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61
Enzyme / Enzymes in Animal Feed: Benefits And Future Uses
« Last post by LamiyaJannat on April 12, 2021, 02:50:30 PM »
Enzymes in Animal Feed

The first enzymes developed by the biotech industry were the arabinoxylans and beta glucanases. Their function was to degrade non-starch polysaccharides, which are the fibrous portions of the grain. These enzymes reduced the viscosity of the non-digested grain in the intestine. The first trials proved that adding exogenous enzymes to wheat-based diets improved digestibility in monogastric animals. These early studies also helped scientists understand the mode of action of these enzymes and enabled them to develop new enzymes capable of working on a wider variety of substrates.

At the beginning of the 1990s, the main topic of conversation among nutritionists and researchers was what they considered to be the inevitable decline of sources of phosphorus in animal feed. The additives and supplements industry responded quickly to this challenge by focusing on enzymes capable of releasing more phosphorous through a molecule usually not present in livestock animals: phytate. Fungal phytase was able to chemically break down the phytate, releasing additional phosphorus in feed for pigs and poultry. While the nutritional matrixes of phytase would not be consolidated until 2000, they showed promising initial values of 0.05 phosphorus and a maximum of 0.10 percent available phosphorus.
When feed enzymes were first used more than a decade ago, their acceptance was limited to phytase applications for reduced phosphorus excretion. Although feed enzymes have been utilised for many years, we have only scratched the surface as research on feed enzyme technology.

The greater understanding of feed enzyme use comes at an ideal time as the demand for high-quality protein across the Globe continues to rise. With advancements in management and technology, animals are in production for a relatively short time. Producers need to maximise that time efficiently in order to meet increased protein requirements, including getting the most out of the feed.

Producers need to get smarter about optimising animal production in a sustainable manner — and enzymes offer an opportunity to do that.

Animal feed is the largest cost item in livestock and poultry production, accounting for 60-70% of total expenses. To save on costs, many producers supplement feed with enzyme additives, which enable them to produce more meat per animal or to produce the same amount of meat cheaper and faster.

Found in all living cells, enzymes catalyse chemical processes that convert nutrients into energy and new tissue. They do this by binding to substrates in the feed and breaking them down into smaller compounds. Enzymes can be classified by the types of substrates they work on. For instance: proteases break down proteins into amino acids, carbohydrases split carbohydrates into simple sugars, and lipases take apart lipids into fatty acids and glycerol.
Commercially-available enzymes can be derived from plants and animals (e.g., actinidin from kiwi and rennet from calf stomachs) as well as microorganisms (e.g., amylase from Bacillus and lactase from Aspergillus).
Enzymes and their modes of action


1) Phytase

The substrate for phytase is phytic acid, which is how phosphorus is stored in plant tissues. Phytic acid is problematic to the animal because it binds minerals and amino acids which become unavailable to the animal. This results in beneficial nutrients being excreted into the environment, resulting in a loss in performance.
Phytase enzymes have been added to monogastric diets for more than a decade. As previously stated, the primary goal and mode of action of phytase are to reduce phosphorus excretion, and its use continues to increase due to diet cost savings. The initial savings are associated with reduced dietary phosphorus cost, but nutritionists also have the flexibility to reduce the amount of soybean meal due to improved amino acid digestibility.


2) Carbohydrase

The carbohydrase class of enzymes includes xylanases, glucanases, and amylases. They act in the stomach to break down and degrade carbohydrates such as fibre, starch, and non-starch polysaccharides into simple sugars that provide energy for use by the animal.

Grain sources such as corn, barley, and wheat have hard coatings on the outside. Much of the coating is physically broken up during feed mill processing, but not completely. The fibrous portion of grain cell walls is indigestible, and 10 to 20 percent is getting through. Carbohydrases will attack and degrade these starchy grain molecules.
One of the most common carbohydrates is xylanase. Xylanase attacks the arabinoxylan structure of corn or wheat, allowing the animal to absorb its components as an energy source. This limits the requirement for supplemental fat or energy in the final diet.


3) Protease

Protease enzymes are the newest technology on the block, with animal or vegetable protein as their substrate. They break down anti-nutritional factors associated with various proteins. Proteases improve the digestion of proteins and increase amino acid availability, which helps release valuable nutrients. The result is improved animal growth and performance and minimal negative effects of undigested protein in the hindgut.

Raw ingredients with low amino acid digestibility respond greatest to an exogenous protease, which is why its greatest value is when alternative ingredients are used in the diet. Proteases help producers manage the nutritional risks associated with feedstuff quality and allow them to best utilise all available feed ingredients.
Proteases are not limited to diets with alternative ingredients. Animals consuming a traditional corn-soybean meal diet cannot utilise 100 percent of the protein fraction. Therefore, adding a protease enzyme to a corn-soybean meal diet will enhance amino acid digestibility and animal performance.


Benefits Of Enzymes In Animal Feed

Even though there are still some segments of the pig and poultry industries that do not use exogenous enzymes, the growth of the enzyme market has been substantial. Since enzymes improve the digestibility of plant-based feed ingredients, they offer immediate economic benefits to animal production. Enzymes have allowed producers to further improve their feed conversion rates, the uniformity of their flocks and herds, and the efficiency of their feed mills since fewer grains are needed to be purchased and processed.

With all these benefits available to producers, the animal nutrition industry is becoming more eager to study enzyme technology in greater depth with the aim of further optimising animal production. Research is ongoing on the effects of degradation of different substrates, different methods of producing enzymes, epigenetic effects of enzymes in the formation and development of the intestine, and interaction with the microbiota and intestinal health, as well as their direct or indirect action on the immune system. As our understanding of enzymes evolves, we should expect a revolution in how we feed our animals.


Future Use Of Enzymes In Animal Feed

The benefits of enzymes are becoming better realised as more research is done. For the animal, enzymes optimise gut health, produce uniform growth and enhance overall health. For the producer, they decrease feed costs and improve profitability. Each type of enzyme has its own specific function and therefore do not interfere with one another.
The bottom line is: the use of enzymes will continue to grow as we learn more about each technology.


Source: By Infinita Biotech
62
Global Challenges / Poultry Bio-Security
« Last post by LamiyaJannat on April 12, 2021, 12:55:07 PM »
Poultry Bio-Security



The Threat of Avian Influenza in Poultry Operations

As the threat of Avian Influenza continues to increase globally and as Governments impose restrictions across avian industries, it is important as ever to understand how to increase your bio-security and protect your livelihood.

