Advantage Flea Control (active ingredient: Imidacloprid) - Information About Advantage Flea Medicine For Dogs and Cats.



This page contains general information about Advantage flea control®, commonly prescribed by veterinarians as a highly-effective, rapid, monthly, spot-on flea control product for cats and dogs. This page contains information on how Imidacloprid (the active ingredient of Advantage flea treatment) works; info on how to use Advantage flea medicine and information on the safety and efficacy of the Advantage flea control product. For added completeness, further information is also provided about Imidacloprid the insecticide (as used on crops and orchards).

Important note: I have researched and written this page to provide information on Imidacloprid from a veterinary perspective. I am not paid to promote Advantage For Dogs and Cats (the trading name of Imidacloprid flea control in Australia) or any of the other products containing the Imidacloprid insecticide (e.g. Advantix®, Advocate®), however, I can say that I have used the product in practice and have found that it acts well as an effective, monthly flea killer for cats and dogs (the function for which it was designed).

Furthermore, in a review of flea control products selected for use in a shelter situation (lots of dogs and cats and loads of fleas coming in the door every day), Advantage for Dogs and Cats was selected by my team as one of the three flea control products favoured for use (nitenpyram and selamectin being the other two), a decision that was based on many factors including: efficacy, safety, speed of action, environmental flea control, animal species treated (ferrets and rabbits also included) and cost-effectiveness.

Advantage®, Advantix® and Advocate® are registered trademarks of Bayer AG, Leverkusen, Germany.



Advantage flea medicine



Advantage Flea Control (Imidacloprid) - Contents:

1) What is the active ingredient of Advantage flea control?

2) What does Imidacloprid do to fleas and other insects? How does the Imidacloprid insecticide work?

3) Does Advantage for cats and dogs (imidacloprid) only kill adult fleas? What about other insect pests?

4) Advantage for dogs and cats - how to use Advantage spot-on flea control (includes information on storage and dosing).

5) CHEAP Advantage Flea Control - a useful veterinary tip on how to reduce the cost of Advantage.

6) How long does Advantage work for once it has been given? Does it really last the full month?

7) Is Advantage flea treatment waterproof? Can I get my dog or cat wet after using it?

8) What age can dogs and cats start having Advantage?

9) Can Advantage be used on other species besides the dog and cat?

10) Can Advantage Imidacloprid be used on pregnant or lactating animals?

11) Advantage flea medicine safety and side effects - How safe is Imidacloprid for pets?

12) How safe is Imidacloprid for people? Can I touch it?

13) Is Advantage flea treatment useful in dogs and cats suffering Flea Allergy Dermatitis (FAD)?

14) Imidacloprid insecticide - a common insecticide used in gardens and orchards.





Advantage flea control



1) What is the active ingredient of Advantage flea control?

The active ingredient in Advantage flea control is a chemical compound called Imidacloprid. The drug is a chloronicotinyl nitroguanidine insecticide belonging to a newer class of chemical insecticides called neonicotinoids.

Imidacloprid is closely related to other neonicotinoid insecticidal compounds including: nitenpyram (Capstar), acetamiprid, clothianidin, dinotefuran, thiacloprid and thiamethoxam, which are used in the control of fleas (imidacloprid, nitenpyram) and a wide range of other garden and crop pests (the use of imidacloprid insecticide in gardens and orchards is discussed in section 14 of this page). These chemicals bind to the post-synaptic nicotinic acetylcholine receptors (nAChR) of insect motoneurones (see next section for full details), causing paralysis of the insects and then death.

The product is adulticidal, meaning that it works to kill adult fleas. Advantage flea treatment is also larvicidal, meaning that it also acts to kill flea larvae present in the host animal's environment.

Imidacloprid as it occurs in Advantage flea control liquid is clear and colourless, tending towards yellow or brown. Advantage spot-on is not quite odorless, however, the smell is mild and in no-way noxious. Imidacloprid has a pH of 6.4 (almost neutral). It is miscible in water, meaning that it will dissolve to form a homogenous solution or suspension with water. Imidacloprid is chemically stable under normal conditions of storage and, although it is not dangerously incompatible with other materials or surfaces, it has been known to stain surfaces (including leather and floorboards). Imidacloprid should not be exposed to strong oxidising agents and nor should it be exposed to extremes of heat as the chemical is capable of boiling and even igniting.

Imidacloprid does not absorb well into the bloodstream or internal tissues when applied topically. Although the MSDS considers Imidacloprid to be non-dangerous when used appropriately, it is considered to be irritant to the eyes and sometimes the skin. Eyes need to be flushed thoroughly with water or an eye irrigation solution if the product gets into the eyes and it is recommended that hands are washed thoroughly with soap and water after the product is applied to pets. The product is extremely bitter tasting (cats that lick it will often salivate profusely with distaste). Imidacloprid can be harmful if significant amounts are swallowed or if the drug is inhaled (which can occur with vaporized forms of the insecticide that are applied to orchards). Should the product be inhaled, swallowed or allowed to contaminate the eyes, medical advice should be sought.

Tests on laboratory animals and cell cultures have determined that the chemical, Imidacloprid (Advantage flea control) does not cause mutations, cancer, fetal malformations (non-teratogenic) or any other reproductive effects. It should therefore be safe to use in pregnant animals and animals intended for breeding (see MSDS publications). Studies have found that the product is non-hypersensitising (i.e. animals tested didn't start to react to it with repeated use); non-photosensitising (it doesn't increase the skin's susceptibility to sun damage) and non-allergenic (animals rarely have allergic reactions to it). It must be mentioned that incidents of skin sensitivity reactions have been known to occur (see side effects section) and that reproductive effects have also been encountered at massively high doses during rodent testing (though the product is not generally considered unsafe to pregnant animals at normal doses).

Imidacloprid is considered compatible with a range of products designed to kill parasitic worms and fleas, including: lufenuron, permethrin, milbemycin, moxidectin, ivermectin, praziquantel, febantel and pyrantel.

Imidacloprid appears in a wide range of insecticidal products designed to kill insect pests in gardens and orchards. It is also included in a range of termite killing products worldwide. As far as flea control products go, Imidacloprid sometimes appears on its own in products (e.g. Advantage For Dogs and Cats), but sometimes it is also present in combination with other active ingredients to increase the spectrum of parasite kill. In Australia, Imidacloprid (10%) is combined with Moxidectin (1-2.5%, depending on the formulation) in the Bayer product: "Advocate" for the purposes of controlling fleas, mites and various parasitic worms, including heartworm. In Australia, Imidacloprid (10%) is also combined with Permethrin (50%) in the Bayer product: "Advantix" for the purposes of controlling fleas, ticks and repelling various insect vectors, including mosquitoes.

The Synonym for Imidacloprid is: Bay-NTN-33893 and
the Chemical Abstracts Service (CAS) registry number is: 138261-41-3

Imidacloprid is a schedule S5 drug.

Other chemical properties of Imidacloprid which are pertinent to those using the product as a plant insecticide:
The product can take the form of colourless crystals.
Imidacloprid is soluble in water. The solubility in water is 0.61g/L at 20 degrees Celsius.
Imidacloprid has a pH of 6.4.
The molecular weight is 255.7 g/mol.
The vapour pressure is 2hPa (3 x 10-12 mmHg) at 20 degrees Celsius, increasing to 11hPa at 55 degrees Celsius.
The density is 1.093-1.103 kg/L at 20 degrees Celsius.
The product boils at 207 degrees Celsius at 1013 hPa pressure.
The chemical has a flash point of 88 degrees Celsius and an ignition temperature of 415 degrees Celsius.
The Soil Sorption Coefficient (Koc) is 156-960, mean values 249-336.
The product is harmful if swallowed or inhaled so take precautions to avoid breathing it in or allowing it to contaminate food or water supplies. There are withholding times and maximum residue limits (MRLs) that must be complied with if Imidacloprid is to be used on crops (including tea, nuts and seeds) destined for human consumption.


To see the MSDS of Advantage For Cats and Dogs:
http://www.bayeranimal.com.au/PDFViewer/DocumentDisplayPage.aspx?CurrentDocumentID=%2bA2aUfpXGNP%2bUgcCTOKeLQ%3d%3d



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2) What does Imidacloprid do to fleas and other insects? How does the Imidacloprid insecticide work?

Advantage flea control spot-ons are administered to dogs, cats, rabbits and ferrets topically (directly on the skin). The Imidacloprid present in the Advantage flea medication does not enter the animal's bloodstream but merely distributes across the treated animal's skin, establishing itself within the superficial epidermis, hair follicles and sebaceous glands of the animal. The Imidacloprid is taken up into the adult flea's body during feeding and also during simple contact (i.e. the flea doesn't have to eat the insecticide to be poisoned - it just needs to touch it). Imidacloprid absorbs into the flea's body through the fine membranes located in the narrow gaps between the flea's chitonous exoskeleton segments (these thin membranes are termed intersegmental membranes).

Flea larvae in the host animal's environment become poisoned when dander (skin flakes) or flea feces (their natural diet) containing imidacloprid drop into the environment from the host animal's skin. The flea larva either consumes the Imidacloprid insecticide through actual consumption of the treated dander (or flea feces) or it takes up the insecticide via direct contact and absorption through the skin (again, no consumption is needed for the flea larva to be poisoned with imidacloprid - it just needs to make contact with the chemical). The flea larvae may also come into contact with the insecticide if the fur of the treated pet comes into direct contact with the larvae (e.g. on a pet bed).

Side note: Even though Imidacloprid is not recommended for oral use, studies have been conducted into the control of fleas on various wild animal species (rats in Uganda, California ground squirrels, black-tailed prairie dogs) using Imidacloprid laced food baits. The wild rodents eat the imidacloprid insecticide within the bait and the fleas then ingest the insecticide that gets absorbed into the animal host's bloodstream. These studies have shown a positive result, with significant declines in flea numbers for such species. It should be mentioned that such flea control in these species is aimed at controlling the fleas which carry human diseases (e.g. plague). The focus is not on saving the rodents from their fleas and this is possibly why the safety aspect of oral imidacloprid on the host animal has not been an over-riding focus in such studies. Oral feeding is also one of the more effective ways to distribute a treatment through a wild animal population (it is sometimes difficult to apply topical treatments to such animals). The studies have found that the oral baits need to be given weekly to maintain blood levels of imidacloprid and thereby maintain a flea control effect.

Once it enters the flea's body, the Imidacloprid kills the adult or larval flea.

How Imidacloprid works:

Imidacloprid is a neonicotinoid chemical, which, loosely translated, means: "new or novel nicotine-related" chemical. Neonicotinoid insecticides are synthetic variations of nicotine: a natural alkaloid compound that exists within the leaves of a variety of plant species of the Genus Nicotiana, including those trees responsible for producing tobacco (as in cigarettes). Imidacloprid and other drugs of the neonicotinoid family (e.g. nitenpyram as found in the flea control product: Capstar) act on the same bodily receptors as the drug nicotine does. These receptors are called nicotinic acetylcholine receptors (nAChR).

Nicotinic acetylcholine receptors in animals:
Nicotinic acetylcholine receptors (nAChR) are found in many locations within the animal nervous system. They are present in the synapses of the nerve bundles (called ganglions) supplying the parasympathetic and sympathetic nervous systems and they are also present on the surface of the animal's muscle cells where the nerves supplying the muscles make close contact (another form of synapse connection whereby the nerve end plate sends a chemical signal (a chemical called acetylcholine or ACh) to the muscle cells over a synaptic gap).

Explanatory author's note: Nerves are not continuous. For example, one nerve doesn't go straight from the brain to a toe. When the brain wants to tell a toe to move, it sends electrical nerve signals to the toe along of chain of interlinking nerves. These nerves communicate by relaying signals to one other in order along the chain. When one nerve wants to relay a signal (say, to the next nerve along the chain or to the muscle it wants to activate, like a toe muscle), it must do so by secreting a chemical called a neurotransmitter. Acetylcholine (abbreviated to ACh) is but one type of neurotransmitter. This neurotransmitter crosses a small gap between the nerve that secreted it (the nerve 'sending the message') and the next nerve or muscle intended for activation. This gap is called a "synapse". The neurotransmitter binds to a receptor on the nerve or muscle intended for activation, causing activation to occur. The receptor that receives ACh and becomes activated is called the acetylcholine receptor (AChR). There are a couple of types of AChR and one type is called a 'nicotinic' AChR because scientists found that the drug "nicotine" also activated this particular acetylcholine receptor in much the same way as true acetylcholine did (i.e. nicotine worked by binding to and activating those particular acetylcholine receptors of the body thereby mimicking the AChR activation effects of the body's own natural ACh).

When nicotine or the body's own acetylcholine activates the 'nicotinic' acetylcholine receptors in the body, it causes activation of the sympathetic and parasympathetic nerves (via activation of the nerve synapse bundles or ganglia supplying them) and also activation/stimulation of the body's muscles. Concurrent activation of the sympathetic and parasympathetic nervous systems through activation of the nicotinic AChR in the neural ganglions produces a wide range of effects, some of which are typical of parasympathetic nerve stimulation and some of which are more typical of sympathetic (flight or fight) nerve stimulation. These include: peripheral blood vessel constriction, effects on the heart rate (sometimes the heart will race, in keeping with sympathetic stimulation, and sometimes it will slow, in keeping with parasympathetic nerve effects), effects on blood pressure (often an increase), pupil dilation, increased mental stimulation and alertness, increased saliva production and increased gastrointestinal activity among other effects. Activation of the body muscles is needed to create muscle contraction and movement.

When taken to extremes (e.g. if someone took excessive and toxic quantities of nicotine or if they took a poison like a carbamate-based snail bait that increased their levels of acetylcholine excessively), the effects of excessive acetylcholine receptor stimulation can be severe and life-threatening, producing extreme blood vessel constriction (with pallor); massive increases in blood pressure; increases in heart rate (to the point of heart palpitations or even life-threatening arrhythmias) or, alternatively, critical heart slowing; profound drooling; excessive gut contractions (to the point of vomiting or diarrhea); hyperactivity (or sometimes depression/lethargy) and extreme muscle activation and contraction, to the extent that the muscles are so over-stimulated they start to tremor uncontrollably (similar in appearance to seizuring), eventually becoming rigidly stiff and immobile and, in essence, completely paralyzed (incapable of moving from the rigid state). Such rigidity in the muscles responsible for moving the rib cage in and out causes the animal to breathe shallowly (some animals become completely incapable of drawing breath in and out and thus the animal dies from a lack of oxygen). Excessive muscle stimulation and rigidity also causes the animal to produce excessive body heat (muscle activity produces heat - which is why we shiver when we are cold - to warm up), causing extreme hyperthermia and often death from excessive body heat.

So where does the flea and the Imidacloprid fit in?
Imidacloprid is a neonicotinoid, meaning that it is related to and resembles nicotine in effect. Similar to the situation described above for nicotine poisoning, Imidacloprid causes excessive stimulation and swamping of the nicotinic acetylcholine receptors, producing rigidity, paralysis and death. The fantastic thing about Imidacloprid, however, is that, due to its chemical structure, it is fairly specific for the nicotinic acetylcholine receptors present on the nerves of insects like fleas. It binds strongly to insect nAChR causing intense activation of these receptors and resultant rigidity and paralysis of the insects (thus killing the fleas). Imidacloprid binds very poorly to the nicotinic acetylcholine receptors of vertebrate animals (e.g. dogs and cats and even birds and fish) and thus it does not have as great an effect on these species (unless given in massive doses). This is the reason why side effects and toxicity effects are very uncommon in animals given Imidacloprid-containing Advantage flea control treatments.

Author's note: insect nicotinic acetylcholine receptors are only found in the central nervous system of the insects, not directly on the muscles as seen in vertebrates. The ultimate effect is still very similar, however. Neonicotinoid insecticides bind to the nicotinic receptors, causing them to become activated and overstimulated. The insect develops rigidity and twitching as a result. Following this period of nerve activation, the neonicotinoid drug does not unbind from the nicotinic receptor in the way that acetylcholine does (in animals, acetylcholine bound to the nAChR degrades, allowing the effect to cease). This results in the nicotinic receptors being swamped and overstimulated to the extent that the nerves become exhausted. The exhausted nerves can not send any signals at all then, (particularly since the receptors are all clogged up with neonicotinoid compounds) and, as a result, the insect becomes fully paralysed.

A 2003 article in the Annual Review of Entomology confirmed the different effect of neonicotinoids on vertebrates versus insects. It showed that neonicotinoid chemicals like Nitenpyram and Imidacloprid were toxic to insects and not to vertebrates (the study focussed on mammals) because of differences in the structure of insect and mammalian nicotinic acetylcholine receptors (nAChR). The neonicotinoid drugs were capable of binding to insect nAChR and causing toxicity signs, but they were not as capable of binding to mammalian nAChR. The active 'binding site' of mammalian nAChR is negatively charged (anionic), whereas the active 'binding site' of insect nAChR (the site on the nicotinic receptor where the neonicotinoid drugs bind to exert their activation effect) is positively charged (cationic). Being positively charged, the insect nAChR is ideally suited to binding with the neonicotinoid chemicals which are negatively charged, whereas, the negatively charged mammalian nAChR would only repel these chemicals, stopping them from exerting an effect.

