Q 3: veterinary pharmaceuticals Flashcards
drugs and hormones in livestock
• animal health • animal welfare • economic return Meets the need of producing more food on less land with fewer farmers • Made intensive livestock-rearing possible
Functional Classification
of Vet Drugs and Hormones
Antibiotics to control disease and promote growth • Hormone and hormone-like substances • Beta-agonists • Topical antiseptics, bactericides, fungicides • Antiparasitic drugs: anthelmintic, coccidiostats • Ionophores to alter stomach microorganisms • Thyreostats • NSAIDS and tranquilizers
Antibiotics
-how are they used
• Therapeutically – treatment of infections • Prophylactically – to prevent disease (especially in intensive farming) • Growth promotion – increase efficiency of feed use
how are hormones used
Natural hormones or synthetic analogues • Natural hormones used to control reproductive cycle • Both used to increase feed efficiency and give leaner meat at reduced cost to producer
what are the common antibiotics used
Tetracyclines: tetracycline, chlortetracycline, oxytetracycline • Ionophores: monensin, lasalocid • Macrolides: erythromycin, tylosin, tilmicosin, tulathromycin • Penicillin and Beta-Lactams: penicillin-G, amoxicillin, ampicillin • Sulfas: sulfamethazine, sulfadiazine • Aminoglycosides: neomycin, gentamycin • Lincosamides: lincomycin, clindamycin
what are the common Hormones
used
Natural hormones: – 17β-estradiol – Testosterone – Progesterone
• Synthetic hormones: – Zeranol – Trenbolone acetate – Melengestrol acetate
• Most applied as implanted pellets
• MGA applied as a feed additive
Antimicrobial Resistance in
Microorganisms AMR
AMR occurs when a AM substance is no longer effective in killing or inhibiting the growth of a pathogenic microorganisms. • Probability of AMR increases with the length of time of exposure. • Some strains contain resistance to AM, survive and reproduce to confer resistance to further generations and possibly to other micro-organisms. • The focus is usually on resistant bacteria, therefore the term “antibiotic resistance”.
AMR: What are the Issues?
Increasing occurrence of AMR
poses a threat to our ability to fight
human and animal infections.
• Effective antibiotics become fewer
in number.
• Treatment becomes more
challenging and more expensive.
“The rise of antimicrobial resistance is a global health crisis. Medicine is losing more and
more mainstay antimicrobials as pathogens develop resistance. …With few replacement
products in the pipeline, the world is heading towards a post-antibiotic era in which
common infections will once again kill. …This will be the end of modern medicine as we
know it.”
Timeline of New Drug Development and AMR
1928: Penicillin (Fleming) • 1930’s: Sulfonamide antibiotics • 1940’s: Penicillin mass produced • 1950’s &1960’s: 2nd gen drugs (phenicols, macrolides) • 1980’s & 1990’s: fewer new drugs, most variations on older drugs • Time between introduction and development of AMR decreasing
AMR: How Does it Develop?
. Use in agri-food industries to treat specific diseases or to prevent illnesses and promote growth 2. Over-use or inappropriate use of AM in human medicine 3. Environmental contamination
What is being done to fight AMR?