When we discuss bio-security, we are referring to the practices aimed at reducing and eliminating the transmission and spread of disease. Bio-security is an essential aspect of all agricultural industries and in this instance, it is the key factor in ensuring better poultry health and protection of your profits and livelihood.

Bio-security can be accomplished by adhering to strict and efficient bio-secure practices that eliminate the transmission of disease, viruses and bacteria amongst your birds.
Your bio-secure practices can be broken down into two simple ways of thinking:

Prevention – Preventing the introduction of new viruses, bacteria etc onto your farm/property
Protection – Protection from the spread of disease, viruses, bacteria etc amongst your livestock.

How you achieve both practices can be simplified and made part of everyday working practices on a farm, ensuring a bio-secure environment.

Prevention

Ensure the poultry production area and housing areas have well established bio-secure zones with appropriate fencing that eliminates access from outside agencies such as wild birds or other animals.
All workers should avoid contact with other farms/poultry premises.
All workers should wear clean clothes and boots upon entering the premises and for visitors, new/clean boots should be provided.
Sharing farming equipment for Poultry such as bird cages should be avoided, as some studies suggest that 90% of disease transmission is from farm-to-farm contact.
Regular cleaning and disinfection of all poultry housing areas and preparation areas.
These are just a few simple tips that are often suggested to those within the poultry industry and the adherence to these procedures should aid in preventing the transmission of disease to your property.

Protection

In the event disease is transmitted to your farm it is essential to protect your healthy livestock from the infected, ensuring minimal loss to livestock.
Make sure you are able to identify signs of infection of various diseases, this is the only way to ensure that you are able to safely and accurately identify those infected.
Act quickly – your immediate and quick reaction is key in ensuring that minimal transmission can occur amongst livestock.
Separate the healthy from the infected and ensure that both are housed in clean, bio-secure areas. Again this is to ensure minimal transmission from one housing zone to another.
Ensure all staff change clothing and boots when moving between healthy and infected housing areas. Additionally, no items should be shared/used between the two zones.
Disposing of fallen stock – this requires a quick and bio-secure solution. A Waste Spectrum incinerator can be used on site when needed. It is a 100% bio-secure method for safely disposing of animal waste such as infected fallen stock and eliminates the necessity to keep infected fallen stock on site whilst waiting to dispose of dead birds through other disposal methods that you might be working with that can be expensive and risk transmission to healthy stock when left unattended for too long.
Machines in our Volkan Range are some of the most frequently used across the poultry industry, varying in sizes depending on operation size they can be used for small holdings up to large broiler operations. As a quick, clean, cost-effective, and bio-secure method for animal waste and animal by-product disposal, incineration can protect your livestock and ultimately protect your livelihood.

As always, our advice is to keep up to date with local legislation and maintain strict bio-security measures however in the meantime our team of experts are always on hand to discuss your waste management needs.


Source: Waste Spectrum Incineration Systems
Checketts Ln, Worcester WR3 7JW, UK
63
Animal Nutrition / Why structural fibre is essential for fresh cows
« Last post by LamiyaJannat on April 12, 2021, 12:47:38 PM »
Why structural fibre is essential for fresh cows

Ensuring structural fibre is available to fresh cows in very early lactation could ease transition by reducing metabolic issues and stabilising rumen function.
This is according to NWF head of technical Adam Clay, who said it was worthwhile splitting off cows for the first five days of their lactation.
He told the UK Dairy Day audience at Telford last week (13 September) that the dietary change faced by fresh cows was often too abrupt after 55-60 days on a low-energy straw-based diet.
In comparison, milking rations contain higher levels of concentrate and lower levels of fibre.He explained: “By putting more structural fibre in the diet we should help rumen pH remain at 6.0-6.2 because we are providing an environment in which fibre-digesting bacteria can thrive and reduce the shock of a rapid change.”

How rations differ

Dry-off
Close-up calving

Milking ration
Straw 5-6kg
4-5kg
0-1kg

Silage 12-14kg DM
10kg DM
12-14kg DM

Concentrate 0kg
2-3kg
3-12kg
ME 8.6-9
ME 10-11
ME 11.5-12.2

Crude protein 13-14%
13-14%
16-19%
Starch 0%

+5-10%
+15%
NDF 45-50%
NDF 40%
NDF 32-38%

But he stressed this couldn’t be done in the main ration as this would limit milk yield.
“If farms can section off a shed for fresh cows up to five days post-calving, this could decrease transition cow problems and sub-acute ruminal acidosis [Sara],” said Mr Clay. “It also gives opportunity to check for rumen fill temperatures, cleansings and feed intake.”

He said the dairy industry had made major progress with transition cow management in recent years, but stressed that the initial few days post-calving required closer scrutiny.

“As a nutritionist on farm I see too often that we are seeing a good transition system and then Sara in fresh cows,” he said.
He admitted that infrastructure was a key challenge to providing fibre to a specific group of cows, but added that top dressing with hay could be an easy solution.


Written By
Michael Priestley
Animal Nutritionist
United States
64
Pet Care Education / How to keep pets safe in cold weather
« Last post by LamiyaJannat on April 12, 2021, 12:40:01 PM »
How to keep pets safe in cold weather

Pets are family. They have their own napping spots in the living room, a place for their toys, special place mats for their food and water dishes and a permanent reservation at the foot of the bed every night. They’re loved, care for and a little bit spoiled.
As a pet owner, I always want to ensure I’m giving my dogs their best life. Part of that means being aware of how extreme weather affects them throughout the year. Recently, the onset of winter weather and snow has prompted me to consider cold weather safety tips.

Understanding your pets’ cold tolerance

A pets’ cold tolerance depends on their coat, size, age and overall health. Being aware of your pet’s cold weather tolerance will help you determine how long your dog should be exposed to cold weather. In general, it’s a good idea to shorten your dog’s walks during periods of inclement weather to protect them from associated health risks.

Factors to consider:

Age. Older pets may have more difficulty walking on snow and ice and may be more prone to falling. Puppies and kittens are likely to loose body heat quicker than full grown adults and should only have limited exposure to extreme cold.

Size. Cats and smaller dogs generally have less tolerance for cold than larger dogs and should have very little exposure. Pets with shorter legs become cold faster because their bellies and bodies are more likely to come into contact with the snow-covered ground.

