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Part Three:
Insecticides
Become Drugs...
so they can be eaten.

 
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If a huge skull and crossbones were suspended above the insecticide department the customer might at least enter it with the respect normally accorded death-dealing materials.”
— Rachel Carson: Silent Spring

what does "Half life" mean?

The biological or terminal half-life of a pesticide or drug is the time it takes to lose half of its pharmacologic or physiologic activity.  It refers to the body's cleansing (detoxification) through the function of kidneys and liver, and subsequent excretion through urine and feces to eliminate a substance from the body.  For “drug” classified pesticides (chews and other FDA-regulated products) half life is used in a medical context, describing the time it takes for the blood plasma concentration of an active ingredient to halve (plasma half-life) its “steady-state.”  

The relationship between the biological and plasma half-life may be influenced by factors of bio-accumulation in tissues (protein binding), active metabolites (see below), and receptor interactions.  Manufacturer conducted premarket clearance testing may not accommodate complications for these issues because studies are commonly brief and limited in scope.  In parallel, half-life is also used as an environmental/chemistry term: to define the persistence or length of time an active ingredient remains available for uptake in the environment.

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pesticides as a dog treat?

won't stain carpeting, upholstery or clothing

Family friendly:
no need to isolate…
you can play with your dog immediately
after treatment

Consumable pesticides are increasing in popularity, as the active ingredient reaches the parasites through the blood, (everywhere in the dog's body), and efficacy is independent from exposure to dirt, sun, shampooing, rain, etc., whereas topical products can be washed away, or broken down by sunlight, etc.

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Comfortis® (2007) and Trifexis® (2011; class: Spinosyn; also marketed as Vethical AcuGuard® and ComboGuard®) are once-monthly beef- flavored chew-able tablets dispensed by veterinarians, aggressively marketed as a convenient and cost-effective alternative to “spot-ons.”  Consumable pest control “won't stain carpeting, upholstery or clothing.”  Moreover, the tablets appeal to parents of small children: since there would be no transferable pesticide on the dog's fur: “Family friendly: no need to isolate… you can play with your dog immediately after treatment.”  Both are produced by Elanco: the animal drug division of Eli Lilly and Co., and because they act systemically, they are classified as drugs, and as such, these products fall under the purview of the US Food & Drug Administration (FDA).   

not yet understood...

Despite their frequency in these household-venue veterinary-prescribed applications, the molecular mechanism of action of spinosyn class pesticides has not been completely elucidated.  What is currently known is that they act on both GABA and nicotinic receptors of the membranes of nerve cells of insects, but target different subunits than other insecticides, and so, although they work similarly to the new classification isoxazolines, they kills fleas, but not ticks.

Spinosyns activate reactions in the flea’s cellular ion channels (the nicotinic acetylcholine receptors or nAChRs), causing a fatal central nervous system reaction (involuntary muscle contractions and tremors resulting from activation of motor neurons) that leads to prostration, hyperexcitation paralysis, and death. The selective toxicity of spinosad between insects and vertebrates may be conferred by the differential sensitivity of the insect versus vertebrate nAChRs.  That they are “less toxic,” however, does not mean that they are not toxic.

Systemic Mode

Pesticides that act systemically bind to blood plasma after injection, ingestion or topical administration, so that they are circulated throughout the body to display efficacy. 

 Systemic delivery of veterinary drugs

Systemic delivery of veterinary drugs

“Systemic circulation”differs from “Pulmonary circulation,”which refers to circulation of blood only between the heart and lungs: in which de-oxygenated blood is pumped from the heart to the lungs and oxygenated blood is returned to back to the heart.

spinosad

 

Intoxication as the Normal Therapeutic Dose?

The active ingredient is Spinosad, a fermentation of the soil bacterium Saccharopolyspora spinosa and S. pogona, discovered to have high pesticidal properties by Eli Lilly in the early 1980s.  Partnering with Dow Chemical, the company isolated and developed spinosad for agricultural uses in the 1990s.  Since that time, several dozen different natural spinosyns have been identified, and several hundreds chemically modified or semi-synthetic derivatives of those fermentation products have been produced in the laboratory.

The National Pesticide Information Center describes a study wherein dogs fed low doses of spinosad over a year showed “effects to [adrenal] gland and immune cells and increases in [certain plasma] proteins and fats.”  The most frequent symptom of intoxication in dogs is vomiting, which also happens as adverse side effect after correct treatment at the therapeutic dose.

After oral administration, Spinosad quickly binds to blood plasma and so circulates throughout the body systemically, reaching “maximum plasma level” in only 2 to 4 hours after administration, with bio-availability (>70%) increased if administered with food.  It is speedily metabolized (killing in 30 minutes) and excreted. 

