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Zoological pharmacology: current status, issues, and potential
Advanced Drug Delivery Reviews 54 (2002) 787–793 www.elsevier.com / locate / drugdeliv
Zoological pharmacology: current status, issues, and potential Robert P. Hunter a , *, Ramiro Isaza b a
Zoological Pharmacology Laboratory, Department of Anatomy and Physiology, College of Veterinary Medicine, Kansas State University, Manhattan, KS 66506 -5802, USA b Department of Clinical Sciences, College of Veterinary Medicine, Kansas State University, Manhattan, KS 66506 -5802, USA Received 28 February 2002; accepted 29 March 2002
Abstract Lack of approved pharmaceutical agents and / or pharmacokinetic data in the literature for exotic, wildlife, and zoo species is a major issue for veterinarians. These practitioners must take approved agents (veterinary or human) and extrapolate their use to non-approved species with little or no scientific basis to support this decision. There is little information concerning pharmacokinetic parameters for drugs in non-domestic species. Zoo veterinarians often have to formulate the medication(s) into a meal, hoping that the animal will ingest it. Due to lack of patient compliance, the veterinarian may have to resort to other means of drug administration. Additionally, due to the value of these animals, the traditional method of ‘trial and error’ for treatment selection and resulting compliance is often inappropriate, and lends itself to a mentality where no zoo veterinarian wants to be the first to administer an agent / formulation in an untested species. This review intends to present the current state of zoological pharmacology and the direction it may be heading. 2002 Elsevier Science B.V. All rights reserved. Keywords: Zoo; Veterinary pharmacology; Pharmacokinetics; Formulations; Zoological medicine; Routes of administration
Contents 1. Introduction ............................................................................................................................................................................ 1.1. ADME in zoological species ............................................................................................................................................. 2. Individual patient administration .............................................................................................................................................. 2.1. Uncooperative patients ..................................................................................................................................................... 2.1.1. Darts ..................................................................................................................................................................... 2.1.2. Manual restraint ..................................................................................................................................................... 2.1.3. Mechanical restraint ............................................................................................................................................... 2.1.4. Food / treats ............................................................................................................................................................ 2.1.5. Training ................................................................................................................................................................ 2.1.6. Long-acting or depo-formulations............................................................................................................................ 2.2. Cooperative and / or debilitated subjects ............................................................................................................................. 3. Herd.......................................................................................................................................................................................
*Corresponding author. Tel.: 1 1-785-532-4524; fax: 1 1-785-532-4557. E-mail address: [email protected] (R.P. Hunter). 0169-409X / 02 / $ – see front matter 2002 Elsevier Science B.V. All rights reserved. PII: S0169-409X( 02 )00068-6
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4. New advances ......................................................................................................................................................................... 5. Needs!.................................................................................................................................................................................... References ..................................................................................................................................................................................
1. Introduction Lack of approved pharmaceutical agents in the United States and pharmacokinetic data in the literature for exotic, wildlife, and zoo species is an issue of concern for zoological veterinarians. There are only eight to 10 compounds approved in the United States for zoo and wildlife species compared to nearly 300 for cattle. For many years, veterinarians have taken approved agents (veterinary or human) and extrapolated their use to exotic species with little or no significant basis for such use. Species differences in drug absorption, metabolism, and excretion of pharmaceutical agents have been well documented for common domestic species. However, there is little information concerning these parameters for drugs in non-domestic species. Aside from pharmacokinetic and pharmacodynamic differences, veterinarians often treat patients that may not accept the drug. They may have to formulate the medication(s) into a meal or treat, hoping that the animal will ingest it. Due to lack of patient compliance, the attending veterinarian may have to resort to other means of drug administration due to the lack of patient cooperation. Additionally, due to the value of these animals, both monetarily and as endangered species, the traditional method of ‘trial and error’ for drug selection is often inappropriate and occasionally false. This lends itself to a mentality where zoological veterinarians are reluctant to be the first to use a given agent or formulation in an un-tested species.
