CVM is happy to welcome Claire M. Lathers, Ph.D., F.C.P., as the Director of CVM's Office of New Animal Drug Evaluation. Dr. Lathers comes to CVM from Barr Laboratories, Inc., Pomona, New York, where she served as the Chief Scientific Officer since 1996. In that position, Dr. Lathers was responsible for guiding the scientific development of the Research and Development Program with overall responsibility for developing clinical bioequivalence protocols and supervising the conduct of these studies at sites within the U.S. as well as internationally.
Dr. Lathers earned her Ph.D. in Pharmacology from the SUNY Buffalo Schools of Medicine and Dental Medicine. Her academic experience has included The Medical College of Pennsylvania (15 years), Albany College of Pharmacy (2 years as President, Dean, and tenured Professor); Uniformed Services University of the Health Sciences; and Gwynedd Mercy College. These academic experiences have provided extensive research, administrative, committee, and teaching opportunities.
In addition, Dr. Lathers worked for FDA's Center for Drug Evaluation and Research as a Pharmacology Reviewer for 5 years, and as a Special Government Expert for 2 years.
As a Visiting Scientist at NASA/USRA, Dr. Lathers has spent 12 years collecting data from subjects in ground-based studies and from astronauts and cosmonauts before, during and after space flight. She has achieved international recognition for her work in the two areas of cardiovascular autonomic dysfunction associated with space flight and with sudden death in persons with epilepsy. The primary focus of Dr. Lathers’ international cardiovascular pharmacology research career has centered on autonomic peripheral and central mechanisms involved in the control and regulation of blood pressure and heart rate and rhythm.
For over 15 years, Dr. Lathers taught 250 hours per year of pharmacology to medical, pharmacy, nursing, and other allied health students, introducing them to the numerous challenges of space flight and pharmacology. She developed innovative international symposia in clinical pharmacology to teach clinical pharmacology, pharmacy, and medical issues in the weightless environment of outer space and then edited the peer-reviewed articles written from these presentations for publication in 3 entire issues of the Journal of Clinical Pharmacology (May and June 1994 and October 1991).
Dr. Lathers has authored or co-authored over 300 publications, including 2 books. She is the Immediate Past-President of the American College of Clinical Pharmacology, having previously served as Regent, Treasurer, President-Elect and President. For her broad contributions to the discipline and to the College, Dr. Lathers was the recipient of the Distinguished Service Award in Clinical Pharmacology in 1997. In addition, The Board of Regents of the American College of Clinical Pharmacology confirmed her as an Honorary Regent with Life-Time Status in 1996.
Dr. Lathers looks forward to the diversity of challenges that her new CVM position holds. Her vast experience in research, academia, industry, and government makes Dr. Lathers a valuable addition to CVM's management team.
CVM VIEW OF DATA ON ANTIMICROBIALS USED IN ANIMALS
Information published recently in the New England Journal of Medicine (NEJM) suggests a direct link between the use of antimicrobials in animals and the development of bacteria resistant to the drug finding their way into people.
The NEJM report was developed from data collected by Health Department officials of the State of Minnesota that showed campylobacter bacteria, a bacteria commonly found in poultry, became increasingly resistant to a fluoroquinolone drug after that drug had been approved for use in poultry. FDA has approved certain fluoroquinolone products for use in poultry to prevent outbreaks of disease caused by bacteria. Further, the report indicates that the resistant campylobacter were found in samples taken from humans suffering from foodborne illness. The poultry products tested in this study originated in 15 poultry processing plants in nine States.
Officials of the Food and Drug Administration’s Center for Veterinary Medicine (CVM) will closely study the data to see what implications the information may have for the use of fluoroquinolones in poultry. FDA shares the concerns about emerging resistance to fluoroquinolones in poultry. FDA has asked the drug manufacturers to collect additional information regarding resistance as part of their existing post-approval monitoring programs. Also, FDA is exploring with the drug sponsors ways to mitigate resistance of public health concern.
In addition, CVM officials have already taken steps to alter the animal drug approval system to be able to make adjustments when antimicrobial resistance becomes a concern, either for human or animal treatment.
The adjustments are incorporated in a philosophy laid out in what is called the "Framework Document". The Framework calls for drugs with the highest risk of creating problems for human therapy to be the least likely to be approved for animal uses. Further, the philosophy calls for monitoring of increases in resistance so that FDA can take actions before a threat to human health develops. The monitoring system, which is already in place, tests human and animal isolates collected at several sites across the U.S. for resistance to 17 antimicrobial drugs
CVM Holds Second Open Forum for Its Stakeholders
by David L. Lynch
CVM held its second open forum for stakeholders on April 28, 1999, as a part of an FDA-wide initiative to solicit feedback from our stakeholders. The Center's meeting took place at the Johnson County Community College in Overland Park, Kansas, while other FDA Center meetings occurred at other locations across the country. The host of the meeting was the FDA Kansas City District Office Director, Mike Rogers, who made everyone, stakeholders and Headquarters CVMers alike, feel welcome. Other Kansas City District Office employees, particularly Tywanna Paul, provided a great deal of assistance to the Center in the planning and logistics of the meeting.
The meeting opened with a welcome by Dr. Linda Tollefson, Director of CVM's Office of Surveillance and Compliance, who also presented to the stakeholder group a summary of what the Center heard at the previous Open Forum, held on September 19, 1998. Dr. Tollefson described the initiatives that the Center had developed to implement the ideas and suggestions that were made at that earlier meeting. She also provided an update on the status of each of those initiatives.
Following that was a satellite broadcast of FDA Commissioner, Dr. Jane Henney and Senior Associate Commissioner, Dr. Linda Suydam, giving their priorities and views on various FDA initiatives. They then took questions from across the country from stakeholders, by phone and telefax, as well as answering questions submitted by the live audience or that had been previously submitted to the stakeholder docket. To help with questions that were too specific for Drs. Henney and Suydam to answer, a panel of representatives from each of the FDA Centers was assembled and standing-by.
After the satellite broadcast, Dr. Stephen Sundlof, Director of the Center for Veterinary Medicine, set the stage for the local CVM meeting by giving an update of the Center's budget situation for Fiscal Year 1999 and what is expected for Fiscal Year 2000. The rest of the afternoon was spent with the two stakeholder panels providing information to the CVM panel. The stakeholder panels were composed of representatives of the industry, producer groups, academia, consumers, and consumer groups. The CVM panel was composed of representatives from each of the CVM offices and Dr. Sundlof. The CVM panel's job was to listen to what the stakeholder panels said and to ask clarifying questions.
Several of the stakeholder panelists reiterated their support (from the September meeting) for CVM maintaining a strong science base, and encouraged the Center to base its regulatory decisions more on scientific data and less on other sources. The hottest topic at the meeting was antimicrobial use in food animals, and discussion of the Center's Framework Document concerning the same topic. Several of the panelists voiced their concerns about the provisions of the Framework Document and encouraged the Center to move forward quickly with its scientific risk assessment of antimicrobial use in food animals. They also supported continued development of the judicious use guidelines for antimicrobials and encouraged the Center to enhance and expand the National Antimicrobial Resistance Monitoring System (NARMS).