Health. Arthritic pets may experience increased discomfort and mobility problems in cold temperatures. Pets with diabetes, heart disease, kidney disease, or hormonal imbalances (such as Cushing’s disease) may have a harder time regulating their body temperature.

Coat length. Long-haired and thick-coated pets have more protection and are more cold tolerant than short-haired pets.

Keep your pets inside

It’s a common misconception that pets are more resistant to cold weather than people because of their fur. The truth is cats, dogs and other pets left outside during periods of cold weather are susceptible to frostbite and hypothermia. Longer-haired and thick-coated dog breeds, such as huskies and other dogs bred for colder climates, are more tolerant; however, no pet should be left outside for long periods in below-freezing weather.

If you are unable to keep your pet inside during cold weather, a proper shelter should be provided.
Use these guidelines:

  • Make sure your pet has always has access to fresh water that has not frozen over.
  • The floor of the shelter should be raised off the ground to to minimize heat loss into the ground.
  • The bedding should be thick, dry and changed regularly to provide a warm, dry environment.
  • The door to the shelter should be positioned away from the wind.
  • Outdoor pets will require more calories in the winter to generate enough body heat and energy to keep them warm.
  • Make sure you are feeding your pet plenty.

Other cold-weather tips

Hitchhikers. During periods of cold weather, outdoor and feral cats will crawl into your vehicle’s engine bay to keep warm. Check under your car, honk the horn and do what you can to encourage feline hitchhikers to leave before you drive off.
Paws. Check your dog’s paws regularly to look for signs of cold-weather injury or damage, such as cracked paw pads or bleeding, and signs of ice accumulation between its toes.

Coats and sweaters. If your dog has a low tolerance for cold weather, you may try a sweater or dog coat. Just make sure you have a few to rotate, so a dry sweater is available each time your dog goes outside. Wet coats and sweaters can make your dog colder faster.

Deicers, antifreeze and other chemicals. On walks in cold weather, your dog’s feet, legs and belly may pick up deicers, antifreeze or other chemicals potentially toxic chemicals. Always wipe down your pet’s feet, legs and belly to remove these chemicals when you get inside. One your own, property consider using pet-safe deicers and clean up antifreeze spills quickly.

Identification. Pets get lost in winter because snow and ice can hide recognizable scents that might normally help your pet find its way home. Make sure your pet’s collar fits well and has a tag with up-to-date contact information. Microchips are also a good option, but keeping the registration information current is just as important.
Ice. If you’re unsure whether or not the ice is thick enough to support your dog, avoid frozen ponds, lakes and other bodies of water.

Hypothermia. If your pet is whining, shivering, seems anxious, slows down or stops moving, seems weak or starts looking for warm places to burrow, they are showing signs of hypothermia and should be taken inside immediately.
Frostbite. Frostbite is hard to detect and may not be fully recognized until a few days. This is why it’s important to take preventative measures.[/size]


Written By
Sara Welch
United States
65
Research / Researchers Find Multiple Effects on Soil from Manure from Cows Administered Ant
« Last post by LamiyaJannat on April 12, 2021, 12:20:14 PM »
Researchers Find Multiple Effects on Soil from Manure from Cows Administered Antibiotics

These effects include alteration of the soil microbiome and ecosystem functions, soil respiration, and elemental cycling
For the study, researchers analyzed ecosystems exposed to manure from cattle given no antibiotics and manure from cattle given a common antibiotic, as well as a control sample not exposed to manure.

Use of antibiotics is under heightened scrutiny due to the increased prevalence of antibiotic-resistant pathogens. While the primary focus is on more stringent use of antibiotics in medical settings, the use of antibiotics in the livestock sector is gaining increased attention.

A new study led by Colorado State University and the University of Idaho found multiple effects on soils from exposure to manure from cows administered antibiotics, including alteration of the soil microbiome and ecosystem functions, soil respiration, and elemental cycling.

The team also saw changes in how plants allocated carbon below ground and take up nitrogen from the soil. In addition, they observed a decrease in ecosystem carbon use efficiency. This means that when antibiotics are used, less carbon is stored in the soil and more is lost to the atmosphere as carbon dioxide.

The study, "Prolonged exposure to manure from livestock-administered antibiotics decreases ecosystem carbon-use efficiency and alters nitrogen cycling," was published Oct. 9 in Ecology Letters.
Carl Wepking, the lead author and a postdoctoral fellow in the Department of Biology at CSU, said the findings give him "pause" due to the widespread use of antibiotics. "There's no environment on earth that is free from the effects of antibiotics," he said.

In the US, 80 percent of antibiotics are used in livestock production. Globally, livestock antibiotic use is projected to increase by 67 percent by the year 2030.

For the study, researchers analyzed ecosystems exposed to manure from cattle given no antibiotics and manure from cattle given a common antibiotic, as well as a control sample not exposed to manure. All of the manure samples were collected from standard dairy operations maintained by researchers from the Virginia Tech Department of Dairy Science.

Previous research on this topic found researchers injecting antibiotics into manure, then adding it to the soil, or adding raw antibiotics to the soil, said Wepking. The design of this study offered a much more realistic and applicable design.

The research team also used a pulse-chase experiment, a technique to examine elemental cycling, focusing on the manure's effect on whole ecosystems. Scientists took samples over the course of seven days, and found that in the presence of antibiotics, carbon traveled into the above ground plant material, to the roots of the plants, into the soil and respired back out as carbon dioxide much faster than any of the others.

"There was much less of that new carbon retained in the system compared with other soils we sampled," explained Wepking, who also serves as executive director of the Global Soil Biodiversity Initiative, which is housed in the School of Global Environmental Sustainability at CSU.

It's often thought that manure is a helpful fertilizer, and that it adds nutrients and carbon to soil but this benefit might be offset if antibiotics are administered to livestock.

While more research is needed, Wepking said given the study's findings, people may want to consider the effects of antibiotics in the soil when using manure as fertilizer.

"Research is expanding more and more, to look at antibiotic exposure and resistance in agricultural landscapes," said Wepking. "It's already well-documented that overuse of antibiotics is a problem for humans, and that we are running out of effective antibiotics to treat bacterial infections. Based on this research, we have learned that antibiotic use also has environmental effects."