1.1. ADME in zoological species While veterinary medicine is ‘one medicine’, there are differences of which practitioners need to be aware. One medicine is a central concept in zoological medicine in that vertebrate species are more similar than dissimilar. This has been applied to extrapolation of physiological function. Little is known about the basic physiology of many exotic species. For small mammals (i.e., rodents, ferrets, and rabbits), much is known since they are common laboratory species. This is helpful
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since they are used as models for human drug absorption, distribution, metabolism, and eliminations (ADME) studies. There are well researched relationships between rodent and human pharmacokinetics [1,2]. However, this is typically using only a few laboratory animal species to establish a relationship, not the thousands of species with which a zoological veterinarian has to deal with. We do know that absorption can vary within a species. Beagles and mongrel dogs have very different gastrointestinal transit times and mouth to small intestine transit times [3]. When you consider the anatomical differences between true monogastrics (canines and felines), hind-gut fermentors (rodents, rabbits, and horses), fore-gut fermentors (Colobus monkeys and kangaroos), and ruminants (sheep, cattle, and goats), the potential differences are staggering. This does not even begin to discuss the differences between classes of organisms, such as the avian digestive system and variations within the avian order. As an example, snake species have the capability to up- and down-regulate the ‘status’ of their digestive systems [4]. This makes prediction of oral drug absorption highly dependent upon the time since the last meal. Due to differences in allometric scaling equations for renal and hepatic clearance parameters, elimination may be quantitatively, as well as qualitatively different between the three main classes of animals [5]. A talented veterinarian must consider the effects of ADME when trying to extrapolate dosages to nontraditional species. With so many variations in anatomy, one would assume that this would also have an effect on distribution, metabolism, and elimination. Avian and reptilian kidneys are different from mammalian tissue. Both classes contain renal tubules that are straight with limited folding. They also do not have the loops of Henle found in mammalian tubules [5]. Glomerular filtration differs between birds and mammal in that birds conduct this process in an intermittent fashion, while mammalian kidneys are constantly performing the filtration process [5]. Expression of cytochrome P-450 enzymes (CYP) varies between species [6–9]. Among ruminant
R.P. Hunter, R. Isaza / Advanced Drug Delivery Reviews 54 (2002) 787–793
species, sheep have a higher microsomal protein concentration that does not correlate to an increase in Phase I metabolism products [10]. Recent research has shown that CYP expression also varies within the canine species [11]. This is not surprising when one considers that there are differences between domestic species to the extent in which Phase II conjugation reactions can occur [12]. This is supported even further by the report of greater differences in N-glucuronidation between domestic species than previously believed [13]. Finally, plasma protein binding can vary between species and is also temperature dependent. This is very important when treating poikilothermic (reptiles, amphibians, and fish) species and conducting pharmacokinetic studies with highly protein-bound pharmaceutical agents [14].
2. Individual patient administration Treating the individual versus the group (herd, flock, etc.) is often a difficult part of zoological pharmacology. The techniques employed to treat the individual depends upon whether or not the patient is ‘cooperative’. In this review, uncooperative will be used in the sense that either the patient is unwilling to accept its treatment or is too dangerous to use traditional, common routes of administration.
2.1. Uncooperative patients In zoological medicine, patients may be uncooperative for a variety of reasons. First, given the wild nature of these animals, treatment can often be difficult. This can also be applied to treatment of animals in zoological collections where direct contact is discouraged, and treatment of the patient is therefore limited. Second, there are inherent risks to those providing primary patient care to the animal (i.e., veterinarians and keepers), such as in dealing with poisonous snakes or large carnivores. Finally, in cooperative or human-habituated patients, behavior can significantly change because of illness or pain so that they no longer lend themselves to traditional pharmaceutical therapy.
2.1.1. Darts When injectable agents are used, darting can be a
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realistic option for short-term treatment of some species. Darts (Fig. 1) can be administered via a blowpipe, compressed air gun, or powder capcharged gun [15]. When selecting this route of administration, the animal must have sufficient muscle mass to allow for injection of the drug and impact of the dart. Severe tissue injury, including hemorrhage, necrosis, and bone fractures can occur whenever darts are used to deliver pharmaceutical agents. Delivery of drugs is also prone to high failure rates. The complexity of the darts often leads to dart failure (i.e., no discharge, missed target). This route is compatible with formulations designed for intramuscular (i.m.) administration. The formulation should not be too viscous, allowing for rapid injection. This is important if the animal is capable of removing the dart shortly after the dart injection, as in primate species. Repeated administration of therapeutic and / or chemical restraining agents within a relatively short period of time can be traumatic for the patient. The interval between dartings should be as large as therapeutically possible in order to reduce the physical and psychological impact to the animal.
2.1.2. Manual restraint Use of manual restraint allows for more traditional administration of drugs (i.e., pilling, gavage, manual injection). Standard, commercially available and compounded formulations can be administered using this method. The use of manual restraint is typically restricted to individual animals that are assumed, by the handler or treatment provider, to be not dangerous either to themselves or the patient. In order for this assumption to be valid, the restrainer must be very knowledgeable of the species being treated and the likely response by the animal to the treatment). 2.1.3. Mechanical restraint Mechanical restraints are those methods typically associated with larger animals. For cattle, an example would be the use of a squeeze chute or crush. Similar mechanisms can be employed for the treatment of non-domestic species. It is not uncommon for squeeze cages to be used for single or limited therapeutic regimens in large carnivores and some primate species. The limitation of this method of restraint and dosing is that the animal soon learns that the cage is where it is treated, thus it is trained
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Fig. 1. Darts used in zoological medicine for immobilization or treatment.
to avoid entering the cage. While mechanical restraint is an excellent option, training an animal to perform certain behaviors for a reward may be a more viable option. In zoological medicine, particularly with respect to ungulates, chute systems are used to eliminate the need for individual immobilizations and the associated risks of that procedure.
2.1.4. Food /treats The use of food as a drug delivery device is often the first choice in exotic animal therapy. It can be very useful for hiding realistic amounts of drug when the agent to be administered can be taste-masked by the food item. In some cases, a traditional oral formulation is simply placed in the oral cavity or inside the food item and then offered to the patient. Another option is to administer an injectable formulation to the food item and then offer this to the animal. This method can be especially helpful in species that do not chew or masticate the food items when they are presented. Examples would be the use of whole fish for marine mammals, mice / rodents for snakes, and bananas for elephants. The issue with these compounded formulations is
that one should pick treatment agents that are not known to have a food effect on absorption. The fact that there is now one more barrier to drug dissolution could, theoretically, dramatically affect bioavailability. There are no studies in zoological species investigating the effect of these laced food items on absolute or relative bioavailability. Oral administration of various anesthetics has been accomplished using pineapple juice, maple syrup, peanut butter, marshmallows, or honey [16,17]. While these were good formulations for the species studied, the animals often remember they were drugged because the carrier was given only when the drug was in the mixture. Recently, carfentanil was administered to chimpanzees (Pan troglodytes) transmucosally / orally by syringing a carfentanil solution onto the oral mucosa of the animals [16]. This was deemed a successful method of anesthesia by the authors (five of five chimps reached at least stage 4 of anesthesia).