Other ideas and suggestions offered by the stakeholder panelists were:
a reiteration of their encouragement for the Center to more strongly enforce current regulations and to remove unapproved animal products from the market, to include more veterinarians and food-animal producers in the Center's decision-making process on antimicrobials and other CVM issues,
to continue and expand the use of compassionate INADs,
to move forward with and finalize the regulations on Veterinary Feed Directives (VFDs), feed mill licensing and minor use/minor species,
to develop a veterinary drug database on the CVM Home Page on the World Wide Web (WWW), and
a plea for better communications between CVM and consumers and veterinary practitioners, particularly concerning the benefits versus the risk of using veterinary drugs.
Currently the Center is analyzing the transcript of the meeting to develop the list of ideas and recommendations provided by the stakeholder panelists, and to develop initiatives to implement them. Keep in mind however, that not every idea or recommendation can be implemented, for example, some are contrary to current law and some would require more resources than the Center can afford to put into them at this time.
The Center considers this meeting highly successful, just as it did the September 1998 meeting, and for the same reasons. CVM received strong support for most initiatives and sound advice and ideas for ways to improve those that were not supported. The Center thanks the Kansas City District Office for their excellent job as hosts, and all of the stakeholders who participated, particularly the panelists who presented their ideas and recommendations.
The January 25-26, 1999, meeting of the Veterinary Medicine Advisory Committee (VMAC) was held to assess the proposed FDA Center for Veterinary Medicine (CVM) Framework Document as it would impact human health through the veterinary drug approval process. The following summarizes the Committee responses to questions posed by the FDA.
Question 1: Framework Concept
FDA's goal is to protect the public health by ensuring that the efficacy of human antimicrobial therapies is not compromised due to use of antimicrobials in food animals while providing for the safe use of antimicrobials in food animals. Do the concepts laid out in the document entitled "A Proposed Framework for Evaluating and Assuring the Human Safety of Microbial Effects of Antimicrobial New Animal Drugs Intended for Use in Food-Producing Animals" provide a sound scientific basis for achieving this goal if implemented?
Committee Recommendations
The Committee understands that the framework document is to help FDA respond, in its regulatory role, to a legal dilemma in the approval of drugs for the animal drug industry. The Committee also understands that the Agency proposes the framework for consistency in the drug approval process.
The Committee concludes that the proposed framework to protect public health by ensuring that the efficacy of human antimicrobial therapies is not compromised due to the use of antimicrobials in food animals, while providing for the safe use of antimicrobials in food animals, provides a basis for achieving this goal. A sound scientific basis for the framework must be put together, utilizing a diverse group of experts working in microbiology from government, industry and academia. This should be done quickly.
The Committee recommends that CVM state publicly how it will handle current and future applications until this process is completed.
Question 2: Categorization of Antimicrobial Drugs Based on Their Importance to Human Medicine
The Agency is proposing that the categorization of antimicrobial drugs for human medicine take into account the usefulness of drugs in both foodborne disease and non-foodborne infectious diseases, when evidence exists that the use of the drug may result in the induction of resistant pathogens or the transfer of resistant elements to human pathogens. This approach recognizes not only the well known risk of resistance transfer through classical foodborne pathogens but also the threat of transfer of resistant bacteria or resistance genes from other intestinal bacteria of food-producing animals resulting in resistant infections of humans with other types of pathogens (e.g., resistant E. coli or Enterococcus). Does the Committee agree with this approach?
Committee Recommendations
The Committee concludes that categorization of antimicrobial drugs for food animals considering the importance of antimicrobial drugs for human medicine is a workable concept. Antimicrobial resistant microbes and the ability of transfer of resistance genes from other bacteria of food animals must be considered. The Committee heard several comments from many members requesting that CVM attempt to simplify the categorization. The Committee also voted to have the Agency consider adding a fourth category.
The Committee recommends that the following sentence from the third paragraph, page 14 of the Framework Document be deleted: "Given our current understanding of the mechanisms of resistance, FDA believes that, generally, it would not appear biologically plausible for resistance to be transferred from animal enteric pathogens to the human respiratory pathogen."
Question 3: Monitoring Threshold Levels
A) Should multiple monitoring threshold levels be established and should they be based on animal data, human data or both? Should the levels be tied to specific actions -- e.g., need for further investigation, need for mitigation strategies, need for withdrawal of product from the market?
B) What organism(s) should be the basis for the monitoring thresholds? In the interest of cost containment, would sentinel organism(s) be designated or should a foodborne pathogen(s) be used?
Committee Recommendations
A) Monitoring threshold levels of antimicrobial resistance is the important tool for the proposed framework, and assures the human safety of the microbial effects of new animal drugs. We encourage the use of human, food-producing and pet animal, and other environmental data such as slaughterhouse samples, for making these decisions. The levels should be tied to specific actions.
B) Some members felt that a broad range of gram negative and gram positive organisms should be used for monitoring antimicrobial resistance and others felt that we do not have enough data to make statements about what organisms should be the basis for monitoring thresholds. The Committee agreed that the sole use of sentinel organisms would be inappropriate. Antimicrobial resistance data should be monitored through the National Antimicrobial Resistance Monitoring System (NARMS), animal health diagnostic laboratory data, FSIS HACCP program within plants, the quality assurance programs that various associations are implementing, and an independent central laboratory for on-farm data using sentinel farms. These activities should be supported by government and industry.
Question 4: Resistance Threshold Levels
The Agency has proposed the creation of different levels of resistance transfer to humans that would be acceptable based on the importance of the drug or drug class in human medicine. Category I antimicrobial drugs would require that the use in food-producing animals results in little or no resistance transfer to humans. Category II antimicrobial drugs would require that a predefined level of maximum resistance transfer be established prior to approval that would depend on several factors, such as the existence of alternatives to the drug, the human pathogens of concern, etc. The level of resistance transfer must be low enough that there is a reasonable certainty of no harm to humans associated with the use of the product in food animals. What criteria should the Agency use to safely define the acceptable level of resistance transfer, if any, for antimicrobial drugs that fall into categories I and II?
Committee Recommendations
The Committee agrees that resistance levels for Category I antimicrobial drugs would require that use in food animals result in little or no resistance transfer to pathogens of human importance. If resistance transfer is detected, FDA and an expert group would review the data and discuss mitigation for the future use of the drug in food animals.
Question 5: On-Farm Post-Approval Monitoring Programs
On-farm post-approval monitoring programs will be necessary for certain antimicrobials (Category I, Category II High, and some Category II Medium products). Should on-farm monitoring be instituted immediately post-approval, or triggered by a change in the data generated from other sources such as NARMS?
Committee Recommendations
Slaughterhouse antimicrobial resistance data is of paramount importance to the framework document for making post-approval monitoring decisions. On-farm antimicrobial resistance monitoring utilizing on-farm health quality assurance programs is encouraged by the Committee for post-approval antimicrobial resistance levels of high category antibiotics. Diagnostic laboratory data and an accredited central laboratory should be developed utilizing government and industry money.
