Growth promoters

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Slide 1 : Growth promoters
Slide 2 : The term "antibiotic growth promoter" is used to describe any medicine that destroys or inhibits bacteria and is administered at a low sub therapeutic dose. According to the National Office of Animal Health (NOAH, 2001), antibiotic growth promoters are used to "help growing animals digest their food more efficiently, get maximum benefit from it and allow them to develop into strong and healthy individuals".
Slide 3 : Possible mechanisms: Suppression of bacteria responsible for mild but often unrecognizable infections. Reduced production of growth depressing toxins by the gut microflora . Reduced use of nutrients by the gut microflora. Increased production of essential nutrients (e.g. vitamins) by the gut microflora.
Slide 4 : Reduced thickness of the gut wall and enhanced nutrient uptake as a result of eliminating the irritant effects of microbial toxins. Reduced ammonia production by the gut microflora resulting in reduced mucosal cell turnover and energy sparing effect. Lower immune stress resulting in a shift in protein synthesis.
Slide 5 : Adverse effects – health and safety Toxic effects following exposure by inhalation of dust, ingestion or skin contact . The possibility of exposing the normal bacterial flora of the skin and mucous membranes (including the gastro-intestinal tract) to levels of antimicrobials that exert a selection pressure for resistance.
Slide 6 : An adverse effect from insufficient active antimicrobial compound results in selection pressure for resistance. Efficacy may be reduced or absent if the feed levels fail to meet the level required to achieve a minimum inhibitory concentration. An adverse effect from receiving the correct dose of the compound; this could be classified as a ‘normal’ side effect for the additive concerned. Toxicity following overdose.
Slide 7 : Mechanism Antibiotics suppress sensitive populations of bacteria in the intestines. It has been estimated that as much as 6 per cent of the net energy in the pig diet could be lost due to microbial fermentation in the intestine (Jensen, 1998). If the microbial population could be better controlled, it is possible that the lost energy could be diverted to growth.
Slide 8 : Thomke & Elwinger (1998) hypothesize that cytokines released during the immune response may also stimulate the release of catabolic hormones, which would reduce muscle mass. Therefore a reduction in gastrointestinal infections would result in the subsequent increase in muscle weight.
Slide 9 : Most antibiotics, around 60 per cent, are used for therapeutic purposes in humans. The farming industry is the second largest consumer of antibiotics after medical practitioners. About 40 per cent of antibiotics are used as growth promoters although antibiotics are also used therapeutically for animals.
Slide 10 : On a world scale, the use of antibiotics as animal growth promoters differs dramatically. Sweden now makes no use of antibiotics for growth promotion purposes. In the USA- pigs are exposed to ß lactam antibiotics, lincosamides, macrolides , tetracyclines, bacitracin, flavophospholipol, pleuromutilins, quinoxalines, virginiamycin and arsenical compounds. Cattle and poultry - flavophospholipol and virginiamycin, ionophores such as monensin to promote growth. Poultry are given arsenical compounds.
Slide 11 : The Animal Health Institute of America (AHI, 1999 ) has estimated that, without the use of growth promoting antibiotics, the USA would require an additional 452 million chickens, 23 million more cattle and 12 million more pigs to reach the levels of production attained by the current practices.
Slide 12 : Australia a range of growth promoters are employed. Pig farmers use arsenical compounds, flavophospholipol, the macrolides kitasamycin and tylosin, the quinoxaline olaquindox, and also virginiamycin, a streptogramin. Poultry producers use arsenical compounds, flavophospholipol, bacitracin and virginiamycin.
Slide 13 : Cattle farmers employ a range of ionophores, namely lasalocid, monensin, narasin and salinomycin. They also employ flavophospholipol and the macrolide oleandomycin. The glycopeptide avoparcin was withdrawn from the Australian market in December 1999.
Slide 14 : The use of growth promoters in the European Community is more limited. The oligosaccharide avilamycin is used in pig and poultry farming, ionophores, namely monensin and salinomycin are used for cattle and pigs. Flavophospholipol is used with a range of livestock, including cattle, pigs, poultry and rabbits.
Slide 15 : In pig production, feed conversion efficiency is improved, along with daily growth rates, by approximately 2.5 per cent. Mortality rates, associated with scouring and proliferative enteritis are 10-15 per cent lower than in countries, such as Sweden.