2.1.5. Training Training an animal to easily accept treatment can be beneficial to both the animal and the veterinarian.
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Training reduces the stress often associated with medical treatment and increases the likelihood of compliance. Training can be as simple as teaching a giraffe or rhinoceros to walk through and stand in a chute for daily physical exams and routine treatments. Training can be more complex, such as teaching a chimpanzee to place its arm through the cage to receive injections.
2.1.6. Long-acting or depo-formulations One could imagine that long-acting formulations would be especially useful to an exotic veterinarian, particularly in the zoological arena. It would be very convenient to administer a pharmaceutical agent only once while the animal is being examined (typically under anesthesia) and not have to perform repeated administrations. Examples of depo-formulations include antibiotic-impregnated beads for the treatment of localized bacterial infections. Implantation of these beads eliminates the need for repeated medication and provides constant antibiotic exposure at the site of infection. Currently, non-absorbable materials, such as polymethylmethacrylate, are typically used as the matrix. This results in the necessity for surgical removal of the implants. It is envisaged by the authors that an absorbable / biodegradable matrix would have increased usage in zoological medicine. Another example of depo-formulations includes the use of progesterone implants for long-term contraception. These custom-made implants, 20% melengestrol acetate in a silastic matrix, are placed subcutaneously and remain active for up to 2 years [18].
2.2. Cooperative and /or debilitated subjects This group of patients can be treated more like traditional veterinary patients. A cooperative patient in zoological medicine is one that will allow the veterinarian to perform a routine physical exam or administer medication on a routine basis with minimal manual restraint. Administration via i.m., s.c., or p.o. routes is the preferred choice when dealing with most exotic patients. This simplifies the selection of an appropriate dosing regimen. However, as mentioned previ-
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ously, there is very limited data on the pharmacokinetics of the majority of pharmaceuticals used in veterinary medicine. Rectal administration is an underutilized route of administration in veterinary medicine. It is also a route that has potential in exotic medicine. By working at the ‘other’ end of the animal, the risk of injury decreases. When patients are properly trained, this procedure can be used for therapeutic purposes. This also provides an opportunity to increase the potential bioavailability of a given agent if it has a high first-pass metabolism. However, due to the possibility of species differences in large colon / rectal motility, the clinician should have a realistic estimate of the retention time of the drug following this route of administration. Metronidazole and famciclovir have been shown to be absorbed after rectal administration to Asian elephants [19] (R.P. Hunter, unpublished data). Topical administration in exotic species is an underutilized method of drug administration. The new formulations of anthelminthic agents lend themselves to the treatment of parasitic infections in zoological species. Historically, mite infestations (Chorioptic sp.) in hedgehogs (Atalerix albiventris) have been treated with either injectable ivermectin or topical amitraz [20]. This treatment has been shown to be effective, but requires weeks to months of therapy. Fleas and lungworms also infest these animals, and with a broad-spectrum topical endectocide, such as selamectin [21,22], treatment could be carried out easily and rapidly and treat both the mite and flea infection with a single compound. With small animals or easily manageable animals, topical is a potentially useful route; however, in most zoo species, getting close enough to apply a topical agent means getting close enough to become injured. Another issue is whether or not the absorption profile of a given agent will be similar to that of the approved domestic species or if absorption will even take place across reptile scales, fish scales, or amphibian skin. Vascular access ports (VAP) in manually restrainable animals allow for serial i.v. drug administration. Surgical procedures for implantation of these devices have been described in laboratory animals. A VAP has been described as a method of treating ferrets with oncology agents [23]. The disadvantage of the
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VAP is that it must be maintained on a routine basis and eventually removed [24,25].
3. Herd The administration of medication to herds of animals instead of the individual differs in several aspects. The first is complexity of dosage regimen calculations and administration of drugs within a group of animals. Since the veterinarian is dosing all the animals in the herd / exhibit, the intended amount of drug to be administered must be calculated based on an estimate of the average ingestion of the medicated feed or water. In addition, if an agent with a relatively narrow therapeutic window is used, such as levamisole, then the estimated weight of the smallest animal should be used as the basis for calculations. This, however, will result in sub-therapeutic administration in most of the herd and could lead to failure of the pharmaceutical agent. Medicated blocks and / or baits can be used, but the amount ingested by a given individual is more difficult to predict. It is not uncommon for fisheating animals to be fed vitamin-laced fish individually, so that each animal in the flock or group is seen eating its daily dose, but this is very labor intensive. In some situations where animals in a group can be fed individually, medicating the food item may be a valid method of medicating the animals.