Imidacloprid is considered to be a "partial agonist" at the insect nAChR, meaning that it binds less strongly to the receptor and does not exert as extreme or rapid a stimulatory effect as a "full agonist" would (though the effect it has is still irreversible, such that it eventually causes the death of the flea, particularly at high doses).

Nitenpyram, another related flea control product, is considered to be a "full agonist" at the insect nAChR, meaning that it binds strongly to and exerts a full stimulatory effect on the insect's nicotinic acetylcholine receptor. Thus, it works more quickly and aggressively to swamp the nAChR receptors on the flea's nerves causing complete over-stimulation and rapid obstruction of nerve signals and resultant paralysis. The effect is faster with Nitenpyram, but the end result of both drugs (Imidacloprid and Nitenpyram) is exactly the same - the death of the flea.

A 2007 study, published in Neurotoxicology, looked into the effect of various neonicotinoids on cockroach neurons and found imidacloprid to produce only about 20-25% of the effect of acetylcholine when applied to cockroach nAChR. Nitenpyram, in contrast, produced an effect that was 60-100% of the effect of acetylcholine (i.e. full effect and much more rapid and powerful). The result was different poisoning symptoms in the cockroaches, with depression and full paralysis observed for the full agonist compounds (e.g. Nitenpyram) and excitation responses predominating before death for the partial agonist compounds like imidacloprid (e.g. reference 54 described roaches poisoned with imidacloprid as showing: reduced leg strength, "then leg tremors, then body shaking and then death"). The reason for the different symptoms is likely to be related to the full/partial agonist difference. The full agonist completely and rapidly binds to and swamps the system, producing extreme spasms and rigidity and immobile, stiff paralysis, whereas the partial agonist binds poorly and exerts a slower, less-complete activation effect on the receptors, resulting in a more gradual onset of effect, characterised by an obvious excitation phase.



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3) Does Advantage for cats and dogs (imidacloprid) only kill adult dog and cats fleas? What about other insect pests?

Advantage flea control kills adult fleas present on the body of the host dog or cat (or ferret). It also kills flea larvae present in the environment of the host animal. Fleas and their larvae are killed through consumption of the insecticide or through absorption of the chemical through their skin.

The effects of Advantage flea control have mainly been studied using various strains of the cat and dog (and ferret) flea species, Ctenocephalides (Ctenocephalides felis and Ctenocephalides canis). This is because these species of flea are common, because they breed and grow rapidly in a laboratory setting (making them easy to study) and because the cat flea in particular is considered to be one of the major parasite pests affecting pets and humans worldwide.

Various studies have shown Imidacloprid to be highly effective against a range of other flea species including: rabbit fleas (Cediopsylla and Spilopsyllus); the oriental rat flea (Xenopsylla cheopis) responsible for transmitting the bubonic plague (Yersinia pestis) throughout much of the third world; the fleas on black-tailed prairie dogs (Cynomys ludovicianus); the human jigger flea (Tunga penetrans); the fleas on California ground squirrels (Spermophilus beecheyi) which are a major vector of plague in the USA; the squirrel fleas (Ceratophyllus sciurorum) infesting farmed mink (Mustela vison) and the flea species, Pygiopsylla hoplia, which infests such Australian marsupial species as the Eastern barred bandicoot (Perameles gunnii), the eastern quoll (Dasyunrus viverrinus), the fat-tailed dunnart (Sminthopsis crassicaudata), the Leadbeater's possum (Gymnobelideus leadbeateri), the yellow-bellied glider (Petaurus australis) and the ring-tailed possum (Pseudocheirus peregrinus).

Advantage flea control works to kill fleas quite rapidly:
According to the manufacturer, Advantage flea control is fast acting, killing adult fleas and flea larvae within 20 minutes of contact with the intersegmental membranes of the insects and stopping them feeding within 5 minutes. The product, though, is applied only to one spot on the animal and, therefore, takes time to distribute across the entire body protecting all of the places fleas hide out. Therefore, whilst fleas in the region of application will probably die within 20 minutes, do not expect to see all fleas all over the body dying within 20 minutes. The fleas have to come into contact with the product, either through the product diffusing across the skin or the fleas crawling onto the regions the imidacloprid has reached.

It's not all doom and gloom though. Distribution across the skin layer seems to be quite rapid (or the fleas move around the pet's body a lot) such that a 98-100% flea kill (body-wide) is generally achieved within 12 hours of dosing. A 2005 study, published in Veterinary Therapeutics compared the speed of flea kill of selamectin, imidacloprid and fipronil-S-methoprene. The study found that imidacloprid had the most significant % flea kill of all the topical preparations by 6 hours, but that by 24 hours after dosing all three products had achieved a >95% flea kill.

A 2003 article published in Veterinary Parasitology confirms this. The study compared the speed of kill and percentage of flea kill between five of the major flea control products on the market at that time (Nitenpyram, Fipronil, Imidacloprid, Selamectin and Cythioate). The results for Nitenpyram were most impressive, but the results for Imidacloprid were not far behind. Within 3 hours, "nitenpyram was 100% effective in cats and 99.1% effective in dogs" and 100% effective in both species at 8 hours. Cythioate (used on cats only in the study) showed a 62.4% and 97.4% flea kill at 3 and 8 hours, respectively. Selamectin (used on dogs only in the study) showed a 39.7% and 74.4% flea kill at 3 and 8 hours, respectively. In dogs, Fipronil showed a 35.9% and 46.5% flea kill at 3 and 8 hours, respectively, whereas, in cats, the respective percentage kills were 24.3% and 62.6%. Imidacloprid in cats showed only a 26.9% flea kill at 3 hours, but then a rapid recovery response and an 82.8% flea kill at 8 hours. In dogs, a similar pattern was seen with a lower % kill (22.2%) at 3 hours, but a high % kill (95.7%) at 8 hours.

The speed of flea kill does tend to wane during the month following dosing with Advantage flea control (as it does for all three major topical preparations prescribed by vets). A 2005 study published in Veterinary Therapeutics demonstrated this. It showed that Imidacloprid (Advantage flea control) had the highest % flea kill within 6 hours of initial dosing (out of Fipronil, Imidacloprid and Selamectin), but that all products had achieved a >95% flea kill by 24 hours of dosing. Fleas were re-introduced to the cats at day 7 (to mimic a reinfestation event) and all three formulations showed a similar effect, with a 68.4% flea kill at 6 hours post flea-introduction and a massive (highly effective) 99.4% flea eradication at 24 hours. At day 21 and then again at day 28, more fleas were introduced and there was no appreciable kill of those fleas within 6 hours. The new fleas did die, but they took longer (up to 2 days were allowed before the % flea kill was determined), showing that the speed of kill declines with the time passed since dosing.

Advantage flea control maintains a high efficacy (% kill) for the full month - depending on the study you read:
Advantage flea control is designed to maintain its high % flea killing effect for at least 1 month following dosing (after which the next dose is due). Whether this actually occurs to a moderately high degree (70-80% flea kills at 28 days) or a really high degree (>90% flea kills at 28 days), however, depends on the study you look at.

The 2005 study published in Veterinary Therapeutics (described above) found that, at the 28-day mark, selamectin was still achieving a 99% flea kill within 2 days of fleas being re-introduced to the treated pet. Fipronil, in contrast, only achieved an 86.4% efficacy in that time and Imidacloprid (Advantage flea control) only achieved a 72.6% flea kill at the 28-day flea-re-introduction mark. From this study it can be said that Advantage is still effective 1 month after dosing, however, its efficacy (% flea kill) at that stage is nowhere near the efficacy seen in the first weeks of dosing. Of the three, selamectin seems to maintain its effect the best and have the highest residual activity. If this is true, then this particular short-fall could be quite easily remedied by dosing Advantage a bit more frequently than monthly (perhaps 2-3 weekly instead).

In contrast to this, a 2001 study published in Veterinary Record did a similar thing. Animals were dosed with either selamectin, fipronil or Advantage and flea populations were re-introduced at days 7, 14, 21, 28 and 35 following dosing. The results, however, were quite different to the 2005 study. In this study, all three treatments maintained exceptional efficacy for the full month with imidacloprid (Advantage flea control) showing a 98-100% flea kill 48 hours after fleas were re-introduced on the 28th day of testing. The study showed no appreciable difference between the three products. This study appears to give confirmation of the manufacturer's claim that Advantage flea control will maintain its excellent effect for a full month after treatment.

In contrast again, a 2008 study published in Veterinary Therapeutics compared the efficacy of imidacloprid, selamectin, fipronil and metaflumizone. This study showed that all flea products had a similar, very high efficacy 24 hours after initial dosing. Imidacloprid was found to have maintained the highest efficacy by day 34 (in contrast the 2005 study, which found that it had the lowest), with a 90.8% flea kill 24 hours after fleas were re-introduced on day 34. The other products, in contrast to this, only showed a meagre 55.7% to 67.4% flea kill when fleas were reintroduced on day 34.

Fleas are still highly susceptible to Advantage flea control (resistance has not yet developed):
It is important that the fleas are not resistant to the flea control product you are using, otherwise no fleas will be killed by it. Since Advantage flea control has been around such a long time and used so heavily, one would expect fleas to now be developing resistance to the product. Incredibly, though, this has not occurred.

A 2011 study published in Medical Veterinary Entomology looked at populations of fleas from countries where Advantage flea control use has been high and prolonged (Australia, Germany, UK, France, USA) to see whether the fleas (Ctenocephalides felis, in this case) were still susceptible to the Imidacloprid insecticide. The results indicated that fleas had not yet developed resistance towards the product.

What does Advantage flea medication do to immature flea stages (eggs, larvae, cocoons):
Advantage flea control kills flea larvae in the environment. Flea larvae in the host animal's environment become poisoned when dander (skin flakes) or flea feces (their natural diet) coated with imidacloprid drop into the environment from the host animal's skin. The flea larva either consumes the Imidacloprid insecticide through actual consumption of the treated dander (or flea faeces) or it takes up the insecticide via direct contact and absorption through the skin (again, no consumption is needed for the flea larva to be poisoned with imidacloprid - it just needs to make contact with the chemical). The flea larvae may also come into contact with the insecticide if the fur of the treated pet comes into direct contact with the larvae (e.g. on a pet bed).

A 2000 study in the Journal of Medical Entomology confirmed that imidacloprid was capable of transferring from the animal's coat and into the local environment at sufficient enough quantities to kill flea larvae. Cats were treated with Advantage flea control and allowed to hang-out on test blankets. There was a 100% failure of adult flea emergence in the flea eggs incubated on imidacloprid contaminated blankets within the first week of treatment.

A different study published in 2001 in Medical Veterinary Entomology also looked at imidacloprid build-up in the environment of treated pets and the subsequent effect on flea larvae. In this study, cats were treated with imidacloprid and allowed to hang out on fleece blankets for 60 to 120 hours over a period of 2-4 weeks. The blankets were stored for 18 weeks and then flea eggs were incubated on them. There was enough insecticide on the blankets to reduce flea larvae survival by >94%. The study found that hot laundering with detergent removed the imidacloprid effect.

A 2001 study published in Parasitological Research examined the in vitro effect of fipronil, imidacloprid and selamectin on flea larvae and adult fleas. Of the three chemicals, only imidacloprid was found to kill flea larvae and flea adults on direct body contact. Imidacloprid killed all fleas and larvae within 1 hour of direct contact (confirming Bayer's claim that fleas start to die within 20 minutes of application), whereas up to 24 hours was needed for all adult fleas to die after exposure to the fipronil or selamectin.

It should also be noted that Advantage flea medication works so quickly, adult fleas rarely get a chance to lay their eggs before they die. The Bayer site says that the product "kills 98-100% of fleas before they can lay their eggs". Thus, the quantity of fertile flea eggs falling from the coat (and into the environment) of an Advantage treated animal is greatly reduced. Environmental contamination with flea eggs is minimized.

How does Advantage flea control affect adult flea feeding times?:
According to the manufacturer, Advantage flea control stops fleas from feeding within 5 minutes, making it highly useful in animals suffering flea allergy dermatitis and helpful in the prevention of flea-transmitted diseases.

In contrast to this, a 2008 study, published in the journal of Veterinary Parasitology, examined the effect of various flea control products, including Advantage flea medication, on flea feeding times and blood consumption quantities. The study found that only Capstar flea control pills (nitenpyram) and topical selamectin caused a statistically significant reduction in blood consumption by fleas. Imidacloprid and Fipronil did not.

A 1998 study in Parasite also looked at the "antifeeding effect of several insecticidal formulations against Ctenocephalides felis on cats." Individual cats were treated with different topical flea control products, including imidacloprid (Advantage flea control). Cats were subsequently infested with unfed fleas in the days to weeks (up to 6 weeks) following the application of the topicals. An hour after fleas were re-introduced, the fleas were combed out and the amount of blood consumed by them was assessed. Topical imidacloprid and fipronil were not shown to prevent fleas from feeding prior to their deaths (comment was not made as to the actual quantity of blood taken up). Still, Bayer does not make the claim that Advantage flea control actually 'prevents' flea feeding, it just states that fleas are stopped from taking up blood very quickly (within 5 minutes).

How does Advantage flea control affect other parasites?:
Advantage flea control kills lice on dogs (Trichodectes canis and Linognathus setosus). It doesn't seem to be registered for killing lice on cats, but I imagine it might (it would be certainly worth a trial).

Imidacloprid exerts a similarly lethal effect on a wide range of crop, orchard, soil and garden pest insect species including, but not restricted to, the soybean aphid, the hemlock woolly adelgid, the potato leafhopper, the Japanese beetle, the grape berry moth, various leaf- and planthoppers, whiteflies, thrips, scales, flea beetles, leaf-miners, mealy bugs, beetles, leaf beetles, termites, locusts and cockroaches.

Imidacloprid is non-selective when it comes to insects and will also kill insect species that are of benefit to gardens, crops and water courses. Honeybees are considered highly susceptible, as are various parasitoid wasps (wasps that prey on pest insect species) and arthropod nymphs that live in waterways.

Advantage For Cats and Dogs (Imidacloprid only) does not kill ticks.

Advantage flea treatment does not kill ascarids (worms).





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4) Advantage for cats and dogs - how to use Advantage spot-on flea control (includes information on storage and dosing).

Advantage flea control spot-ons are given to dogs and cats over weaning age (over 6 weeks of age). A full applicator of Advantage flea control is applied directly to the dog or cat's skin, usually between the shoulderblades (where it can not be licked off). The particular dose (size of applicator) chosen depends on the species and size of the animal (though there are tricks for getting the best bang for your buck, which I have provided in section 5). Animals are generally given a dosage volume that is equivalent to an effective dosage rate of 10mg/kg Imidacloprid.

Advantage for small cats and kittens up to 4kg (Advantage orange packet) - each monthly dose contains 0.4ml of imidacloprid 100g/L liquid.
Advantage for cats over 4kg (Advantage violet/Advantage purple) - each monthly dose contains 0.8ml of imidacloprid 100g/L solution.
Advantage for small dogs and puppies (and ferrets and rabbits) up to 4 kg (Advantage dark green) - each monthly dose contains 0.4ml of imidacloprid 100g/L solution.
Advantage for dogs (and rabbits and ferrets) 4-10kg (Advantage turquoise) - each monthly dose contains 1ml of 100g/L Imidacloprid solution.
Advantage for dogs 10-25kg (Advantage red/Advantage maroon) - each monthly dose contains 2.5ml of 100g/L Imidacloprid solution.
Advantage for dogs over 25kg (Advantage blue) - each monthly dose contains 4ml of 100g/L Imidacloprid solution.

If the dog is over 25kg, it is recommended that the dose be divided along the animal's back to improve speed of distribution of the imidacloprid insecticide. 1 spot is applied between the shoulder-blades, one between the hips (on the dorsum, just behind the lumbar spine) and one spot is placed in between.

It is also recommended that the dose be split in this manner (2-3 spots along the dorsum) if you are treating rabbits for fleas.

If the dog is over 50kg, the dog gets two of the Advantage blue vials. It is recommended that the dose be divided along the animal's back to improve speed of distribution of the imidacloprid insecticide. 1 applicator is applied between the shoulder-blades and the other is divided with one spot going between the hips (on the dorsum, just behind the lumbar spine) and the other spot going somewhere between the two.

Advantage for cats and dogs is generally available in packs of 4 (to last one animal 4 months) or 6.