Source: Colorado State University
University Square, 1311 S College Ave, Fort Collins, CO 80524, USA
66
Anthelmintic / Resistance to Anthelmintics
« Last post by LamiyaJannat on April 07, 2021, 04:47:44 PM »
Resistance to Anthelmintics

The development of nematode and trematode resistance to various groups of anthelmintics is a major problem. Compared with development of antibiotic resistance in bacteria, resistance to anthelmintics in nematodes has been slower to develop under field conditions. However, resistance is becoming widespread, because relatively few chemically dissimilar groups of anthelmintics have been introduced over the past several decades. Most of the commonly used anthelmintics belong to one of three chemical classes, benzimidazoles, imidazothiazoles, and macrocyclic lactones, within which all individual compounds act in a similar fashion. Thus, resistance to one particular compound may be accompanied by resistance to other members of the group (ie, side-resistance).

In nematodes of small ruminants, and especially in Haemonchus contortus, resistance to all classes of broad-spectrum anthelmintics has reached serious levels in many parts of the world. Resistance also has been found in Trichostrongylus spp, Cooperia spp, and Teladorsagia spp in sheep and goats. Reports of multiple resistance to most major classes of anthelmintics are increasing. Recently, resistance to monepantel has occurred in the field (New Zealand) in at least two nematode species (Teladorsagia circumcincta and Trichostrongylus colubriformis) after being administered on 17 separate occasions to different stock classes and in <2 yr of the product first being used on the farm.

Resistance to benzimidazoles is widespread in cyathostome nematodes of horses. Parascaris equorum resistance to macrocyclic lactones (ivermectin and moxidectin) has been reported in many countries. Macrocyclic lactone resistance in cyathostomes is only occasionally suspected, however, and the problem is still not considered to be serious.

There are limited reports of resistance against levamisole, pyrantel, and benzimidazoles in Oesophogostomum dentatum in pigs.

Multidrug (benzimidazoles and macrocyclic lactones) resistance in cattle nematodes has been documented on farms in New Zealand, the Americas, and Europe, and this will probably become more widespread. In most cases of resistance against macrocyclic lactones, Cooperia spp were identified as the resistant worm species, but macrocyclic lactone resistance is also emerging in Ostertagia ostertagi. The full extent of anthelmintic resistance in cattle nematodes is unknown.

The development of significant levels of resistance seems to require successive generations of helminths exposed to the same class of anthelmintic. However, evidence suggests that genes for resistance are invariably present, at a low frequency, for any given anthelmintic. Selection for resistance simply requires the preferential killing of the susceptible parasites and survival of the parasites with the resistance genes. Side-resistance is frequently seen between members of the benzimidazole group because of their similar mechanisms of action; control of benzimidazole-resistant parasites by levamisole can be expected because of its different mode of action. Although there is no evidence for cross-resistance between levamisole and benzimidazoles, this does not mean that worms resistant to both kinds of drugs will not evolve if both types of anthelmintics are used frequently. Nematodes resistant to levamisole are cross-resistant to morantel because of the similarities of their mechanisms of action. When resistance to the recommended dose rate of an avermectin appears in some species of nematodes, a milbemycin, at its recommended dose rate, may still be effective. However, there is side-resistance among the avermectins and the milbemycins, which are within the same class of anthelmintics, and continued use of either subgroup will select for macrocyclic lactone resistance.

Recently, it was demonstrated in Haemonchus contortus and Onchocerca volvulus that macrocyclic lactone anthelmintics can affect β-tubulin, although no mechanistic explanation for this has been published. However, it suggests that macrocyclic lactone use may select for benzimidazole resistance, because benzimidazole resistance appears to be largely due to a single polymorphism being selected. However, benzimidazole resistance was widely reported before the commercial use of macrocyclic lactones. Ivermectin resistance has usually been reported in areas of the world where benzimidazole resistance is already widespread. In using anthelmintic combinations or rotations, consideration should be given to the genetic interactions in the parasite between benzimidazole and macrocyclic lactone anthelmintics in terms of selection for the alleles that confer benzimidazole resistance.
Every exposure of a target parasite to an anthelmintic exerts some selection pressure for development of resistance. Therefore, management practices designed to reduce exposure to parasites and to minimize the frequency of anthelmintic use should be recommended. The development of an anthelmintic resistance problem may theoretically be delayed by rotating chemicals with different modes of action annually between dosing seasons. Drug combinations may be another appropriate choice, provided the anthelmintics used in the combination are both effective and select for different resistance mechanisms.

In parasite control, economic benefit is best obtained by careful management practices. Planned (or targeted) treatment of a whole flock or herd should be based on the biology, ecology, and epidemiology of the parasite(s), with particular reference to climatic conditions. There is a trend among parasitologists to recommend replacing current practice for worm control involving repeated dosing of whole groups of animals with “targeted selective treatments” in which only individual animals showing clinical signs or reduced productivity are given drugs.


By
Jozef Vercruysse , DVM, Ghent University;
Edwin Claerebout , DVM, PhD, DEVPC, Department of Virology, Parasitology and Immunology, Faculty of Veterinary Medicine, Ghent University
67
Anthelmintic / Safety of Anthelmintics
« Last post by LamiyaJannat on April 07, 2021, 04:45:27 PM »
Safety of Anthelmintics

Most anthelmintics have wide safety margins, ie, the dosage that can be given to an animal before adverse effects are induced is much higher than the dosage recommended for use. The wide safety margin of benzimidazoles is because of their greater selective affinity for parasitic β-tubulin than for mammalian tissues. Nonetheless, this selective toxicity is not absolute; some toxic effects based on antimitotic activity (teratogenicity or embryotoxicity) can occur in some target species, and some benzimidazoles, depending on the dose rate, are contraindicated in early pregnancy.

The safety index (SI) is not as wide for levamisole (SI = 4–6), nor for most of the chemicals active against liver flukes (SI = 3–6). Mammalian toxicity with levamisole is seen more often than with benzimidazoles, although toxic signs are unusual unless the normal therapeutic dosage is exceeded. Levamisole toxicity in the host animal is largely an extension of its antiparasitic effect, ie, cholinergic-type signs of salivation, muscle tremors, ataxia, urination, defecation, and collapse. In fatal levamisole poisoning, the immediate cause of death is asphyxia due to respiratory failure. Atropine sulfate can alleviate such signs. Levamisole may cause some inflammation at the site of SC injection, but usually this is transient. Toxicity increases if other anticholinergic drugs (eg, organophosphates) are given at the same time.