4. New advances Even with reluctance to be the first to use a given agent or formulation in an untested species, zoological medicine is constantly exploring new therapies and drug delivery options as they become available from human or veterinary medicine. For example, the transmucosal formulation of fentanyl (Actiq , Cephalon) is currently under investigation for use as part of a pre-anesthetic protocol in great apes (R.P. Hunter, unpublished data). The new oral flea control products currently on the market for use in canine and feline pets have the potential for use in large carnivores. Flea infestations occur, and these products could make flea control much easier. Instead of the more dangerous administration of topical prod-
ucts, usually requiring general anesthesia to apply, canine or feline zoo species could be treated with a pill hidden in a meat ball. The ability to develop and utilize bio-degradable implants for therapeutic purposes is of interest to zoological veterinarians. Because the animal is handled less frequently, this route of administration decreases the stress of repeated oral or injectable administration.
5. Needs! ‘‘No presently available chemical restraint agent is equally effective and safe for use with all 45,000 1 vertebrate species’’ [26]. This statement relates not just to chemical restraint, but to therapeutic use in general within zoological medicine. Changes need to happen in minor species drug approval to make it easier for the needed information to get into the hands of veterinarians. The Minor Use and Minor Species Animal Health Act of 2001 has been introduced in the United States Congress to address the lack of drug availability for minor species [27]. This includes food animal, companion pets, wildlife, and zoo species. An increase in basic pharmacokinetic parameters in zoological species will increase the therapeutic options for veterinarians treating these animals. Any pharmacokinetic or pharmacodynamic studies in these species would be welcomed. Some of the specific needs for zoological medicine are formulations that would allow for administration of therapeutic agents via the drinking water or milled into the feed. This means that the flavor of the therapeutic agent must be masked so that a sick animal will consume the medication. It must be stable in direct sunlight, and its efficacy not altered by other compounds in the medicated food. Other routes of administration that have not been used to their full extent in zoological medicine are rectal, depo, and topical. Increased information and formulations that would allow for administration of appropriate therapeutic agents would be of great benefit for use in debilitated animals and / or certain zoo species. To this end, biodegradable and traditional implant technology in combination with current and future therapeutic agents would increase the arsenal available to veterinarians who must deal with nontraditional species on a regular basis.
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We have attempted in this review to bring to light some of the issues that face veterinarians on a daily basis when they deal with nontraditional species. The authors fully recognize that it is not economically feasible to develop every drug for every species. However, target approvals and / or research could greatly increase the efficacy and safety of current and future therapeutics. Also, this type of targeted approach would increase the quality of care provided to zoological species under our care.
References [1] J.E. Riviere, T. Martin-Jimenez, S.F. Sundlof, A.L. Craigmill, Interspecies allometric analysis of the comparative pharmacokinetics of 44 drugs across veterinary and laboratory animal species, J. Vet. Pharmacol. Ther. 20 (1997) 453–463. [2] R.S. Obach, J.B. Baxter, T.E. Liston, B.M. Silber, B.C. Jones, F. MacIntyre, D.J. Rance, P. Wastall, The prediction of human pharmacokinetic parameters from preclinical and in vitro metabolism data, J. Pharmacol. Exp. Ther. 283 (1997) 46–58. [3] K. Sagara, H. Mizuta, M. Ohshiko, M. Shibata, K. Haga, Relationship between the phasic period of interdigestive migrating contraction and the systemic bioavailability of acetaminophen in dogs, Pharm. Res. 12 (1995) 594–598. [4] S.M. Secor, E.D. Stein, J. Diamond, Rapid upregulation of snake intestine in response to feeding: a new model of intestinal adaptation, Am. J. Physiol. 266 (1994) G695– G705. [5] D.L. Frazier, M.P. Jones, S.E. Orosz, Pharmacokinetic considerations of the renal system in birds: Part I. Anatomic and physiologic principles of allometric scaling, J. Avian Med. Surg. 9 (1995) 92–103. [6] H. Souhaili-El Amri, A.M. Batt, G. Siest, Comparison of cytochrome P-450 content and activities in liver microsomes of seven animal species, including man, Xenobiotica 16 (1986) 351–358. [7] R. Pearce, D. Greenway, A. Parkinson, Species differences and interindividual variation in liver microsomal cytochrome P450 2A enzymes: effects on coumarin, dicumarol, and testosterone oxidation, Arch. Biochem. Biophys. 298 (1992) 211–225. [8] R.R. Dalvi, V.A. Nunn, J. Juskevich, Hepatic cytochrome P-450-dependent drug metabolizing activity in rats, rabbits and several food-producing species, J. Vet. Pharmacol. Ther. 10 (1987) 164–168. [9] C.R. Short, W. Flory, W. Flynn, Hepatic drug metabolizing enzyme activity in the channel catfish, Ictalurus punctatus, Comp. Biochem. Physiol. 89C (1988) 153–157. [10] J.D. Baggot, Clinical pharmacokinetics in veterinary medicine, Clin. Pharmacokinet. 22 (1992) 254–273.
