• Suramin (Bayer 205®, Germanine®, Naphuride®, Moranyl®, Antrypol®). The compound was developed in 1920. It is best administered by slow intravenous infusion, as intramuscular administration (10% solution in distilled water) is very painful. Suramin is excreted extremely slowly by the body. This is important in allergy (exfoliative dermatitis). It can cause substantial proteinuria. When a test dose of 200 mg is tolerated well, the daily dose is 20 mg/kg (max. 1 g per dose; 1 g of the base = 10 ml of a 10% solution). This is to be repeated 5 times with intervals of a few days. There are several treatment regimens, such as 1 g on days 1, 3, 7, 14 and 21 (in adults) or on days 3, 10, 17, 24 and 31. Fever sometimes initially occurs due to lysis of trypanosomes. Suramin also kills Onchocerca volvulus filaria. Patients with active onchocerciasis can exhibit severe side effects to suramin. Suramin is frequently used for reducing the total number of trypanosomes, in order to reduce toxicity when Arsobal is administered.

-

• Pentamidine was developed in 1941. It is less active than suramin and not active against T. b. rhodesiense. There are two water-soluble salts: pentamidine isethionate (Pentacarinat®), to be dissolved in sterile distilled water (not with physiological saline) and (hard to obtain): pentamidine dimethane sulphonate (Lomidine®), already dissolved as 4% base. Intramuscular injections are painful and are best given with the patient lying down since they cause a drop in blood pressure. If possible, slow IV administration is better. Rapid IV injection causes acute hypo­ten­sion and should be avoided. Hypoglycaemia can sometimes occur (release of insulin from the pancreas). This medicine is also used in pneumocystosis in AIDS patients. The dose is 3-4 mg base/kg/day for one week or every 2 days with a total of 10 injections (in adults). Alternatively, injections can be given on days 1, 3, 5, 13, 15 and 17. To calculate the dose: 1.7 mg salt is approximately equivalent to 1 mg of base. The usual dose for an adult person is between 150 and 300 mg per injection. Adrenalin and fluid are given intravenously if acute hypotension occurs.

• 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.]

  -

• 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.

  
  

T. b. gambiense: early stage:

• Or DFMO 100 mg/kg IV 4 times per day for 14 days

• Or Pentamidine 4 mg base/kg/day IM on days 1 to 7

• Or Suramin test dose 5 mg/kg, then 20 mg/kg/day (max. 1 g) IV on days 3, 10, 17, 24, 31

• Or Pentamidine 4 mg base/kg IM on days 1, 3, 13, 15, 17 + Suramin 20 mg/kg on days 1 and 13

*

T. b. gambiense, late stage:

• Or DFMO 100 mg/kg IV 4 times per day for 14 days

• Prednisolone 1 mg/kg, starting 1 day before the rest of the medication, followed by

• Suramin or Pentamidine 1 to 2 injections, followed by

• Arsobal 3-4 series of one injection per day for 3-4 days with 7-10 days’ rest period in between

• Or Arsobal 2.2 mg/kg/day for 10 days with prednisolone throughout the whole period

*

T. b. rhodesiense

• Suramin test dose (check urine for protein and cylinders), then 1 g per week for 6 weeks. The first dose can be given fractionated over 2 days. Quicker alternative scheme: days 1, 3, 6, 14, 21

• Arsobal may be supplemented with prednisolone

• A high (double) dose of DFMO gives a favourable result in 50% of cases, if combined with suramin

Suramin:

• First test dose + ivermectine if onchocerciasis is suspected.

• Check urine. Then 10% solution by slow IV infusion, maximum 1 g per infusion

• Maximum 5 injections. Example: Days 1, 3, 7, 14, 21

Pentamidine:

• 4 mg base/kg/day IM or slow IV infusion; max 300 mg base per infusion.

• Glucose if hypoglycaemia. Example: 10 daily injections

Ornidyl®

• 100 mg/kg/6 hours daily IV infusion for 14 days or second choice-orally. Expensive.

Melarsoprol:

• Prednisolone before and during treatment!

• Usually preceded by Suramin or Pentamidine.

• Exclusively by IV infusion; usually 3 series of 3 ampoules (adults): 3 x 3

• 1 week’s rest between series.

• Dose = usually 3.6 mg/kg, maximum 200 mg. (various schemes)

• New scheme: 2.2 mg/kg for 10 consecutive days.

