Introduction
Choosing an appropriate drug and dosage is difficult for veterinarians due to a lack of research in elephant pharmacology. Clinical application of drug use in elephants for safe, reliable, and effective results necessitates the establishment of a treatment response curve or blood concentration profile for each individual drug and species (African vs. Asian). There is some evidence of a possible species (African vs. Asian) difference, but poorly documented. Because of the difficulty in obtaining accurate pharmacokinetic information, it is more common to select a drug dosage and frequency interval by using what has been effective for other species, specifically the cow and horse. With this strategy, the potential for dosage and treatment errors increases alarmingly as the size (weight) disparity between the animals treated increases.6
Where treatment monitoring with serum concentrations of the drug is difficult to obtain, extrapolation of treatment regimens between species of extraordinary size difference may be done by metabolic scaling to establish drug dosage rates and frequency intervals. The principle of metabolic scaling of pharmacokinetic parameters is based on the well-established scaling of physiologic processes across animals of various sizes.
The goals of this paper are to cover what anti-inflammatories are currently used now with Asian and African elephants in North America zoos, review standard equine doses, and discuss metabolic scaling attempts.
Methods
A survey was sent to forty zoos in the United States, that hold two or more elephants, to determine how zoo veterinarians currently use anti-inflammatories in both African and Asian elephants. The median dosages and treatment intervals were determined for the most commonly used anti- inflammatories from the twenty zoos that responded. Of the respondents, ten held African elephants, and ten held Asian elephants. Although not asked about in the survey, it is assumed the reported dosages are mainly reflective of use on adult elephants.
Standard equine dosages were obtained.4 These represent referenced dosages that are commonly used for horses and have been determined by pharmacokinetic studies.
Allometric (metabolic) scaling involves the concept of the relationships of organic function and systems to body size. There is a direct relationship between metabolic rate and size within the five major taxa of animals. These taxa include placental mammals, marsupial mammals, passerine birds, non-passerine birds, and reptiles. Many biologic parameters have been measured and demonstrate a logarithmic, linear relationship with body weight.
Some examples include cardiac output, capillary density, kidney filtration rate, and oxygen consumption.5 Metabolic scaling for drugs is based on body weight converted to metabolic size. The uptake, distribution, and elimination of a drug depends on physiologic processes, which scale allometrically.1,3,5 This concept has been used in human medicine for over 30 years, and more recently in veterinary nutrition and antineoplastic drugs. Metabolic scaling and calculation worksheets have been covered by other authors, and I refer the reader to the following references.2,6,7 Specific minimum energy cost (SMEC) doses and treatment intervals were calculated for a 3200-kg elephant using the horse as a model species and referenced equine dosages.4
A literature search was done, but no published articles were found for anti-inflammatory use in elephants.
Results
Results are presented in Table 1.
Table 1. Comparison of dosage determination of anti-inflammatories
|
|
Zoo veterinarians
|
Equine formulary
|
Metabolic scaling*
|
Pharmacokinetics
|
|
Flunixin
|
1.0 q 24 h
|
1.1 q 12/24 h
|
0.7 q 40 h
|
None
|
|
Ibuprofen
|
0.5–4 q 24 h
|
None
|
None
|
None
|
|
Phenylbutazone
|
1–2 q 24 h
|
4 q 24 h
|
2.5 q 40 h
|
None
|
*Metabolic scaling dosages based on a 3200-kg elephant.
All dosages are in mg/kg.
Discussion
Dosages for anti-inflammatories used in elephants were close to reported equine levels. Although ibuprofen is used with elephants, there is not an established dosage for equines to use as a model species in metabolic scaling. There are no reported pharmacokinetic studies with anti-inflammatories in elephants, and it is an area in need of research to allow clinicians to more accurately use this class of drugs. Phenylbutazone use has the most potential for adverse side effects of the three drugs compared. Currently it is being used by zoo veterinarians at a treatment interval much shorter than predicted by metabolic scaling and could be a health risk if used as such on a chronic basis.
Dosages for polysulfated glycosaminoglycans (Adequan®), glycosaminoglycan enhancers (Cosequin®), acetaminophen, aspirin, butorphanol and Ketofen were reported in the survey, but by only one source each and were not included in the comparisons.
Metabolic scaling appears to determine dosages that have excessively long treatment intervals, but pharmacokinetic studies are needed to confirm this. The difference can be related to the following biologic functions: biotransformation of the drug, tissue receptor sites, plasma protein binding, enzyme systems, and drug distribution. Drugs that are minimally biotransformed most likely will be therapeutically effective at metabolically scaled dosages. At this time, zoo veterinarians are not routinely using metabolic scaling formulas to calculate elephant drug dosages.
Due to the difficulties of giving oral or intramuscular medications, the potential to limit their use in elephant care is real. Anti-inflammatories are useful for their properties of reducing soft tissue swelling and providing analgesia. Both of these aspects are difficult to assess clinically in a large, relatively inactive animal. The field of pharmacology research in elephants can be helped with several collaborative projects between zoos that hold multiple individual elephants.
Literature Cited
1. Calder, W.A. 1984. Size, Function, and Life History. Harvard University Press, Cambridge: 139–153.
2. Jensen, JM., J.H. Johnson. 1992. Husbandry and Medical Management of Ostriches, Emus and Rheas. Wildlife and Exotic TeleConsultants, College Station: 97–99.
3. Peters, R.H. 1987. The Ecological Implications of Body Size. Cambridge University Press, Cambridge: 45–53.
4. Plumb, D.C. 1991. Veterinary Drug Handbook. PharmaVet Publishing, White Bear Lake: 523–527.
5. Schmidt-Nielsen, K. 1984. Scaling: Why Is Animal Size So Important? Cambridge University Press, Cambridge, England.
6. Sedgwick, C.J. 1993. Allometric scaling and emergency care: the importance of body size. In: Fowler, M.E., ed. Zoo and Wild Animal Medicine. 3rd ed. W.B. Saunders Company, Philadelphia: 34.
7. Sedgwick, C.J., and R. Borkowski. 1996. Allometric scaling: extrapolating treatment regimens for reptiles. In: Mader, D.R., ed. Reptile Medicine and Surgery. W.B. Saunders Company, Philadelphia: 237–238.