 Serotonin: the brain's primary chemical and neurotransmitter of electrical impulses

As is common to many competing products, manufacturer conducted premarket clearance study indicated depression/lethargy as the primary adverse effect.  This would likely be due (but not researched) to its effect on serotonin level: the primary chemical and neurotransmitter that supports regulating cognition, mood and social behavior, appetite and digestion, sedation/sleep, memory, and sexual desire and function.  It has been hypothesized that Spinosad may deplete concentrations of important amino acids such as L-tryptophan, a biosynthetic precursor for creating serotonin.  Note that the second most-common adverse
effect is inappetence. 

Then, in descending frequency: in-coordination/(vestibular syndrome), diarrhea, itching, trembling, hyper-salivation and seizures (abnormal activity in the brain).

There is no antidote for spinosad poisoning.  Treatment consists in preventing further exposure together with supportive and symptomatic measures.

 

convulsions

blindness

depression

aggression

paralysis

death

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If Spinosad is administered concomitant to Invermectin (examples: Ivomec® , Merial's Heartgard®, Intervet's Tri-Heart Plus®, for treatment and prevention from heartworm disease (dirofilariasis: transmitted by mosquitoes, demodectic and sarcoptic mange, or ear mites) it can impart a serious synergistic effect that manifests as mydriasis (pupil dilation), hyper-salivation and hyperactivity, broad skin disorders, convulsions, stupor, blindness, depression, aggression, paralysis, and death.

Why combine macrocyclic lactones?

This is an increasingly common scenario that is consumer-driven, as some states are plagued by a range of pests that create market-niche for multi-use products.  These pesticides are known as endectocides because they show high efficacy against a broad spectrum of both endoparasites (parasites that live inside a host, e.g., nematodes: such as gastrointestinal roundworms) and ectoparasites (parasites that live outside a host, e.g. mites, lice, several insect larvae). 

There are no patent protections for this category of two structurally different chemical groups: avermectins and milbemycins.  The largest part of the active ingredient administered is usually excreted through the feces and the amount metabolized (chemically converted for use in the body) is typically small. 

As a macrocyclic lactone, Invermectin can be problematic when used in dogs with the MDR-1 gene mutation (e.g. Collies), that makes them sensitive to pesticides that may pass the blood-brain barrier (BBB), a highly selective semipermeable membrane barrier that separates circulating blood from the brain and extracellular fluid in the dog's central nervous system (see: part 2). 

 Snickers: the past as prologue... but now, each day a new begining... 

Snickers: the past as prologue... but now, each day a new begining... 

Does [Insert Name of Pesticide “Chew”]
Kill Dogs?
(Or): Failure of the Regulatory Process

 

Milbemycin oxime

Elanco's third entry is Trifexis® (2011) : fleas, heartworm, intestinal worms) adds milbemycin oxime (Novartis: Switzerland: another macrocyclic lactone class pesticide) to spinosad, positioned as the monthly “3-in-one Parasite Protection: Fleas, Heartworms, and Intestinal Parasites”  beef-flavor chew (an artificial flavoring of pork-based proteins and hydrolyzed soy).

By 2018, at least 1,500 canine deaths (some within hours of administering a first dose) attribed to Trifexis® have been reported to the FDA.  Investigation is focusing on milbemycin oxime, being imported from China. 

Other than reports similar to Elanco's earlier drug, a further 1,500 complaints are related to ataxia, (loss of muscle control: which had been added to the list of possible side effects in 2012).  In a statement, the FDA indicated it is monitoring the “adverse reaction” reports—expecting they may be under-reported—or which may be cross-triggered by accompanying health or environmental issues.

As a macryocyclic lactone-class insecticide, Trifexis® works by is increasing the flow of chloride ions in the synapses of neurons, which causes hyper-polarization of the cell membranes.  This causes a general blockage of the stimulus mechanisms in the central nervous system of the insect, to which it is “selectively more toxic” than the dog (see: discussion “Sodium Ion Nerve Channels” on previous page).  Unlike most other veterinary drugs, milbemycin oxime was not developed through agricultural applications, and as such, there are no thorough studies on its environmental impact.

Peak plasma concentration (Cmax) is reached 2 to 4 hours after administration, and subsequently declines with a “half-life” of 1-3 days. Bioavailability is about 80%.

Elanco does provide safety information on its web pages, but critics note that that information is accessed only by moving through a range of sub-menu.  The company offers that Trifexis® is “rigorously tested and approved as safe by the FDA and other regulatory authorities around the world,” and that “Many veterinarians… have such confidence… that they prescribe it for their own dogs.”  The page describes that Elanco monitors “trends” in adverse reporting by consumers, and in turn, sends this information to the FDA (which federal law requires); and which is obviously conditioned by low reporting, as few consumers are even aware of or complete the reporting process (less than 10% actually report).