Because of their low absorption from the gut, tetrahydropyrimidines have a high safety margin. Adverse effects (vomiting in dogs and cats) are rare. Toxicity increases when other cholinergic drugs (eg, levamisole, organophosphates) are used simultaneously.

The margin of safety for organophosphates is generally less than that of the benzimidazoles, and strict attention to dosage is necessary. Generally, their toxicity is additive; thus, concurrent use of other cholinesterase-inhibiting drugs should be avoided. Atropine and 2-PAM are used as antidotes to organophosphate toxicity (also see Organophosphates (Toxicity)). Organophosphates also can be hazardous to people. Being lipid soluble, they are readily absorbed through unbroken skin. Sprays, collars, and washes of organophosphates used for small animals can present significant hazards to young infants after ingestion, inhalation, or transcutaneous absorption.
Mammals are generally not adversely affected by macrocyclic lactones. The SI for the macrocyclic lactones is typically wide, but both abamectin and moxidectin are contraindicated in calves and foals <4 mo old, respectively, because of narrow safety margins in these classes of stock. Otherwise, single administration at ~10 times and multiple administration at 3 times the recommended therapeutic dose levels do not have any secondary effects on healthy host animals.

Mammalian safety appears to depend on P-glycoprotein activity in the blood-brain barrier. A P-glycoprotein deficiency in certain animals decreases the ability to pump avermectins, milbemycins, and other drugs across cell membranes. The net effect is an increase in systemic bioavailability, because animals deficient in P-glycoprotein are not able to actively pump the macrocyclic lactones out of the CNS or efficiently process these drugs. This decreases the ability to redistribute, metabolize, and excrete macrocyclic lactones, as well as antineoplastic drugs, opioids, acepromazine, digoxin, and ondansetron, resulting in toxicity with what would be considered normal doses in most animals. There have been cases of CNS depression in cattle breeds (Murray Grey) and in individual dogs of multiple breeds, but these were first recognized in purebred and crossbred Collies. Nervous signs (idiosyncratic reactions), including depression, muscle weakness, blindness, coma, and death, were seen when high doses were administered.

Because salicylanilides, substituted phenols, and aromatic amides are general uncouplers of oxidative phosphorylation, their SIs are lower than those of many other anthelmintics. Nonetheless, they are safe if used as directed. Adverse effects are most commonly seen in animals that are severely stressed, in poor condition nutritionally or metabolically, or have severe parasitic infections. Mild anorexia and unformed feces may be seen after treatment at recommended dosages. High dosages may cause blindness, hyperthermia, convulsions, and death—classic signs of uncoupled phosphorylation.

The amino-acetonitrile derivatives target a nematode-specific receptor that is absent in mammals and other organisms. Because of this specific mode of action, monepantel has a very favorable safety profile. Monepantel has been administered to lambs in doses up to 30 times higher than the recommended dose without any adverse effects. In addition, repeated oral administration of monepantel at three times the recommended dose every 5 days over an entire reproductive cycle was not associated with any treatment-related adverse effects on the reproductive performance of rams or ewes or on the viability of their offspring, and it was systemically very well tolerated.

Emodepside appears to be of low acute toxicity in a variety of laboratory animal species and by a variety of routes. Although overt signs of toxicity include depressed neurologic and respiratory function, they occur only at dose rates far in excess of the recommended therapeutic dose in cats. Repeated treatment at three times the therapeutic dose was tolerated in pregnant and lactating dams/queens, so adverse effects on reproductive function of the dams and/or kitten health are not anticipated when the product is administered at the recommended treatment dose. Safety in dogs was established only for puppies ≥12 wk old.
The combination of derquantel and abamectin did not result in any adverse clinical effects in ewes and lambs under field conditions, other than a commonly reported, mild, transient coughing.


By
Jozef Vercruysse , DVM, Ghent University;
Edwin Claerebout , DVM, PhD, DEVPC, Department of Virology, Parasitology and Immunology, Faculty of Veterinary Medicine, Ghent University
68
Anthelmintic / Withholding Periods After Anthelmintic Treatment
« Last post by LamiyaJannat on April 07, 2021, 04:43:03 PM »
Withholding Periods After Anthelmintic Treatment

Last full review/revision Sep 2014 | Content last modified Oct 2014 Most anthelmintics have withholding periods if milk or meat from treated animals is intended for human consumption; the specific requirements for each must be observed. Of the benzimidazoles, thiabendazole is absorbed and excreted most quickly; fenbendazole, oxfendazole, and albendazole are absorbed and excreted over a longer period, which necessitates withholding periods of 8–14 days before slaughtering for meat and 3–5 days before milking for human consumption. Other members of the group have withholding periods between these extremes, but withholding periods are longer for bolus formulations.

A similar relationship between the rate of metabolism and activity against immature parasites also exists with certain fasciolicides. Closantel, rafoxanide, and nitroxynil bind more strongly to blood proteins than does oxyclozanide, and therefore remain in the blood for longer periods. While this greater persistence is associated with greater activity against immature liver flukes, the withholding period for slaughter is also longer: 21–77 days for closantel, rafoxanide, and nitroxynil, compared with 3–14 days for oxyclozanide. The low plasma-protein binding of diamfenetide, coupled with the rapid excretion of its active metabolite, necessitates only a short withdrawal time. Similarly, withholding periods for milk vary widely. Closantel and nitroxynil cannot be used in lactating animals when milk is intended for human consumption, whereas oxyclozanide has a withdrawal time of only 60 hr.

Levamisole and morantel are rapidly excreted; thus, withholding periods for meat are short, and frequently there is no, or only a short, withholding period for milk. However, in some countries, levamisole cannot be used in lactating animals when milk is intended for human consumption.

Ivermectin and doramectin are excreted in milk and are not recommended when milk is intended for human consumption. Commensurate with the long period of activity of macrocyclic lactones, ivermectin, abamectin, doramectin, and moxidectin have significant withholding periods before slaughter (eg, 35 days), which vary with the formulations and local regulations. Residual concentrations of moxidectin in milk after topical administration are below threshold limits, resulting in no milk withholding period in many countries. The chemical structure of the macrocyclic lactone molecule has been manipulated to change the milk partitioning coefficients in lactating dairy animals. For example, only 0.1% of the total dose of eprinomectin is eliminated in the milk, resulting in no withholding period for milk worldwide.

Monepantel has a withdrawal period of 7–14 days for meat and is not approved for use in lactating animals producing milk for human consumption.