FDA PARTICIPATES IN ANIMAL DRUG WORKSHOP IN CHINA
by Michael Smedley, Geoffrey Wong, Lonnie Luther, Ph.D. (FDA/CVM Office of New Animal Drug Evaluation) and Michael Spangenberg (formerly FDA Office of Regulatory Affairs)
In April 1999, a FDA Center for Veterinary Medicine (CVM) and Office of Regulatory Affairs (ORA) delegation participated in an Animal Drug Current Good Manufacturing Practice (cGMP) Workshop in Suzhou, China. This workshop was coordinated by Dr. C.K. Hsu, President of Shared Enterprises, Devon, PA, and sponsored by the Chinese Ministry of Agriculture (MOA). Prior to the Workshop, the FDA delegation visited the MOA’s National Institute for Control of Veterinary Bioproducts & Pharmaceuticals, which conducts animal drug residue testing and drug product testing, in Beijing, China. This facility also houses the country's herbal standards. While in Beijing, the FDA delegation also met and held discussions with the Deputy Director General of the Bureau of Animal Production & Health, MOA, Madame Jin Lan Feng. She is the highest ranking veterinarian in China and oversees all government veterinarians in China. The delegation also held discussions with Dr. Zhongwu Feng, the Director of the Veterinary Drugs and Apparatus Administration Division. The MOA regulates drugs, biologics, and herbal medicines for animals. The main responsibility of the Veterinary Drugs and Apparatus Administration Division is to implement the regulations of the animal drug administration, and to advise and approve animal drug standards, approve new drugs, bioproducts, and feed additive products. The MOA has a close partnership with the Provincial and Municipality Bureaus. The objectives for the Animal Drug cGMP Workshop were to improve drug quality, to promote development of the animal drug industry, to benefit farmers, to improve local human health, and to promote future international trade. After meeting with the MOA representatives in Beijing, the FDA delegation participated in the "Conference on Current Good Manufacturing Practices for the Animal Health Industry" in Suzhou. Mr. Michael Smedley from CVM presented lectures entitled, "Overview of the Current Good Manufacturing Practices in the U.S." and "Center for Veterinary Medicine’s Approach to cGMPs and the Pre-Approval Compliance Program." Mr. Geoffery Wong presented lectures entitled, "Relationship Between Veterinary Drug Master Files and cGMPs" and "Quality of Animal Drug Products in Relation to U.S. Filing Requirements for Chemistry/Manufacturing Changes." Dr. Lonnie Luther presented a lecture entitled "Generic Animal Drug Approval Requirements." Mr. Michael Spangenberg (formerly of ORA) presented a lecture entitled "FDA cGMP Inspections" and he also conducted two mock cGMP inspections.
The animal drug cGMPs are currently being written in China. However, they are not currently being enforced. The Chinese government plans to implement cGMPs for all animal drug facilities within the next five years. Dr. Feng stated that in the future, every animal drug manufacturer should meet cGMPs or their license will be revoked. The conference attendees represented China's animal drug industry, Provincial and Municipality local governments, and National government. In addition to the conference presentations, Investigator Spangenberg organized and conducted two separate mock cGMP inspections for the approximately 100 conference attendees. The mock inspection technique employed was geared towards demonstrating to the conference attendees what acceptable cGMPs might look like, as opposed to finding objectionable conditions within the drug manufacturing operations of the two (2) volunteer firms. The first mock inspection covered finished animal health products: soluble powders and Type A premixes for medicated feeds. Six separate areas of the firm’s drug manufacturing operations were selected for cGMP show-and-tell/demonstration purposes, which included the firm’s microbiological testing laboratory, GC chemical testing laboratory, batch production control records, label storage, raw material inventory identification and control, bulk component raw material storage integrity, in-process product transfer system cleanability, cleaning validation issues, stability, reserve, and sampling issues. The second mock inspection covered active pharmaceutical ingredients for animal health products. Eight separate areas of the firm’s drug manufacturing operations were selected for cGMP demonstration purposes, which included: raw material inventory identification and control, label storage, high performance liquid chromatography chemical testing laboratory, production equipment identification, production in-process control equipment calibrated and traceable to national standards, process water system monitoring, and environmental control systems. Both mock inspections were well received by the conference attendees and generated numerous questions during follow-up question and answer sessions. After the workshop, the FDA delegation toured a fermentation bulk chemical plant, in Zhejiang, China which was run by the Chinese government. This facility produced a number of fermentation products. The delegation also met with representatives from the Shanghai Animal Husbandry Office and visited the Shanghai Municipal Control Institute of Veterinary Drug and Feedstuff, and the Shanghai Animal Husbandry & Veterinary Station. These laboratories conduct animal drug residue testing, drug product testing, and animal diagnostic testing. 
On their final day in China, the FDA delegation visited the Shanghai JiaDing Breeding Stock Farm for swine and observed a poultry operation at a government owned farm and processing plant. The breeding farm was established in 1958, and breeding of the Meishan pig started in 1963. There are currently 1300 pigs on the farm. Only 180 are Meishan, with the others being cross breeds. Some breeds were imported to China from Lincoln, Nebraska, and the Meishan swine have been imported to the United States as well. The Meishan pig is very popular in China because of its large litter size and preferred taste to the local population. However, the Meishan pig is approximately 50 percent fat; therefore, it does not promote a healthy diet. One purpose of this breeding farm is to breed a pig with lower fat content, higher litter size, and of quality taste to the local population. The trip provided FDA a better understanding of China's animal drug industry. It also provided the opportunity to develop an excellent working relationship with the Chinese regulatory officials. Hopefully, it also provided the Chinese with a better understanding of 
FDA's cGMP regulations. FDA HELPS INDUSTRY PREPARE FOR Y2K As the millennium approaches, there is growing concern regarding the impact of Y2K issues on the identity, strength, quality, purity, and potency, as well as safety, efficacy, and availability of products regulated by FDA. The animal health and feed industries are not exempt from computer problems at the beginning of the year 2000. Since virtually every organization's systems are composed of various layers of hardware and software that can be compromised by the Y2K problem, all businesses are vulnerable to potential Y2K mishaps. Computer errors may cause the shut-down of vital systems in communication and transportation, in addition to critical infrastructure systems such as power, water, banking, and telecommunications networks. For CVM-regulated products, date coding problems may result in process failures, the production and distribution of adulterated and/or misbranded products, and even product shortages. The FDA recommends that regulated industries take preventive measures to ensure that they have a Y2K effort in place including:
Completion of any renovation in sufficient time to ensure a period of monitoring and problem resolution prior to when Y2K problems are expected to occur.
For mission critical systems, review by an independent contractor/auditor to verify the Y2K compliance status of the systems. (For computerized systems regulated by the FDA, assure all changes have been validated and are in compliance with applicable GMPs).
Development of contingency plans to ensure business processes will continue unabated regardless of impact of Y2K.