The WHO suggests the following:
Policy makers can help by:
• strengthening resistance tracking and laboratory capacity
• regulating and promoting appropriate use of medicines
Policy makers and industry can help by:
• fostering innovation and research and development
• Promoting cooperation and information sharing among all
stakeholders
Health workers and pharmacists can help by:
• enhancing infection prevention and control
• only prescribing and dispensing antibiotics when truly needed
• prescribing and dispensing the right antibiotic(s) to treat the illness
Governmental Efforts to Fight AMR
The fight against AMR has become highly politicized
• There are may vested interests in industry that fight regulations
• Some attempts to collaborate with industry to “voluntarily” reduce AM
use, especially for growth promotion purposes: US FDA Guidance #213
• California just enacted (October 10) legislation to require a
veterinarian’s prescription for therapeutic antibiotic uses in livestock,
ban other uses (including low-dosage levels used to prevent diseases),
and require that data be collected on antibiotic us
e
• In Canada, Health Canada has responded by:
– strengthening surveillance systems that monitor AMR
– strengthening the responsible use of antimicrobials in human and veterinary medicine
– strengthen regulations for veterinary medicines and medicated feeds
– encourage practices that reduce use of antibiotics
DES, Hormones and
International Trade
The “Hormone Dispute” with the EU
• 1950’s to 1980’s: Diethylstilbestrol (DES) incidents >> negative public sentiment • 1988: The EU banned the use of some natural and synthetic hormones used a growth promoters and banned them from imported meats and products • The US and Canada considered this a restrictive trade practice and have fought the ban through the WTO • Internal ban lead to “black market”, alleged involvement of the “Mafia” and a murder of a veterinarian in Belgium • Natural Hormones – 17β-Estradiol – Testosterone – Progesterone • Synthetic Hormones – Zeranol – Trenbolone acetate – Melengestrol acetate
Intrinsic resistance:
Ability of microorganisms to
thrive in presence of AM due to inherent
characteristics
Acquired resistance:
Development of AMR due to
mutation and acquisition of genetic material from
other micro-organisms
Horizontal gene transfer:
transfer of genetic
material between organisms other than usual
reproduction by mobile DNA elements via plasmids
or bacteriophages.
when did antibiotic discovery and production peak
1960
DES, Hormones and
International Trade
Diethylstilbestrol (DES) • Non steroidal synthetic estrogen (female sex hormone) and anabolic agent • First synthesized in 1938 by Leon Golberg but not patented • Was given to pregnant women to prevent complications during pregnancy • Found to cause cancer and other complications in mothers and children • Given to cattle, chickens, sheep to stimulate growth and improved feed utilization (1954-1980) • US “Delaney Clause”: ban use of cancercausing substances in food production • Other anabolics developed: melengestrol, trenbolone, zeranol
European Attitudes Towards Drugs in
Foods
Europeans willing to pay more for their food and support small farmers • 1950’s: Paris Les Halles porters ingesting DES from eating chicken necks • 1980: DES in baby food in Italy and France • Past wrong decisions: thalidomide (1962), DES (1971) • Other “crises”: Mad cow disease (BSE), dioxins in feed
• World Trade Organization (WTO)
– determines rules governing international
trade
– settles disputes
Sanitary and Phytosanitary Standards
SPS
– scientifically justifiable standards
– based on perceived need to protect human,
animal, plant health
Timeline
1985: EU banned use of hormones for growth
promotion in livestock production in EU
• 1989: EU bans imported meat and products
produced using banned products; US takes
retaliatory trade measures
• 1996: US and Canada take dispute to WTO;
authorized to retaliate
• 1997-2008: Numerous reviews and reports;
back-and-forth on scientific evidence
• 2009: US and EU sign MOU to settle dispute:
EU to allow non-hormone-treated beef from
US in exchange for relaxation of penalties
• 2011: US removes sanctions
• 2012: The EU ratifies agreement
“Raised without the use of hormones or steroids” A certain fast-food chain started an ad campaign in 2013 with the slogan “Better Beef”
Trying to respond to consumer feedback on
desire to have more transparency on where food
was coming from and who was raising it
• Started with slogan “Better Beef”
• Cdn beef producers not happy
• Implication was that beef produced by using
standard practices was inferior
• Using hormones aid in producing beef using less
feed and land area
• Changed slogan to “Raised without the use of
hormones or steroids”
• Antibiotics used for treatment of disease only