In combination with abamectin, derquantel has a withholding period of 14 days for meat and is not approved for use in lactating animals producing milk for human consumption.


By
Jozef Vercruysse , DVM, Ghent University;
Edwin Claerebout , DVM, PhD, DEVPC, Department of Virology, Parasitology and Immunology, Faculty of Veterinary Medicine, Ghent University
69
Anthelmintic / Pharmacokinetics of Anthelmintics
« Last post by LamiyaJannat on April 07, 2021, 04:40:08 PM »
Pharmacokinetics of Anthelmintics

After administration, anthelmintics are usually absorbed into the bloodstream and transported to different parts of the body, including the liver, where they may be metabolized and eventually excreted in the feces and urine. The disposition of anthelmintics throughout the body is considerably more complex than can be described by a set of pharmacokinetic parameters in the peripheral circulation. Improved drug performance requires knowledge of drug behavior in the multicompartmental system, including the complex interaction between formulation and route of administration, physicochemical properties of the compound, and physiology of the compartment into which the drug is distributed.
Although many helminth parasites reside in the lumen or close to the mucosa, others live at sites such as the liver and lungs; for action against these, absorption of drug from the GI tract, injection site, or skin is essential. Intestinal parasites come in contact not only with the unabsorbed drug passing through the GI tract but also with the absorbed fraction in the blood as they feed on the intestinal mucosa, and with any that is recycled into the gut. This is an important aspect of efficacy of many of the benzimidazoles.

The pharmacokinetics of an anthelmintic, its rate of metabolism and excretion, and its safety profile determine the length of the withdrawal time; this period can vary among species and can also be affected by route of administration and dose. The usual site of metabolism of anthelmintics is the liver, where oxidation and cleavage reactions commonly occur.

Benzimidazoles and Probenzimidazoles:

With a few exceptions, eg, albendazole, oxfendazole, and triclabendazole, only limited amounts of any of the benzimidazoles are absorbed from the GI tract of the host. The limited absorption is probably related to the poor water solubility of these drugs. The little absorption that occurs is generally rapid, 2–7 hr after dosing with flubendazole and 6–30 hr after dosing with albendazole, fenbendazole, and oxfendazole, depending on the species. Many of the benzimidazoles and their metabolites re-enter the GI tract by passive diffusion, but the biliary route is the most important pathway for secretion and recycling of benzimidazoles in the GI tract.

A number of benzimidazoles (eg, febantel, thiophanate, netobimin) exist in the form of prodrugs that must be metabolized in the body to the biologically active benzimidazole carbamate nucleus. Febantel is hydrolyzed to the active metabolite fenbendazole, and netobimin undergoes processes of reduction, cyclization, and oxidation to yield albendazole sulfoxide. Benzimidazole sulfoxides such as oxfendazole and albendazole sulfoxide bind poorly to parasite β-tubulin and probably act as prodrugs for fenbendazole and albendazole, respectively. The thiometabolites have high affinity for helminth tubulin.

Metabolism of the benzimidazoles is variable and may alter their activity; eg, albendazole is rapidly and reversibly oxidized to its sulfoxide form. The sulfoxide may be irreversibly oxidized to its sulfone, which is significantly less active than the sulfoxide. Similarly, fenbendazole and oxfendazole (fenbendazole sulfoxide) are interchangeable, but the oxidation product fenbendazole sulfone is less active and is not reduced back to the sulfoxide or thio metabolites.

In ruminants, the benzimidazoles are most effective if deposited into the rumen. Administration directly into the abomasum, via the esophageal groove, may shorten the duration for drug absorption and increase the rate of excretion in the feces, which may reduce efficacy. For example, immediate arrival of oxfendazole in the abomasum after dosing reduces its efficacy from 91% to 45% against thiabendazole-resistant strains of Haemonchus contortus. The rumen acts as a drug reservoir from which plasma concentrations can be sustained, slowing the passage of unabsorbed drug through the GI tract.

Imidazothiazoles:

The absorption and excretion of levamisole is rapid and not affected by the route of administration or ruminal bypass, because it is highly soluble. In cattle, blood concentrations of levamisole peak <1 hr after SC administration. These concentrations decline rapidly; 90% of the total dose is excreted in 24 hr, largely in the urine.

Tetrahydropyrimidines:

Pyrantel tartrate (or citrate) is well absorbed by pigs and dogs, less well by ruminants. The pamoate salt (synonym embonate) of pyrantel is poorly soluble in water; this offers the advantage of reduced absorption from the gut and allows the drug to reach and be effective against parasites in the large intestine, which makes it useful in horses and dogs.

Metabolism of pyrantel is rapid, and the metabolites are excreted rapidly in the urine (40% of the dose in dogs); some unchanged drug is excreted in the feces (principally in ruminants). Blood concentrations usually peak 4–6 hr after PO administration.

Morantel is the methyl ester analogue of pyrantel and, in ruminants, it tends to be safer and more effective than pyrantel. It is absorbed rapidly from the upper small intestine of sheep and metabolized rapidly in the liver; ~17% of the initial dose is excreted in the urine as metabolites within 96 hr after dosing.

Macrocyclic Lactones:

Macrocyclic lactones are hydrophobic, an important characteristic of this class of anthelmintics. Regardless of their route of administration, macrocyclic lactones are distributed throughout the body and some concentrate in adipose tissue. Liver tissue contains the highest residue for the longest, reflecting the route of elimination. Although the magnitude of lipophilicity differs among chemical types, the limited vascularization and slow turnover rate of body fat and the slow rate of release or exchange of drug from these lipid reserves can prolong the residence of drug in the peripheral plasma. Ivermectin is arguably the least lipophilic macrocyclic lactone, with the possible exception of eprinomectin. Moxidectin is ~100 times more lipophilic than ivermectin. Doramectin is less lipophilic than moxidectin but more than ivermectin or eprinomectin.

Ivermectin was the first commercially available macrocyclic lactone and has been the most extensively studied. When given IV, ivermectin has an elimination half-life of 32–178 hr, depending on species. Despite the higher dose rate of the injectable formulation in pigs (300 mcg/kg) compared with that of cattle (200 mcg/kg), the maximum concentration (Cmax) and area under the curve (AUC) in peripheral plasma in pigs are about one-third those in cattle. Although the elimination half-life after SC and IV administration of ivermectin is of similar duration, slow absorption from the injection site may broaden the concentration-time profile, with Cmax in peripheral plasma of cattle occurring as late as 96 hr. The Cmax and AUC in pigs and goats are considerably lower than those in cattle, horses, and sheep. Pigs, and possibly goats, may metabolize ivermectin faster than other species.