FDA intends to raise the awareness of regulated industries to the potential Y2K problems during routine field inspection activities. It is impossible to predict the extent of the Y2K impact on CVM's customers, but steps have been taken to ensure that CVM's internal computer systems are Y2K-ready. The steps taken at CVM began with determination of the Y2K compliance status of our inventory of hardware, system software, and application software. Remedial actions have been taken for identified problems, such as upgrading the BIOS of affected desktop computers and LAN servers, applying software service patches, and upgrading to the Y2K compliant version of system software. Compliance strategy has also taken the form of installing newer, compliant versions of desktop operating systems and office automation software. Another strategy has involved the planned re-development of mission-critical database systems by conversion to applications for the LAN environment with the stipulation of Y2K compliance. In these cases, the database applications were subjected to and passed independent verification of Y2K compliance following a prescribed testing process. Finally, CVM is preparing business process continuity contingency plans for major activities in the event of unanticipated power outages from Y2K-related problems. The Center for Veterinary Medicine (CVM) has identified two major areas that may be vulnerable to potential Y2K computer problems. Those areas are: 1. Sole source suppliers of significant ingredients or finished products. 2. Supplies, especially bulk drug substances, from foreign sources. CVM has appointed a Y2K Working Group to identify possible problems and to develop a Y2K Rapid Response Plan. The Group has mapped out precautionary steps to assure adequate communication in the event of emergency conditions. Teams have been formed to handle both anticipated and unanticipated issues resulting from Y2K computer problems. In addition, the Center has established contacts with other units of FDA, other Federal agencies, State counterparts, industry trade associations, and consumer groups. To provide industries with information and guidance on Y2K issues, FDA has been alerting them in direct correspondence, speeches, public appearances, meetings, workshops, and guidance documents. In order to avert problems before they become public health or regulatory issues, FDA and CVM will continue to work with regulated industries to disseminate and exchange information related to Y2K issues. For more information regarding Y2K, visit the FDA Home Page. For specific Y2K concerns related to animal health, you may contact CVM at 301-594-1736.
by Susan B. Harper, D.V.M., M.S., ACLAM
For thousands of years, man has attempted to improve animal genetics by selective breeding. Targeted mating strategies are based on the presence or absence of specific traits that can be identified and transmitted to offspring. Improvements have been limited to naturally occurring events or mutations. Starting in the early 1970’s, the advent of recombinant DNA technology has introduced a variety of new techniques intended to accelerate and refine the process of genetic manipulation.
Transgenics is the science of intentionally introducing a foreign gene or genetic construct (series of genes and associated regulatory elements) into the genome of a target animal. Initial work involved a splicing technique to insert foreign genetic materials into mammalian cells maintained in culture. This in vitro work rapidly progressed into laboratory rodents, providing a more targeted and proactive approach for the establishment of new animal models for biomedical research. The results have been very successful and provide a unique and precise mechanism for the study of a variety of specific conditions or diseases with a genetic basis or influence.
The development of transgenic applications in livestock is a logical progression for this technology. Insertion of modified human gene constructs into livestock is being utilized to create "designer production animals" capable of producing useful proteins, tissues, and organs for pharmaceutical and biomedical use. Additionally, the manipulation of indigenous gene sequences has the potential to convey enhanced disease resistance and/or improve production in target animals. The primary objective in using transgenic technology in animal agriculture is to improve the quality of livestock by altering the animal’s biochemistry, hormonal balance, or harvested protein products. Scientists hope to produce animals that are larger and leaner, grow faster and are more efficient at using feed, more productive, or more resistant to disease.
Process To Create a Transgenic Animal
There are several techniques for the production of a transgenic animal and new processes are continually being developed or refined. All have the same primary objective, which is the successful integration of a functional sequence of a DNA strand (a transgene) into a chromosome within the host genome. Most of the following methods for introducing transgenes into animals have been used since the 1980’s.
Viral Vector-Mediated Transgene Introduction
The first genetically altered embryos were created using viral vectors in the early 1970’s. This technique is still in use. A viral vector (or phage) is first modified so that it will not replicate or cause disease in the target cells of the host embryo. The gene(s) of interest is incorporated into the viral genome and the virus is then used to infect an early stage embryo. The viral vector binds uniformly to the embryonic cells and acts as a vehicle to allow transfer and integration of the transgene into the host genome. Many of the experimental human gene therapy trials currently underway use basic viral vectors as a means of "gene-delivery" to susceptible cells or tissues in a very similar procedure.
An advantage to using viral vectors is that usually only a single copy of the transgene is integrated into the genome. If the viral transfection is applied to oocytes prior to fertilization, then the novel gene will be present in all cells of the resulting embryo as though it had been contributed by the maternal germline.
The major disadvantage of this system is the time and labor-intensive process to prepare the viral vector. There is also a remote possibility that the modified viral vector may revert to its original state or recombine with other pathogenic viruses.
Pronuclear-Mediated Transgene Introduction (Microinjection)
Most existing transgenic animal lines have been produced using pronuclear microinjection. This technique involves the injection of genetic material into an early-stage embryo to create what are called germ-line transgenic animals.
The gene (or genes) of interest is first identified and the nucleotides for that segment of DNA is sequenced. Frequently, there is a special segment of DNA in addition to the gene of interest, which is referred to as a promoter. The promoter is a regulatory segment of DNA located on the same chromosome as the gene of interest. It influences or controls expression of the gene. An endogenous promoter may be modified during transgene assembly in order to increase the likelihood that the gene will function in the targeted tissues of the host animal. The promoter can also be used to turn the gene on or off as needed. For example, a promoter sequence that requires a specific dietary "trigger" substance can be used to turn on genes for important hormones in animals so that the hormone is only produced when the animal is fed the appropriate trigger. A majority of the current research focuses on the understanding and development of useful promoter sequences to control transgenes and mechanisms for more precise insertion of the transgene into the recipient animal.
The prepared DNA construct (transgene and promoter) is usually replicated in a plasmid vector to produce multiple exact copies for microinjection into the pronucleus of an embryo. The injection volume is quite small (approximately 2 to 3 picoliters) and is accomplished by means of a very fine glass micropipet which is able to penetrate the cell membrane of the fertilized ovum without damage. Although many copies of the transgene construct are injected, the actual number of copies that eventually incorporate into the host genome will vary. If the transgene successfully integrates into one of the chromosomes of the pronucleus, the transferred genetic material should be present in every cell of the resulting animal and have the potential to be transmitted to future offspring.
A major disadvantage of the pronuclear microinjection system is that the rate of integration of the transgene may not be uniform between cells. Certain cell populations may not include the new DNA or may have multiple copies. Likewise, it is not always possible to specify, or target, the locus (or specific location) of integration for the transgene into the host DNA. Frequently, integration site may be a critical determinant of the transgene’s expression and function may be impaired even though the transgene is present. Similarly, if the integration of the transgene disrupts a functional DNA sequence in the host’s genome, an insertional mutation may result which interferes with the function of the existing gene.
Targeted Transgene Insertion by Homologous Recombination (Embryonic Stem Cell)
The use of homologous recombination has facilitated the development of targeted transgene insertion and, by consequence, the production of better-defined transgenic research models. The term homologous recombination refers to the exchange of DNA fragments between two DNA molecules at an identical site, which allows insertion of the transgene to be targeted to a specific location on the chromosome.
Undifferentiated embryonic stem (ES) cells have the potential to differentiate into any type of cell within the developing organism. These cells are harvested from a blastocyst stage embryo and cultured in an in vitro environment. The transgene is attached to a DNA construct that is analogous to a segment of the host DNA (except for the presence of the transgene). The new DNA-transgene is then introduced into the nuclei of ES cells in culture by means of a vector or by electroporation (the application of an electric current to enhance cell membrane permeability). As cell division occurs, the novel DNA replaces the existing segment and is incorporated into the nucleus of some of the new cells. Transgene positive cells are identified and sorted using various selection techniques, including survival selection (positive-negative selection) and polymerase chain reaction (PCR) amplification. The modified ES cells are then injected directly into a normal blastocyst embryo.