Advantage is available at vet clinics and can usually be purchased over the counter.

The fur is parted and the Advantage flea control solution is applied directly to the skin. The skin should be clean and dry.

Do not apply the solution to wet skin.

Do not allow pets to the lick the solution (usually they can't reach behind their shoulders, but some can). Animals do not usually ingest much of the solution if they lick it because the taste is so bad (cats will react by salivating and frothing at the mouth), however, excessive ingestion can be toxic, so owners need to be mindful of not letting their animal lick.

Though the product is not considered highly dangerous if you get it on your hands during application, it is recommended that you wash your hands thoroughly with soap and water to remove it.

Unweaned puppies and kittens will be protected from fleas if you treat the mother (the Advantage from her coat will distribute to the coats of her nursing babies). You do not need to treat the unweaned pups or kittens individually. Once the pups or kittens have weaned, you can start them on Advantage flea control.

Advantage flea medicine is designed to be given monthly. Owners who want to use it more often (it is not typical that you would need to unless you are bathing your animal a lot) should never apply the product more frequently than weekly. The company suggests that washing animals with soap-based shampoos regularly will cause the Advantage to become prematurely ineffective (not last the full month) and suggests that pet owners wash their pets with soap-free shampoos if they are using Advantage. Other forms of wetting (swimming, rain) do not appear to deactivate the Advantage, but if you think they are, you can use the product more often (just not more often than weekly). If you are using the product in ferrets, you may need to give the product more frequently (Advantage flea control does not last a full month in ferrets - see study at the end of this section).

Be aware that some animals may lose their hair at the site of Advantage application. This is generally short-lived and the hair will usually grow back.

Also be aware that Advantage for cats and dogs can stain some surfaces (e.g. leather and polished floor boards). Animals should be kept off such surfaces until the Advantage solution has thoroughly dried on their coats.

All canine and feline pets in the household should be treated at the same time with Advantage flea control products. This is because untreated pets can act as reservoirs for the flea life cycle.

Treatment should begin in Late Winter or Early Spring at the start of the flea season. Treatment can, however, start anytime fleas are noticed on our canine and feline friends. If flea numbers are very high in the environment, the Advantage flea treatment, used properly, will eventually result in decent overall flea control, however, adding in a flea treatment that is specifically designed to control flea larvae and eggs in the environment (e.g. Lufenuron) can also be helpful at speeding up the elimination of fleas from the environment. Advantage is compatible with Lufenuron. Treating the environment for fleas (flea bombs, vacuuming, steaming) is also beneficial.

Advantage flea control can also be given to clean (flea-free) animals to protect them when they enter a flea-risk environment (e.g. dog show, vet, groomer, dog training, friend's house containing fleas and so on). This will prevent the animal from catching fleas and bringing a flea problem back to your house. Apply Advantage flea control about 2-3 days (no less than 24 hours) before going to the flea-risk environment.

Advantage flea control should be stored at room temp (below 30C), in a cool, dry place, well away from direct sunlight. It should not be exposed to temperatures under 0 degrees or greater than 50 degrees Celsius as such temperatures will deactivate the imidacloprid and render the product ineffective.

Advantage flea control must be stored well away from food, drink or animal food as contamination of these products with imidacloprid will render them unfit (unsafe) for human or animal consumption.

For safety, Advantage flea control should be kept out of reach of children. The product is irritant to the eyes and potentially toxic if ingested.

Advantage flea control can be used with other commonly used products and medications including: heartworm preventatives, all-wormers, vaccines, antibiotics and some other flea control products (e.g. Lufenuron).

An important note on ferrets and Advantage:
A 2001 study in Medical Veterinary Entomology looked at the control of cat fleas in domestic ferrets (Mustela putorius furo) using Imidacloprid. Ferrets were given the usual topical dose of 10mg/kg Imidacloprid (e.g. a ferret up to 4kg would get 0.4ml of the 100g/L Advantage flea control solution). Within 8 hours of treatment, 95.3% of fleas had gone and by 24 hours the efficacy was 100%. Fleas were then reintroduced weekly to see if the Advantage flea control would protect the ferret for the full month. Fleas were applied 1 week after initial dosing and 92.9% of them were dead within 24 hours. Fleas applied 2 weeks after dosing had greater survival with only 55.7% of fleas killed by 24 hours. At 3 and 4 weeks post-dosing, there was no appreciable death of re-introduced fleas. This suggests that Advantage is useful against fleas in ferrets but that it needs to be given more often (1-2 weekly) to maintain its effect.

Information sheets:
http://www.bayeranimal.com.au/default.aspx?Page=50&ItemId=75
http://www.bayeranimal.com.au/PDFViewer/DocumentDisplayPage.aspx?CurrentDocumentID=%2bA2aUfpXGNP%2bUgcCTOKeLQ%3d%3d
http://www.bayeranimal.com.au/PDFViewer/DocumentDisplayPage.aspx?CurrentDocumentID=OCqHyRh37u9Om4AajzlYMQ%3d%3d
http://www.bayeranimal.com.au/PDFViewer/DocumentDisplayPage.aspx?CurrentDocumentID=XpWm37T%2bVbaj7DMSVMm8UQ%3d%3d



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5) CHEAP Advantage Flea Control - a useful veterinary tip on how to reduce the cost of Advantage.

All of the different Advantage products have the exact same concentration of imidacloprid solution in them: 100g/L. The only difference between the little vials that you put on dogs and cats of different weights is the quantity of liquid in the vial. That's it. Nothing more.

The cool thing is, the price of Advantage does not go up in proportion to the quantity of imidacloprid present in the vials. A 6-month pack of Advantage for cats weighing over 4 kg has 0.8ml of solution in each vial and a 6-month pack of Advantage for cats weighing under 4kg has only 0.4ml solution in each vial, but the price of the two products is very similar (i.e. the 0.8ml vials do not cost double the 0.4ml vials). The same goes with the dog products. The difference in price between a pack of Advantage blue (4ml per vial) and a pack of Advantage dark green (0.4ml per vial) is not that huge (it is certainly NOT 10 times the cost).



Therefore, you can save a lot of money if you have multiple pets or pets of different sizes by buying the larger packs and dispensing the appropriate dosage volumes out to each animal yourself (use a needle and syringe to draw up the correct amount for the weight of each animal and then remove the needle and apply the drawn-up dose to the animal's skin as per normal).

Say you have two cats under 4kg. You could buy a 6-month pack of "Advantage for cats under 4kg (Advantage orange)" and use one of the 0.4ml vials on each cat. This would be fine, but every month you'd be using up two vials and thus your 6-month pack would only last 3 months between the two animals. Alternatively, you could buy a 6-month pack of "Advantage for cats over 4kg (Advantage violet)" and divide the 0.8ml vial into two doses of 0.4ml. You could then apply the required 0.4ml to each animal meaning that you would only use up one vial per month on the two animals and thus your packet of Advantage would last you the full 6 months, saving you from buying more.

The same kind of thing applies to the dog formulations. Say you had a dog of 23kg and a dog of 8kg. The 23kg dog needs to have Advantage maroon, which contains 2.5ml per vial, but the 8kg dog needs to have Advantage turquoise, which only has 1ml per vial. Rather than buying two separate packs of Advantage for the two dogs, you could just buy a pack of Advantage blue which has 4ml per vial. Then you could dispense 2.5ml out to the big dog and 1ml out to the smaller dog and still have 0.5ml left over which would be enough (0.4ml dose) to treat a cat or small dog under 4 kg in weight. And all for the cost of a single packet.

Important points if you are planning on dividing doses:
1) Check that the concentration of drug is the same for all different formulations (100g/L). It currently is, but this can change at any stage should the company decide to alter its packaging. If all pack-types have the same concentration of drug and only differ in the quantity of solution present in each vial, then dividing the doses as I have described above should work fine.

2) Throw out all unused portions of the solution. Once you have opened a vial and dispensed the doses between your animals, do not feel tempted to keep the 'left over' liquid. Open packs can leak (the drug is potentially toxic) and there is no guarantee the left over solution will remain effective once heat and light and moisture has gotten to it.

3) Wear gloves when dividing up the doses into syringes. You don't want to get any insecticide chemical on your hands so get yourself a box of disposable surgical gloves (they'll last years) to protect yourself from the outset.

4) Use a needle and syringe to draw up the correct amount for each animal. A 1ml syringe is best for cats and small dogs where the volume you want to draw up (e.g. 0.4ml or 0.8ml) is under 1ml. Larger syringes can be used for larger volumes.

5) Make sure you weigh your animal using scales (e.g. go to your vet and weigh your pet/s). Do not guess your pet's weight as incorrect guessing could result in under-dosing or over-dosing.

6) Place all needles and syringes in a 'sharps container' after use and keep them well out of reach of minors. The needles and syringes can be returned to your vet or a needle disposal center for safe disposal. Never put needles in the bin - they need to be disposed of properly.

7) If you are worried about having needles on your premises, you can simply buy syringes instead. You can then just squeeze the contents of an Advantage vial out into a small, disposable, clean plastic container and suck the required amount up in the syringes without any need for a needle at all! These syringes and the container can go into the bin. Better yet, you could squeeze the contents of the vial out into the depression in the 'blister pack' that the Advantage vial was resting in and suck it up from there. Dispose of the packaging with the syringe following dosing.


Amounts needed of 100g/L spot-on imidacloprid solution:
Kittens and small cats up to 4kg - 0.4ml.
Cats over 4kg - 0.8ml.
Puppies and dogs under 4kg - 0.4ml.
Dogs 4-10kg - 1ml.
Dogs 10-25kg - 2.5ml.
Dogs over 25kg (to 50kg) - 4ml.

Much thanks goes to Bayer for packaging their Advantage flea control product in this convenient, uniformly concentrated way. It is a good company that designs its products for the added convenience of customers who own multiple pets.

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6) How long does Advantage work for once it has been given?

The company that manufactures Advantage flea control topical states that the product will maintain its effectiveness for 1 month following dosing (after which the next dose is due). Whether this efficacy (% flea kill) actually occurs to a moderately high degree (70-80% flea kill at 28 days) or a super high degree (>90% flea kill at 28 days), however, depends on the study you read. There are quite a few studies that have been performed looking into the efficacy of flea control products over time and their results can be somewhat variable.

A 2005 study published in Veterinary Therapeutics demonstrated that the speed of flea kill does tend to wane during the month following Advantage flea treatment dosing (as it does for all three of the major topical preparations prescribed by vets). The study showed that Imidacloprid (Advantage flea control) had the highest % flea kill within 6 hours of initial dosing (out of Fipronil, Imidacloprid and Selamectin), but that all products had achieved a >95% flea kill by 24 hours of dosing. Fleas were re-introduced to the cats at day 7 (to mimic a reinfestation event) and all three formulations showed a similar effect, with a 68.4% flea kill at 6 hours post flea-introduction and a massive (highly effective) 99.4% flea eradication at 24 hours. At day 21 and then again at day 28, more fleas were introduced and there was no appreciable kill of those fleas within 6 hours. The new fleas did die, but they took longer (up to 2 days before the % flea kill was determined), showing that the speed of kill declines with the time passed since dosing.

The 2005 study found that, at the 28-day mark, selamectin was still achieving a 99% flea kill within 2 days of fleas being re-introduced to the treated pet. Fipronil, in contrast, only achieved an 86.4% efficacy in that time and Imidacloprid (Advantage flea control) only achieved a 72.6% flea kill at the 28-day flea-re-introduction mark. From this study it can be said that Advantage is still effective 1 month after dosing, however, its efficacy (% flea kill) at that stage is nowhere near the efficacy seen in the first weeks of dosing. Of the three, selamectin seemed to maintain its effect the best during that study and have the highest residual activity. If this study is representative of the true situation, this particular short-fall in maintenance of efficacy could be quite easily remedied by dosing Advantage a bit more frequently than monthly (perhaps 2-3 weekly instead).

In contrast to this, however, a 2001 study published in Veterinary Record did a similar thing and achieved vastly different results. Animals were dosed with either selamectin, fipronil or imidacloprid (Advantage) and flea populations were re-introduced at days 7, 14, 21, 28 and 35 following dosing. In this study, all three treatments maintained exceptional efficacy for the full month with imidacloprid (Advantage flea control) showing a 98-100% flea kill 48 hours after fleas were re-introduced on the 28th day of testing. The study showed no appreciable difference between the three products. If this study is representative of the true situation, then it appears to give confirmation of the manufacturer's claim that Advantage flea control will maintain its excellent effect for the full month after treatment.

In contrast again, a 2008 study published in Veterinary Therapeutics compared the efficacy of imidacloprid, selamectin, fipronil and metaflumizone and showed imidacloprid to be superior. Although all flea products had a similar, very high efficacy 24 hours after initial dosing, it was imidacloprid that was found to have maintained the highest efficacy by day 34, with a 90.8% flea kill 24 hours after fleas were re-introduced on day 34. The other products, in contrast to this, only showed a meagre 55.7% to 67.4% flea kill when fleas were reintroduced on day 34.

Yet another study was performed using "naturally infested" dogs and cats living in household situations in Tampa, Florida. Households were divided into two groups with pets being treated with either imidacloprid or fipronil. The flea control products were given every month for 3 months. The study, published in Veterinary Parasitology in 2000, showed that imidacloprid had achieved a 95.3% flea kill 24 hours after the first dose and that the effectivity was still super high after 28 days (just prior to the next dose being given) with a 97.4% effectiveness recorded. Fipronil showed similar results (97% at day 28). Flea burdens on the pets after 3 months of dosing were reduced by 99.5% with imidacloprid (96.5% fipronil) and flea burdens within the house itself were found to have dropped by 99% with imidacloprid (98.6% for fipronil). This shows that imidacloprid is highly effective in a 'real world' situation and not just in lab.

Overall, I would be content to say that Advantage flea control most likely maintains a very high level of effectiveness over the month following dosing.

An important note on ferrets and Advantage:
A 2001 study in Medical Veterinary Entomology looked at the control of cat fleas in domestic ferrets (Mustela putorius furo) using Imidacloprid. Ferrets were given the usual topical dose of 10mg/kg Imidacloprid (e.g. a ferret up to 4kg would get 0.4ml of the 100g/L Advantage flea control solution). Within 8 hours of treatment, 95.3% of fleas had gone and by 24 hours the efficacy was 100%. Fleas were then reintroduced weekly to see if the Advantage would protect the ferret for the full month. Fleas were applied 1 week after initial dosing and 92.9% of them were dead within 24 hours. Fleas applied 2 weeks after dosing had greater survival with only 55.7% of fleas killed by 24 hours. At 3 and 4 weeks post-dosing, there was no appreciable death of re-introduced fleas. This suggests that Advantage is useful against fleas in ferrets but that it needs to be given more often (1-2 weekly) to maintain its effect (caution with dosing though as ferrets can be susceptible to toxicity with certain drugs).

An important note on bathing dogs:
The manufacturer states that Advantage flea control is capable of maintaining its month-long effectiveness in animals that are regularly wetted (swimming, bathing, rain), but that more frequent application may be needed in animals that are regularly shampooed with soap-containing shampoos. The manufacturer advises washing dogs and cats with a soap-free shampoo if the effectiveness of advantage flea control is to last the month.



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7) Is Advantage flea treatment waterproof? Can I get my dog or cat wet after using it?

According to the manufacturer, Advantage flea control will maintain its efficacy after periods of wetting. The manufacturer states that dogs and cats who bathe, swim and who are wetted by rainfall will still be protected by Advantage.

Advantage may, however, lose its efficacy more rapidly in dogs and cats who are shampooed often with a soap or detergent containing shampoo. This is probably because Advantage distributes through the oily layer of the coat and such shampoos will act to strip away these oils, taking the Advantage flea control with it. The manufacturer recommends bathing Advantage flea control treated dogs and cats with soap-free shampoos.

If you are concerned about frequent wetting deactivating your Advantage flea control, you can give Advantage more often than monthly. Do not apply the product more frequently than weekly, however.

Advantage should only be applied to clean, dry skin, never wet skin.

It is recommended that dogs and cats not be bathed for at least 2 days following application of the spot-on.

A 2010 Veterinary Therapeutics article examined the distribution patterns of Advantage flea control in the skin of beagles. The Imidacloprid present in the Advantage flea medication was found to distribute widely across the treated animal's skin, establishing itself within the superficial epidermis, hair follicles and sebaceous glands of the animal. The establishment of imidacloprid deposits deep within the sebaceous glands and hair follicles is thought to be the main reason why Advantage flea control maintains its effect for 1 month following dosing and why it is thought to maintain its effect "despite post treatment bathing, shampooing, and/or swimming."



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8) What age can dogs and cats start having Advantage flea control?

According to the manufacturer, Advantage flea control is safe to use in animals from the time of weaning (6 weeks).

