administered. Resistance to melarsoprol occurs. Melarsoprol should never be given without first trying suramin (less Jarisch-Herxheimer-like reactions). There are several quite complicated treatment schemes. One injection per day for 3-4 days is sometimes given, followed by 1 week’s rest. This can be repeated three times (total = 9 to 12; usually 3 x 3 ampoules for an adult person). A more cautious scheme uses half the dosage at the beginning. In April 2000 it was shown in quite a large study (500 patients) in Angola that a regimen with ten daily injections of 2.2 mg of melarsoprol/kg bodyweight in combination with prednisolone was easier and cheaper and just as good as the conventional interrupted schemes for treatment of T. b. gambiense.

  
  

Category: Medicine Notes