The advantage of this system is that only a single copy of the transgene is incorporated into the new cells. Also, the site of integration is highly controlled. Unfortunately, the system is very time-consuming, in that the DNA sequence of the segment of interest for the host cell must be known in order for the transgene to be constructed.
Cloning
The recently much-publicized successful cloning of livestock has raised interest in the use of this technology for the production of transgenic animals. Cloning is the process of nuclear transfer, as opposed to single gene transfer, and results in the production of genetically identical animals (clones).
The nucleus of an unfertilized oocyte is removed and replaced with nuclear material harvested from a cell from an existing animal of the same species. The donor cells are frequently of epithelial origin and contain a full complement of DNA (diploid), in contrast to the unfertilized oocyte with half the total (haploid). A modified gene sequence can be introduced into the cultured donor cells prior to nuclear exchange. The nuclei of cells that successfully incorporate the transgene are identified, isolated, and inserted into recipient oocytes. Cell division is activated and the resulting embryos are implanted into the uterus of a foster recipient.
The major advantage of this system is that the generation of a large number of animals from a single donor is possible. Of course, the technology is still in the early stages and specific procedural elements are frequently being modified or evolving. Ethical issues related to the transfer of this technology into human medicine are the source of much debate.
Conclusion
Although these technologies are primarily restricted to research settings at the current time, it is inevitable that they will be incorporated into more traditional situations in the near future. It is very difficult to anticipate or comprehend the ultimate impact that will result. Consequently, a basic understanding and appreciation of the science involved is essential to the critical assessment of these ideas.
CONSENT DECREE ENTERED IN DRUG TISSUE RESIDUE CASE
On March 23, 1999, the U.S. District Court for the Central District of California accepted and entered a Consent Decree of Permanent Injunction between the United States and Ivan A. Wood, doing business as Woodcrest Dairy. Woodcrest Dairy is a livestock producer located in Ontario, California.
An FDA investigation of Woodcrest Dairy’s operations revealed that since 1993, Mr. Wood caused numerous illegal drug tissue residues in livestock intended for food in spite of multiple written notifications from FDA, the U.S. Department of Agriculture (USDA), and the California Department of Food and Agriculture warning him of previous violations and the need to improve poor husbandry practices in his business.
Under the terms of the Consent Decree, Mr. Wood voluntarily agreed to be permanently restrained and enjoined from directly or indirectly introducing or causing to be introduced into interstate commerce any livestock or their tissues until the corrective actions enumerated in the decree are established and implemented. Some of these corrective actions are: (1) the implementation of adequate recordkeeping practices documenting the administration of drugs and withdrawal periods in livestock; (2) the establishment of a drug inventory and accountability system that will help to prevent future sales or distribution of animals that may contain illegal drug tissue residues; (3) the presence of a system that will prevent the administration of drug in excess of approved dosage, sale of animals before drug withdrawal period, storage of expired drugs and extra-label use of drugs; (4) the implementation of a system ensuring the segregation between medicated and unmedicated animals. In addition, Mr. Wood cannot cause the adulteration of food or drugs at any time in the future. Failure to comply with the terms of this Consent Decree may result in civil or criminal penalties.
The FDA’s Los Angeles District Office conducted the investigation that lead to this Consent Decree. The FDA/CVM’s Division of Compliance, the FDA’s Office of the Chief Counsel, and the U.S. Department of Justice’s Office of Consumer Litigation were responsible for the case processing and legal procedures.
by Tania D. Woerner, V.M.D.
March 27 & 28 of 1999, marked the first gathering of forty-five equine veterinarians from the states of Oregon, Idaho, Washington, and Maryland at the Idaho Equine Hospital in Nampa, Idaho. The group of eager participants listened to prominent equine medicine speakers Virginia Reef, DVM, Dip ACVIM; N. Ed Robinson, B. Vet. Med., Ph.D., MRCVS; Joseph Bertone, DVM, MS, Dip ACVIM; and Frank Andrews, DVM, MS, Dip ACVIM. The speakers focused on the topics of Equine Musculoskeletal Ultrasonography, Chronic Respiratory Disease, Neurologic Disease and Gastric Ulcer Disease.
The hands-on ultrasound portion of the conference was held in the Idaho Equine Hospital, a large animal medical and surgical facility. The hospital, built in 1998, has several conference rooms, a client consultation room, an operating room, two padded recovery rooms, an ultrasound room, a radiology room, and several general examination rooms with stocks. Three barns provide housing for the inpatient caseload. The hospital offers a full spectrum of medical services (endoscopy, ultrasound, radiology, etc) and surgical procedures such as laser surgery, arthroscopic surgery, and colic surgery. Six full-time veterinarians are employed by the hospital: Lionel C. Ickes, DVM; William J. Maupin, DVM; Shawn Gleason, DVM; Stuart Shoemaker, DVM, DACVS, Liz Scott, DVM; and Joseph J. Bertone, DVM, MS, DACVIM.
The conference was sponsored by Boehringer Ingelheim, Elwood, Kansas, Merial LLC, Iselin NJ, and MWI Distributors, Nampa, Idaho. Universal Medical Systems, Inc., of Bedford Hills, NY, provided the ultrasound equipment for the hands-on laboratory.
Lectures were held next to the clinic at the Idaho Center, (across the parking lot from the hospital) home of the Idaho Stampede. The rodeo club overlooking the arena, decorated with various "stampede" memorabilia provided a pleasant environment for the lectures, not to mention the exquisitely prepared breakfast and lunch served to the participants.
Overview of presentations on Chronic Respiratory Disease, Equine Musculoskeletal Ultrasonography, Neurologic Disease & Gastric Ulcer Disease
Chronic Respiratory Disease: Dr. N. Ed Robinson, is the Matilda Wilson Professor of Large Animal Clinical Sciences and directs the pulmonary laboratory at Michigan State University College of Veterinary Medicine. His research has focused on pulmonary disease in horses.
Dr. Robinson began with a review of the anatomy and physiology of the equine pulmonary system. Did you know that the horse breathes 375 gallons of air per minute? The majority of the speech was dedicated to what is known as "heaves", or chronic obstructive pulmonary disease (COPD). The now accepted terminology for this condition is Recurrent Airway Disease (RAD). Horses that are stabled and fed indoors are subjected to organic dust; composed of molds, fungal parts, rodent feces, insect parts, mite parts, and endotoxin (bacteria parts). The equine respiratory system responds to the foreign particles in three major ways: cough, bronchospasm and increased production of mucus. When these protective mechanisms overreact to the environmental stimuli, the horse is said to have "heaves". Clinical signs of heaves are a persistent cough and difficulty expiring air, often resulting in exercise intolerance.
It is estimated that 27 percent of Thoroughbreds in training in the United States have heaves. Even higher estimates of 33 percent have been reported in the United Kingdom and 54 percent in Sweden. Research has also shown that there may be a genetic component to the disease. When the condition persists, irreversible thickening of the bronchioles occurs. Dr. Robinson’s research has demonstrated that these irreversible changes may occur earlier than previously thought, within days of the initial episode of airway bronchospasm. Studies conducted at Michigan State University demonstrated that short exposures (7 hours) to an environment high in organic dust, such as a barn, may initiate the clinical signs of heaves. After a single exposure, 6-7 weeks of pasture rest is typically required for the heavey horse to recover.