Advantage flea control is apparently safe to use in puppies and kittens (tiny doses) from a few days old, however, because pups and kittens of this age are normally still feeding on their mother, the manufacturer recommends not treating the unweaned puppies and kittens individually (accidental overdose could potentially result in toxicity), but instead treating the mother only. The Advantage flea control solution will distribute from the coat of the mother to her unweaned puppies and kittens, thereby protecting them from fleas.



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9) Can Advantage be used on other species besides the dog and cat?

Absolutely. The manufacturer of Advantage flea control says that Advantage can be used to treat fleas on ferrets and rabbits as well as cats and dogs.

Studies have also been conducted on a range of other animal species, showing that imidacloprid (the active ingredient of Advantage flea control) is well-tolerated by a range of vertebrate species including: mustelids (e.g. mink, ferrets), rodents (e.g. rats, prairie dogs, squirrels, guinea pigs) and marsupials (e.g. bandicoots). Advantage flea control products are officially registered for use in dogs, cats, rabbits and ferrets only, however, and the use of this product on other species is therefore "off-label" and can not be in any way guaranteed or advised (see your vet for information and doses).

Ferrets and Advantage flea control:
A 2001 study in Medical Veterinary Entomology looked at the control of cat fleas in domestic ferrets (Mustela putorius furo) using Imidacloprid. Ferrets were given the usual topical dose of 10mg/kg Imidacloprid (e.g. a ferret up to 4kg would get 0.4ml of the 100g/L Advantage flea control solution). Within 8 hours of treatment, 95.3% of fleas had gone and by 24 hours the efficacy was 100%. Fleas were then reintroduced weekly to see if the Advantage would protect the ferret for the full month. Fleas were applied 1 week after initial dosing and 92.9% of them were dead within 24 hours. Fleas applied 2 weeks after dosing had greater survival with only 55.7% of fleas killed by 24 hours. At 3 and 4 weeks post-dosing, there was no appreciable death of re-introduced fleas. This suggests that Advantage is useful against fleas in ferrets but that it needs to be given more often (1-2 weekly) to maintain its effect (caution with dosing though as ferrets can be susceptible to toxicity with certain drugs). Otherwise, if you want to use Imidacloprid to kill fleas in ferrets, consider using Advocate instead (see 2008 study below), which seems to last longer.

A 2008 study published in Parasitological Research looked at the efficacy of Advocate (imidacloprid 10% and moxidectin 1%) against fleas (Ctenocephalides) in ferrets. Treated ferrets were given 0.4ml of topical Advocate. Each ferret was then reinfested with fleas every 7 days with the final re-infestation of fleas being applied at day 28. Fleas counts were taken 24 and 48 hours after each reinfestation to assess the efficacy (flea kill) of Advocate. Efficacy was 100% 24 hours after initial dosing and at 1 and 2 weeks after treatment. At 3 weeks, the % flea kill was >97% and >90% at 4 weeks. None of the ferrets showed any adverse effects from the Advocate flea control.

Mink and imidacloprid insecticide:
A 2005 Denmark study published in Parasitological Research examined the treatment of squirrel fleas in farmed mink (Mustela vison). A 10% w/v solution of imidacloprid (the same concentration as Advantage flea control) was one of the products tested, along with imidacloprid 10%/permethrin 50% solution (Advantix) and phoxim (at various test concentrations). The mink were given only 0.1ml of the 10% imidacloprid solution (less than the dose given to ferrets in the above study) topically at days 0 and 28 and the effectiveness was assessed at day 56. At day 56, the efficacy was 91.9% in the imidacloprid group (the 2-month mark). Higher rates of efficacy were seen in some of the phoxim groups. Given how ferrets seem to need dosing more frequently than monthly, it would interesting to have seen what the efficacy levels were for the imidacloprid-treated mink at weeks 1 and 2. I imagine they would have been higher.

California ground squirrel and imidacloprid insecticide:
A 2009 study in the Journal of Vector Ecology examined the control of fleas in the California ground squirrel using orally administered baits laced with imidacloprid insecticide. The baits were put out weekly for 5 weeks and a very high % of flea control was achieved (100% in some cases), showing that oral imidacloprid baits may be very effective in controlling flea infestations in such wild rodents. Since the fleas on the ground squirrel are important vectors of plague in the USA, eradicating fleas in such animals is considered to be of high importance.

Rats and imidacloprid insecticide:
A 2010 study in the Journal of Medical Entomology examined the control of fleas in rats in Uganda using orally administered baits laced with imidacloprid insecticide. The baits (rodent-targeted, wax-based bait cubes) were put out weekly. A good % of flea control was achieved, showing that oral imidacloprid baits may be effective in controlling flea infestations in such wild rodents. The study did find that the baits had to be given weekly to maintain any kind of flea-killing effect. Since the fleas on the rats are important vectors of bubonic plague in third world countries like Uganda, eradicating fleas in such animals is considered to be of high importance.

Marsupials and imidacloprid insecticide:
In 2001, Healesville Sanctuary trialled imidacloprid treatment on a range of wild marsupial species including: the eastern barred bandicoot (Perameles gunnii), the eastern quoll (Dasyunrus viverrinus), the fat-tailed dunnart (Sminthopsis crassicaudata), the Leadbeater's possum (Gymnobelideus leadbeateri), the yellow-bellied glider (Petaurus australis) and the ring-tailed possum (Pseudocheirus peregrinus). The topical dose used was approximately 10mg/kg and, at 27 days after dosing, no live fleas (Pygiopsylla hoplia) were found and no side effects or adverse reactions had been noted. The results were published in the Journal of Zoo and Wildlife Medicine.

Black-tailed prairie dog and imidacloprid insecticide:
A 2011 study in the Journal of Vector Ecology examined the control of fleas in the black-tailed prairie dog using orally administered grain baits laced with imidacloprid insecticide. The grain baits were put out once and maintained a moderately high level of flea control for up to 90 days. Better results were achieved with a repeat dosing on several sites. While significant flea control was achieved, showing that oral imidacloprid baits may be very effective in controlling flea infestations in such wild rodents, the results were not as good as those seen with certain topical insecticides used on such species. Since the fleas on the prairie dog are vectors of sylvatic plague in the USA, eradicating fleas in such animals is considered to be of high importance.

Birds and imidacloprid insecticide:
While imidacloprid insecticide is not generally considered highly toxic to birds, the effect of imidacloprid on birds has been studied because of the potential risks posed to avian species through use of imidacloprid insecticide in gardens, crops and orchards. The acute LD50 (dose at which 50% of individuals die from ingestion or other forms of contact with a test substance) varies depending on the species of bird with some species of birds being highly susceptible to imidacloprid toxicity and others being relatively resistant. For example, the acute LD50 for Japanese quail is only 31mg/kg, but 152mg/kg in bobwhite quail. Note that these are oral poisoning doses (imidacloprid is not recommended for oral use), not topical doses (which is the usual way of giving imidacloprid to animals to treat fleas.)

Invertebrates and imidacloprid insecticide:
Imidacloprid exerts a lethal effect on a wide range of crop, orchard, soil and garden pest insect species including, but not restricted to, the soybean aphid, the hemlock woolly adelgid, the potato leafhopper, the Japanese beetle, the grape berry moth, various leaf- and planthoppers, whiteflies, thrips, scales, flea beetles, leaf-miners, mealy bugs, beetles, leaf beetles, termites, locusts and cockroaches.

Imidacloprid is non-selective when it comes to insects and will also kill insect species that are of benefit to gardens, crops and water courses. Honeybees are considered highly susceptible, as are various parasitoid wasps (wasps that prey on pest insect species) and arthropod nymphs that live in waterways. For this reason, care must be taken to ensure that Imidacloprid does not contaminate water supplies and outdoor environments with valuable, non-pest insect populations. Imidacloprid must never be allowed to contaminate beehives and major pollen sources as bees are highly susceptible to poisoning.

Additionally, sublethal doses of imidacloprid insecticide can also be harmful to beneficial insect populations without actually killing them outright. Sublethal levels of imidacloprid can: reduce growth rates, reduce population growth, reduce feeding rates, increase respiration rates, reduce response times to predators, slow maturation, reduce longevity, and reduce the numbers of eggs and offspring produced. Earthworms affected by imidacloprid produce fewer casts and shorter burrows, resulting in reduced soil aeration. Bees are highly susceptible to imidacloprid and often die. Those bees exposed to sublethal doses show reduced reflexes, reduced learning responses, reduced brood production and reduced feeding (especially of pollens or sugars tainted with imidacloprid).

A 2012 study published in Ecotoxicology looked at the effect experienced by five different species of aquatic arthropods (cladoceran types) when they were exposed to imidacloprid insecticide, commonly applied to rice fields in Japan. It found that Ceriodaphnia was more sensitive to imidacloprid than Moina and Daphnia species, making it potentially a more sensitive bioindicator of imidacloprid water contamination than other aquatic arthropod species (Daphnia is generally the species studied when water contamination events are suspected). Interestingly, all aquatic arthropods studied were found to be less susceptible to imidacloprid than certain other aquatic species, including certain: fish, insects, crustaceans, molluscs and worms. This puts into question the use of aquatic arthropods as the sole indicators of insecticide contamination of waterways.

Other studies into aquatic arthropods have showed that, while some species are highly susceptible to a single insecticide 'event' (a single pulse of insecticide contamination into the waterway), other species need multiple 'events' (multiple pulses) before they begin to die off. Knowing which species are affected by individual events and which species are affected by multiple events can help environmental regulators to recognise ongoing contamination episodes.



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10) Can Advantage Imidacloprid be used on pregnant or lactating animals?

According to the manufacturer, Advantage flea control is safe to use in pregnant and lactating animals.

Advantage flea control is apparently safe to use in puppies and kittens (tiny doses) from a few days old, however, because pups and kittens of this age are normally still feeding on their mother, the manufacturer recommends not treating the unweaned puppies and kittens individually (accidental overdose could potentially result in toxicity), but instead treating the mother only. The Advantage flea control solution will distribute from the coat of the mother to her unweaned puppies and kittens, thereby protecting them from fleas.

According to the MSDS, tests on laboratory animals and cell cultures have determined that the chemical, Imidacloprid (Advantage flea control) does not cause mutations, cancer, fetal malformations (non-teratogenic) or any other reproductive effects. It should therefore be safe to use in pregnant animals and animals intended for breeding.

Toxicity studies have been done on rats and rabbits whereby rats and rabbits were fed massive doses of imidacloprid while pregnant. At massive doses (100mg/kg given every day from days 6-15 of pregnancy), rats showed signs of poisoning and evidence of reduced embryonic development. Rabbits given massive doses (72 mg/kg daily between days 6-18 of pregnancy) also showed signs of poisoning (some of the mothers died) with reduced embryo growth and bone formation and even fetal death. While these findings do indicate that fetal growth retardation and even deformity are possible with imidacloprid (and so can not be 100% guaranteed of not occurring in pregnant animals given Advantage flea control), it must be emphasised that the doses used to get these effects were enormous (way above levels used in flea control programs) and that they were given orally. Advantage flea control is used topically and so should not be absorbed into the bloodstream and tissues at significant levels. Thus, the risk to an animal's pregnancy should be considered to be extremely low, which is what the Advantage manufacturer also says.



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11) Advantage flea medicine safety and side effects - How safe is Imidacloprid for pets?

Imidacloprid is a neonicotinoid, meaning that it is related to and resembles nicotine in effect. Thus, it causes stimulation of the nicotinic acetylcholine receptors (nAChR), producing excessive muscle activity, rigidity, paralysis and death. The fantastic thing about Imidacloprid, however, is that, due to its chemical structure, it is specific for the nicotinic acetylcholine receptors present on the nerves of insects like fleas. It binds strongly to insect nAChR causing intense activation of these receptors and resultant rigidity and paralysis of insects (thus killing the fleas). Imidacloprid binds very poorly to the nicotinic acetylcholine receptors of vertebrate animals (e.g. dogs and cats and even birds and fish) and thus it does not have anywhere near as much of an effect on these species. This is the reason why side effects and toxicity effects are very uncommon in animals given Imidacloprid-containing Advantage flea control medication.

A 2003 article in the Annual Review of Entomology confirmed this. It showed that neonicotinoid chemicals like Imidacloprid were toxic to insects and less so to vertebrates (the study focussed on mammals) because of differences in the structure of insect and mammalian nicotinic acetylcholine receptors (nAChR). The neonicotinoid drugs were capable of binding to insect nAChR and causing toxicity signs, but they were not as capable of binding to mammalian nAChR. The active 'binding site' of mammalian nAChR is negatively charged (anionic), whereas the active 'binding site' of insect nAChR (the site on the nicotinic receptor where the neonicotinoid drugs bind to exert their activation effect) is positively charged (cationic). Being positively charged, the insect nAChR is ideally suited to binding with the neonicotinoid chemicals which are negatively charged, whereas, the negatively charged mammalian nAChR would repel these chemicals, stopping them from exerting much of an effect.

Imidacloprid is also considered to be relatively safe because it does not cross the blood-brain-barrier of vertebrates anywhere near as well as it crosses into the central nervous system of insects.

Additionally, Advantage flea control is applied topically (to the skin). It does not absorb into the bloodstream or internal tissues through the skin very well and therefore severe toxicity reactions are considered to be very rare when the product is applied to the skin as per instructions. Most reports of overt toxicity occur as a result of the product being ingested or inhaled, which is completely inappropriate and against the manufacturer's directions for use of the product.


More common side effects (not that common though):
Sometimes the hair can fall out of the coat at the site of Advantage application. This is not considered to be a major issue (except in showing animals) and the hair will usually grow back uneventfully.

The product is extremely bitter tasting. Cats allowed to lick the product will often salivate profusely with distaste. Due to the terrible taste, they will rarely consume enough of the imidacloprid insecticide to become poisoned, however, if an owner notices that a large amount of the product has been consumed, veterinary attention should be sought for the product can be toxic if ingested in large volumes.

Skin and eyes:
Although the MSDS considers Imidacloprid to be largely non-dangerous when used appropriately, Advantage flea control is considered to be irritant to the eyes and sometimes the skin. If the product gets into the eyes, the eyes need to be flushed copiously with clean water or an eye irrigation solution (veterinary advice should also be sought).

Studies in guinea pigs and rabbits have found that the product is, for the most part, non-hypersensitising (i.e. animals tested didn't start to react to it with repeated use); non-photosensitising (it doesn't increase the skin's susceptibility to sun damage) and non-allergenic (animals rarely have allergic reactions to it). It should be mentioned that incidents of skin sensitivity and allergic reaction have been known to occur in people and animals exposed to topical Imidacloprid insecticide (e.g. Advantage flea control), however, these reactions are not considered common or typical.

Effects on cells and reproduction:
Tests on laboratory animals and cell cultures have determined that the chemical, Imidacloprid (Advantage flea control) does not damage DNA. The chemical, therefore, has not been found to cause mutations, cancer, fetal malformations (non-teratogenic) or any other reproductive effects. It should therefore be safe to use in pregnant animals and animals intended for breeding.

Toxicity studies have been done on rats and rabbits whereby rats and rabbits were fed massive doses of imidacloprid while pregnant. At massive doses (100mg/kg given every day from days 6-15 of pregnancy), rats showed signs of poisoning and evidence of reduced embryonic development. Rabbits given massive doses (72 mg/kg daily between days 6-18 of pregnancy) also showed signs of poisoning (some of the mothers died) with reduced embryo growth and bone formation and even fetal death. While these findings do indicate that fetal growth retardation and even deformity are possible with imidacloprid (and so can not be 100% guaranteed of not occurring in pregnant animals given Advantage flea control), it must be emphasised that the doses used to get these effects were enormous (way above levels used in flea control programs) and that they were given orally. Advantage flea control is used topically and so should not be absorbed into the bloodstream and tissues at significant levels. Thus, the risk to an animal's pregnancy should be considered to be extremely low, which is what the Advantage manufacturer also says.

The product is toxic if ingested or inhaled:
Imidacloprid can be harmful if significant amounts are swallowed or if the drug is inhaled (which can occur with vaporized or aerosolized forms of the imidacloprid insecticide that are applied to orchards and gardens). Should the product be inhaled or swallowed, medical advice should be sought. The product should never be stored near food or water to prevent these from becoming contaminated.

Author's note - it is unlikely that aerosolisation and inhalation of imidacloprid insecticide will occur during the application of Advantage flea control to a pet's fur. The issue of inhalation toxicity is more of a concern in animals and people who are exposed to large volumes of imidacloprid that are being sprayed onto orchards, crops or garden beds. In these situations, "Advantage" is not the brand of product being used but another commercial insecticide product containing imidacloprid.