but some news articles imply no antibiotics used
at all
• Beef sourced from Australia, Montana and
Vegreville, AB (Spring Creek Farms)
Method of Production Claims:
Canadian Guidelines
Regulations require that labels and claims “be
accurate, truthful and not misleading”
Raised without the use of added hormones:
• No hormones shall be administered in any
way to the animal that forms the food
product
• Applies to animals where use is permitted
• “Hormone free” is misleading
• “No growth stimulants is misleading
Raised without the use of antibiotics:
• No antibiotics given from birth to harvest
• Vitamins and minerals OK but low levels
• Veterinary biologicals are permitted:
– vaccines, antisera, antimicrobial feed
ingredients
Health Canada
Veterinary Drugs Directorate
• Assess potential hazards to human health • Conducts risk assessments • Ensures drugs meet strict quality and manufacturing standards and potency • Evaluates safety and effectiveness of drugs to use with livestock • Ensures proper labelling
Canadian Food Inspection Agency
• Responsible for: food safety, animal health and plant health • Inspects federally registered establishments • National Chemical Residue Monitoring Program: Conducts sampling and analyses of samples to ensure compliance with standards • About 90% of samples analyzed by contract labs, balance by CFIA labs • Centre for Veterinary Drug Residues in Saskatoon
Risk Assessment for Vet
Drugs and Hormones
Health Canada – Veterinary Drugs Directorate • Reviews pharmacokinetic and metabolic study data • Reviews human toxicity/carcinogenicity data to set Allowable Daily Intakes (ADI) • Establishes Total Residue Levels (TDL) based on dietary patterns • Establishes Maximum Residue Limits (MRLs) • Sets appropriate withdrawal/withholding times • In some cases, a drug or hormone is banned
Maximum Residue Limits
MRLs
No adverse health effects over a lifetime of eating foods with MRL levels of residues • MRLs only apply to edible tissues • Banned substances: no MRL • Use scientific assessments from other countries • Try to harmonize MRLs with other jurisdictions
Banned Substances
Some drugs and hormones have been banned due to adverse effects:
• Chloramphenicol: broad-spectrum antibiotic associated with aplastic
anaemia, a usually fatal blood disorder affecting the bone marrow; no known
safe dose
• Nitrofurans: broad-spectrum antibiotic considered carcinogenic
• Clenbuterol and derivatives: Used to treat respiratory infections in horses and
to promote growth in livestock; associated with food poisoning incidents in
China and Europe
• Diethylstilbestrol: a synthetic oestrogen; used as growth promoter; banned in
Europe late 1970s due to concerns about cancer; led to banning of other
oestrogenic compounds
Sampling Approaches
Monitoring or Data Gathering o non-biased, probe for problems, profile information o healthy animals, carcasses not detained • Surveillance o limited directed, identify suspected problems o suspect animals, carcasses held • Compliance o directed, deal with identified problems o sample 5 subsequent shipments to ensure compliance • Total Diet (Food Basket) Studies
Key Aspects of Residue
Analyses in Animal Matrices
Extensive range of drugs – great variation in structures, physicochemical properties, biological activity • Range of concentrations: < 0.001 - > 100 ug/kg • Complexities of the matrices • Different stabilities and need for marker compounds (metabolites) • Variations in ratios of parent compounds to metabolites between species
The IDEAL Analytical Procedure
Wide applicability to analytes and matrices • Wide analytical range of concentrations • Sensitive (detection limit < regulatory limit) • Precise, accurate and selective • Unambiguous identification • Minimal sample preparation • High sample throughput • Low cost per sample • Small capital investment
Real World: Different Kinds
of Analytical Methods
Methods are optimized for specific purposes: • Screening – identify samples without residues • Quantitation – determine concentration of residues • Confirmation – unambiguous identification of residues
Screening for Drug Residues
• Quickly and cheaply identify those samples that do NOT contain the target residues • Allow the negative samples to safely enter the food system • Pass along suspect samples for additional testing: confirmation and quantitation • Many antibiotics are detected in suspect carcasses using on-site antimicrobial growth inhibition tests • Laboratory screening using chemical testing methods
Confirmation and
Quantitation of Residues
A violative result requires: Present and identified and concentration exceeds the Regulatory Limit (“zero” or MRL) • Need an appropriate method that gives full or complementary information enabling identification of a substance with high confidence • Generally done by instrumental methods using Mass Spectrometer