• Stop in case of polyneuropathy or reactional encephalopathy

• Diminazene (Berenil®). Discovered in 1955. Officially registered only for veterinary use. Can be administered intramuscularly (less painful than IM Pentacarinat®). Daily dose 5-7 mg/kg, to be repeated after 2 and 4 days. Can be useful in cases of resistance, but in view of the official restriction it is used very rarely. It was initially considered to be quite neurotoxic, but in practice this does not appear to be such a big problem. Other commercial names for diminazene are Veriben®, Ganasegur®, Ganaseg®, Azidine®. Cross-resistance between diminazene, used in the treatment of animal trypanosomiasis, and melarsoprol used in the treatment of African trypanosomiasis in man can be selected with relative ease. Both drugs, or their active metabolites, can enter trypanosomes via the P2 aminopurine transporter, and loss of this transporter can impair uptake of the drugs into parasites. It is therefore possible that melarsoprol resistance is linked to selection of diminazene resistance through treatment of animals. At present, this is still a hypothesis. Since selection of resistance to diminazene in animals might lead to melarsoprol resistance in humans, caution must be exercised in the choice of trypanocide used to clear cattle of trypanosomes. Therefore, although resistance to isometamidium and homidium can arise more quickly in cattle than can resistance to diminazene, these drugs could be better choices in terms of implications for human health.

• Nifurtimox (Lampit®): Cf. Chagas' disease. Very difficult to obtain outside South America. Its place in therapy is not very clear. Sometimes used in cases of melarsoprol resistance (several schemes, including 15 mg/kg/day PO for 60 days). Toxic to the central nervous system (more toxic at higher doses such as 30 mg/kg/day).

• Cymelarsene. Structurally very closely related to melarsoprol.

• IMOL 881 (experimental). Is yet to be evaluated.

• Trybizine. This is a diamidine that can cure acute trypanosomiasis in cattle and rodents. It was developed in China. Attempts are being made to synthesise analogues that are less toxic and that pass through the blood-brain barrier

• Megazol. A fairly active, but still experimental 5-nitro-imidazole derivative. However, the substance is mutagenic in the Ames test. Megazol does not contain arsenic. [The Ames test screens possible carcinogens. The test uses a specific histidine synthesis deficient Salmonella strain. If the tested substance causes mutations that restore the ability to produce histidine, the substance is regarded as potentially carcinogenic].

• Experimental. The surface glycoproteins (VSG) are anchored in the cell membrane with a glycosyl phosphatidyl inositol (GPI) anchor (see above). When GPI synthesis is blocked by elimination of any single gene along the biochemical pathway, the parasite dies. A search is now being made for suitable inhibitors of an enzyme from this reaction chain that is specific to the trypanosome. Trans-sialidase is another enzyme that is being closely investigated. Trypanosomes are themselves unable to produce sialic acid. In trypanosomes, many enzymes of the pentose phosphate pathway and several other pathways are related to cyanobacterial isoforms rather than to those of eukaryotes. This association has led to a suggestion that the ancestors of trypanosomatids harboured a now lost endosymbiont at some time in their evolutionary past. The pathway's third enzyme (6-phosphogluconate dehydrogenase) is essential to trypanosomes. The search is on to determine if structural differences to its mammalian counterpart could be exploited in design of selective inhibitors. DB289 is an experimental, orally available prodrug, which is converted after absorption into a trypanocidal dicationic form. Acidocalcisomes are membrane-bound acidic cell compartments rich in calcium and pyrophosphate. Inhibitors of such acidocalsisomes (e.g. pamidronate, a bisphosphonate) could be useful, but have still to be tested in formal trials.

• V

  Megazol.

  eterary: Homidium, isometamidium and diminazene are drugs used in cattle, sheep and goats. Suramin, quinapyramine and melarsomine are used in horses, camels and buffalos.

After treatment, the patient should have a regular follow-up for 2 to 3 years for possible relapse (T. b. gambiense: check every 6 months). The first sign of relapse is often an increase in the cell count in the cerebrospinal fluid, followed by a rise in its protein content. Recurring fever, drowsiness and chronic headache are also signs of relapse.

African trypanosomiasis is a very serious disease for the individual patient. A major danger of sleeping sickness is the risk of attaining epidemic proportions. Systematic detection and treatment of cases requires active searching (specialised mobile service, vertical strategy). An initial screening with CATT (Card Agglutination Test for Trypanosomiasis), and detection of suggestive clinical signs is generally used for Trypanosoma brucei gambiense. If one or both of these is positive, a lymph node aspiration is carried out. If negative, this is followed by a parasitological blood examination. If positive, a lumbar puncture should be carried out.

Passive treatment of patients who come to the hospital is less expensive but also less effective. There are in fact infected persons who can sometimes remain asymptomatic for a long time. Their role in the epidemiology is yet to be elucidated. It is practically impossible to control the disease by treating only the ill patients. Chemoprophylaxis with pentamidi­ne is not used, except in very exceptional situations.