Studies in rats showed that the LD50 for oral Imidacloprid is about 450 mg/kg (in this species), which is a high dose, with one study differentiating between male and female rats (female rats were thought to be more sensitive to Imidacloprid with an LD50 of 380mg/kg). In mice, the LD50 was found to be 130mg/kg for males and 170mg/kg for females. An LD50 is the dose that will kill half of the study population. When you consider that Advantage flea control treatment is only dosed at 10mg/kg, there is little chance you'd ever give enough of an accidental overdose to a pet to cause death (unless the pet had a severe anaphylactic reaction of some kind). Additionally, you wouldn't give Advantage flea control orally, which is what the oral LD50 refers to.

Of perhaps more significance, when considering a topical drug such as Advantage flea control is the dermal LD50. In rat studies, the dermal LD50 was estimated at greater than 5000 mg/kg. In another study, rabbits had a paste containing 1000mg/kg of imidacloprid applied to their skin for 6 hours a day for just over 2 weeks and no adverse effects were noted. These are monster doses and owners would be struggling to ever overdose an animal's skin in Advantage flea control to this level of toxicity.

The signs of Imidacloprid poisoning:
The signs of imidacloprid poisoning in animals (animals are generally poisoned through oral consumption of the insecticide) are similar to those of acetylcholine overstimulation or nicotine poisoning (as described in section 2 of this web page). Many of the adverse effects are nicotinic excitatory effects including: hyperactivity, panting, nervousness, increased tear production (lacrymation), marked gastrointestinal effects (vomiting, diarrhea, salivation) and moderate to severe neurological signs (difficulty breathing, incoordination of the gait, tremors, seizures, trembling, pupil dilation), some of which have the potential to result in death (e.g. seizures, respiratory failure). In seeming contrast, some animals have shown signs of depression and lethargy, rather than excitation, when overdosed with imidacloprid.

The signs of imidacloprid poisoning generally come on quickly (sometimes within 15 minutes of large-scale ingestion) and resolve within the day, should the animal survive the episode. Animals that receive a lethal dose and can not be revived generally succumb within 24 hours. Animals that survive tend to make a full recovery without residual long term or delayed side effects.

Caution with imidacloprid combination products in cats:
Some imidacloprid flea products (e.g. Advantix) include other ingredients (e.g. permethrins) that may be toxic to cats. Such products should not be used in felines and care should be taken if using the product in households containing both dogs and cats, particularly in situations where the cat may groom or snuggle up with the treated dog. I personally would not use Advantix on my dog if I had a cat that spent a lot of time with the dog or its environment, just in case the permethrin component transferred to the cat and produced poisoning signs.

The product is compatible with a range of medications:
Imidacloprid is considered compatible with a range of products designed to kill parasitic worms and fleas, including: lufenuron, permethrin, milbemycin, moxidectin, ivermectin, praziquantel, febantel and pyrantel.

Invertebrates and imidacloprid insecticide:
Imidacloprid exerts a lethal effect on a wide range of crop, orchard, soil and garden pest insect species including, but not restricted to, the soybean aphid, the hemlock woolly adelgid, the potato leafhopper, the Japanese beetle, the grape berry moth, various leaf- and planthoppers, whiteflies, thrips, scales, flea beetles, leaf-miners, mealy bugs, beetles, leaf beetles, termites, locusts and cockroaches.

Imidacloprid is non-selective when it comes to insects and will also kill insect species that are of benefit to gardens, crops and water courses. Honeybees are considered highly susceptible, as are various parasitoid wasps (wasps that prey on pest insect species) and arthropod nymphs that live in waterways. For this reason, care must be taken to ensure that Imidacloprid does not contaminate water supplies and outdoor environments with valuable, non-pest insect populations. Imidacloprid must never be allowed to contaminate beehives and major pollen sources as bees are highly susceptible to poisoning.

Additionally, sublethal doses of imidacloprid insecticide can also be harmful to beneficial insect populations without actually killing them outright. Sublethal levels of imidacloprid can: reduce growth rates, reduce population growth, reduce feeding rates, increase respiration rates, reduce response times to predators, slow maturation, reduce longevity, and reduce the numbers of eggs and offspring produced. Earthworms affected by imidacloprid produce fewer casts and shorter burrows, resulting in reduced soil aeration. Bees are highly susceptible to imidacloprid and often die. Those bees exposed to sublethal doses show reduced reflexes, reduced learning responses, reduced brood production and reduced feeding (especially of pollens or sugars tainted with imidacloprid).



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12) How safe is Imidacloprid for people? Can I touch it?

As a flea control product, "Advantage For Dogs and Cats" is considered to be quite safe to the humans in the family so long as the product is used according to directions (i.e. topically).

People do not need to wear gloves when handling the product, but should the product make contact with the skin, the manufacturer advises washing the product off thoroughly with soap and water. This is to prevent the product being inadvertently consumed or accidentally put into the eye (e.g. if the person rubs their eyes with insecticide-covered hands or eats food from contaminated hands). It is also to prevent the person from suffering some form of allergic or sensitivity reaction to the chemical (e.g. contact dermatitis), which has been known to occur in individuals from time to time.

The product should never be allowed to make contact with the eyes as it is quite irritating. Eyes contaminated with Advantage flea control should be washed out immediately with an eye irrigation solution or, if none is on-hand, plain water. Medical advice should then be sought.

Advantage flea control must be kept out of reach of children, who might accidentally consume the product or get it in their eyes.

Advantage flea control and other imidacloprid-containing products should never be stored close to food or water sources that are intended for human consumption. This is to prevent leaked product from accidentally being consumed.

Advantage flea control must never be consumed and aerosolized forms of imidacloprid (e.g. crop insecticide forms of the chemical) must never be inhaled. Both consumption and inhalation are considered major routes by which humans become poisoned with imidacloprid. Used according to directions (applied topically to pets), it is unlikely that severe poisoning should occur with Advantage flea control.

Imidacloprid toxicity is much more likely to occur when imidacloprid insecticide is used incorrectly on crops that humans then eat (e.g. without regard to withholding times and maximum residue limits); when imidacloprid insecticide is allowed to contaminate drinking water supplies; when imidacloprid is inhaled during crop or orchard application or when individuals try to commit suicide through the deliberate consumption of large volumes of imidacloprid containing products (Advantage flea control has been used in attempted suicide on several occasions).

Eye and skin protection (e.g. gloves, coveralls) are not usually needed when pet owners are applying Advantage flea control to their pets (just wash your hands with soap after using and avoid getting the product in the eyes). Eye and skin protection, as well as ventilatory protection (e.g. respirators), should be used by folks applying imidacloprid insecticides to crops, orchards and gardens as, with such large volume spraying, there is much opportunity for the imidacloprid to make contact with the skin or eyes or be inhaled (which can result in toxicity).


The signs of Imidacloprid poisoning:
Signs of imidacloprid toxicity in humans are similar to those described in section 11 on animal toxicity and relate to the generalized overstimulation of the nicotinic acetylcholine receptors (nAChR) in the human body (as described in section 2 of this web page). Many of the adverse effects are nicotinic excitatory effects including: fever, pupil dilation, sweating, irritability, increased heart rates (sometimes abnormally reduced heart rates), heart palpitations, hypertension, chest pain, panting (increased respiratory rates), nervousness/agitation, headaches, marked gastrointestinal effects (vomiting, stomach ache) and moderate to severe neurological signs (difficulty breathing, dizziness, disorientation, delerium, twitching, incoordination, incoherence, finger tremors, muscle spasms, short term memory disturbance, weakness). Loss of consciousness, hypothermia, reduced heart rates, reduced respiration rates and cardiac arrest occur in those severely poisoned, just prior to death. In some cases, people affected with toxic levels of imidacloprid have died, commonly of respiratory failure caused by either an inability of the person to coordinate the muscles of respiration (the spasming chest muscles make it impossible for the chest to rise up and down with respiration) or through aspiration pneumonia (often the result of inhaling vomitus) or both. In seeming contrast, some people have shown signs of depression, fatigue, drowsiness and lethargy, rather than excitation, when exposed to toxic levels of imidacloprid through ingestion or inhalation.


Clinical examples of Imidacloprid poisoning in journals:
A study published in 2007 in Environmental Geochemistry and Health looked at imidacloprid residues in soils, water samples, fruits and vegetables in Palestine during 1998 and 1999. The study revealed imidacloprid residues in many of the samples of food (e.g. highest residues were found in eggplants) with some of the levels being above the maximum residue limit recommended for human consumption. Consumed in excess, such contaminated food could potentially pose a toxicity risk for humans in those parts.

A case report published in Chudoku Kenkyu (Japan) in 2011, looked at six cases of subacute imidacloprid toxicity admitted to a medical centre in Japan. The affected people had ingested large amounts of imidacloprid in domestic fruits and tea leaves as a direct result of high personal consumption of these products, which also happen to have high imidacloprid maximum residue limits set for their sale in Japan (i.e. Japan allows quite high levels of imidacloprid to be present in foodstuffs available for human consumption, leading to an increased potential for toxicity in humans who ingest a lot of such produce). Affected people showed many of the signs described previously for imidacloprid toxicity (in particular: head-aches, fatigue, finger tremors and short-term memory disturbance, as well as a range of gastrointestinal and cardiac signs) and were diagnosed by ion chromatography techniques performed on their urine, targeted at detecting 6-chloronicotinic acid (a common metabolite of imidacloprid). The people were treated with supportive care and advised to restrict their intake of fruits and tea.

A retrospective study published in Clinical Toxicology in 2009 looked at 70 cases of acute imidacloprid poisoning presented to hospitals and reported to the Taiwan National Poison Center. Most cases were attempted suicides (the insecticide was ingested) and presented with mild to moderate symptoms of nicotinic overstimulation (similar to nicotine poisoning). Some patients did die (2/70) from respiratory failure or aspiration pneumonia (likely related to the inhalation of saliva and vomitus in the tremoring or barely conscious patient). The study found that atropine and ventilator support were particularly appropriate in the management of such cases in hospital.

A case report of an attempted suicide with imidacloprid, along with the clinical signs of poisoning, was published in 2011 in the Journal of Associate Physicians of India. A similar case study was published in 2008 in the Journal of Emergency Medicine. It describes the death of a person following the deliberate consumption of fatal quantities of imidacloprid insecticide.


What about exposure to small amounts of Imidacloprid insecticide all the time?
Studies into imidacloprid have found that the chemical does not damage DNA and that it has not been found to cause mutations, cancer, fetal malformations (non-teratogenic) or any other reproductive effects, even when animals (rodents are the typical study population) are exposed to them over long spans of time. The conclusion drawn from this is that low level, chronic exposure to imidacloprid (e.g. in fruits and vegetables grown under conditions of imidacloprid insecticide use) should not be harmful to people long term. This is a comforting thought, given that imidacloprid is now one of the major insecticides used on crops and orchards and even on substances like rice and tea all over the world and an insecticide that people are probably eating tiny amounts of on a weekly basis.

Regulatory guidelines for the use of insecticides in products intended for human consumption often refer to a Reference Dose or RfD. For imidacloprid, the RfD is 0.057 mg/kg/day. The Reference Dose is the quantity of a chemical "that a person could be exposed to every day for the rest of their life with no appreciable risk of adverse health effects. The reference dose is typically measured in milligrams (mg) of chemical per kilogram (kg) of body weight per day." A person of 80kg in weight could, by this formula, safely consume 80x0.057 = 4.56mg of imidacloprid daily with no ill-effect.

Whether the substance really is all that safe or not at constant, low levels over the course of decades is probably impossible to say for sure given that most studies are done on rodents (not humans) and most humans are exposed to whole swathes of potential carcinogens (both known or unknown) every day, making it impossible to say for sure exactly which of a whole range of chemicals caused any one cancer or immune disease. If a man dies of cancer, how can anyone really say whether or not it was the imidacloprid in his oranges that contributed to the problem or the chemical pollutants drifting through the very air he breathes? When you think of how long it took to confirm and prove that smoking causes cancer, you can only imagine how difficult it would be to pinpoint a particular ubiquitous pesticide as causing problems. So far, Imidacloprid has not been found to cause cancer in animal and cell studies, but that does not 100% guarantee its safety. Just as we once used DDT on our crops before we realised how unsafe it was, in years to come, we may eventually find out that other, currently 'safe', pesticides we are putting on our food are not so safe at all.

In the absence of such certainty, it is probably best, as with all man-made chemicals, to reduce the consumption and exposure of imidacloprid wherever possible. Strict compliance with maximum residue limits and withholding periods in food is but one way of doing this as is taking care not to pollute soils and waterways with run-off containing imidacloprid insecticides. Consuming organically-grown foods where possible can also help to reduce your intake of such pesticides.

A study published in Toxicology Mechanisms and Methods in 2005 looked at the "human exposure to imidacloprid from dogs treated with Advantage". Dogs were treated with topical Advantage flea control (364mg/dog - the actual dose rate is not stated in the abstract) and residue levels of imidacloprid in the dog's blood and on the fur (sampled during a 5-minute patting session using a collection glove) were sampled at 24 and 72 hours and then weekly. Imidacloprid was not detected in the blood after a week and transferable residues were present on the fur out to 4-5 weeks post-dosing (which is expected, given the product is designed to last for a full month as per the manufacturer's design). It is thus expected that humans who treat their animals with Advantage flea control will inevitably be exposed to low-levels of imidacloprid residue on the coats of their animals, particularly during periods of patting and close interaction. Whether this low-level chronic exposure will pose a health risk to pet owners and other animal handlers (e.g. vets) remains to be seen.


Examples of low-level, chronic pesticide exposure in real life situations:
A study published in 2007 in Environmental Geochemistry and Health looked at imidacloprid residues in soils, water samples, fruits and vegetables in Palestine during 1998 and 1999. The study revealed imidacloprid residues in many of the samples of food (e.g. highest residues were found in eggplants) with some of the levels being above the maximum residue limit recommended for human consumption. Consumed in excess, such contaminated food could potentially pose a toxicity risk for humans in those parts. Humans eating such food would certainly be exposed to low-level chronic imidacloprid insecticide ingestion, even if they were not outright poisoned by it.

A case report published in Chudoku Kenkyu (Japan) in 2011, looked at six cases of subacute imidacloprid toxicity admitted to a medical centre in Japan. The affected people had ingested large amounts of imidacloprid in domestic fruits and tea leaves as a direct result of high personal consumption of these products, which also happen to have high imidacloprid maximum residue limits set for their sale in Japan (i.e. Japan allows quite high levels of imidacloprid to be present in foodstuffs available for human consumption, leading to an increased potential for toxicity in humans who ingest a lot of such produce). Affected people showed many of the signs described previously for imidacloprid toxicity (in particular: head-aches, fatigue, finger tremors and short-term memory disturbance, as well as a range of gastrointestinal and cardiac signs) and were diagnosed by ion chromatography techniques performed on their urine, targeted at detecting 6-chloronicotinic acid (a common metabolite of imidacloprid). The people were treated with supportive care and advised to restrict their intake of fruits and tea.

The 2011 Bulletin of Environmental Contamination and Toxicology looked at levels of pesticides contained in fresh potatoes sold in farmer's markets in Alberta. Residues were found for three insecticides, one of which was imidacloprid. Although residues found were all below Canada's maximum residue limits for potatoes, the study does show the need for vigilance of inspectors in this regard and point to a high potential for consumers to be exposed to chronic, long-term ingestion of imidacloprid, the true, ongoing, cumulative safety of which may not be known for decades. No residues were found in organically grown potatoes sampled at the time.

The journal, Chromatography A, in 2008 described a technique to detect levels of imidacloprid in bovine milk samples. The levels found were lower than maximum residue limits set by the EU, however, the important thing to note is that residues were found, showing that it is not only fruit and vegetables that could pose a risk to humans of imidacloprid ingestion, but sources we'd barely expect such as bovine milk. Care needs to be taken with amounts of imidacloprid contained in fruit and vegetable 'seconds' used to feed livestock animals that are then either converted to meat products or farmed for their milk.



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13) Is Advantage flea treatment useful in dogs and cats suffering Flea Allergy Dermatitis (FAD)?

Animals with flea allergy dermatitis are allergically sensitized to fleas such that they have a severe skin reaction (itching, scratching, rashing) each time a flea bites them. In such animals, the immune system is reacting inappropriately and extremely to elements (antigens) that are present in the flea's saliva and/or feces. The usual thinking has been that it can take a single flea bite to set a flea allergic animal off on a path of scratching (you might not even see any fleas on the animal - the flea has simply jumped on, bitten and then jumped off again, leaving the animal to itch away).

The best flea control products for helping flea allergic dogs and cats are those that kill all adult fleas (i.e. high effectiveness) in a very short period of time (fast-acting), whilst at the same time limiting adult flea feeding times (which is where allergic sensitization occurs - when the animal is exposed to the flea's saliva and droppings). Those that also rapidly wipe out flea populations in the home environment (i.e. those that also kill flea larvae or stop flea eggs from hatching) get extra points because, once a flea population is gone from a household, it is highly likely that flea allergy dermatitis problems will resolve.

