Brief Summary of Minutes of Annual Meeting

REGIONAL COORDINATORS' REPORTS Northeast Region: Dr. Paul Bowser Hydrogen Peroxide Project: ADR 259 Hydrogen Peroxide as a Therapeutic Compound for Bacterial Gill Disease in Fish. (INAD 9493) During this reporting period one manuscript based on this project has been published in the peer-reviewed scientific literature. No additional work has been performed on this project during this study period. Species Grouping Project: INAD 10-320 Oxytetracycline in Fish INAD 10-823 Romet-30 in Fish INAD 11-145 Florfenicol in Fish A primary constraint in the availability of therapeutic compounds for the Aquaculture Community is the relatively large number of fish species that are currently cultured or that have significant potential as commercial species. Currently, research in support of a label for a therapeutic compound must be performed separately for each species for which the label is desired. We have undertaken a project designed to show the similarities in how drugs are handled by different fish species with the goal of supporting a species (crop) grouping concept for fish. We have conducted these studies in a collaborative effort with the Western Region NRSP7. Within this context, to date we have completed the following preliminary Human Food Safety/Tissue Depletion Studies using the following test articles as model compounds: Oxytetracycline: 1. Walleyes, freshwater fish, 15C and 20C 2. Tilapia, freshwater fish, 25C and 30C 3. Hybrid Striped Bass, saltwater fish, 20C and 25C 4. Summer Flounder, saltwater fish, 17C and 20C Romet-30: 1. Walleyes, freshwater fish, 20C and 25C 2. Tilapia, freshwater fish, 25C and 30C 3. Hybrid Striped Bass (would not accept the ration; see below) 4. Summer Flounder, saltwater fish, 17C and 20C Florfenicol: 1. Walleyes, freshwater fish, 20C and 25C 2. Tilapia, freshwater fish, 25C and 30C 3. Hybrid Striped Bass, saltwater, 20C, 25C Data from these species will be compared to data currently available where available for the cold water species, rainbow trout (freshwater) and Atlantic salmon (marine). Data from studies of Oxytetracycline in the four species indicated above has been published in several peer-reviewed manuscripts. In addition to the species grouping effort with Oxytetracycline, we completed one cold water temperature Human Food Safety/Tissue Depletion Study in rainbow trout. This study was completed at the request of CVM/FDA. The study involved medicating market size rainbow trout and following elimination of the test article in the edible portion of the fish (filet with skin on, but descaled). The study was conducted at 8C. Oxytetracycline concentration in the edible portion never exceeded the 2.0 mg/Kg action level at any time during the study. Several attempts were made to conduct human food safety studies or Romet-30 in hybrid striped bass. Although extremely active feeding on a non-medicated ration was observed during acclimation, the hybrid striped bass refused to consume the Romet-medicated ration on all attempts to initiate a trial. As a result, hybrid striped bass were eliminated from our testing matrix for Romet-30. The Sponsor has reported that they have developed a product that circumvents the palatability problem and we anticipate efforts to complete the Human Food Safety/Tissue Elimination studies in that species. More recently, we have completed Human Food Safety/Tissue Depletion Studies using Aquaflor (Florfenicol, Schering-Plough; 10 mg drug/kg fish/day for 10 days) as a model compound, with studies completed in walleyes (20C, 25C), tilapia (25C, 30C) and hybrid striped bass (20C, 25C). In a related effort requested by the sponsor (Schering-Plough), we have evaluated the question of fish size using our standard testing protocol for Human Food Safety/Tissue Elimination studies. This study was also conducted in light of the recent communication with the sponsor that they anticipate a label dose of 15 mg drug/Kg fish/day for 10 days for the treatment of Streptococcus infection in tilapia. The in-life portion of the Tilapia size studies have been completed: 1. Tilapia  100 gm, freshwater fish, 25C, 15 mg/Kg, 10d 2. Tilapia  250 gm, freshwater fish, 25C, 15 mg/Kg, 10d 3. Tilapia  500 gm, freshwater fish, 25C, 15 mg/Kg, 10d Samples from these studies are being analyzed in a cooperative effort with the Western Region NRSP7. Usefulness of the findings: The Human Food Safety Studies completed to date in fish are consistent with what was expected; namely that the elimination of therapeutic compounds from the edible portion of the fish tested are within the withdrawal times currently specified for labels, or available in the literature for oxytetracycline, Romet-30 and Aquaflor (Florfenicol) in trout, salmon and catfish. North Central Region: Dr. Ronald W. Griffith 1. CIDRg in sheep: Dr. Dennis Hallford at New Mexico State University has submitted the results of the tissue residue study to CVM. CVM has requested additional data on the stability of progesterone in liver and muscle tissues of normal ewes to demonstrate that there was no loss of progesterone in these tissues when stored frozen for up to 6 months. Dr. Lynn Friedlander at CVM recently gave us some guidance as to the specifics of the stability assays that were needed. Dr. Hallford has submitted a draft protocol for the stability study to CVM for review. A teleconference to discuss the protocol is being scheduled. Dr. Hallford is currently preparing to collect tissues and would like to begin the stability study at the end of May 2006 if possible. 