Vector control can yield good results. Active participation of the population is needed in order to set up and maintain tsetse fly traps. These usually consist of a piece of textile of a certain colour, size and shape, that may or may not be impregnated with an insecticide ("imitation cows"). Various models have been developed. One of the more frequently used types is the biconical Challier-Laveissière trap. Other types used for control include for example Vavoua, Ngu, Lancien, pyramidal and bipyramidal traps. Some traps are preferentially used for sampling (glue traps, epsilon and F3 traps). Mobile electric traps can also be used for this latter purpose. Older, no longer used traps include Morris, Harris, Moloo, Swynnerton and Langridge traps. The effectiveness of various traps is increased by baits and attractants (octenol, acetone, butanone, carbon dioxide (CO₂), propylphenol, methylphenol). The use of pour-on insecticides on cattle looks very promising. The insecticide is applied directly to the hide. Cattle-dips, where cattle walk or swim through insecticide-containing water, were primarily developed for tick control (control of “East Coast fever”, a severe infection caused by Theileria parva), but could also play a role in tsetse fly control.

Tsetse flies contain bacterial symbionts, including rickettsia-like organisms, in the epithelium of the midgut and also in aggregates of certain cells, so-called mycetocytes. Transgenic symbionts are being studied to obtain tsetse flies resistant to trypanosomes. The development of a vaccine is difficult due to the antigenic variation of the parasites.

Female tsetse flies copulate only once in their lifetime. If this is with a sterile male, they cannot reproduce. The mass release of sterile male tsetse flies to control the insect population raises ethical problems. The sterile males are, indeed, not refractory to trypanosomes and their release thus temporarily increases the number of potential vectors. This technique was nevertheless used, for example in Zanzibar from 1994 to 1998. After a preliminary reduction of the tsetse fly population (Glossina austeni) with traps and screens, several million insects were produced over several years in the Tsetse Trypanosomiasis Research Institute in Tanga, Tanzania. Approximately 70,000 sterile male flies were released weekly. This led to the complete disappearance of the natural vector population. The intention was especially to control the animal disease nagana. Since Zanzibar lies tens of kilometres off the continental African coast, future reinfestation is unlikely.

Drug	Target Receptor	Mechanism of Action
Phenytoin	Inhibits Na+ channels	Modifies neuronal excitability; for Partial seizures Many drug and OC interactions, induces hepatic enzymes Adverse: gingival hyperplasia, hirsutism, interfere w/ thyroid tests
Carbamazepine	Inhibits Na+ channels	Decreases synaptic transmission; Partial seizures Many drug and OC interactions, induces own hepatic enzymes Adverse: epoxide int., liver damage, leukopenia, LFTs required
Oxcarbazepine	Inhibits Na+ & Ca++ channels Enhances K+ currents	Metabolite is active form Adverse: hyponatremia, less hepatic enzyme induction
Phenobarbitol (barbiturate)	GABAa, inhibits Ca channels	Enhance inhibition, GABA binding, Partial and Tonic-clonic Adverse: accumulation, addiction, cross tolerance, induces CYP450, drug and OC interactions
Primidone (barbiturate)	Inhibits Na+ channels	Metabolized to phenobarbitol and PEMA; Partial and Tonic-clonic Adverse: sedation/intoxication immediately after administration, induces CYP450, drug and OC interactions
Gabapentin	Unknown	Amino acid analog of GABA; wide usage, no interactions Partial seizure adjunct therapy
Tiagabine	GABA (GAT-1) uptake inhibitor	availability of GABA, inhibition Partial seizure adjunct therapy
Zonisamide	Inhibits Na & Ca (T type) channels	Sulfonamide derivative, Partial seizure adjunct therapy Adverse: allergies, renal calculi, teratogen, few interactions
Levetiracetam	Inhibits K+ rectifier channel, inhibits Ca (N type) channel	Inhibits negative modulation of GABAa by Zn++ and b-carboline, no interactions discovered yet, Partial seizure adjunct therapy
Felbamate	Inhibits NMDA receptors	GABA transmission, glutamate excitation, Refractory cases Adverse: affects CYP450 to lesser degree, aplastic anemia, liver failure, LFTs required
Vigabatrin	Inhibits GABA transaminase degradation enzyme	Not approved in US. GABA availability, Refractory cases Adverse: irreversible visual field deficits
Ethosuximide	Inhibits Ca (T type) channels	Absense seizures, few interactions Adverse: skin reactions, blood dyscrasias
Valproic acid/ Sodium Valproate	Inhibits Na & Ca (T type) channels & GABA-T	GABA synthesis, membrane hyperpolarization, Broad Spectrum Adverse: hepatotoxicity in children, pancreatitis, LFTs required, inhibits CYP450
Lamotrigine	Inhibits Na+ channels, inhibits glutamate release	For Lennox-Gastaut syndrome in children, Broad Spectrum Adverse: Stevens-Johnson syn, few drug and OC interactions
Topiramate	Inhibits Na channels, AMPA/KA antagonist	GABA transmission, glutamate excitability, Broad Spectrum Adverse: myopia, oligohydrosis, metabolic acidosis, weight loss, affects CYP450 to lesser degree