Advantage flea control works to kill fleas quite rapidly:
According to the manufacturer, Advantage flea control is fast acting, killing adult fleas and flea larvae within 20 minutes of contact with the intersegmental membranes of the insects and stopping them feeding within 5 minutes. It is important to mention, however, that the product is applied only to one spot on the animal and, therefore, takes time to distribute across the entire body of the animal, protecting it at all sites where the fleas hide out. Therefore, whilst fleas in the region of application will likely die within 20 minutes, you should not expect to see all fleas all over the body dying within 20 minutes. The fleas have to come into contact with the product, either through the product diffusing across the skin or the fleas crawling onto the regions the imidacloprid has reached.

It's not all doom and gloom though. Distribution across the skin layer seems to be quite rapid (or the fleas move around the pet's body a lot) such that a 98-100% flea kill (body-wide) is generally achieved within 12 hours of dosing. A 2005 study, published in Veterinary Therapeutics compared the speed of flea kill of selamectin, imidacloprid and fipronil-S-methoprene. The study found that imidacloprid had the most significant % flea kill of all the preparations by 6 hours, but that by 24 hours after dosing all three products had achieved a >95% flea kill.

A 2003 article published in Veterinary Parasitology confirms this. The study compared the speed of kill and percentage of flea kill between five of the major flea control products on the market at that time (Nitenpyram, Fipronil, Imidacloprid, Selamectin and Cythioate). The results for Nitenpyram were most impressive, but the results for Imidacloprid were not far behind. Within 3 hours, "nitenpyram was 100% effective in cats and 99.1% effective in dogs" and 100% effective in both species at 8 hours. Cythioate (used on cats only in the study) showed a 62.4% and 97.4% flea kill at 3 and 8 hours, respectively. Selamectin (used on dogs only in the study) showed a 39.7% and 74.4% flea kill at 3 and 8 hours, respectively. In dogs, Fipronil showed a 35.9% and 46.5% flea kill at 3 and 8 hours, respectively, whereas, in cats, the respective percentage kills were 24.3% and 62.6%. Imidacloprid in cats showed only a 26.9% flea kill at 3 hours, but then a rapid recovery response and an 82.8% flea kill at 8 hours. In dogs, a similar pattern was seen with a lower % kill (22.2%) at 3 hours, but a high % kill (95.7%) at 8 hours.

Author's hint: If you want to help the product to distribute over the coat a bit quicker, you can apply the spot-on to several points along the flea allergic animal's back, rather than putting it all between the shoulderblades. If doing this, it might be good idea to put an E-collar (Elizabethan Collar) on the pet for 24 hours to stop the pet licking off the flea control liquid.

The speed of flea kill does tend to wane during the month following Advantage flea control application (as it does for all three major topical preparations prescribed by vets). A 2005 study published in Veterinary Therapeutics demonstrated this. It showed that Imidacloprid (Advantage flea control) had the highest % flea kill within 6 hours of initial dosing (out of Fipronil, Imidacloprid and Selamectin), but that all products had achieved a >95% flea kill by 24 hours of dosing. Fleas were re-introduced to the cats at day 7 (to mimic a reinfestation) and all three formulations showed a similar effect, with a 68.4% flea kill at 6 hours post flea-introduction and a massive (highly effective) 99.4% flea eradication at 24 hours. At day 21 and then again at day 28, more fleas were introduced and there was no appreciable kill of those fleas within 6 hours. The new fleas did die, but they took longer (up to 2 days before the % flea kill was determined), showing that the speed of kill declines with the time passed since dosing (allowing fleas to do more feeding and thereby cause reactions before they die).

Author's hint: To maintain high efficacy and speed of kill, you can apply Advantage more frequently than monthly. Applying Advantage flea control every 2 weeks (at least in the initial stages of your flea control program) is safe for the flea allergic pet and will ensure that speed of kill and % of flea kill are optimised. It will also ensure that higher levels of imidacloprid residues enter the environment of the pet (e.g. bedding), helping to kill flea larvae stages present in the carpet and bedding and thereby helping to eliminate the flea problem quicker.

Advantage flea medication and flea feeding times:
According to the manufacturer, Advantage flea control stops fleas from feeding within 5 minutes, making it useful in animals suffering flea allergy dermatitis (FAD) and helpful in the prevention of flea-transmitted diseases.

In contrast to this, a 2008 study, published in the journal of Veterinary Parasitology, examined the effect of various flea control products, including Advantage flea medication, on flea feeding times and blood consumption quantities. The study found that only Capstar flea control pills (nitenpyram) and topical selamectin caused a statistically significant reduction in blood consumption by fleas. Imidacloprid and Fipronil did not.

A 1998 study in Parasite also looked at the "antifeeding effect of several insecticidal formulations against Ctenocephalides felis on cats." Individual cats were treated with different topical flea control products, including imidacloprid (Advantage flea control). Cats were subsequently infested with unfed fleas in the days to weeks (up to 6 weeks) following the application of the topicals. An hour after fleas were re-introduced, the fleas were combed out and the amount of blood consumed by them was assessed. Topical imidacloprid and fipronil were not shown to prevent fleas from feeding prior to their deaths (comment was not made as to the actual quantity of blood taken up).

On this basis, it follows that Advantage flea control will not prevent fleas from biting and feeding and, thus, it won't 100% prevent flea sensitised animals from receiving the flea bites that cause the allergic reactions and scratching to occur. The good thing about the product is, however, that Advantage flea control can kill fleas through contact alone and many fleas will die upon contact with the pet without ever having actually bitten it (this is of benefit in cases of FAD).

The other thing to note is that Advantage flea control medicine does destroy flea larvae, which is a good thing in cases of flea allergy. With flea allergy dermatitis, you do want to aim for rapid and complete destruction and removal of the flea life stages (flea eggs, larvae and cocoons) present in the pet's environment. Adult fleas only come from the immature flea stages present in the environment and if these are nullified, adult fleas will stop hatching out of the environment and thus flea control will be achieved. With no adult fleas about, the animal with flea allergic dermatitis will improve and most likely its condition will resolve significantly. At that stage, it will no longer matter if the product allowed fleas to feed for 2 minutes or 20, because no fleas means no bites at all!

Advantage flea medication kills flea larvae really well - no emerging fleas means no flea bites!:
Advantage flea control kills flea larvae in the environment. Flea larvae in the host animal's environment become poisoned when dander (skin flakes) or flea feces (their natural diet) coated with imidacloprid drop into the environment from the host animal's skin. The flea larva either consumes the Imidacloprid insecticide through actual consumption of the treated dander (or flea faeces) or it takes up the insecticide via direct contact and absorption through the skin (again, no consumption is needed for the flea larva to be poisoned with imidacloprid - it just needs to make contact with the chemical). The flea larvae may also come into contact with the insecticide if the fur of the treated pet comes into direct contact with the larvae (e.g. on a pet bed).

A 2000 study in the Journal of Medical Entomology confirmed that imidacloprid was capable of transferring from the animal's coat and into the local environment at sufficient enough quantities to kill flea larvae. Cats were treated with Advantage flea control and allowed to hang-out on test blankets. There was a 100% failure of adult flea emergence in the flea eggs incubated on imidacloprid contaminated blankets within the first week of treatment.

A different study published in 2001 in Medical Veterinary Entomology also looked at imidacloprid build-up in the environment of treated pets and the subsequent effect on flea larvae. In this study, cats were treated with imidacloprid and allowed to hang out on fleece blankets for 60 to 120 hours over a period of 2-4 weeks. The blankets were stored for 18 weeks and then flea eggs were incubated on them. There was enough insecticide on the blankets to reduce flea larvae survival by >94%. The study found that hot laundering with detergent removed the imidacloprid effect.

A 2001 study published in Parasitological Research examined the in vitro effect of fipronil, imidacloprid and selamectin on flea larvae and adult fleas. Of the three chemicals, only imidacloprid was found to kill flea larvae and flea adults on direct body contact. Imidacloprid killed all fleas and larvae within 1 hour of direct contact (confirming Bayer's claim that fleas start to die within 20 minutes of application), whereas up to 24 hours was needed for all adult fleas to die after exposure to the fipronil or selamectin.

It should also be noted that Advantage flea medication works so quickly, adult fleas rarely get a chance to lay their eggs before they die. The Bayer site says that the product "kills 98-100% of fleas before they can lay their eggs". Thus, the quantity of fertile flea eggs falling from the coat (and into the environment) of an Advantage treated animal is greatly reduced. Environmental contamination with flea eggs is minimized.

Advantage flea control has been studied in real-life situations and on animals with flea allergy dermatitis:
Veterinary Therapeutics in 2000, looked at the "Efficacy of imidacloprid on dogs and cats with natural infestations of fleas, with special emphasis on flea hypersensitivity." A large population of dogs and cats (some 3272 animals) with flea allergy dermatitis skin lesions were given Advantage flea control topically, in accordance with directions. The study found that fleas were killed rapidly and that animals were prevented from being reinfested by fleas for at least 28 days following the single dose. Some animals were washed and even shampooed during the study without this affecting the efficacy of the treatment (I would still exercise caution if using soapy shampoos though) and all animals showed improvement in their clinical flea allergy signs regardless of living conditions (e.g. flea burden in the environment), coat type or body size. The study showed Advantage flea control to be highly beneficial in helping to treat animals with flea allergy dermatitis.

Although the theory has always been that 'a single bite' can be enough to get a flea allergy animal scratching for weeks, it may be the case that a bit more is needed (a number of bites, perhaps, sustained over time). Advantage does not 100% prevent flea bites and yet it has been shown to resolve the signs of flea allergy dermatitis in a large study (above). This suggests that a rapid and high % flea kill sustained over a full month, along with a major effect at reducing the flea populations in the animal's environment are as important, if not more so, than merely stopping individual fleas from biting.

Yet another study was performed using "naturally infested" dogs and cats living in household situations in Tampa, Florida. Households were divided into two groups with pets being treated with either imidacloprid or fipronil. The flea control products were given every month for 3 months. The study, published in Veterinary Parasitology in 2000, showed that imidacloprid had achieved a 95.3% flea kill 24 hours after the first dose and that the effectivity was still super high after 28 days (just prior to the next dose being given) with a 97.4% effectiveness recorded. Fipronil showed similar results (97% at day 28). Flea burdens on the pets after 3 months of dosing were reduced by 99.5% with imidacloprid (96.5% fipronil) and flea burdens within the house itself were found to have dropped by 99% with imidacloprid (98.6% for fipronil). This shows that imidacloprid is highly effective at getting rid of fleas in a 'real world' situation and not just in a lab. Once the fleas are gone from the pet and its environment, it follows that flea allergy dermatitis signs will resolve.

In summary - Advantage flea control is a good product to use on animals with flea allergic dermatitis:
Overall, it would seem that Advantage flea treatment is a very sound flea control product to give to pets suffering from flea allergy dermatitis. It works fast, gives a high % flea kill, kills fleas by contact (no feeding needed) even though it doesn't quite prevent flea feeding (which would be ideal), lasts for a month, can be given 2-weekly if needed and it kills flea larvae in the environment, thereby helping to cripple the flea life cycle and flea population.

Advantage flea control can be used with other medications and drugs:
Advantage flea control is compatible with Lufenuron, which is a flea control pill that acts to stop flea eggs from hatching. Giving Advantage flea control, along with Program flea control (Lufenuron) can help to achieve an aggressive flea killing effect and flea larvae killing effect (Advantage flea control) along with an inhibitory effect on flea eggs (Program). Rapid eradication of fleas results from adult fleas dying on contact with the Advantage treated animal as well as eradication of the flea eggs and larvae in the environment. If you have a badly allergic pet and a massive flea burden in your home, it would be worth considering combining the two products (at least for the first few months) for extra speedy flea eradication.

Additionally, Advantage flea medication is compatible with corticosteroid administration (prednisolone, dexamethasone and so on). Corticosteroids are commonly given to flea allergy dogs and cats to reduce the severity of the allergic skin reaction and lessen the signs of skin irritation associated with the flea allergy dermatitis condition.

Advantage flea control can be used to prevent fleas from coming home:
Advantage flea control can also be given to clean (flea-free) animals to protect them when they enter a flea-risk environment (e.g. dog show, vet, groomer, dog training, friend's house containing fleas and so on). This will prevent the animal from catching fleas and bringing a flea problem back to your house. Apply Advantage flea control about 2-3 days (no less than 24 hours) before going to the flea-risk environment.



Advantage flea treatment - TOP



14) Imidacloprid insecticide - a common insecticide used in gardens and orchards.

As a result of its efficacy and its good safety profile (the product is considered to be of low-toxicity to vertebrates, including man), the neonicotinoid insecticide, Imidacloprid, is now commonly used to kill insect pests on crops, orchards and gardens worldwide.

Imidacloprid use as an insecticide:
Imidacloprid exerts a lethal effect on a wide range of crop, orchard, soil and garden pest insect species including, but not restricted to, the soybean aphid, the hemlock woolly adelgid, the potato leafhopper, the Japanese beetle, the Asian Long-horned beetle (a wood-boring pest of Canadian maple trees), the grape berry moth, various leaf- and planthoppers, whiteflies, thrips, scales, flea beetles, leaf-miners, mealy bugs, beetles, leaf beetles, termites, locusts and cockroaches.

The insecticide is applied to many varieties of crops and plants, some of which are intended for animal or human consumption including, but certainly not limited to: tea, soybeans, oranges and other citrus fruits, wine and table grapes, sugar beets, tomatoes, potatoes, sunflowers, eggplants, cabbages, mustard crops, bananas, cauliflowers, spinach, apples (residues have been found in applesauce made from treated apples), olives (including olives used in olive oil, though the imidacloprid tends to remain in the olive cake and not enter the oil in significant quantities), maize, buckwheat, canola, cotton and rice. Imidacloprid insecticide is also used in certain termite-killing preparations used to kill or prevent termites in houses, wood crops and wood structures.

Imidacloprid insecticide can be applied to plants in a multitude of ways. The insecticide is generally applied at the soil level because most plants take it up through the roots very well (from there it diffuses out to the rest of the plant's tissues: leaves, flowers, fruits and pollens, protecting them from insect pests and also some allies - discussed further on). The chemical is applied to the soil via irrigation (in solution with water) or applied directly to the soil in the form of releasing granules or in-furrow application (e.g. as seen in rice fields). The chemical can, alternatively, be directly applied to the seeds which are planted (as a seed coating or 'dressing') such that the chemical is there for the seedling to take up as it emerges from the treated husk. Imidacloprid can, alternatively, be applied to the stems of trees and to the foliage (in the forms of sprays and drenches). A 2006 article in the Journal of Economic Entomology looked at different ways of applying imidacloprid insecticide to forests to control a pest called hemlock woolly adelgid. The study trialled injection of the tree's trunk, soil injection of imidacloprid near the base of the trunk, injection of imidacloprid into the soil throughout the entire area beneath the tree's canopy and a soil drench at the base of the trunk. All soil treatments had an effect on the parasites, but the trunk injections did not. Residues of imidacloprid lasted for long periods of time in these trees, suppressing adelgids for > 2 years.

Not all of the plant is evenly protected in all cases. Depending on the method of application and amount of imidacloprid applied, some parts of plants may be more well-protected than others. Studies on tomato plants and sugar beets found, for example, that concentrations of imidacloprid declined towards the tops of the plants, but not the bottoms nearest the roots (where the insecticide was applied). A lot of research goes into determining where the imidacloprid ends up on treated plants and in what volumes and whether these quantities will be protective and what their impact will be on humans, other insects and the environment. That research is then used to find better, safer and more effective ways of applying imidacloprid (or perhaps an alternative insecticide) to crops.

For example, Pest Management Science published a study in 2012 looking at soil application of imidacloprid for the control of pests in vineyards. It found that the vines would not take up imidacloprid applied to soils prior to wetting (rain or watering), but that excellent protection of grape vines against a range of insect pests was achieved if the imidacloprid was provided to the soil and the new to late season vine roots via irrigation means (dissolved in water). Such a study achieves a great deal because it shows that irrigation can deliver the necessary insecticide thereby reducing the need for imidacloprid to be sprayed onto the foliage (as sometimes occurs). Foliage spraying of imidacloprid is problematic for many reasons: it increases the risk of imidacloprid inhalation and poisoning to vine growers, it increases the risk of insecticide drifting into fragile environments and waterways and it increases the exposure of insecticide to 'good' insects like parasitic wasps and honeybees. Also, knowing that imidacloprid can't just be applied to dry soil is also helpful as you don't want to contaminate an environment with a pesticide only to find that it doesn't even work, but just leaches away into the environment and water table.