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[11] S.M. Lankford, S.A. Bai, J.A. Goldstein, Cloning of canine cytochrome P450 2E1 cDNA: Identification and characterization of two variant alleles, Drug Metab. Disp. 28 (2000) 981–986. [12] S.A. Brown, Pharmacokinetics: dispositions and fate of drugs in the body, in: H.R. Adams (Ed.), Veterinary Pharmacology and Therapeutics, 8th Edition, Iowa State University Press, Ames, IA, 2001, pp. 15–56. [13] S.-H.L. Chiu, S.-E.W. Huskey, Species differences in Nglucuronidation, Drug Metab. Disp. 26 (1998) 838–847. [14] Y. Igari, Y. Sugiyama, S. Awazu, M. Hanano, Interspecies difference in drug protein binding-temperature and protein concentration dependency: effect on calculation of effective protein fraction, J. Pharm. Sci. 9 (1981) 1049–1053. [15] M. Bush, Remote drug delivery systems, J. Zoo Wild. Med. 23 (1992) 159–180. [16] K.S. Kearns, B. Swenson, E.C. Ramsey, Oral induction of anesthesia with droperidol and transmucosal carfentanil citrate in chimpanzees (Pan troglodytes), J. Zoo Wild. Med. 31 (2000) 185–189. [17] J.C. Thurmon, W.J. Tranquilli, G.J. Benson, Anesthesia of wild, exotic, and laboratory animals, in: J.C. Thurmon, W.J. Tranquilli, G.J. Benson (Eds.), Lumb and Jones’ Veterinary Anesthesia, 3rd Edition, Williams & Wilkins, Baltimore, MD, 1996, pp. 686–735. [18] J.F. Kirkpatrick, J.W. Turner, Reversible contraception in nondomestic animals, J. Zoo Wild. Med. 22 (1991) 392–408. [19] F.M.D. Gulland, P.C. Carwardine, Plasma metronidazole levels in an Indian elephant (Elephas maximus) after rectal administration, Vet. Rec. 120 (1987) 440. [20] T.L. Lightfoot, Therapeutics of African pygmy hedgehogs and prairie dogs, Vet. Clin. N. Am. Exot. Anim. Pract. 3 (2000) 155–172. [21] Anonymous, Selamectin: an endectocide for companion animal use, Comp. Cont. Ed. Pract. Vet. 9 (Suppl) (1999) 32–35. [22] C.A. Thomas, Revolution姠: a unique endectocide providing comprehensive, convenient protection, Comp. Cont. Ed. Pract. Vet. 9 (Suppl) (1999) 2–25. [23] K.M. Rassnick, W.J. Gould, J.A. Flanders, Use of a vascular access system for administration of chemotherapeutic agents to a ferret with lymphoma, J. Am. Vet. Med. Assoc. 206 (1995) 500–504. [24] A. Woolf, J. Curl, C. Gremillion-Smith, The use of subcutaneous ports in the woodchuck (Marmota monax), Lab. Anim. Sci. 39 (1989) 620–622. [25] R.P. Hunter, M.J. Lynch, J.F. Ericson, W.J. Millas, A.M. Fletcher, N.I. Ryan, J.A. Olson, Pharmacokinetics, oral bioavailability and tissue distribution of azithromycin in cats, J. Vet. Pharmacol. Ther. 18 (1995) 38–46. [26] M.E. Fowler, Chemical restraint, in: M.E. Fowler (Ed.), Restraint and Handling of Wild and Domestic Animals, 2nd Edition, Iowa State University Press, Ames, IA, 1995, pp. 36–56. [27] C. Pickering, Minor Use and Minor Species Animal Health Act of 2001–House Resolution 1956. United States Congress, 2001.
Zoological pharmacology: current status, issues, and potential Robert P. Hunter a , *, Ramiro Isaza b a
Zoological Pharmacology Laboratory, Department of Anatomy and Physiology, College of Veterinary Medicine, Kansas State University, Manhattan, KS 66506 -5802, USA b Department of Clinical Sciences, College of Veterinary Medicine, Kansas State University, Manhattan, KS 66506 -5802, USA Received 28 February 2002; accepted 29 March 2002
Abstract Lack of approved pharmaceutical agents and / or pharmacokinetic data in the literature for exotic, wildlife, and zoo species is a major issue for veterinarians. These practitioners must take approved agents (veterinary or human) and extrapolate their use to non-approved species with little or no scientific basis to support this decision. There is little information concerning pharmacokinetic parameters for drugs in non-domestic species. Zoo veterinarians often have to formulate the medication(s) into a meal, hoping that the animal will ingest it. Due to lack of patient compliance, the veterinarian may have to resort to other means of drug administration. Additionally, due to the value of these animals, the traditional method of ‘trial and error’ for treatment selection and resulting compliance is often inappropriate, and lends itself to a mentality where no zoo veterinarian wants to be the first to administer an agent / formulation in an untested species. This review intends to present the current state of zoological pharmacology and the direction it may be heading. 2002 Elsevier Science B.V. All rights reserved. Keywords: Zoo; Veterinary pharmacology; Pharmacokinetics; Formulations; Zoological medicine; Routes of administration
Contents 1. Introduction ............................................................................................................................................................................ 1.1. ADME in zoological species ............................................................................................................................................. 2. Individual patient administration .............................................................................................................................................. 2.1. Uncooperative patients ..................................................................................................................................................... 2.1.1. Darts ..................................................................................................................................................................... 2.1.2. Manual restraint ..................................................................................................................................................... 2.1.3. Mechanical restraint ............................................................................................................................................... 2.1.4. Food / treats ............................................................................................................................................................ 2.1.5. Training ................................................................................................................................................................ 2.1.6. Long-acting or depo-formulations............................................................................................................................ 2.2. Cooperative and / or debilitated subjects ............................................................................................................................. 3. Herd.......................................................................................................................................................................................