In ruminants, the macrocyclic lactones are, like benzimidazoles, most effective if deposited directly into the rumen. A 3- to 4-fold decrease in Cmax and AUC of ivermectin after intra-abomasal compared with intraruminal administration has been reported. Significantly, time to maximal concentration of ivermectin was reduced from 23 hr to 4 hr with the former route of delivery.

Concentrations of ivermectin are high in digesta sampled from the distal intestine, indicating that biliary secretion is an important pathway for clearance of macrocyclic lactones. This pathway also has been conclusively demonstrated for clearance of benzimidazole compounds. The extended high concentration in bile is influenced by prolonged exchange of drug from lipid reserves and the enterohepatic recycling of biliary compounds through the portal and biliary pools. The macrocyclic lactones are primarily excreted in the feces, the remainder (<10%) in the urine. The more lipophilic macrocyclic lactones are also excreted in milk.

Salicylanilides and Substituted Phenols:

Secretion via the liver and bile is especially important for drugs active against adult Fasciola spp. The fasciolicidal effects of salicylanilides (such as rafoxanide) in sheep depend on persistence of the drug in plasma, which influences their transport throughout the body and rate of elimination. Closantel, rafoxanide, and oxyclozanide have long terminal half-lives in sheep (14.5, 16.6, and 6.4 days, respectively), which are related to the high plasma-protein binding (>99%) of these three drugs. Residues in liver are detectable for weeks after administration. Associated with persistence, however, is the need for longer withholding periods. Oxyclozanide also is bound to plasma protein and then metabolized in the liver to the anthelmintically active glucuronide and excreted in high concentration in the bile duct, where it encounters the mature flukes.

Immature flukes in the liver parenchyma ingest mainly liver cells, which contain little anthelmintic; plasma-protein binding limits entry of the drug into the tissue cells. As the flukes grow and migrate through the liver, they cause extensive hemorrhaging and come into contact with anthelmintic bound to plasma protein. When they reach the bile ducts, they are in the main excretory channels for the active metabolites of the fasciolicides and are exposed to toxic concentrations. This may explain why mature flukes are more vulnerable to most fasciolicides than immature ones. The higher concentrations of fasciolicides and their metabolites in feces than in urine suggest that the bile ducts are their main excretory pathways.
It is important to understand the pharmacokinetics of prescribed anthelmintics. For example, nitroxynil has good efficacy against F hepatica in cattle and sheep and against H contortus, but because rumen bacteria metabolize and destroy the activity of nitroxynil, it must be injected.

Amino-acetonitrile Derivatives

After PO administration, monepantel is quickly absorbed into the bloodstream and metabolized to a major extent within 4 hr into monepantel sulfone. The sulfone expresses in vitro anthelmintic activity similar to that of the parent molecule and is responsible for the anthelmintic effect in animals, because 95 % of the administered dose is metabolized into the sulfone. The Cmax of monepantel sulfone was 4 fold-higher compared with that measured for the parent compound. After PO administration in sheep of the recommended dosage of 2.5 mg/kg, the elimination half-life of the sulfone metabolite in plasma was 48.7 hr, with a mean residence time of 79.3 hr. Approximately 27% of the administered dose is excreted through the feces in the form of the sulfone derivative. The remaining amount is further metabolized and partly excreted through urine (up to 30% of the administered dose). In addition to the sulfone, the parent monepantel contributes to the anthelmintic activity against abomasal nematodes, because the concentration of the parent monepantel is considerably higher in the abomasum than in plasma.

Cyclic Octadepsipeptides

Studies in rats have been done to assess the general distribution, metabolism, and excretion patterns of emodepside after PO and IV administration. Bioavailability after PO administration is ~50%. Emodepside is distributed throughout the whole organism, but highest concentrations are found in fat tissues, where it forms a deposit that is slowly released. Emodepside is excreted predominantly via the bile and then eliminated in the feces. Approximately half of the administered dose is excreted within the first 24 hr. The elimination half-life after both PO and IV administration is 39–51 hr. Approximately 45%–56% of the administered dose is excreted unchanged, the rest in the form of inactive metabolites. After topical administration in cats, emodepside is absorbed slowly into the bloodstream. Maximum plasma levels are reached 2–3 days after treatment. Absorption after PO administration in dogs is higher if administered to fed animals.

Spiroindoles


Pharmacokinetics demonstrate that after a single oral administration, maximum concentrations of derquantel were reached at 4.2 hr. The terminal half-life of derquantel was 9.3 hr, and the absolute bioavailability was 56.3%. Metabolism of derquantel is extensive and complex. Derquantel undergoes biotransformation to a large number of metabolites over a short time and, as a result, extensive variation in metabolites has been found in tissues and over time periods.

Praziquantel

Praziquantel is rapidly and almost completely absorbed from the GI tract. After absorption, praziquantel is distributed to all organs; it is believed to re-enter the intestinal lumen via the mucosa and bile in dogs. Praziquantel is rapidly hydroxylated into inactive forms in the liver and secreted in bile. It has a wide safety margin.

By
Jozef Vercruysse , DVM, Ghent University;
Edwin Claerebout , DVM, PhD, DEVPC, Department of Virology, Parasitology and Immunology, Faculty of Veterinary Medicine, Ghent University
70
Anthelmintic / Mechanisms of Action of Anthelmintics
« Last post by LamiyaJannat on April 07, 2021, 04:34:53 PM »
Mechanisms of Action of Anthelmintics

Anthelmintics must be selectively toxic to the parasite. This is usually achieved either by inhibiting metabolic processes that are vital to the parasite but not vital to or absent in the host, or by inherent pharmacokinetic properties of the compound that cause the parasite to be exposed to higher concentrations of the anthelmintic than are the host cells. While the precise mode of action of many anthelmintics is not fully understood, the sites of action and biochemical mechanisms of many of them are generally known. Parasitic helminths must maintain an appropriate feeding site, and nematodes and trematodes must actively ingest and move food through their digestive tracts to maintain an appropriate energy state; this and reproductive processes require proper neuromuscular coordination. Parasites must also maintain homeostasis despite host immune reactions. The pharmacologic basis of the treatment for helminths generally involves interference with the integrity of parasite cells, neuromuscular coordination, or protective mechanisms against host immunity, which lead to starvation, paralysis, and expulsion or digestion of the parasite.