Slide 16 : HUMAN HEALTH AND THE CONSEQUENCES OF USING ANTIBIOTIC GROWTH PROMOTERS Gassner & Wuethrich (1994) have demonstrated the presence of chloramphenicol metabolites in meat products and have concluded that a link with the presence of these antibiotic residues in meat and the occurrence of aplastic anaemia in humans cannot be ruled out.
Slide 17 : In 1998, Bonner reported that, in 1983, an outbreak of food poisoning caused by a resistant strain of salmonella was linked to hamburgers made from cattle fed with chlortetracycline. Tacket al. (1985) reported an outbreak of multi-drug resistant Salmonella enterica var. Enteritis following consumption of raw milk.
Slide 18 : Growth promoters may act as masking agents for proper sanitation by reducing the pathogen load. The fundamentally unhygienic conditions of intensive broiler chicken production have been criticized. Broilers are reared in confined housing: this allows any pathogen to spread through the cohort rapidly.
Slide 19 : Fluoroquinolone-resistant strains are emerging around the world. Engberg et al. (2001) reviewed in vitro macrolide and quinolone resistance prevalence and trends in campylobacter isolated from humans, showing a temporal relationship between use of quinolones in food animals and resistant isolates in humans. Endtz et al. (1991) reported that the use of fluoroquinolones to treat respiratory diseases in poultry seems to have led to the development of fluoroquinolone-resistant Campylobacter in the gut of treated birds.
Slide 20 : Antibiotic resistance in E. coli is widespread globally, with agents such as the penicillins found to be of decreasing efficacy against it (Heritage et al., 2001). LeClerc (1996) warns about the dangers of complacency by reporting high rates of mutation in E. coli O157, following observations that they could acquire resistance determinants easily by horizontal gene transfer.
Slide 21 : Vancomycin-resistant enterococci were first isolated in Europe in the mid-eighties but quickly spread to the USA. Edmond et al. (1996) found that patients with blood-borne infections caused by vancomycin-resistant enterococci had over double the mortality of patients who were infected with enterococci susceptible to amoxycillin and vancomycin.
Slide 22 : It has been suggested that the use of antibiotic growth-promoters, in particular the drug avoparcin, has contributed to the emergence of vancomycin-resistant enterococci. Both drugs are glycopeptides and the van genes found in enterococci confer resistance to both drugs. Use of avoparcin as a growth promoter increases the selective pressure for resistance within the animal.
Slide 23 : The European Commission banned the use of avoparcin as a growth promoter on the grounds of unknown risk. Del Grosso et al. (2000) found that, after the ban, a decrease was observed in contamination of meat products by vancomycin-resistant enterococci. The reduction was statistically significant in poultry (from 18.8 per cent to 9.6 per cent) but not in pork products (from 9.7 per cent to 6.9 per cent), allowing the conclusion that avoparcin withdrawal has been successful in reducing VRE contamination in meat products.
Slide 24 : The European Commission no longer permits "medically important" antibiotics to be used as antibiotic growth-promoters, due to possible risks of compromise of therapy. However, this needs to be a global effort.
Slide 25 : In the early 1970s, the UK banned the use of tetracycline and penicillin for growth promotional purposes. In March 1999, the Center for Science in the Public Interest, the Environmental Defense Fund, and others petitioned the FDA to ban, for purposes of growth promotion, six antibiotics used in or related to those used in human medicine, including penicillin, tetracycline, erythromycin, lincomycin, tylosin, and virginiamycin. The FDA has recently launched a Task Force (FDA, 2001) to tackle the subject of the use of antimicrobials in agriculture but many politicians have greeted it with negativity.
Slide 26 : THE ALTERNATIVES TO ANTIBIOTIC GROWTH PROMOTERS In-feed enzymes In-feed enzymes are routinely added to pig and poultry feeds and work by helping to break down certain components of the feed, such as -glucans, proteins and phytates, that the animal may have problems digesting. They are produced as fermentation products from fungi and bacteria and seem to only have a positive effect on the animal.