Additionally, not all of the imidacloprid makes it into the plant tissues unchanged. Imidacloprid gets broken down by plants into various metabolites, some of which are active against insect pests in their own right. Some are even more toxic to certain insect pests than the parent compound, imidacloprid. These metabolites must also be taken into account when considering imidacloprid's risk to the environment, humans and other species (e.g. 'good' insects like parasitoid wasps and bees). For example, the olefin metabolite and 5-hydroxyimidacloprid metabolite are both considered to be more toxic to honeybees than the imidacloprid parent compound alone is.


Imidacloprid's persistence in soil:
Because of the risks to animals, people, valuable insect species and the environment (especially waterways and sensitive habitats) posed by large-scale spraying of Imidacloprid onto plant foliage, Imidacloprid tends to, for the most part, be applied to soil directly or to seeds grown in soil. How long it lasts in the soil depends on many factors, including the type of soil, the amount of organic matter present and the opportunity for run-off to occur. Soil persistence is important for farmers and agri-scientists to take account of because long persistence in soils can help to reduce the frequency with which the product must be applied to the soil, whereas, rapid depletion of the product from soils may indicate a problem with the chemical breaking down quickly (thus needing reapplication more often to maintain effect). It might also indicate a problem with the chemical leaching into nearby waterways and environments, posing environmental risk.

Soil half-life can vary widely, from as little as 40 days to as much as 4 months, depending on soil type and the presence of organic matter (including fertilizers). Soil with lots of organic matter (including certain non-agricultural soils and well fertilized soils) seems to hold imidacloprid for longer (higher sorption and persistence in soil). On the flip-side, soil with lots of dissolved organic carbon does not tend to hold imidacloprid insecticide (poor sorption) all that well, presumably because the carbon and the imidacloprid compete for binding sites in the soil. If soil is already saturated with high concentrations of imidacloprid, newly applied imidacloprid will not tend to bind to the soil very well (it will leach away). There is, thus, little benefit in applying more imidacloprid to soil that is already highly concentrated with the chemical or that has loads of dissolved organic carbon. Such application will only result in imidacloprid leaching away into ground water or water courses.

Pest Management Science looked at the "persistence and metabolism of imidacloprid in different soils of West Bengal". The study found that metabolites (break-down products) of imidacloprid appeared by day 30 in all three soil types (alluvial soil, lateritic soil and coastal alkaline soil) and that imidacloprid lasted the shortest amount of time (shortest half-life) in lateritic soil types.


Imidacloprid will kill 'good' invertebrates:
Imidacloprid is non-selective when it comes to insects and will also kill insect species that are of benefit to gardens, crops and water courses. Honeybees are considered highly susceptible, as are various parasitoid wasps (wasps that prey on pest insect species), lacewings (which drink imidacloprid contaminated nectar), Anagyrus pseudococci (which feeds on nectar) and arthropod nymphs that live in waterways. For this reason, care must be taken to ensure that Imidacloprid does not contaminate water supplies and outdoor environments with valuable, non-pest insect populations. Imidacloprid must never be allowed to contaminate beehives and major pollen and nectar sources as bees (and other nectar feeding species) are highly susceptible to poisoning. Bees generally take up imidacloprid present in the pollen of treated plants.

Additionally, sublethal doses of imidacloprid insecticide can also be harmful to beneficial insect populations without actually killing them outright. Sublethal levels of imidacloprid can: reduce growth rates, reduce population growth, reduce feeding rates, increase respiration rates, reduce response times to predators, slow maturation, reduce longevity, and reduce the numbers of eggs and offspring produced. Earthworms affected by imidacloprid produce fewer casts and shorter burrows, resulting in reduced soil aeration. Bees are highly susceptible to imidacloprid and often die (the oral LD50 for bees ranges from 3.7 to 40.9 ng per bee and contact LD50 ranges from 59.7 to 242.6 ng per bee). Those bees exposed to sublethal doses show reduced reflexes, reduced learning responses, reduced brood production and reduced feeding (especially of pollens or sugars tainted with imidacloprid).

A 2007 article in Environmental Entomology showed that imidacloprid applied to soils was taken up into the nectar of buckwheat flowers. This imidacloprid, along with its metabolites, was found to have numerous adverse effects on the nectar-feeding parasitoid, Anagyrus pseudococci, which exhibited: reduced survival, trembling and altered behavior. The article makes comment that adverse behavioural and mortality effects are also well known in bees exposed to the imidacloprid affected pollen and nectar of canola, sunflowers and maize and that similar effects have also been seen in pink lady beetles and green lacewings.

Another study published in 2011 in the Journal of Economic Entomology examined the effect of imidacloprid and thiamethoxam on beneficial parasitoid species present in cotton fields, citrus orchards and vegetable patches. Imidacloprid applied to leaves had an adverse effect on each of the six species studied (insects were thought to be poisoned through direct body contact with the imidacloprid).

A 2012 article in Naturwissenschaften showed that sublethal imidacloprid exposure increased the levels of Nosema in the gut of bees. This organism is a pathogen of bees and its increase suggests that low levels of imidacloprid, even when not at levels high enough to cause death or impact on bee foraging activities, may adversely impact upon the bee's immune system, making it more likely to succumb to secondary pathogens and parasites that it would normally be resistant to. The abstract ends by saying: "Interactions between pesticides and pathogens could be a major contributor to increased mortality of honey bee colonies, including colony collapse disorder, and other pollinator declines worldwide." It is a scary thought and of much concern in the face of massive bee declines worldwide.

It should be remembered that foliage spraying is not the only means by which pollens accumulate imidacloprid and thereby poison bees. Even when imidacloprid is applied to seed, the plant that grows from that treated seed will take up and accumulate imidacloprid residues in the pollens and nectar. Almost 70% of pollen samples taken randomly from bees in 5 regions in France had detectable levels of imidacloprid or its metabolites.

Environmental Quality published an article in 2008 showing that the deciduous leaves falling from imidacloprid treated maple trees in autumn in Canada contained enough imidacloprid to adversely affect populations of decomposer organisms feeding on the dead leaves. Samples of imidacloprid-containing dead leaves were applied to aquatic (water) and terrestrial (land) microcosms. While the study did not reveal any effect on the survival of aquatic leaf-shredding insects or earthworms, adverse effects were noticed in these species including: weight loss, reduced feeding rates and reduced decomposition rates, with the end result that decomposition activities were abnormally slowed.

A 2012 study published in Ecotoxicology looked at the effect experienced by five different species of aquatic arthropods (cladoceran types) when they were exposed to imidacloprid insecticide, commonly applied to rice fields in Japan. It found that Ceriodaphnia was more sensitive to imidacloprid than Moina and Daphnia species, making it potentially a more sensitive bioindicator of imidacloprid water contamination than other aquatic arthropod species (Daphnia is generally the species studied when water contamination events are suspected). Interestingly, all aquatic arthropods studied were found to be less susceptible to imidacloprid than certain other aquatic species, including certain: fish, insects, crustaceans, molluscs and worms. This puts into question the use of aquatic arthropods as the sole indicators of insecticide contamination of waterways.

Other studies into aquatic arthropods have showed that, while some species are highly susceptible to a single insecticide 'event' (a single pulse of insecticide contamination into the waterway), other species need multiple 'events' (multiple pulses) before they begin to die off. Knowing which species are affected by individual events and which species are affected by multiple events can help environmental regulators to recognise ongoing contamination episodes and situations that pose increased risks for such episodes (e.g. run-off periods associated with periods of high rainfall). A 2011 article in Aquatic Toxicology looked at the "Macroinvertebrate community response to repeated short-term pulses of the insecticide imidacloprid" and showed that, while some macroinvertebrates died after only a single imidacloprid exposure event (e.g. caddisflies), other species needed repeated exposures to imidacloprid to experience die off (e.g. ephemerids and dipteran larvae). The study showed that a lot of factors were at play, including the pulse size (concentrations of insecticide in the water), pulse duration, the number and frequency of the pulses, as well as insect factors including the life-stages of the macroinvertebrates at the time of the pulses (e.g. newly emerged versus older) and the temperature of the water (macroinvertebrates were more sensitive to the lethal effects of the insecticide during summer, when temperatures were higher). Knowing such things can influence how and when pesticides like imidacloprid are applied, therefore reducing the impact on the environment (e.g. applying them at a time of year when there is unlikely to be heavy rainfall and run-off into water ways).

Environmental Toxicology and Chemistry in 2007 looked at the effect of pulse exposures of imidacloprid on two aquatic species: the mayfly (Epeorus longinmanus) and on an aquatic oligochaete called Lumbriculus variegatus. The article commented that such imidacloprid pulse events were most likely to occur during periods of runoff from imidacloprid treated soils and crops (e.g. after rainfall or flooding). Imidacloprid was found to be "highly toxic" to mayflies of early and later larval stages with short pulses of imidacloprid found to be highly lethal to them. Those that didn't die immediately suffered from inhibited feeding ability, which lasted several days (some individuals did not recover from this). The oligochaete was less sensitive than the mayfly to imidacloprid pulses, but did show reduced mobility when imidacloprid levels were sustained over several days (4 days straight).


Imidacloprid can impact upon birds and fish:
While imidacloprid insecticide is not generally considered highly toxic to vertebrates like birds and fish, the effect of imidacloprid on birds and fish has been studied because of the potential risks posed to avian and aquatic species through use of imidacloprid insecticide in gardens, crops and orchards. Birds can potentially be poisoned through the ingestion of imidacloprid-containing nectar, pollen, fruit and vegetation and exposed dermally to foliage sprays. Fish, like aquatic arthropods, can be affected by run-off of imidacloprid into waterways and some fish may also eat arthropods that have been poisoned by imidacloprid pulses.

The acute LD50 (dose at which 50% of individuals die from ingestion or other forms of contact with a test substance) varies depending on the species of bird or fish with some species being highly susceptible to imidacloprid toxicity and others being relative resistant. For example, the acute oral LD50 for Japanese quail is only 31mg/kg, but 152mg/kg in bobwhite quail.

As with invertebrates, care must be taken to ensure that Imidacloprid does not contaminate water supplies and outdoor environments with sensitive, valuable, wild bird and fish populations.


Acute imidacloprid poisoning is more possible in orchard and crop situations:
In section 12 of this page, the acute toxic effects of imidacloprid on humans was discussed. Most cases of acute imidacloprid poisoning and even death have occurred by ingestion of the chemical (often a deliberate suicide attempt), however, accidental poisoning has occurred through the inhalation of aerosolised spray and dust-forms of the compound. Humans are most likely to encounter potentially dangerous imidacloprid aerosols and dusts on farms, where large volumes of the insecticide are being sprayed onto plant crops. People involved in such environments and work-places should take care to wear protective clothing (including eye protection) and respirators to avoid inhaling this insecticide. Insecticides should not be stored or used where there is the potential for contamination of human food or drinking water (including water tanks) to occur.

Should spillage of imidacloprid insecticide occur, all personnel involved in the clean-up should wear protective clothing, including respiratory protection and eye protection. Spillage should not be allowed to spread or enter soil, water courses or drains. Absorbent materials like sawdust or peat should be used to bind up any spillage and this bound insecticide/binder mix should then be scooped into sealable containers. Detergent, along with small amounts of water, can be used to clean surfaces. The water and detergent and insecticide mix, along with any cleaning implements, should then be put into similar sealable containers. Relevant authorities should then be contacted for safe disposal of the insecticide-containing waste.


Chronic human exposure to imidacloprid insecticide?
Studies into imidacloprid have found that the chemical does not damage DNA and that it has not been found to cause mutations, cancer, fetal malformations (non-teratogenic) or any other reproductive effects, even when animals (rodents are the typical study population) are exposed to them over long spans of time. The conclusion drawn from this is that low level, chronic exposure to imidacloprid (e.g. in fruits and vegetables grown under conditions of imidacloprid insecticide use) should not be harmful to people long term. This is a comforting thought, given that imidacloprid is now one of the major insecticides used on crops and orchards and even on substances like rice and tea all over the world and an insecticide that people are probably eating tiny amounts of on a weekly basis.

Regulatory guidelines for the use of insecticides in products intended for human consumption often refer to a Reference Dose or RfD. For imidacloprid, the RfD is 0.057 mg/kg/day. The Reference Dose is the quantity of a chemical "that a person could be exposed to every day for the rest of their life with no appreciable risk of adverse health effects. The reference dose is typically measured in milligrams (mg) of chemical per kilogram (kg) of body weight per day." A person of 80kg in weight could, by this formula, safely consume 80x0.057 = 4.56mg of imidacloprid daily with no ill-effect.

Whether the substance really is all that safe or not at constant, low levels over the course of decades is probably impossible to say for sure given that most studies are done on rodents (not humans) and most humans are exposed to whole swathes of potential carcinogens (both known or unknown) every day, making it impossible to say for sure exactly which of a whole range of chemicals caused any one cancer or immune disease. If a man dies of cancer, how can anyone really say whether or not it was the imidacloprid in his oranges that contributed to the problem or the chemical pollutants drifting through the very air he breathes? When you think of how long it took to confirm and prove that smoking causes cancer, you can only imagine how difficult it would be to pinpoint a particular ubiquitous pesticide as causing problems. So far, Imidacloprid has not been found to cause cancer in animal and cell studies, but that does not 100% guarantee its safety. Just as we once used DDT on our crops before we realised how unsafe it was, in years to come, we may eventually find out that other, currently 'safe', pesticides we are putting on our food are not so safe at all.

In the absence of such certainty, it is probably best, as with all man-made chemicals, to reduce the consumption and exposure of imidacloprid wherever possible. Strict compliance with maximum residue limits and withholding periods in food is but one way of doing this as is taking care not to pollute soils and waterways with run-off containing imidacloprid insecticides. Consuming organically-grown foods where possible can also help to reduce your intake of such pesticides.


Examples of low-level, chronic pesticide exposure in real life situations:
A study published in 2007 in Environmental Geochemistry and Health looked at imidacloprid residues in soils, water samples, fruits and vegetables in Palestine during 1998 and 1999. The study revealed imidacloprid residues in many of the samples of food (e.g. highest residues were found in eggplants) with some of the levels being above the maximum residue limit recommended for human consumption. Consumed in excess, such contaminated food could potentially pose a toxicity risk for humans in those parts. Humans eating such food would certainly be exposed to low-level chronic imidacloprid insecticide ingestion, even if they were not outright poisoned by it.

A case report published in Chudoku Kenkyu (Japan) in 2011, looked at six cases of subacute imidacloprid toxicity admitted to a medical centre in Japan. The affected people had ingested large amounts of imidacloprid in domestic fruits and tea leaves as a direct result of high personal consumption of these products, which also happen to have high imidacloprid maximum residue limits set for their sale in Japan (i.e. Japan allows quite high levels of imidacloprid to be present in foodstuffs available for human consumption, leading to an increased potential for toxicity in humans who ingest a lot of such produce). Affected people showed many of the signs described previously for imidacloprid toxicity (in particular: head-aches, fatigue, finger tremors and short-term memory disturbance, as well as a range of gastrointestinal and cardiac signs) and were diagnosed by ion chromatography techniques performed on their urine, targeted at detecting 6-chloronicotinic acid (a common metabolite of imidacloprid). The people were treated with supportive care and advised to restrict their intake of fruits and tea.

The 2011 Bulletin of Environmental Contamination and Toxicology looked at levels of pesticides contained in fresh potatoes sold in farmer's markets in Alberta. Residues were found for three insecticides, one of which was imidacloprid. Although residues found were all below Canada's maximum residue limits for potatoes, the study does show the need for vigilance of inspectors in this regard and point to a high potential for consumers to be exposed to chronic, long-term ingestion of imidacloprid, the true, ongoing, cumulative safety of which may not be known for decades. No residues were found in organically grown potatoes sampled at the time.

The Pesticide Data Program of the USA's Department of Agriculture examined imidacloprid residues in a range of fruits and vegetables in 2006. Although residues found (bananas, cauliflowers and spinach were commonly found to have detectable levels) were all below the allowable maximum residue limits, the study does show the need for vigilance of inspectors in this regard and point to a high potential for consumers to be exposed to chronic, long-term ingestion of imidacloprid, the true, ongoing, cumulative safety of which may not be known for decades.

The journal, Chromatography A, in 2008 described a technique to detect levels of imidacloprid in bovine milk samples. The levels found were lower than maximum residue limits set by the EU, however, the important thing to note is that residues were found, showing that it is not only fruit and vegetables that could pose a risk to humans of imidacloprid ingestion, but sources we'd barely expect such as bovine milk. Care needs to be taken with amounts of imidacloprid contained in fruit and vegetable 'seconds' used to feed livestock animals that are then either converted to meat products or farmed for their milk.