Cellular Integrity:

Several classes of anthelmintics impair cell structure, integrity, or metabolism: 1) inhibitors of tubulin polymerization—benzimidazoles and probenzimidazoles (which are metabolized in vivo to active benzimidazoles and thus act in the same manner); 2) uncouplers of oxidative phosphorylation—salicylanilides and substituted phenols; and 3) inhibitors of enzymes in the glycolytic pathway—clorsulon.

The benzimidazoles inhibit tubulin polymerization; it is believed that the other observed effects, including inhibition of cellular transport and energy metabolism, are consequences of the depolymerization of microtubules. Inhibition of these secondary events appears to play an essential role in the lethal effect on worms. Benzimidazoles progressively deplete energy reserves and inhibit excretion of waste products and protective factors from parasite cells; therefore, an important factor in their efficacy is prolongation of contact time between drug and parasite. Cross-resistance can exist among all members of this group, because they act on the same receptor protein, β-tubulin, which is altered in resistant organisms such that none of the benzimidazoles can bind to the receptor with high affinity.

Uncoupling of oxidative phosphorylation processes has been demonstrated for the salicylanilides and substituted phenols, which are mainly fasciolicides. These compounds act as protonophores, allowing hydrogen ions to leak through the inner mitochondrial membrane. Although isolated nematode mitochondria are susceptible, many fasciolicides are ineffective against nematodes in vivo, apparently due to a lack of drug uptake. Exceptions are the hematophagous nematodes, eg, Haemonchus and Bunostomum.

Clorsulon is rapidly absorbed into the bloodstream. When Fasciola hepatica ingest it (in plasma and bound to RBCs), they are killed because glycolysis is inhibited and cellular energy production is disrupted.

Neuromuscular Coordination:

Interference with this process may occur by inhibiting the breakdown or by mimicking or enhancing the action of neurotransmitters. The result is paralysis of the parasite. Either spastic or flaccid paralysis of an intestinal helminth allows it to be expelled by the normal peristaltic action of the host. Specific categories include drugs that act via a presynaptic latrophilin receptor (emodepside), various nicotinic acetylcholine receptors (agonists: imidazothiazoles, tetrahydropyrimidines; allosteric modulator: monepantel; antagonist: spiroindoles), glutamate-gated chloride channels (avermectins, milbemycins), GABA-gated chloride channels (piperazine), or via inhibition of acetylcholinesterases (coumaphos, naphthalophos).
Organophosphates inhibit many enzymes, especially acetylcholinesterase, by phosphorylating esterification sites. This phosphorylation blocks cholinergic nerve transmission in the parasite, resulting in spastic paralysis. The susceptibility of cholinesterases by host and parasite varies, as does the susceptibility of these different species to organophosphates.
The imidazothiazoles are nicotinic anthelmintics that act as agonists at nicotinic acetylcholine receptors of nematodes. Their anthelmintic activity is mainly attributed to their ganglion-stimulant (cholinomimetic) activity, whereby they stimulate ganglion-like structures in somatic muscle cells of nematodes. This stimulation first results in sustained muscle contractions, followed by a neuromuscular depolarizing blockade resulting in paralysis. Hexamethonium, a ganglionic blocker, inhibits the action of levamisole.

Monepantel, the only commercially available amino-acetonitrile derivative, is a direct agonist of the mptl-1 channel, which is a homomeric channel belonging to the DEG-3 family of nicotinic acetylcholine receptors. Binding of monepantel to the receptor results in a constant, uncontrolled flux of ions and finally in a depolarization of muscle cells, leading to irreversible paralysis of the nematodes. These receptors are unique in that they are found only in nematodes.

Derquantel, a semisynthetic member of the spiroindole class of anthelmintics, is an antagonist of B-subtype nicotinic acetylcholine receptors located at the nematode neuromuscular junction; it inhibits 45-pS channels, leading to a flaccid paralysis of nematodes.

Piperazine acts to block neuromuscular transmission in the parasite by hyperpolarizing the nerve membrane, which leads to flaccid paralysis. It also blocks succinate production by the worm. The parasites, paralyzed and depleted of energy, are expelled by peristalsis.

The macrocyclic lactones act by binding to glutamate-gated chloride channel receptors in nematode and arthropod nerve cells. This causes the channel to open, allowing an influx of chloride ions. Different chloride channel subunits may show variable sensitivity to macrocyclic lactones and different sites of expression, which could account for the paralytic effects of macrocyclic lactones on different neuromuscular systems at different concentrations. The macrocyclic lactones paralyze the pharynx, the body wall, and the uterine muscles of nematodes. Paralysis (flaccid) of body wall muscle may be critical for rapid expulsion, even though paralysis of pharyngeal muscle is more sensitive. As the macrocyclic lactone concentration decreases, motility may be regained, but paralysis of the pharynx and resultant inhibition of feeding may last longer than body muscle paralysis and contribute to worm deaths. None of the macrocyclic lactones are active against cestodes or trematodes, presumably because these parasites do not have a receptor at a glutamate-gated chloride channel. Emodepside acts presynaptically at the neuromuscular junction, where it attaches to a latrophilin-like receptor. This receptor belongs to the group of so-called G-protein coupled receptors. Stimulation of the latrophilin-like receptor by emodepside activates a signal transduction cascade via Gq-protein and phospholipase C, causing an increase in intracellular calcium and diacylglycerol levels. At the end of the signal transduction cascade, vesicles containing inhibitory neuropeptide fuse with presynaptic membranes. After fusion of these membranes, inhibitory neuropeptides may be released into the synaptic cleft to then stimulate a postsynaptic receptor. Recent findings indicate that a second emodepside target is the calcium-activated potassium channel slo-1. Binding to the latrophilin receptor and the slo-1 ion channel leads to inhibition of pharyngeal pumping, paralysis, and death.

The mode of action of praziquantel is not certain, but it rapidly causes tegumental damage and paralytic muscular contraction of cestodes, followed by their death and expulsion.[/size]

By
Jozef Vercruysse , DVM, Ghent University;
Edwin Claerebout , DVM, PhD, DEVPC, Department of Virology, Parasitology and Immunology, Faculty of Veterinary Medicine, Ghent University


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