Changing the environment in which the horse lives is the best way to treat heaves. Housing horses outdoors, with an open-sided shed for protection from the wind and rain is ideal. Horses that are particularly sensitive should not be fed hay (high in organic dust), but instead fed a complete feed or alfalfa pellets. If horses must be housed indoors, they should be bedded in wood shavings or shredded paper and fed a complete feed or alfalfa pellets. Dr. Robinson also believes that shipping in a trailer exposes the horse to high levels of organic dust. Studies have demonstrated that if long trailer rides (>6 hours) are planned, it is best to allow the horse to rest off the trailer for at least 6-8 hours to clear its airways of organic dust and debris. A horse will do this naturally by lowering its head or lying down.
Many times it is not feasible to house horses outdoors or feed a complete feed, and in addition, a few horses may not respond to even these measures. Under these circumstances it becomes necessary for pharmacologic management of horses with heaves. There are several classes of therapeutic pharmaceutics which are important in the treatment of heaves. The first-line treatment is steroids, but more attention is now being placed on the quaternary ammonium products (ipratropium bromide) and the b -2 adrenergics (clenbuterol, albuterol, salbuterol, etc.). The steroid that is most commonly used first in the treatment of an episode of heaves is dexamethasone, a very potent steroid that acts quickly to reduce airway inflammation and suppress the allergic immune response.
According to Dr. Robinson, human asthmatics are now treated earlier in the course of their disease with steroids to prevent the irreversible thickening of the airways. Unfortunately, horses cannot be maintained on dexamethasone for more than 7-10 days because of the potential for causing laminitis, a very serious condition of vascular compromise in the horses’ hooves causing chronic lameness and even loss of structural support of the foot. The quaternary ammonium compounds have not yet been developed for use in the horse, but research efforts are focused on these compounds to explore their potential bronchodilatory effects in the horse.
The b -2 adrenergics, in addition to causing bronchodilation, also are slightly anti-inflammatory and improve mucociliary clearance. Boehringer Ingelheim is the sponsor for Ventipulmin (clenbuterol) syrup, the first b -2 adrenergic approved by the FDA for the treatment of heaves in horses. It is administered twice-a-day at the dose of 0.5 mL per 100 pounds body weight for 3 days. If there is no improvement, the dose is increased incrementally up to 2.0 mL per 100 pounds. If there is still no improvement, the horse is considered a non-responder, and clenbuterol should be discontinued. Ventipulmin can be administered safely up to 30 days.
Boehringer Ingelheim is investigating a variety of bronchodilators and antiinflammatories to be administered using a specially designed face mask, which allows for the administration of aerosolized inhalant products. A disposable rubberized administration device that fits inside the horse's nostril is also being developed by 3M. With the invention of the face mask and the nasal delivery system, inhaled steroids such as beclomethasone and fluticasone will also be possible. Using steroids and b -2 adrenergics (bronchodilators) together has a synergistic effect in alleviating the clinical signs of heaves.
Another drug used in human asthmatics is furosemide, more commonly known as Lasix. It works by causing the release of prostaglandin E2 (a protective prostaglandin) and affecting the non-cholinergic, non-adrenergic receptors in the airways resulting in bronchodilation. The overall message is that effective pharmacologic agents are being developed for treating the horse with heaves and that the inhaled treatments are becoming more practical for use in the horse.
Equine Musculoskeletal Ultrasonography with Hands On Laboratory: Dr. Virginia Reef is the Director of Large Animal Cardiology and Diagnostic Ultrasonography and Chief of Sports Medicine and Imaging at the University of Pennsylvania's New Bolton Center. She is a world renowned expert in ultrasonographic imaging.
Dr. Reef’s lecture focused on the diagnosis and treatment of the "bowed tendon". A "bowed tendon" is a common injury of racehorses and nearly always occurs in the front legs involving the superficial digital flexor tendon. A bowed tendon can be a career-ending injury for a racehorse. The clinical signs of a bowed tendon are swelling, lameness, heat and pain on palpation. These clinical signs are not consistent. In fact, only 50 percent of horses with tendon damage exhibit lameness. In addition, inflammation of the tissues surrounding the tendon may look very similar to a bowed tendon. The use of diagnostic ultrasonography has revolutionized the diagnosis of tendon injury and allows for the differentiation of tendon damage from uncomplicated soft tissue swelling surrounding the tendon. Dr. Reef and Dr. Ronald Genovese, a specialist in equine distal limb ultrasound, have developed objective methods of quantifying tendon injury using ultrasonography. These objective measurements are then used to monitor tendon healing and permit the tailoring of rehabilitation to the individual horse.
Traditional treatments of "bowed" tendons consist of puncturing the tendon multiple times with a needle or other sharp instrument (tendon splitting), cutting the fetlock annular ligament which restricts the movement of the flexor tendon and cutting the superior check ligament, which anchors the superficial flexor tendon to the radius in the forearm of the horse. None of these treatments, including just resting the horse, have been proven to be effective and recurrence of the same injury is common. In 1998, Boehringer Ingelheim, gained FDA approval for BAPTEN (beta-aminoproprionitrile fumarate), a substance which blocks lysyl oxidase, the enzyme responsible for collagen cross-linking. Injection of BAPTEN into the lesion in the tendon is administered approximately one to three months after the initial tendon injury. This treatment is coupled with a controlled exercise program. At four months post-treatment it became apparent that there was a better sonographic quality of tendon repair (i.e., more parallel fiber alignment) in the BAPTEN treated horses as compared to the placebo treated. Generally, 6 months of low intensity exercise following treatment is necessary to ensure that adequate time has passed for collagen cross-linking to occur and for the tendon to regain its strength.
The ultrasound laboratory was held at the Idaho Equine Hospital. The veterinary staff served as instructors and demonstrated ultrasound techniques using two different ultrasound systems (Sonovet 600 & Ausonics Impact VFI). Participants were trained to evaluate the equine umbilicus, abdomen, chest, eye, tendons and reproductive tract of the mare.
Equine Neurology: Dr. Joseph Bertone is a member of the Idaho Equine Hospital. He is board certified in Large Animal Medicine and has published and presented information in the areas of shock, physiology and neurology. He is a renowned speaker in the area of equine internal medicine.
Dr. Bertone presented an overview of equine neurology and the diseases associated with the neurologic system. Equine Protozoal Myeloencephalitis (EPM) a devastating neurologic disease caused by a protozoan organism (Sarcocystis neurona) was discussed in depth. EPM affects all breeds of horses, but is more commonly reported in Standardbreds and Thoroughbreds. There is no age restriction; however, the disease appears to affect younger horses (average age is 4 years), typically when competing or racing. The disease often presents as an asymmetrical gait deficit, which may be confused with lameness. Dr. Bertone discussed the neurologic examination and special tests that can be conducted to differentiate EPM from other types of neurologic disease and lameness. EPM is treatable, but often times not curable as the residual damage in the central nervous system is often irreversible. Standard treatment is long-term administration of a combination of a sulfonamide antimicrobial drug and pyrimethamine. Although this combination is not approved for treatment of EPM, extensive research is underway to determine the effectiveness of this combination and several other pharmacologic agents such as diclazuril (Clinacox), toltrazuril (Baycox) and nitazoxanide.