Elanco has faced down persistent criticism from consumers, most especially from social media outlets, and counters that: “There are many positive experiences posted, but many negative posts also appear. Unfortunately, it is often the negative information that gets attention and prompts questions, and ultimately concerns by pet owners. Readers of this information often accept what they read as factual and unbiased data.”

 
 

creating an Adversarial Relationship
with the consumer...

 

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How the regulatory process for drug approval Favors the manufacturer


Both the US and international standards and methodology for approval of veterinary drugs stand in Elanco’s favor.  Premarket clearance studies are designed and conducted by the manufacturer itself.  Those studies are generally limited, both in scope and number, and are brief—generally only a few months in duration (for Trifexis®: 180 days)—and as such, do not incorporate concern for long-term or “chronic/sub-acute” exposure, nor to real life/in home applications, to which these products are designed for.  This is troubling, in that Elanco's labeling acknowledges that both spinosad and milbemycin oxime plasma concentrations increased throughout the study.

It's important to understand that veterinary professionals (as well as insurance companies and legal experts) identify and define adverse effect according to “clinical symptoms” that are “observable.”  That is: signs that are strictly visible (evident because they can be seen) to the Manufacturer’s study team, or, otherwise identified in some other tangential way.  Thus, it is only “acute” (immediate or nearly so) adverse reaction that would be noted during the research process (see: “Pharmacovigilance...” on first page).

This imbedded limit on “scientific” definition constrains the framework of how veterinary drugs are evaluated, submitted for regulatory approval, and marketed: since “sub-acute” (systemic, or internal) reactions are not identified as relevant in any way.  Although the ability of a dog to tolerate a powerful insecticide or drug depends on his total immune response—which can be influenced by a myriad of factors, including heredity, general health, as well as environmental, food, or stress pressures—that is only relevant to the extent that an adverse reaction would manifest both swiftly and visibly.

Because Elanco’s premarket clearance testing identified only “vomiting, depression/lethargy, itching, decreased appetite, and diarrhea” as common side effects, this became the range that veterinary professionals continue to use as exclusionary (that is: not on the list = not related to the prescribed drug); and thereby embedded as a self-limiting framework that advantages both the manufacturer and the prescribing veterinarian.  There is thus no “footprint” to milbemycin oxime poisoning that can be isolated: within these limitations, even a necropsy may be regarded as unpersuasive.

Elanco is thus armed—in fairness: as all manufacturers are—with a powerful weapon to deflect consumer criticism.  Their statement continues: “Intentional or not, the full details of case discussions are often not disclosed.  Individual patient variables as well as other diseases and underlying conditions are commonly omitted, often because the owner either does not understand the medical aspects of their pet’s illness and/or has become convinced it was a reaction to the product and considers the additional data as incidental or immaterial.  Such nonprofessional interpretations based on self-diagnosis, or input from peers, often facilitates an unwarranted atmosphere of mistrust and concern.”

 Bandit: targeting a low-flying gull... 

Bandit: targeting a low-flying gull... 

Everything we have on file is within expectations. We remain convinced that the value and benefit of this product still far exceeds the rare risk of these things happening, as unfortunate as they are... there is no certainty that the reported drug caused the adverse event(s)...
[there is] no established link between Trifexis use and death.”
— Elanco Animal Health

The resulting cerebral and cortical deficits associated with this macryocyclic lactone-class insecticide include: Ataxia (uncoordinated movements: added in 2012 to package warnings: from postmarket surveillance), hypermetria (excessive or disproportionate movement of bodily parts beyond the intended goal), disorientation, hyperesthesia (excessive reaction to tactile stimuli), tremors, mydriasis (dilatation of the pupils), recumbency (inability to rise), depression (see: discussion above), blindness (attributed to detachment of the retina), seizures (added in 2012) and coma (persistence unconsciousness).  

Further consumer reporting has included claims of pancreatitis, “fly biting,” (an air snapping behavior common in epileptic dogs), seizures, confusion or “restless wandering,” limb weakness and paralysis, sudden-onset heart disease,disease, lethargy, aggression, and vestibular syndrome. 

In dogs without the MDR-1 gene defect, the dominant poisoning symptom with macryocyclic lactone-class insecticides is mydriasis (dilatation of the pupils) together with incomplete and deregulated pupillary reflex.  Mydriasis in both eyes is the most sensitive indicator of macryocyclic lactone-class intoxication.  Because the regulatory approval process does not require long-term testing for approval, it is the consumer himself that provides this information and critics note that while many reports (including death) are “first dose,” many occurred after months or repeated dosing, suggestive of issues of bio-accumulation, or, when a dog’s immune system may eventually be exhausted and overcome, including from unrelated environmental, health, or food-related pressure.

Elanco's labeling also acknowledges that both spinosad and milbemycin oxime plasma concentrations increased over time throughout the study; this may account for adverse event reports for dogs months into treatment.

