By J.G. du Toit
Veterinarians continue to experience problems with the availability of critical veterinary medicines due to the SA Health Products Regulatory Authority (SAHPRA) refusing the importation of the Active Pharmaceutical Ingredients (API’s). Applications to import API’s going back to June 2023 are either refused or not processed, and the situation is getting critical with another two essential veterinary medicines, Azaperone and Isometamidium.
Why do wildlife veterinarians prefer to use Azaperone? Chemical structure Azaperone is a compound with the molecular formula C19H22FN3O. Its chemical structure is characterised by a piperazine ring substituted with a 3-(4-fluorobenzoyl)propyl group and a 2-pyridinyl group.
FDA (Source)
Mechanism of action
Azaperone, a tranquiliser of the butyrophenone family, is often used for short-term tranquilisation or in combination with opioids (etorphine/fentanyl) and/or alpha-2 adrenergic agonists (Detomidine/medetomidine). Butyrophenones have dopaminergic (D2) antagonistic effects, resulting in tranquilisation and the potentiation of immobilisation. Further, azaperones’ effect on the alpha1-adrenergic receptors results in peripheral vasodilation.
Azaperone counteracts the respiratory depressant effect of opiates, and given to rhinos at therapeutic doses, it produces deeper breathing. Azaperone also has effects on the central and peripheral noradrenergic system.
It causes slight bradycardia with reduced cardiac output and dilation of peripheral blood vessels with a drop in blood pressure (important with opioids in rhino immobilisation). All effects of azaperone have worn off after 6 – 8 hours (short acting, which is important because there is no product that can be used as an antidote). Immobilised animals are not at risk or vulnerable after immobilisation.
Indications for use specifying the target species
• In some species, such as African elephants that are sensitive to opioid-induced hypertension, the addition of azaperone may reduce the risk of pulmonary oedema.
• Short half-life makes it a safe sedative to use in all herbivorous wildlife species.
• Mixtures – In recent years, mixtures containing a very low dose of potent opioid combined with a higher dose of the alpha-2 adrenergic agonist medetomidine, either alone or in combination with azaperone, have gained increasing popularity.
Advantages of azaperone
• The product is safe to use in wildlife with the right drug combinations.
• The product takes effect in 20 minutes.
• It is short-acting, and it is not necessary to administer an antidote.
• A relatively cheap product that makes darting of less expensive wildlife species possible.
• Suppresses aggression in swine species.
• It will prevent adrenaline-induced cardiac fibrillation. • Will lower blood pressure, especially in rhinos.
• The product is concentrated (100 mg/mℓ) and can be compounded in a dart with a small volume of 2 mℓ. However, the commercial product Stresnil is 40 mg/mℓ and does not fit into a 2 mℓ dart with most commonly used immobilisation combinations.
• Can mix easily with water-soluble immobilising agents. The latter cannot mix with Valium, which is not water soluble and will precipitate.
Effect on the industry
• Animal mortalities can be expected to increase during capture operations.
• Animal mortalities can be expected to increase during quarantine periods.
• Capture costs will increase.
• The increase in capture costs may influence ranchers not to sell animals at auctions, with a loss of income for owners.
• Owners would rather hunt animals at a cost to biodiversity.
• Owners who will not sell on game auctions will lead to a loss of income for wildlife veterinarians.
The role of the wildlife veterinarian
I foresee that claims will slowly build up due to financial losses in the industry. The wildlife veterinarians must organise themselves through the wildlife group and build up a database with forensic evidence of animal losses; date, species, age, sex, value and reason for the mortality related to drugs not available. This data can be used in a court of law if necessary.
How do large animal veterinarians control trypanosomiasis?
Trypanosomiasis
During 1920 – 1965, game animals were killed to eliminate wildlife that hosts the trypanosoma parasite. A total 778 152 animals were killed in Botswana, Zimbabwe and KwaZulu-Natal. This method was eventually stopped by the pressure of conservationists. The next method was to target the tsetse fly that transmits the parasite between animals. The flies were sprayed with DDT using aircraft. The first spraying was done on 26 November 1845. The tsetse fly was largely eliminated in the early 1950s with this spraying method. Using 230 Harris traps, the number of flies caught in them dropped from 22,007 in November 1945 to 3705 in March 1946 and by September 1946, 291 Harris traps caught only 405 flies. The influence on the environment was severe on apex species such as the fish eagle. The eggs of the birds did not hatch. In 1953, the spraying with DDT was stopped when only one fly was caught.
Epidemiology
The agent, a tsetse-borne trypanosomiasis, is a widespread protozoal disease affecting wildlife, livestock and people in sub-Saharan Africa. African animal trypanosomiasis (AAT) is a very important disease of domestic livestock in sub-Saharan Africa. According to the Food and Agriculture Organisation of the United Nations (FAO), it is probably the only disease which has profoundly affected the settlement and economic development of a major part of a continent. Animal trypanosomiasis affects the health and productivity of livestock. It occurs in 37 sub-Saharan countries covering about 9 million km2, an area which corresponds approximately to one-third of Africa’s total land area.
The epidemiology of AAT in tsetse-infected areas of Africa is determined by four biological factors, namely: trypanosomes, tsetse flies, reservoir hosts and livestock. The Trypanosoma brucei complex comprises three morphologically identical subspecies: T. brucei brucei, T. b. rhodesiense, and T. b. gambiense. Only T. brucei brucei is pathogenic to cattle; the other subspecies cause acute sleeping sickness in humans in East Africa and chronic sleeping sickness in West Africa.
The vector, tsetse flies (Glossina spp.), are found only in Africa. They are the biological and/or mechanical vector of trypanosomes and constitute a potent and constant threat to humans and livestock over much of subSaharan Africa. Tsetse feed exclusively on blood. They are holometabolous insects with females giving birth to full-grown larvae, which rapidly pupate in the soil. The tsetse fly is very sensitive to environmental conditions and will not survive in areas that are too hot, too dry, or too high above sea level. The hosts are several usually dark coloured wildlife species such as warthog, bush pig, duiker, bush buck, kudu, buffalo, black rhino, and monitor lizard.
These animals are the natural hosts of tsetse and may acquire prolonged, symptomless trypanosome infections. Nagana is still a controlled disease in South Africa, and it has reappeared in northern KwaZuluNatal. The tsetse was present in the areas north and east of the Lebombo Mountains. With climate change, the tsetse fly moved west towards Pongola and south to Matubathuba.
Clinical signs
The clinical signs in cattle are a fluctuating fever, listlessness, anaemia, loss of weight and enlarged lymph nodes. Wild animals can carry the parasites without showing signs of the disease and therefore serve as a source of infection for tsetse flies.
Treatment
Trypanocidal drugs are the most widely applied method that farmers use to treat and prevent trypanosomiasis in sub-Saharan Africa. Currently, the three large animal practices that treat cattle with Isometamidium chloride save the lives of about 20,000 head of cattle per annum. These cattle belong to communal farmers.
Conclusion
Urgent intervention at the ministerial level is required to find a workable solution for this crisis. Under the current conditions, veterinarians are compromised and cannot offer proper veterinary care to wildlife and livestock. There are already two appeal applications with the Minister of Health brought by V-Tech to obtain access to Yohimbine and Trilostane, but the list appears to be getting longer by the day. We can only hope that SAHPRA will engage with interested parties to find workable solutions to avert a further crisis.