Dr. Bertone also discussed the procedure for collection of cerebrospinal fluid (CSF), necessary to diagnose EPM. Collection of CSF requires a 8-inch needle, proper restraint and sedation and correct anatomic placement of the needle. CSF fluid is subjected to a test named the Western Immunoblot test to determine if antibodies to the protozoan are present. Detection of antibodies in the CSF is somewhat problematic in that blood contamination, either from the introduction of the needle during the procedure, or from trauma to the spinal cord or brain, may result in a false positive test result. It has been shown that up to 45 percent of the normal horse population has been exposed to the organism and carries antibodies in the blood. Only those that have antibodies in the blood and in the CSF are considered to have active disease. Two tests, the albumin quotient and the IgG index have been developed to help rule out the blood contamination as the cause for a positive test result. It is now known that a very small amount of blood contamination may result in a positive test. Research is underway in this area to refine the Western Immunoblot test. Dr. Bertone also presented videotapes of neurologic horses and discussed the neurologic examination as the horse was being examined.
Equine Gastric Ulcer Disease (EGUD): Dr. Frank Andrews is a Professor and Section Chief of Large Animal Medicine, University of Tennessee College of Veterinary Medicine. His research focus is gastric physiology and gastric ulcer disease in horses. He is well published and considered an international expert on this subject.
Dr. Andrews reviewed the anatomy and physiology of the equine stomach. The equine stomach is separated into two portions. The upper portion of the stomach is lined by squamous epithelium. The lower portion is lined by glandular epithelium. Gastric ulcers in adult horses are most commonly found in the squamous portion of the equine stomach. The squamous portion is more sensitive to acid than the glandular portion because the glandular portion is able to secrete a protective layer of mucus. Clinical signs of gastric ulcers in horses are variable and may include mild signs of abdominal discomfort (colic), poor appetite, weight loss, and poor performance. A definitive diagnosis can only be made by gastric endoscopy, which requires a 3 meter endoscope. The horse must be fasted at least 12 hours prior to the procedure. The stomach is insufflated with air and the contents are aspirated. Most horses are mildly sedated for this procedure.
Dr. Andrew’s research has shown that the pH of the gastric fluid is dependent on the diet of the horse. The horse’s digestive tract is best suited to continuous grazing, not intermittent feeding of large meals. Domestication of the horse has imposed our eating habits upon the horse, some of which may have deleterious effects. For example, it has been shown that large concentrate grain meals result in more acidic gastric contents. The consumption of hay, especially alfalfa hay, has the ability to buffer some of the acid that is produced. Studies have shown that subjecting a horse to a strenuous exercise program (race training) may induce ulcers. Modifying the feeding schedule and environment of a horse may allow for management of gastric ulcers. Smaller grain concentrate meals should be fed along with better quality and continuously accessible hay. Ideally horses should be housed outdoors and have continuous grazing. Once again the demands of a performance horse may make this type of management difficult and pharmacologic agents should be considered.
A visit to the anti-ulcer section of your local pharmacy reveals the variety of over-the-counter medications available to humans suffering from gastric ulcers. In contrast, the first gastric ulcer medication (GastroGard/omeprazole) was developed by Merial LLC and FDA approved in 1998. Omeprazole acts by irreversibly binding to the enzyme responsible for the production of acid from the parietal cells in the stomach. It is approved for human prescription use as Prilosec. GastroGard is available as an oral paste and is to be administered once-a-day for a period of 28 days, after which the dose is halved and administered for at least four more weeks. Dr. Andrews conducted clinical trials with omeprazole and demonstrated by gastric endoscopy that omeprazole was 77 percent effective in healing ulcers after a period of 28 days and that in 84 percent of horses, recurrence of ulcers could be prevented by continued administration of omeprazole for an additional four weeks of treatment. Other medications for the treatment of gastric ulcer disease such as cimetidine (Tagamet), ranitidine (Zantac) and sucralfate (Carafate) are not approved for use in the horse and have not been subjected to the well-controlled studies necessary to confidently predict effectiveness. Following the lecture, Dr. Andrews showed videotapes of gastric examinations conducted during the studies. The videotapes clearly showed the ulcers prior to treatment and the resolution of ulcers following treatment.
The following firms/individuals received warning letters for offering animals for slaughter that contained illegal drug residues:
M&P Dairy, Casa Grande, AZ
Jim Ward, MN DAK Dairy, Cleveland, MN
Carl M. Sousa, White River Dairy, Stratford, CA
Horizon Dairy, Chandler, AZ
Neil Zwart, Neil Zwart Dairy, Kingsburg, CA
Stephen E. Haines, Haines Farms, Cortland, NY
Paul Pires, Westside Holsteins, Los Banos, CA
Robert Thomas, Louisville, OH
Mark St. Pierre, Richford, VT
Augustino R. Dominguez, Corcoran, CA
These violations involved illegal residues of oxytetracycline in dairy cows, streptomycin in cows, penicillin in a cow, gentamicin in a cow, neomycin in a cow, oxytetracycline and sulfadimethoxine in a dairy cow, and gentamicin in a feeder steer.
Warning letters were sent to the following firms/individuals for violations from Good Manufacturing Practices (GMPs):
Ralph T. Oldham, Oak Grove Pork Farm, Inc., Oak Grove, LA
Paul V. Sella, Jr., Producers Feed Company, Isola, MS
A warning letter was sent to D. Michael Hoover, Michael Hoover Dairy Farm, Tyrone, PA, for offering a cow for slaughter which contained violative residues of penicillin and sulfadimethoxine and offering for sale for slaughter another cow which contained violative residues of gentamicin.
Steve Fricke, Buckley Brothers, Inc., Wilmington, OH, received a warning letter for having significant deviations from the requirements in Title 21, Code of Federal Regulations, Part 589.2000 -- Animal Protein Prohibited in Ruminant Feed.
A warning letter was sent to Arend Van Vliet and John G. Visser, Partners, Rock Creek Dairy, Farmington, CA, offering a bull calf for sale with illegal residues of neomycin and for having a history of offering animals for sale for human food use which were adulterated with drug residues.