Slide 27 : Competitive exclusion products The mechanism : -by allowing such bacteria to colonise the gastrointestinal tract, potential pathogens are prevented from colonising the gut. This is the competitive exclusion principle. These products are often administered to newborn animals, especially poultry, to colonise the gastrointestinal tract and prevent Salmonella and Campylobacter infections.
Slide 28 : Probiotics According to Fuller, a probiotic is a live microbial food supplement that beneficially affects the host animal or human by improving the intestinal microbial balance ( includes fermented food products, e.g. yogurt, curd, and lyophilized bacteria etc). In recent years, probiotics have been given a more precise definition as mono or mixed cultures of live microorganisms which, when applied to animal or man, beneficially affect the host by improving the properties of the indigenous microflora.
Slide 29 : The term probiotic was derived from the Greek word, meaning for life. This term was first introduced in 1953 by Kollath. The concept of probiotics is very ancient. The first recorded probiotic was fermented milk for human consumption.
Slide 30 : Types of probiotics Probiotics can be in powder form, liquid form, gel, paste, granules or available in the form of capsules, sachets, etc . Probiotics can be bacteria, moulds, yeast. But most probiotics are bacteria. Among bacteria, lactic acid bacteria are more popular. Lactobacillus acidophilus, L. casei, L. lactis, L. helviticus, L. salivarius, L. plantrum, L. bulgaricus, L. rhamnosus, L. johnsonii, L. reuteri, L. fermentum, L. delbrueckii, Streptococcus thermophilus, Enterococcus faecium, E. faecalis, Bifidobacterium bifidum, B. breve, B. longum and Saccharomyces boulardii are commonly used bacterial probiotics.
Slide 31 : A probiotic may be made out of a single bacterial strain or it may be a consortium as well. e.g., LB17 “live” probiotic contains 17 strains of lactic bacteria (10 lactobacillus + 2 bifidobacterium), digestive enzymes, amino acids, vitamins and minerals.
Slide 32 : Stimulation of protective cytokines including interleukin (IL)-10 and transforming growth factor (TGF) and suppression of pro-inflammatory cytokines such as tumor necrosis factor (TNF) in the mucosa of patients with pouchitis and Crohn's disease (CD). Saccharomyces boulardii may limit the migration of T-helper 1 (TH1) cells in inflamed colon tissue in inflammatory bowel disease (IBD) in experimental studies.
Slide 33 : Probiotics Probiotics are similar to competitive exclusion products. They are believed to improve the overall health of an animal by improving the microbial balance in its gut. Mechanisms: By colonising the gut in large numbers, the probiotic bacteria exclude pathogens and thus prevent them from causing infection. They act as a stimulus for the immune system, following increased surveillance by leukocytes, potential pathogens are eliminated. Probiotics have a strong, positive influence on intestinal metabolic activities, such as increased production of vitamin B12, bacteriocins, and propionic acid.
Slide 34 : They incerase the levels of circulating immunoglobulins especially immunoglobulin A in infants infested with rotavorin. They enhance the nonspecific immuno phagocytic activity of circuiting blood granulocytes. They potentiate intestinal immune response to viral infection. They secrete certain proteolytic enzymes which digest the bacterial toxins. They alter the initiation and or promotional events of the chemically induced tumors by binding to the chemical carcinogen.
Slide 35 : Possible Mechanisms Four hypothesis have been proposed (I) nutrients may be protected against bacterial destruction; (ii) absorption of nutrients may improve because of a thinning of the small intestinal barrier; (iii) the antibiotics may decrease the production of toxins by intestinal bacteria; (iv) there may be a reduction in the incidence of subclinical intestinal infections.
Slide 36 :
Slide 37 : Bambermycin (synonyms: moenomycin, flavophospholipol and flavomycin) is a glycolipid antibiotic produced by Streptomyces species including S. bambergiensis, S. ghanaensis, S. geysirensis, and S. ederensis. The product is manufactured as a complex of very similar components of which moenomycin A, a phosphorus-containing glycolipid is the main component.
Slide 38 : Mechanism of action. Bambermycin inhibits peptidoglycan synthesis by inhibiting peptidoglycan polymerases through impairment of the transglycolase activities of penicillin-binding proteins (PBPs). This inhibition results in a specific block of the formation of the murein polysaccharide strands . The formation of the linear glycan strands of peptidoglycan is inhibited when the membrane intermediate N-acetylglucosaminyl-N-acetylmuramyl-(pentapeptide)- pyrophosphoryl-undecaprenol is used as a substrate .