2. CIDRg in goats: The Western Region is taking the lead in this project. Dr. Hallford has obtained normal goat milk and has reported that he is nearly ready with the validation of progesterone in milk. He has not yet attempted the validation in goat meat and liver. The North Central Region will help out with this project as needed. 3. Nuflor in veal calves: No current activity with these studies. WESTERN REGION: DRS. ARTHUR L. CRAIGMILL/LISA TELL ADR#325 - Florfenicol for sheep for respiratory diseases. Project is on hold awaiting confirmation of additional data required. Funds expended to date on this project exceed $200,000 of Western Region expenses. Of interest in this process is that the time and money spent on method validation exceeded the amount spent on analyzing the actual samples. ADR#324 - Progesterone Ciders for goats. The TAS study is complete and we are awaiting a report from the principal investigator. ADR#272 - Romet for gamebirds. The PBPK model for the birds will be accomplished during the summer of 2006. Whole animal studies have been run in all species for serum pharmacokinetics of midazolam, the CYP3 market substrate. ADR#299 - Pirlimycin for dairy goats. No progress since last meeting. ADR#295 - Strontium chloride for Salmonids. Nothing to report from Steve Schroeder the PI. ADR#311 - Lincomycin for honeybees Data were accepted by CVM and a Public Master File has been published. SOUTHERN REGION: DR. ALISTAIR I. WEB The GLP inspections of our ivermectin assay and in vivo sections by the Western Region have been completed and all issues addressed satisfactorily. RABBITS ADR #107 Ivermectin & Rabbits The assay has been validated and the in vivo depletion stage is completed. The assay is being bridged with beef [species the residue method was developed in]. FISH ADR #271 CRUDE CARP PITUITARY The TAS report has not found favor with FDA. The author is preparing a rebuttal and we will see if the report is salvageable. What is groups view on funding any repeat on the project given this and low likelihood of a manufacturer being found. ADR#235 Ovaprim UFL Tropical Fish [Roy Yanong] and Syndel are working with CVM to define needs. At present our only involvement is to provide GLP support for any TAS studies. This may be an alternative to CCPE as a spawning aid. ADR #236 metomidate Following a teleconference with CVM, UFL Tropical Fish [Roy Yanong] has been evaluating behavioral changes as markers of efficacy of metomidate for sedation during transport. Pilot studies have not been promising. This may push them back to studying cortisol depression as an index of stress relief. My anesthesiologist hat is concerned as this group of drugs has a potent depressant effect on adrenal function in mammals, which would confound their study. BIRDS ADR #280 FENBENDAZOLE & GAMEBIRDS The TAS report is nearly complete but lacks investigators final input and QA . We are waiting for Western Regions depletion assay results and it is hoped that there will be a fast turn round in submitting that to CVM. DEER ADR #210 Fenbendazole & Red Deer & ADR  216 Fenbendazole & Fallow We had an in-person conference with CVM and Intervet to spell out requirements but Intervet is seeking more clarification  especially TAS kinetic requirements. Plan at the moment is that NRSP-7 will do the TAS and human safety and the efficacy, conducted by Intervet, will follow  risk there is if the effective dose is higher that that used in the two former studies they would have to be repeated. The investigator for the TAS and human safety work has been identified but has cooling ardor. Intervet have limited their interest to white tailed deer but I have made it clear to FDA NRSP-7s goal is for Cervid. In the conference studies of WTD, red deer/elk and fallow deer would gain a Cervid label. ADR #294 Lasalocid And Deer / ADR #298 Lasalocid And Goats A teleconference was held November 18th 2005 to define requirements and develop budgets. Like the FBZ project, Alpharma will do the efficacy after the TAS and Human safety with the same risks involved. We have investigators lined up for both deer and goat work at UFL. Problem is that Alpharma will only proceed if there is a zero withdrawal time

(1) Smith, G. W., Gehring, R., Craigmill, A. L., Webb, A. I., and Riviere, J. E. Extralabel intramammary use of drugs in dairy cattle. J Am Vet Med Assoc 2005, 226, 1994-6. (2) KuKanich, B., Gehring, R., Webb, A. I., Craigmill, A. L., and Riviere, J. E. Effect of formulation and route of administration on tissue residues and withdrawal times. J Am Vet Med Assoc 2005, 227, 1574-7. (3) Haskell, S. R., Payne, M., Webb, A., Riviere, J., and Craigmill, A. L. Antidotes in food animal practice. J Am Vet Med Assoc 2005, 226, 884-7. (4) Gehring, R., van der Merwe, D., Pierce, A. N., Baynes, R. E., Craigmill, A. L., and Riviere, J. E. Multivariate meta-analysis of pharmacokinetic studies of ampicillin trihydrate in cattle. Am J Vet Res 2005, 66, 108-12. (5) Gehring, R., Haskell, S. R., Payne, M. A., Craigmill, A. L., Webb, A. I., and Riviere, J. E. Aminoglycoside residues in food of animal origin. J Am Vet Med Assoc 2005, 227, 63-6.