|
Company |
Generic and (Brand) Names |
Indications |
Routes/Remarks: |
|---|---|---|---|
| Merial Ltd. (NADA 141-123) |
Omeprazole (GastroGard®) Rx | Horses and foals 4 weeks of age and older. For the treatment and prevention of gastric ulcers. | ORAL: For treatment of gastric ulcers, 1.8 milligrams of omeprazole per pound of body weight once daily for 4 weeks. For prevention of recurrence of gastric ulcers, 0.9 milligram per pound of body weight once a day for another 4 weeks. Do not use in horses intended for human consumption. Federal Register: 04/15/99. |
| Alpharma, Inc. (NADA 141-112) |
Narasin/Nicarbazin (Maxiban TM) Bacitracin Methylene Disalicylate (BMD®) Roxarsone (3-Nitro®) | Broiler chickens. For prevention of coccidiosis caused by Eimeria tenella, E. necatrix, E. acervulina, E. maxima, E. brunetti, and E. mivati, and as an aid in the prevention of necrotic enteritis caused or complicated by Clostridium spp. or other organisms susceptible to bacitracin, and for increased weight gain, improved feed efficiency, improved pigmentation. | MEDICATED FEED: The NADA provides for using approved narasin and nicarbazin, bacitracin methylene disalicylate, and roxarsone Type A medicated articles to make Type C medicated broiler chicken feeds. This use of Type A medicated articles to make Type C medicated feeds is limited to manufacture in a licensed feed mill. Federal Register: 04/15/99. |
| Elanco Animal Health, Division of Eli Lilly and Co. (NADA 141-113) | Narasin/Nicarbazin (Maxiban®), Roxarsone (3-Nitro®) | Broiler chickens. For prevention of coccidiosis, for increased rate of weight gain, improved feed efficiency, and improved pigmentation. | MEDICATED FEED: The NADA provides for combining approved narasin/nicarbazin and roxarsone Type A medicated articles to make combination drug Type C medicated broiler chicken feeds. This use of Type A medicated articles to make Type C medicated feeds is limited to manufacture in a licensed feed mill. Federal Register: 04/26/99. |
| Roche Vitamins, Inc. (NADA 141-109) |
Lasalocid, Bacitracin Zinc | Turkeys. For the prevention of coccidiosis caused by Eimeria meleagrimitis, E. gallopavonis, and E. adenoeides, and for increased rate of weight gain and improved feed efficiency. | MEDICATED FEED: The NADA provides for the use of 20 percent of lasalocid Type A medicated articles and bacitracin zinc Type A medicated articles containing 50 grams per pound bacitracin activity in making Type C medicated feed containing 68-113 g/ton lasalocid and 4-50 g/t bacitracin zinc. Federal Register: 05/18/99. |
ABBREVIATED NEW ANIMAL DRUG APPROVALS
|
Company |
Generic & (Brand) Names |
Indications |
Routes/Remarks |
|---|---|---|---|
| Phoenix Scientific, Inc. (ANADA 200-258) |
Sulfadimethoxine (SDM) | Chickens, turkeys, dairy calves, heifers, beef cattle. In drinking water for the treatment of coccidiosis, fowl cholera, and infectious coryza in chickens and turkeys and in drinking water or drench for treatment of shipping fever, pneumonia, calf diphtheria and foot rot in dairy calves, dairy heifers, and beef cattle. | ORAL: The NADA is a generic copy of Pfizer's NADA 46-285 (Albon®). Federal Register: 04/15/99. |
| Pliva d.d. (ANADA 200-232) |
Oxytetracycline (Geomycin 200) | Swine, cattle. For the treatment of bacterial infections susceptible to oxytetracycline. | INTRAMUSCULAR AND INTRAVENOUS: Intramuscular use in swine for treatment of bacterial enteritis, pneumonia, and leptospirosis, and in sows as an aid in the control of infectious enteritis in suckling pigs. Intramuscular/ intravenous use in cattle for the treatment of bacterial pneumonia and shipping fever complex, pink eye, foot rot, wooden tongue, diphtheria, leptospirosis, wound infections, acute metritis. The ANADA is a generic copy of Pfizer, Inc.'s NADA 113-232 (Linquamycin7 LA-2007). Federal Register: 04/30/99. |
SUPPLEMENTAL NEW ANIMAL DRUG APPROVALS
|
Company |
Generic & (Brand) Names |
Indications |
Routes/Remarks |
|---|---|---|---|
| Fort Dodge Animal Health (NADA 141-043) |
Trenbolone Acetate and Estradiol Benzoate (Synovex®Plus TM) | Cattle - steers fed in confinement for slaughter. For increased rate of weight gain. | SUBCUTANEOUS: In the supplemental NADA, the increased rate of weight gain is added to the already approved use for improved feed efficiency. An ADI for trenbolone is established at 0.4 microgram per kilogram of body weight per day. Federal Register: 04/15/99. |
| Boehringer-Ingelheim Vetmedica, Inc. (NADA 48-271) |
Dichlorvos (Task®) Rx | Dogs and Cats. For the removal and control of certain intestinal roundworms and hookworms. | ORAL: The supplemental NADA adds additional tablet sizes. Adds use in cats and puppies in addition to approved use in dogs and kittens. Federal Register: 04/15/99. |
| Fleming Laboratories, Inc. (NADA 10-005) |
Piperazine | Chickens, Turkeys, and Swine. For the treatment of certain parasitic infections. | ORAL: NAS/NRC DESI supplement reflects compliance with review and FDA conclusions based on review. A tolerance of 0.1 ppm for piperazine in edible tissues of poultry and swine is established. Federal Register: 04/29/99. |
| PennField Oil Co. (NADA 138-935) |
Chlortetracycline Hydrochloride | Cattle. For the treatment of bacterial enteritis and bacterial pneumonia. | MEDICATED FEED: The supplement provides for a revised withdrawal period of 1-day following feeding of Type B and Type C chlortetracycline feeds to cattle. Federal Register: 05/03/99. |
| Merial Ltd. (NADA 128-409) |
Ivermectin (Ivomec®) | Cattle. For 28-day persistent control of lungworms in addition to use for control and treatment of various parasites and various persistent uses. | INTRAMUSCULAR: The supplement provides for the increase from 21 days. A tolerance for ivermectin residues in cattle muscle of 10 ppb is established. Federal Register: 05/17/99. |
| Merial Ltd. (NADA 140-833) |
Ivermectin Clorsulon (Ivomec® Plus) | Cattle. For 28-day persistent control of lungworms in addition to use for control and treatment of various parasites and various persistent uses. | INTRAMUSCULAR: The supplement provides for the increase from 21 days. A tolerance for Ivermectin residues in cattle muscle of 10 ppb is established. Federal Register: 05/17/99. |
| Roche Vitamins, Inc. (NADA 40-209) |
Sulfadimethoxine Ormetoprim (Rofenaid®40) | Chukar partridge. For the prevention of coccidiosis. | MEDICATED FEED: The supplement provides for the use of Rofenaid?40 Type A medicated articles to make Type C chukar partridge feeds. Also, tolerances of 0.1 ppm each are established for sulfadimethoxine and ormetoprim residues in edible chukar partridge tissues. Federal Register: 05/17/99. |
| Hoechst Roussel Vet (NADA 131-675) | Fenbendazole | Swine. Revised feeding instructions to allow for restricted feeding of sows. | MEDICATED FEED: The supplement provides clarification of the amount of the drug in Type C medicated swine feeds to be fed to the animals for treatment. Federal Register: 05/18/99. |
| Schering-Plough Animal Health Corp. (NADA 30-315) | Selenium, Vitamin E Injection | Horses, dogs, cattle, sheep, swine. | SUBCUTANEOUS: The supplement provides for removing from the specifications of those ingredients other than the active ingredients. Federal Register: 05/24/99. |
SUPPLEMENTAL ABBREVIATED NEW ANIMAL DRUG APPROVALS
|
Company |
Generic & (Brand) Names |
Indications |
Routes/Remarks |
|---|---|---|---|
| Boehringer Ingelheim Vetmedica, Inc. (ANADA 200-008) | Oxytetracycline (OxytetTM 200) (Bio-Mycin® 200) | Cattle, swine. In beef and nonlactating dairy cattle for treatment of bacterial pneumonia, shipping fever, pinkeye, foot rot, diphtheria, bacterial enteritis, wooden tongue, leptospirosis, wound infections, acute metritis. In swine for treatment of bacterial enteritis. | SUBCUTANEOUS AND INTRAMUSCULAR: The ANADA provides for a 28-day withdrawal period for subcutaneous use of oxytetracycline in cattle and for intramuscular use in swine. Federal Register: 05/17/99. |
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