Risks to trade of inappropriate imidacloprid application:
Aside from the risks posed to humans through the inappropriate use of imidacloprid insecticide and incorrect adherence to withholding times and maximum residue limits, there is also a huge risk to trade as well. Economies are all interlinked and everyone trades with everyone else. Different countries have different residue limits for imidacloprid and other such insecticides in fruit and vegetables and, failure to comply with these rules can result in exports not being accepted by stricter countries. The EU is probably the hardest market to get into with very strict controls on the levels of pesticides permitted into produce intended for human consumption.

The following link is a link to an Australian Pesticides and Veterinary Medicines Authority PDF, spelling out the rules on imidacloprid use in oranges destined for overseas and EU sale.
http://www.apvma.gov.au/registration/assessment/docs/tan_imidacloprid.pdf



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Advantage flea control links:

To go from this Advantage flea treatment page to my detailed Flea Control Page, click here.

To go from this Advantage flea medicine page to the Flea Pictures page, click here.

Bayer Advantage Flea Control Product Sheets and MSDS:
http://www.bayeranimal.com.au/default.aspx?Page=50&ItemId=75
http://www.bayeranimal.com.au/PDFViewer/DocumentDisplayPage.aspx?CurrentDocumentID=%2bA2aUfpXGNP%2bUgcCTOKeLQ%3d%3d
http://www.bayeranimal.com.au/PDFViewer/DocumentDisplayPage.aspx?CurrentDocumentID=OCqHyRh37u9Om4AajzlYMQ%3d%3d
http://www.bayeranimal.com.au/PDFViewer/DocumentDisplayPage.aspx?CurrentDocumentID=XpWm37T%2bVbaj7DMSVMm8UQ%3d%3d



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Advantage Flea Control References and Suggested Reading:

1) Arthropods. In Bowman DD, Lynn RC, Eberhard ML editors: Parasitology for Veterinarians, USA, 2003, Elsevier Science.

2) Insecticides. In Bowman DD, Lynn RC, Eberhard ML editors: Parasitology for Veterinarians, USA, 2003, Elsevier Science.

3) External Infestations - Small Animals. In Wroth O, editor: MIMS IVS Annual. St Leonards, 2001, Havas MediMedia.

4) Bayer web publications:
4a) http://www.bayeranimal.com.au/default.aspx?Page=50&ItemId=75
4b) http://www.bayeranimal.com.au/PDFViewer/DocumentDisplayPage.aspx?CurrentDocumentID=%2bA2aUfpXGNP%2bUgcCTOKeLQ%3d%3d
4c) http://www.bayeranimal.com.au/PDFViewer/DocumentDisplayPage.aspx?CurrentDocumentID=OCqHyRh37u9Om4AajzlYMQ%3d%3d
4d) http://www.bayeranimal.com.au/PDFViewer/DocumentDisplayPage.aspx?CurrentDocumentID=XpWm37T%2bVbaj7DMSVMm8UQ%3d%3d

5) Genchi C, Traldi PG, Bianciardi PP. Efficacy of imidacloprid on dogs and cats with natural infestations of fleas, with special emphasis on flea hypersensitivity. In: Veterinary Therapy, 2000 Spring;1(2):71-80.

6) Dryden MW, Denenberg TM, Bunch S. Control of fleas on naturally infested dogs and cats and in private residences with topical spot applications of fipronil or imidacloprid. In: Veterinary Parasitology, 2000 Nov 1;93(1):69-75.

7) Hutchinson MJ, Jacobs DE, Mencke N. Establishment of the cat flea (Ctenocephalides felis felis) on the ferret (Mustela putorius furo) and its control with imidacloprid. In: Medical Veterinary Entomology, 2001 Jun;15(2):212-4.

8) Jacobs DE, et al. Accumulation and persistence of flea larvicidal activity in the immediate environment of cats treated with imidacloprid. In: Medical Veterinary Entomology, 2001 Sep;15(3):342-5.

9) Cadiergues MC, Caubet C, Franc M. Comparison of the activity of selamectin, imidacloprid and fipronil for the treatment of dogs infested experimentally with Ctenocephalides canis and Ctenocephalides felis felis. In: Veterinary Record, 2001 Dec 8;149(23):704-6.

10) Baker RT, Beveridge I. Imidacloprid treatment of marsupials for fleas (Pygiopsylla hoplia). In: Journal of Zoo and Wildlife Medicine, 2001 Sep;32(3):391-2.

11) Viradiya K, Mishra A. Imidacloprid poisoning. In: Journal of Associate Physicians India, 2011 Sep;59:594-5.

12) Van Timmeren S, Wise JC, Isaacs R. Soil application of neonicotinoid insecticides for control of insect pests in wine grape vineyards. In: Pest Management Science, 2012 Jan 30. doi: 10.1002/ps.2285.

13) Mohr S, et al. Macroinvertebrate community response to repeated short-term pulses of the insecticide imidacloprid. In: Aquatic Toxicology, 2011 Dec 8;110-111C:25-36.

14) Pettis JS, et al. Pesticide exposure in honey bees results in increased levels of the gut pathogen Nosema. In: Naturwissenschaften, 2012 Feb;99(2):153-8.

15) Jachowski DS, Skipper S, Gompper ME. Field evaluation of imidacloprid as a systemic approach to flea control in black-tailed prairie dogs, Cynomys ludovicianus. In: Vector Ecology, 2011 Jun;36(1):100-7.

16) Chopade H, et al. Skin distribution of imidacloprid by microautoradiography after topical administration to beagle dogs. In: Veterinary Therapeutics, 2010 Winter;11(4):E1-E10.

17) Rust MK, et al. Large-scale monitoring of imidacloprid susceptibility in the cat flea, Ctenocephalides felis. In: Medical Veterinary Entomology, 2011 Mar;25(1):1-6.

18) Borchert JN, et al. Evaluation of rodent bait containing imidacloprid for the control of fleas on commensal rodents in a plague-endemic region of northwest Uganda. In: Journal of Medical Entomology, 2010 Sep;47(5):842-50.

19) Borchert JN, Davis RM, Poché RM. Field efficacy of rodent bait containing the systemic insecticide imidacloprid against the fleas of California ground squirrels. In: Journal of Vector Ecology, 2009 Jun;34(1):92-8.

20) Schnieder T, Wolken S, Mencke N. Comparative efficacy of imidacloprid, selamectin, fipronil-(S)-methoprene, and metaflumizone against cats experimentally infested with Ctenocephalides felis. In: Veterinary Therapeutics, 2008 Fall;9(3):176-83.

21) McCoy C, Broce AB, Dryden MW. Flea blood feeding patterns in cats treated with oral nitenpyram and the topical insecticides imidacloprid, fipronil and selamectin. In: Veterinary Parasitology, 2008 Oct 1;156(3-4):293-301.

22) Wenzel U, et al. Efficacy of imidacloprid 10%/moxidectin 1% (Advocate/Advantage Multi) against fleas (Ctenocephalides felis felis) on ferrets (Mustela putorius furo). In: Parasitology Research, 2008 Jun;103(1):231-4.

23) Dryden MW, et al. Comparative speed of kill of selamectin, imidacloprid, and fipronil-(S)-methoprene spot-on formulations against fleas on cats. In: Veterinary Therapeutics, 2005 Fall;6(3):228-36.

24) Klimpel S, et al. Field trial of the efficacy of a combination of imidacloprid and permethrin against Tunga penetrans (sand flea, jigger flea) in dogs in Brazil. In: Parasitology Research, 2005 Oct;97

25) Larsen KS, Siggurdsson H, Mencke N. Efficacy of imidacloprid, imidacloprid/permethrin and phoxim for flea control in the Mustelidae (ferrets, mink). In: Parasitology Research, 2005 Oct;97

26) McTier TL, et al. Comparison of the activity of selamectin, fipronil, and imidacloprid against flea larvae (Ctenocephalides felis felis) in vitro. In: Veterinary Parasitology, 2003 Aug 29;116(1):45-50.

27) Craig MS, et al. Human exposure to imidacloprid from dogs treated with advantage(r). In: Toxicology Mechanisms and Methods, 2005;15(4):287-91.

28) Jacobs DE, Hutchinson MJ, Ewald-Hamm D. Inhibition of immature Ctenocephalides felis felis (Siphonaptera: Pulicidae) development in the immediate environment of cats treated with imidacloprid. In: Journal of Medical Entomology, 2000 Mar;37(2):228-30.

29) Franc M, Cadiergues MC. Antifeeding effect of several insecticidal formulations against Ctenocephalides felis on cats. In: Parasite, 1998 Mar;5(1):83-6.

30) Mehlhorn H, Hansen O, Mencke N. Comparative study on the effects of three insecticides (fipronil, imidacloprid, selamectin) on developmental stages of the cat flea (Ctenocephalides felis Bouché 1835): a light and electron microscopic analysis of in vivo and in vitro experiments. In: Parasitology Research, 2001 Mar;87(3):198-207.

31) Prabhaker N, et al. Compatibility of two systemic neonicotinoids, imidacloprid and thiamethoxam, with various natural enemies of agricultural pests. In: Journal of Economic Entomology, 2011 Jun;104(3):773-81.

32) Taira K, et al. Detection of chloropyridinyl neonicotinoid insecticide metabolite 6-chloronicotinic acid in the urine: six cases with subacute nicotinic symptoms. In: Chudoku Kenkyu, 2011 Sep;24(3):222-30.

33) Phua DH, et al. Neonicotinoid insecticides: an emerging cause of acute pesticide poisoning. In: Clinical Toxicology, 2009 Apr;47(4):336-41.

34) Angioni A, Porcu L, Pirisi F. LC/DAD/ESI/MS method for the determination of imidacloprid, thiacloprid, and spinosad in olives and olive oil after field treatment. In: Journal of Agricultural and Food Chemistry, 2011 Oct 26;59(20):11359-66.

35) Thompson TS, et al. Pesticides in fresh potatoes sold in farmers' markets in Alberta, Canada. In: Bulletin of Environmental Contamination and Toxicology, 2011 Nov;87(5):580-5.

36) Van Timmeren S, et al. Comparison of foliar and soil formulations of neonicotinoid insecticides for control of potato leafhopper, Empoasca fabae (Homoptera: Cicadellidae), in wine grapes. In: Pest Management Science, 2011 May;67(5):560-7.

37) Seccia S, et al. Determination of neonicotinoid insecticides residues in bovine milk samples by solid-phase extraction clean-up and liquid chromatography with diode-array detection. In: Journal of Chromatography A, 2008 Dec 19;1214(1-2):115-20.

38) Kreutzweiser DP, et al. Are leaves that fall from imidacloprid-treated maple trees to control Asian longhorned beetles toxic to non-target decomposer organisms? In: Journal of Environmental Quality, 2008 Mar-Apr;37(2):639-46.

39) Krischik VA, Landmark AL, Heimpel GE. Soil-applied imidacloprid is translocated to nectar and kills nectar-feeding Anagyrus pseudococci (Girault) (Hymenoptera: Encyrtidae). In: Journal of Environmental Entomology, 2007 Oct;36(5):1238-45.

40) Daraghmeh A, et al. Imidacloprid residues in fruits, vegetables and water samples from Palestine. In: Journal of Environmental Geochemistry and Health, 2007 Feb;29(1):45-50.

41) Blasco C, et al. Screening and evaluation of fruit samples for four pesticide residues. In: Journal of AOAC International, 2005 May-Jun;88(3):847-53.

42) Sarkar MA, et al. Persistence and metabolism of imidacloprid in different soils of West Bengal. In: Pest Management Science, 2001 Jul;57(7):598-602.

43) Oi M. Time-dependent sorption of imidacloprid in two different soils. In: Journal of Agricultural and Food Chemistry, 1999 Jan;47(1):327-32.

44) Hayasaka D, et al. Differences in susceptibility of five cladoceran species to two systemic insecticides, imidacloprid and fipronil. In: Ecotoxicology, 2012 Mar;21(2):421-7.

45) Shadnia S, et al. Fatal intoxication with imidacloprid insecticide. In: American Journal of Emergency Medicine, 2008 Jun;26(5):634.

46) Alexander AC, et al. Effects of insecticide exposure on feeding inhibition in mayflies and oligochaetes. In: Environmental Toxicology and Chemistry, 2007 Aug;26(8):1726-32.

47) Sánchez-Bayo F, et al. Ecological effects of imidacloprid on arthropod communities in and around a vegetable crop. In: Journal of Environmental Science and Health, part B, 2007 Mar-Apr;42(3):279-86.

48) Cowles RS, Montgomery ME, Cheah CA. Activity and residues of imidacloprid applied to soil and tree trunks to control hemlock woolly adelgid (Hemiptera: Adelgidae) in forests. In: Journal of Economic Entomology, 2006 Aug;99(4):1258-67.

49) Tomizawa M, Casida JE. Neonicotinoid insecticide toxicology: mechanisms of selective action. In: Annual Review of Pharmacology and Toxicology, 2005;45:247-68.

50) Schenker R, et al. Comparative speed of kill between nitenpyram, fipronil, imidacloprid, selamectin and cythioate against adult Ctenocephalides felis (Bouché) on cats and dogs. In: Veterinary Parasitology, 2003 Mar 10;112(3):249-54.

51) Tomizawa M, Casida JE. Selective toxicity of neonicotinoids attributable to specificity of insect and mammalian nicotinic receptors. In: Annual Review of Entomology, 2003;48:339-64.

52) Melhorn H: Encyclopedia of Parasitology, Volume 1, 3rd ed. Berlin, 2008, Springer-Verlag.

53) Riviere JE, Papich MG, Veterinary Pharmacology and Therapeutics 9th ed. USA, 2009, Wiley-Blackwell.

54) Rose et al. Pesticides. In : Marquardt H, et al. Toxicology, USA, 1999, Academic Press, page 691.

55) The Autonomic Nervous System: The Adrenal Medulla. In: Guyton AC, Hall JE, Textbook of Medical Physiology, 9th ed. Sydney, 1996, WB Saunders Company.

56) Tan J, Galligan JJ, Hollingworth RM. Agonist actions of neonicotinoids on nicotinic acetylcholine receptors expressed by cockroach neurons. In: Neurotoxicology. 2007 Jul;28(4):829-42.

57) Imidacloprid. In Plumb DC, Plumb's Veterinary Drug Handbook, 5th ed. USA, 2005, Blackwell Publishing.

58) http://npic.orst.edu/factsheets/imidacloprid.pdf

59) http://en.wikipedia.org/wiki/Imidacloprid_effects_on_bees - toxic to bees.

60) http://www.beekeeping.com/articles/us/imidacloprid_bayer.htm

61) http://www.apvma.gov.au/registration/assessment/docs/tan_imidacloprid.pdf



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Pet Informed is not in any way affiliated with any of the companies whose products appear in images or information contained within this Advantage flea control article. Any images, taken by Pet Informed, are only used in order to illustrate certain points being made in the article. Pet Informed receives no commercial or reputational benefit from any of these companies for mentioning their products and can not make any guarantees or claims, either positive or negative, about these companies' products, customer service or business practices. Pet Informed can not and will not take any responsibility for any death, damage, illness, injury or loss of reputation and business or for any environmental damage that occurs should you choose to use one of the mentioned products on your pets, poultry or livestock (commercial or otherwise) or indoors or outdoors environment. Do your homework and research all flea control products carefully before using any flea products on your animals or their environments.

Copyright March 3, 2012, Dr. O'Meara, www.pet-informed-veterinary-advice-online.com.

Capstar and Program are registered trademarks of Novartis Animal Health Australasia Pty Ltd.
Revolution is a registered trademark of Pfizer Animal Health.
Comfortis is a registered trademark of Elanco Companion Animal Health.
Advantage for Dogs and Cats, Advocate and Advantix are registered trademarks of Bayer Australia Ltd.


Please note: the aforementioned flea prevention, flea control and flea treatment guidelines and information on the flea life cycle are general information and recommendations only. The information provided is based on published information and on recommendations made available from the drug companies themselves; relevant veterinary literature and publications and my own experience as a practicing veterinarian. The advice given is appropriate to the vast majority of pet owners, however, given the large range of flea medication types and flea prevention and control protocols now available, owners should take it upon themselves to ask their own veterinarian what treatment and flea prevention schedules s/he is using so as to be certain what to do. Owners with specific circumstances (high flea infestation burdens in their pet's environment, pregnant bitches and queens, very young puppies and kittens, flea infested ferrets, flea infested rabbits, dog, cat and rabbit breeders, livestock and poultry producers, multiple-dog and cat environments, animals with severe flea allergy dermatitis, animals on immune-suppressant medicines, animals with immunosuppressant diseases or conditions, owners of sick and debilitated animals etc. etc.) should ask their vet what the safest and most effective flea protocol is for their situation.

Please note: the scientific flea names mentioned in this fleas life cycle article are only current as of the date of this web-page's copyright date. Parasite scientific names are constantly being reviewed and changed as new scientific information becomes available and names that are current now may alter in the future.