*Corresponding author. Tel.: 1 1-785-532-4524; fax: 1 1-785-532-4557. E-mail address: [email protected] (R.P. Hunter). 0169-409X / 02 / $ – see front matter 2002 Elsevier Science B.V. All rights reserved. PII: S0169-409X( 02 )00068-6
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R.P. Hunter, R. Isaza / Advanced Drug Delivery Reviews 54 (2002) 787–793
4. New advances ......................................................................................................................................................................... 5. Needs!.................................................................................................................................................................................... References ..................................................................................................................................................................................
1. Introduction Lack of approved pharmaceutical agents in the United States and pharmacokinetic data in the literature for exotic, wildlife, and zoo species is an issue of concern for zoological veterinarians. There are only eight to 10 compounds approved in the United States for zoo and wildlife species compared to nearly 300 for cattle. For many years, veterinarians have taken approved agents (veterinary or human) and extrapolated their use to exotic species with little or no significant basis for such use. Species differences in drug absorption, metabolism, and excretion of pharmaceutical agents have been well documented for common domestic species. However, there is little information concerning these parameters for drugs in non-domestic species. Aside from pharmacokinetic and pharmacodynamic differences, veterinarians often treat patients that may not accept the drug. They may have to formulate the medication(s) into a meal or treat, hoping that the animal will ingest it. Due to lack of patient compliance, the attending veterinarian may have to resort to other means of drug administration due to the lack of patient cooperation. Additionally, due to the value of these animals, both monetarily and as endangered species, the traditional method of ‘trial and error’ for drug selection is often inappropriate and occasionally false. This lends itself to a mentality where zoological veterinarians are reluctant to be the first to use a given agent or formulation in an un-tested species.
1.1. ADME in zoological species While veterinary medicine is ‘one medicine’, there are differences of which practitioners need to be aware. One medicine is a central concept in zoological medicine in that vertebrate species are more similar than dissimilar. This has been applied to extrapolation of physiological function. Little is known about the basic physiology of many exotic species. For small mammals (i.e., rodents, ferrets, and rabbits), much is known since they are common laboratory species. This is helpful
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since they are used as models for human drug absorption, distribution, metabolism, and eliminations (ADME) studies. There are well researched relationships between rodent and human pharmacokinetics [1,2]. However, this is typically using only a few laboratory animal species to establish a relationship, not the thousands of species with which a zoological veterinarian has to deal with. We do know that absorption can vary within a species. Beagles and mongrel dogs have very different gastrointestinal transit times and mouth to small intestine transit times [3]. When you consider the anatomical differences between true monogastrics (canines and felines), hind-gut fermentors (rodents, rabbits, and horses), fore-gut fermentors (Colobus monkeys and kangaroos), and ruminants (sheep, cattle, and goats), the potential differences are staggering. This does not even begin to discuss the differences between classes of organisms, such as the avian digestive system and variations within the avian order. As an example, snake species have the capability to up- and down-regulate the ‘status’ of their digestive systems [4]. This makes prediction of oral drug absorption highly dependent upon the time since the last meal. Due to differences in allometric scaling equations for renal and hepatic clearance parameters, elimination may be quantitatively, as well as qualitatively different between the three main classes of animals [5]. A talented veterinarian must consider the effects of ADME when trying to extrapolate dosages to nontraditional species. With so many variations in anatomy, one would assume that this would also have an effect on distribution, metabolism, and elimination. Avian and reptilian kidneys are different from mammalian tissue. Both classes contain renal tubules that are straight with limited folding. They also do not have the loops of Henle found in mammalian tubules [5]. Glomerular filtration differs between birds and mammal in that birds conduct this process in an intermittent fashion, while mammalian kidneys are constantly performing the filtration process [5]. Expression of cytochrome P-450 enzymes (CYP) varies between species [6–9]. Among ruminant
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species, sheep have a higher microsomal protein concentration that does not correlate to an increase in Phase I metabolism products [10]. Recent research has shown that CYP expression also varies within the canine species [11]. This is not surprising when one considers that there are differences between domestic species to the extent in which Phase II conjugation reactions can occur [12]. This is supported even further by the report of greater differences in N-glucuronidation between domestic species than previously believed [13]. Finally, plasma protein binding can vary between species and is also temperature dependent. This is very important when treating poikilothermic (reptiles, amphibians, and fish) species and conducting pharmacokinetic studies with highly protein-bound pharmaceutical agents [14].
2. Individual patient administration Treating the individual versus the group (herd, flock, etc.) is often a difficult part of zoological pharmacology. The techniques employed to treat the individual depends upon whether or not the patient is ‘cooperative’. In this review, uncooperative will be used in the sense that either the patient is unwilling to accept its treatment or is too dangerous to use traditional, common routes of administration.
2.1. Uncooperative patients In zoological medicine, patients may be uncooperative for a variety of reasons. First, given the wild nature of these animals, treatment can often be difficult. This can also be applied to treatment of animals in zoological collections where direct contact is discouraged, and treatment of the patient is therefore limited. Second, there are inherent risks to those providing primary patient care to the animal (i.e., veterinarians and keepers), such as in dealing with poisonous snakes or large carnivores. Finally, in cooperative or human-habituated patients, behavior can significantly change because of illness or pain so that they no longer lend themselves to traditional pharmaceutical therapy.