Slide 39 : PBP 1b, which is the polymerase responsible for this reaction in Escherichia coli, is inhibited by bambermycin. PBP 1a and PBP 3 of E. coli are also sensitive to the action of bambermycin . Recently, PBP 1c, which possesses transglycolase activity , was shown to be inhibited by bambermycin. In Streptococcus pneumoniae, PBP 2a is the target.
Slide 40 : Spectrum of activity. Bambermycin is active primarily against gram-positive organisms; to some extent, it also inhibits certain gram-negative bacteria, such as Pasteurella and Brucella . Its spectrum of activity covering staphylococci and streptococci is similar to that of penicillin G and in some respects to that of the macrolide antibiotics . Members of the Enterobacteriaceae are only slightly susceptible.
Slide 41 : Pharmacokinetics and toxicity. Bambermycin is absorbed poorly after oral administration in several animal species. A slight absorption was detected only when high doses were administered . When administered parenterally, bambermycin remains unchanged, being slowly excreted in the urine . In chickens, oral doses of 20 ppm did not produce residues in tissues or organs .
Slide 42 : Effects on intestinal flora. Bambermycin reduces the number of C. perfringens organisms in the intestines, a fact which contrasts with the relative insensitivity of this species to this agent in vitro. No influence was noted on the counts of enterococci, coliforms and lactobacilli in the feces of broilers . In one study, the number of E. coli organisms in swine feces was decreased while the total numbers of enterococci remained the same. The number of E. faecalis strains, however, was dramatically decreased .
Slide 43 : Streptogramins The streptogramins always consist of an A component and a B component which act synergistically. They belong to the MLS (macrolide-lincosamide-streptogramin) group of antibiotics. Both the streptogramin A and streptogramin B components are macrocyclic lactone peptolides, as are the macrolides. The lincosamides are devoid of a lactone ring . The group A components are polyunsaturated cyclic peptolides, and the group B compounds are cyclic hexadepsipeptides .
Slide 44 : Only three streptogramins have been marketed either as therapeutics or for growth promotion: virginiamycin, pristinamycin, and quinupristin/dalfopristin. Virginiamycin has been used both in topical preparations for human and veterinary medicine and as a growth promoter in animal feed.
Slide 45 : It is produced by Streptomyces virginiae as a natural mixture of two chemically different components, virginiamycin M (a streptogramin A component) and virginiamycin S (a streptogramin B component), that work synergistically. Pristinamycin, produced by S. pristinaspiralis , has been used orally and topically in human medicine.
Slide 46 : Activity. The combination of the streptogramin A and B components acts by binding to the bacterial 23S rRNA of the 50S ribosomal subunit to form a stable dalfopristin (virginiamycin M) (A component)- ribosome-quinupristin (virginiamycin S) (B component) complex, which irreversibly inhibits protein synthesis, resulting in bacterial cell death . Individually, the components cause only bacteriostatic. The streptogramin A component inhibits the elongation phase in the ribosomal assemblage of the proteins .
Slide 47 : It interferes with - peptidyl transferase and also triggers a conformational change in the ribosome, which increases the affinity for the streptogramin B components . The streptogramin B component prevents the extension of polypeptides (peptide chain elongation) and induces the detachment of incomplete protein chains . Streptogramin -narrow spectrum, against gram-positive bacteria (mainly staphylococci, streptococci, and enterococci) and some gram-negative cocci. .
Slide 48 : Resistance genes and mechanisms. Resistance to streptogramins Target site alteration is mediated by the erm genes, affecting the binding of the B component of the streptogramins to the bacterial ribosome. In enterococci, resistance mediated by an acetyl transferase that inactivates the A component of the streptogramin complex and is encoded by the vat(D) (formerly satA) gene. Recently, a new gene, vat(E) (formerly satG), that also encodes an acetyltransferase has been reported.
Slide 49 : Resistance - efflux of streptogramins and is encoded by the vga(A) (formerly vga) Gene or the vga(B) gene in staphylococci. The vga(A) gene encodes a putative ATP binding protein . Another gene, mrs(A) [referring to both mrs(A) and mrs(B)], is found solely in staphylococci and encodes active transport of the streptogramin B component.
