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| Drug Summary and History |
The use of hormone therapy to induce spawning in fish is critical to the success of many aquaculture programs. A wide variety of federal, state, tribal, and private aquaculture/fisheries programs, including a number of programs that involve the restoration of threatened/endangered species, are dependent upon hormone treatment to complete final gamete maturation and ensure successful spawning. The time of spawning is by its own nature a stressful period for all fish species. Both sexes are undergoing significant changes in physiology, morphology, and behavior (Hoar 1969). Increased cortisol levels and other inherent endocrine changes associated with spawning have a suppressive effect on the immune system that often results in increased susceptibility to a host of diseases (Maule and Schreck, 1990; Schreck, 2000). The handling required during the spawning of fish for artificial propagation complicates an already delicate situation. This is particularly true for wildstock species that must endure the added stresses of capture, handling, and confinement in an un-natural environment. The longer it is necessary to hold wild fish in captivity, the greater the likelihood of adversely affecting both the health of the fish and ultimate spawning success. In fact, with respect to many wildstock species, the stresses of capture and holding is sufficient to cause complete reproductive failure unless spawning is induced by hormone treatment. Additionally, certain species have limited or depressed populations and in some cases may even be considered threatened/endangered. Hormone treatment of these fish is essential to ensure viable population numbers and to meet recovery/restoration objectives. In order to maintain the health of both wildstock and domestic brood fish, it is beneficial to minimize overall fish handling. During the course of normal spawning operations at an aquaculture facility, it may be necessary to handle and examine individual fish weekly over a 6-8 week period. Such procedures can be extremely stressful to valuable broodstocks, severely compromising overall fish health and potential fecundity. Successful hormone treatment can reduce handling requirements to a single hormone administration event followed by predictable gamete collection, thereby greatly reducing overall fish handling. Studies have shown that final gamete maturation (ovulation and spermiation) in fish can be induced by the administration of a variety of hormones (Donaldson and Hunter 1983; Goetz 1983). Investigations have found that synthetic analogues of gonadotropin releasing hormones (GnRHa) to be one of the most effective means of inducing final gamete maturation. These compounds, which may be similar to native gonadotropins found in either fish or mammals, are attractive choices as they typically exhibit both high biological activity and low species specificity. Although a number of these analogues are available, the most commonly used analogue for fish culture to date has been luteinizing hormone releasing hormone (LHRHa; Alvarino et al. 1992; Donaldson et al. 1981; Erdahl and McClain 1987; Fitzpatrick et al. 1984; Taranger et al. 1992; and Van der Kraak et al. 1983). Effective treatment has been reported using both injection and pellet implant therapy. The use of implants that contain GnRH analogues has been evaluated over the last 15 years (Crim et al., 1983a). In early attempts to use implants, GnRHa was imbedded in cholesterol pellets that contained cellulose to affect release rate (Sherwood et al., 1988). Using this methodology, a 5% carboxymethyl cellulose / 95% cholesterol pellet containing mammalian GnRHa (mGnRHa) released an initial burst of mGnRHa followed by a sustained release of peptide over the next 28 days. Several researchers have demonstrated that these types of implants were capable of inducing maturation in a variety of species including: Atlantic salmon (Crim et al., 1983a; Crim and Glebe, 1984), herring (Carolsfeld et al., 1988), sea bass (Almendras et al., 1988), rainbow trout (Crim et al., 1983b; Crim et al., 1988) and milkfish (Lee et al., 1986; Marte et al., 1988). In all of these studies, mGnRHa implants induced maturation either in advance of, or synchronously within, a population. The inclusion of salmon GnRHa (sGnRHa) instead of mGnRHa in Ovaplant® implants designed for inducing maturation in cultured fish is a logical one. In both in vitro and in vivo studies, sGnRHa has been found to be more potent in effect than mGnRHa for many species including: goldfish (Peter et al., 1985, 1987), Atlantic salmon (Crim et al., 1988), rainbow trout (Crim et al., 1988; Weil et al., 1992), winter flounder (Crim et al., 1988) and catfish (Namvongchong et al., 1992b; Schulz et al., 1994). This potency may be attributed to high pituitary binding affinity and gonadotropin hormone (GtH) releasing capacity, even though sGnRH itself may not be an indigenous form for some of the species tested (Schulz et al., 1993). Moreover, sGnRHa produces a sustained level of GtH from pituitary cells with a low therapeutic dose (Peter et al., 1987). Additionally, sGnRHa either as peptide alone or as Ovaprim® (sGnRH + a domperidone, Syndel International, Inc.) has proven to effective in inducing final gamete maturation in a variety of cultured fish including, but not limited to, chinook salmon (Powell, 1995), coho salmon (Powell et al., 1998), catfish (Namvongchong et al., 1992b; Schulz et al., 1993), and ricefield eel (Tao and Lin, 1993). Furthermore, sGnRHa is an attractive therapy for aquaculture use as it has been shown to be ineffective in mammals (Millar et al., 1993), and has a short half life in fish (Goren et al., 1990; Zohar et al., 1990; Weil et al., 1992). Conversely, mGnRHa is superactive in humans and has a prolonged half life in fish and water (Sherwood and Harvey, 1986) which potentially could constitute a human safety risk. Collectively, the above-described considerations indicate that sGnRHa (Ovaplant®) is an attractive choice for further evaluation and development as a candidate compound for a new animal drug approval for use to induce final gamete maturation in a variety of fish species. . |
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