2.1.1. Darts When injectable agents are used, darting can be a
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realistic option for short-term treatment of some species. Darts (Fig. 1) can be administered via a blowpipe, compressed air gun, or powder capcharged gun [15]. When selecting this route of administration, the animal must have sufficient muscle mass to allow for injection of the drug and impact of the dart. Severe tissue injury, including hemorrhage, necrosis, and bone fractures can occur whenever darts are used to deliver pharmaceutical agents. Delivery of drugs is also prone to high failure rates. The complexity of the darts often leads to dart failure (i.e., no discharge, missed target). This route is compatible with formulations designed for intramuscular (i.m.) administration. The formulation should not be too viscous, allowing for rapid injection. This is important if the animal is capable of removing the dart shortly after the dart injection, as in primate species. Repeated administration of therapeutic and / or chemical restraining agents within a relatively short period of time can be traumatic for the patient. The interval between dartings should be as large as therapeutically possible in order to reduce the physical and psychological impact to the animal.
2.1.2. Manual restraint Use of manual restraint allows for more traditional administration of drugs (i.e., pilling, gavage, manual injection). Standard, commercially available and compounded formulations can be administered using this method. The use of manual restraint is typically restricted to individual animals that are assumed, by the handler or treatment provider, to be not dangerous either to themselves or the patient. In order for this assumption to be valid, the restrainer must be very knowledgeable of the species being treated and the likely response by the animal to the treatment). 2.1.3. Mechanical restraint Mechanical restraints are those methods typically associated with larger animals. For cattle, an example would be the use of a squeeze chute or crush. Similar mechanisms can be employed for the treatment of non-domestic species. It is not uncommon for squeeze cages to be used for single or limited therapeutic regimens in large carnivores and some primate species. The limitation of this method of restraint and dosing is that the animal soon learns that the cage is where it is treated, thus it is trained
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Fig. 1. Darts used in zoological medicine for immobilization or treatment.
to avoid entering the cage. While mechanical restraint is an excellent option, training an animal to perform certain behaviors for a reward may be a more viable option. In zoological medicine, particularly with respect to ungulates, chute systems are used to eliminate the need for individual immobilizations and the associated risks of that procedure.
2.1.4. Food /treats The use of food as a drug delivery device is often the first choice in exotic animal therapy. It can be very useful for hiding realistic amounts of drug when the agent to be administered can be taste-masked by the food item. In some cases, a traditional oral formulation is simply placed in the oral cavity or inside the food item and then offered to the patient. Another option is to administer an injectable formulation to the food item and then offer this to the animal. This method can be especially helpful in species that do not chew or masticate the food items when they are presented. Examples would be the use of whole fish for marine mammals, mice / rodents for snakes, and bananas for elephants. The issue with these compounded formulations is
that one should pick treatment agents that are not known to have a food effect on absorption. The fact that there is now one more barrier to drug dissolution could, theoretically, dramatically affect bioavailability. There are no studies in zoological species investigating the effect of these laced food items on absolute or relative bioavailability. Oral administration of various anesthetics has been accomplished using pineapple juice, maple syrup, peanut butter, marshmallows, or honey [16,17]. While these were good formulations for the species studied, the animals often remember they were drugged because the carrier was given only when the drug was in the mixture. Recently, carfentanil was administered to chimpanzees (Pan troglodytes) transmucosally / orally by syringing a carfentanil solution onto the oral mucosa of the animals [16]. This was deemed a successful method of anesthesia by the authors (five of five chimps reached at least stage 4 of anesthesia).
2.1.5. Training Training an animal to easily accept treatment can be beneficial to both the animal and the veterinarian.
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Training reduces the stress often associated with medical treatment and increases the likelihood of compliance. Training can be as simple as teaching a giraffe or rhinoceros to walk through and stand in a chute for daily physical exams and routine treatments. Training can be more complex, such as teaching a chimpanzee to place its arm through the cage to receive injections.
2.1.6. Long-acting or depo-formulations One could imagine that long-acting formulations would be especially useful to an exotic veterinarian, particularly in the zoological arena. It would be very convenient to administer a pharmaceutical agent only once while the animal is being examined (typically under anesthesia) and not have to perform repeated administrations. Examples of depo-formulations include antibiotic-impregnated beads for the treatment of localized bacterial infections. Implantation of these beads eliminates the need for repeated medication and provides constant antibiotic exposure at the site of infection. Currently, non-absorbable materials, such as polymethylmethacrylate, are typically used as the matrix. This results in the necessity for surgical removal of the implants. It is envisaged by the authors that an absorbable / biodegradable matrix would have increased usage in zoological medicine. Another example of depo-formulations includes the use of progesterone implants for long-term contraception. These custom-made implants, 20% melengestrol acetate in a silastic matrix, are placed subcutaneously and remain active for up to 2 years [18].