Slide 50 : Pharmacokinetics. Orally administered virginiamycin is not absorbed from the guts of animals . No residual effect. Pristinamycin is not water soluble and therefore not applicable parenterally . Quinupristin /dalfopristin, a water-soluble derivative of pristinamycin, is administered only by injection . A new streptogramin under development (RPR 106972) showed good oral absorption .
Slide 51 : Effects on intestinal flora. The number of C. perfringens organisms in the intestines of chickens was reduced by the addition of 55 ppm of virginiamycin to feed . Virginiamycin reduces the mortality and severity of necrotic enteritis caused by C. perfringens . Combination with a competitive exclusion flora (a preparation based on whole cecal contents of healthy chickens), virginiamycin was shown to protect chickens against an S. enterica serotype Typhimurium infection .
Slide 52 : Avilamycin Avilamycin belongs to the oligosaccharide (orthosomycin) group of antibiotics and is used only for growth promotion . Recently, another antibiotic of this group, everninomycin for use in human medicine. Avilamycin is produced by Streptomyces viridochromogenes.
Slide 53 : Activity. Avilamycin acts through binding with the 30S subunit of the ribosome and interferes with the polypeptide-synthesizing function by affecting the attachment of aminoacyl tRNA to the ribosomes . Recent findings- also binds, or solely binds, to the 50S subunit . Active against gram-positive bacteria.
Slide 54 : Resistance Resistance mechanism, mediated by a methyl transferase (EmtA), has been described recently in an E. faecium strain from an animal. The gene encoding this resistance (emtA) was located on a plasmid borne transposable element.
Slide 55 : Pharmacokinetics. Avilamycin administered orally at 60 ppm is excreted almost exclusively in the feces, and only very small residues are found in the tissues of swine and rats . Everninomycin can be administered only by intravenous injection.
Slide 56 : Effects on intestinal flora The number of C.perfringens organisms in chicken intestines was reduced by adding 10 ppm of avilamycin to the feed . Avilamycin also prevents necrotic enteritis caused by C. perfringens in broilers. At relatively high doses, avilamycin reduced stress-induced post weaning diarrhea in piglets.
Slide 57 : Bacitracin Polypeptide antibiotic produced by Bacillus licheniformis, is a mixture of several major components—the most important of which are A, B and C—and at least 13 other minor components. Bacitracin is more stable as a zinc salt and is used both as a growth promoter and in some topical preparations in human and veterinary medicine.
Slide 58 : Activity Bacitracin forms a complex with C55-isoprenyl pyrophosphate, a carrier for the N-acetylmuramyl peptapeptide intermediates for the synthesis of the peptidoglycan. Dephosphorylation by the C55-isoprenyl pyrophosphatase is inhibited, thereby not allowing for the recycling of the carrier and inhibiting the bacterial cell wall formation. Bacitracin is active mainly against gram-positive bacteria.
Slide 59 : Resistance mechanisms Resistance mechanisms have been described among gram-negative bacteria, in the bacitracin-producing organism B. licheniformis, and only very recently in other gram-positive bacteria . The bacA gene in E. coli was found to encode a protein that increases isoprenol kinase activity. bacA gene, which resides on the bacterial chromosome, confers resistance by phosphorylation of undecaprenol, thereby increasing the level of the carrier C55-isoprenyl phosphate.
Slide 60 : Pharmacokinetics and toxicity Nephrotoxic when administered parenterally. Absorbed very little or not at all from the intestines, because of this, no residues can be found in meat when the product is administered orally. Allergic reactions
Slide 61 : Effects on intestinal flora Decreases in the number of enterococci. Necrotic enteritis caused by C. perfringens in chickens was prevented by the addition of bacitracin at doses of 55 to 110 ppm to the feed. C. perfringens organisms was decreased by the use of bacitracin.
Slide 62 : Ionophore Antibiotics Sources : Streptomyces spp., although Streptoverticillium, Nocardiopsis,Nocardia, and Actinomadura spp. are also known to produce them . Divided into three major classes on the basis of their transport modes: Neutral ionophores e.g., valinomycin Carboxylic ionophores e.g., Monensin, Lasolasid and salinomycin Channel-forming quasi-ionophores. e.g., gramicidin
Slide 63 : Ionophores are able to lower high activation energy required for transportation of ions across the polar phase and consequently abolish the gradients of Ca++, Mg++, Na+ or K+ ion across the membrane .
Slide 64 : Carboxylic ionophores (also called polyether antibiotics) are subdivided into monovalent and divalent polyether antibiotics, depending on their preferential transport. The ionophores incorporated into animal feed all belong to the carboxylic group. Examples of channel-forming quasi-ionophores viz., gramicidin and the polyene antibiotics, the best-known representatives of which are the antimycotic agents nystatin and amphotericin B.
Slide 65 : They are not used therapeutically in humans. In animals the ionophores are used mainly for growth promotion and as “coccidiostats,” in the prevention of coccidiosis. Monensin, lasalocid, salinomycin, narasin, and maduramycin are used in Europe. Only monensin (in bovines) and salinomycin (in pigs) are effectively registered as growth promoters. The other registered ionophores can be used in poultry feed as coccidiostats.
Slide 66 : Monensin is a monovalent carboxylic ionophorous polyether antibiotic produced by Streptomyces cinnamonensis that was previously referred to as monensic acid. It transports Na more efficiently than K. Lasalocid is a divalent ionophore antibiotic. Although it transports bivalent ions such as Ca and Mg very well , it is also an efficient K carrier.
Slide 67 : Salinomycin is a monovalent carboxylic ionophorous polyether antibiotic which is produced by the fermentation of a Streptomyces albus strain isolated from soil in Japan. It transports K more efficiently than Na. Narasin, also a monovalent ionophore, is produced by a strain of Streptomyces aureofaciens and carries K more efficiently than Na.
Slide 68 : Monensin controls swine dysentery caused by Brachyspira (formerly Serpulina) hyodysenteriae and has been proven active against an Enterococcus-like pathogen in rainbow trout . Lasalocid can be used in the treatment of Mycoplasma infections in chickens . Salinomycin is effective in controlling swine dysentery.
Slide 69 : Mechanism of action. Polyether antibiotics interfere with the natural ion transport systems of both prokaryotic and eukaryotic cells. Ionophores lower the energy barrier necessary for the transmembrane transport of ions and catalyze an electro neutral cation-proton exchange across the barrier. They abolish the gradients of Ca2, Mg2, K, and Na, causing cell death.
Slide 70 : Resistance. Streptomyces longisporoflavus, which produces tetronasin, a polyether antibiotic not used in animal feed, contains genes encoding an ATP-dependent efflux system which defends the bacterium against the action of tetronasin.
Slide 71 : The pH of the medium can also influence the activity of ionophores . The addition of blood and incubation in a CO2-enriched atmosphere alter MIC results . Serum proteins inhibit the ion transport capacities of ionophores in erythrocytes and the antimalaria activities of ionophores.
Slide 72 : Pharmacokinetics and toxicity The ion transport capacity of ionophores does not discriminate between bacterial and mammalian membranes. Since they have good oral absorption , these products are quite toxic for mammalians and birds. Horses and rabbits seem to be susceptible to ionophore intoxications. Both acute and chronic intoxication found with maduramycin in cattle fed poultry litter . Ionophore intoxication is also well known in birds.
Slide 73 : Effects on intestinal flora Inhibits C. perfringens (types A and C) in chickens and turkeys ,can be used to prevent necrotic enteritis. Narasin has is also effective in the treatment and prevention of C. perfringens infections in chickens. In pigs, salinomycin reduces the lesions and the presence of Lawsonia intracellularis, causing proliferative entheropathy in the intestines in fattening pigs.
Slide 74 : Other Growth-Promoting Antibacterials Quinoxalines. Carbadox and olaquidox are synthetic antibacterials that act by inhibiting DNA synthesis. They are active mainly against gram-negative bacteria . They are used mainly in the prevention of swine dysentery caused by Brachyspira hyodysenteriae. Efrotomycin. Efrotomycin, an elfamycin antibiotic, is used solely as a growth promoter.
Slide 75 : Ionophores (LD50 mg/kg of bodyweight)
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