2.2. Cooperative and /or debilitated subjects This group of patients can be treated more like traditional veterinary patients. A cooperative patient in zoological medicine is one that will allow the veterinarian to perform a routine physical exam or administer medication on a routine basis with minimal manual restraint. Administration via i.m., s.c., or p.o. routes is the preferred choice when dealing with most exotic patients. This simplifies the selection of an appropriate dosing regimen. However, as mentioned previ-
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ously, there is very limited data on the pharmacokinetics of the majority of pharmaceuticals used in veterinary medicine. Rectal administration is an underutilized route of administration in veterinary medicine. It is also a route that has potential in exotic medicine. By working at the ‘other’ end of the animal, the risk of injury decreases. When patients are properly trained, this procedure can be used for therapeutic purposes. This also provides an opportunity to increase the potential bioavailability of a given agent if it has a high first-pass metabolism. However, due to the possibility of species differences in large colon / rectal motility, the clinician should have a realistic estimate of the retention time of the drug following this route of administration. Metronidazole and famciclovir have been shown to be absorbed after rectal administration to Asian elephants [19] (R.P. Hunter, unpublished data). Topical administration in exotic species is an underutilized method of drug administration. The new formulations of anthelminthic agents lend themselves to the treatment of parasitic infections in zoological species. Historically, mite infestations (Chorioptic sp.) in hedgehogs (Atalerix albiventris) have been treated with either injectable ivermectin or topical amitraz [20]. This treatment has been shown to be effective, but requires weeks to months of therapy. Fleas and lungworms also infest these animals, and with a broad-spectrum topical endectocide, such as selamectin [21,22], treatment could be carried out easily and rapidly and treat both the mite and flea infection with a single compound. With small animals or easily manageable animals, topical is a potentially useful route; however, in most zoo species, getting close enough to apply a topical agent means getting close enough to become injured. Another issue is whether or not the absorption profile of a given agent will be similar to that of the approved domestic species or if absorption will even take place across reptile scales, fish scales, or amphibian skin. Vascular access ports (VAP) in manually restrainable animals allow for serial i.v. drug administration. Surgical procedures for implantation of these devices have been described in laboratory animals. A VAP has been described as a method of treating ferrets with oncology agents [23]. The disadvantage of the
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VAP is that it must be maintained on a routine basis and eventually removed [24,25].
3. Herd The administration of medication to herds of animals instead of the individual differs in several aspects. The first is complexity of dosage regimen calculations and administration of drugs within a group of animals. Since the veterinarian is dosing all the animals in the herd / exhibit, the intended amount of drug to be administered must be calculated based on an estimate of the average ingestion of the medicated feed or water. In addition, if an agent with a relatively narrow therapeutic window is used, such as levamisole, then the estimated weight of the smallest animal should be used as the basis for calculations. This, however, will result in sub-therapeutic administration in most of the herd and could lead to failure of the pharmaceutical agent. Medicated blocks and / or baits can be used, but the amount ingested by a given individual is more difficult to predict. It is not uncommon for fisheating animals to be fed vitamin-laced fish individually, so that each animal in the flock or group is seen eating its daily dose, but this is very labor intensive. In some situations where animals in a group can be fed individually, medicating the food item may be a valid method of medicating the animals.
4. New advances Even with reluctance to be the first to use a given agent or formulation in an untested species, zoological medicine is constantly exploring new therapies and drug delivery options as they become available from human or veterinary medicine. For example, the transmucosal formulation of fentanyl (Actiq , Cephalon) is currently under investigation for use as part of a pre-anesthetic protocol in great apes (R.P. Hunter, unpublished data). The new oral flea control products currently on the market for use in canine and feline pets have the potential for use in large carnivores. Flea infestations occur, and these products could make flea control much easier. Instead of the more dangerous administration of topical prod-
ucts, usually requiring general anesthesia to apply, canine or feline zoo species could be treated with a pill hidden in a meat ball. The ability to develop and utilize bio-degradable implants for therapeutic purposes is of interest to zoological veterinarians. Because the animal is handled less frequently, this route of administration decreases the stress of repeated oral or injectable administration.
5. Needs! ‘‘No presently available chemical restraint agent is equally effective and safe for use with all 45,000 1 vertebrate species’’ [26]. This statement relates not just to chemical restraint, but to therapeutic use in general within zoological medicine. Changes need to happen in minor species drug approval to make it easier for the needed information to get into the hands of veterinarians. The Minor Use and Minor Species Animal Health Act of 2001 has been introduced in the United States Congress to address the lack of drug availability for minor species [27]. This includes food animal, companion pets, wildlife, and zoo species. An increase in basic pharmacokinetic parameters in zoological species will increase the therapeutic options for veterinarians treating these animals. Any pharmacokinetic or pharmacodynamic studies in these species would be welcomed. Some of the specific needs for zoological medicine are formulations that would allow for administration of therapeutic agents via the drinking water or milled into the feed. This means that the flavor of the therapeutic agent must be masked so that a sick animal will consume the medication. It must be stable in direct sunlight, and its efficacy not altered by other compounds in the medicated food. Other routes of administration that have not been used to their full extent in zoological medicine are rectal, depo, and topical. Increased information and formulations that would allow for administration of appropriate therapeutic agents would be of great benefit for use in debilitated animals and / or certain zoo species. To this end, biodegradable and traditional implant technology in combination with current and future therapeutic agents would increase the arsenal available to veterinarians who must deal with nontraditional species on a regular basis.
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We have attempted in this review to bring to light some of the issues that face veterinarians on a daily basis when they deal with nontraditional species. The authors fully recognize that it is not economically feasible to develop every drug for every species. However, target approvals and / or research could greatly increase the efficacy and safety of current and future therapeutics. Also, this type of targeted approach would increase the quality of care provided to zoological species under our care.
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