There is no antidote for milbemycin oxime poisoning.  Treatment consists in in preventing further exposure together with supportive and symptomatic measures.

 

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A not so "independent" review

In 2014—as consumer criticism escalated—Elanco issued a press release describing that the company had completed a “thorough review and analysis” of owner-submitted adverse experience reports (AER).  Critics noted that the “independent” veterinary pathologist Elanco provided to review certain necropsy reports (animal autopsies: of a litter of seven puppies, three were administered Trifexis®, and died) had a prior 20-year history of working for Eli Lilly, Elanco's parent company. 

He did not examine the dogs remains, but studied only the pathology reports, in what can reasonably be faulted as self-limiting: “What we look for are underlying causes, pre-existing conditions – any other indication that the dog had any other reason [other than Trifexis®] for dying.”

 

Milbemycin oxime is the primary active ingredient in Sentinel® Flavor Tabs® (milbemycin oxime/lufenuron) and Sentinel® Spectrum® (Virbac/Norvartis Animal Health US, 2011: milbemycin oxime/ lufenuron/ praziquantel).  Lufenuron is a growth development inhibitor: there is no antidote for lufenuron poisoning.  Treatment consists in preventing further exposure together with supportive and symptomatic measures. 

Praziquantel is an isoquinolines-class insecticide (toxic to tapeworms), of which the molecular mode of action of is not precisely known at present. Peak plasma concentration (Cmax) is reached within the first hour after administration, although only a small portion enters systemic circulation to body organs. This is because the portal vein system brings it first to the liver where it is partly metabolized to inactive metabolites. Metabolism occurs mainly in the liver and the kidneys. Excretion is through urine at >80%, the rest through the bile to the feces; with elimination half-life at approximately 2 hours.


New Classifications

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Isoxazoline-class
ectoparasiticides

New-classification carbamoyl benzamide phenyl isoxazoline (CBPI: or simply isoxazoline) ectoparasiticides are known as non-competitive GABA receptor antagonists.  They inhibit transmission of neuronal signals by binding γ-aminobutyric acid (GABA)-gated chloride channels (GABACls) and L-glutamate-gated chloride channels (GluCls).  This blocks pre- and post-synaptic transfer of chloride ions across cell membranes (chemical pathways where charged ions from dissolved salts (including sodium, potassium, calcium, and chloride) pass through otherwise impermeable cell membranes.

Isoxazolines are systemic pesticides that bind to blood plasma and circulate through the body and all organs.

Many physiological processes rely on these ion channels, which are gated to open and close in response to certain stimuli.  Closing the gates results in hyperexcitation paralysis of the central nervous system of susceptible insects, leading to death.  Isoxazolines are comparable in potency to fipronel (class: phenylpyrazole ectoparasiticide).

 

Afoxolaner

In 2013, the FDA approved Merial’s (Frontline Vet Labs) NexGard™, a chewable prescription 30-day flea-tick control.  The active ingredient is afoxolaner, a new classification isoxazoline-based compound (CBPI, an ectoparasiticide-insecticide/acaricide-flea adulticide: see: Bravecto®, below)

As a systemic insecticide, fleas and ticks must attach and commence feeding in order to be exposed to the active substance (fleas: 8 hours; ticks: 48 hours).  Peak plasma levels (Cmax) were reached between 2 and 12 hours after administration, with a bioavailability of approximately 74%.  Elimination of the metabolites and the parent compound occurrs mainly via biliary excretion and to a lesser extent through urine.

By mid-2016, the FDA’s Center for Veterinary Medicine (CVM) had recorded 7,740 complaints of adverse reactions to Nexgard™, 2,048 of which were submitted in only six months between mid-June of 2015 and 06 January 2016; with a further 3,317 compiled by mid-October.  May of 2017 saw the addition of a further 1,417 reports.  The reports included, in order of frequency: vomiting, lethargy, skin reactions/dermatitis/erythema, seizures, panting, anorexia, (bloody) diarrhea, polydipsia (exessive thirst), loss of muscle coordination, fever, systemic endocrine and renal disorders, facial swelling, incontinence, anxiety, tachycardia (abnormally high heart rate), and death.  Interpreted “allergic” reactions included obsessive and violent itching.  Owing to limitations (most especially under-reporting), the CVM database is admittedly incomplete.

There is no antidote for afoxolaner poisoning. Treatment consists in preventing further exposure together with supportive and symptomatic measures.

In January 2015 the European Medicines Agency approved Sanofi's (Merial) NexGard® Spectra™ beef-flavored chew, combining afoxolaner and milbemycin oxime (see above).

 Jade: elderberries & licorice...

Jade: elderberries & licorice...

Transforming consumer perception:
a Pesticide becomes a “Drug”

 

fluralaner

 

In May of 2014, the FDA approved Bravecto® for marketing in the US.  Intervet Inc., dba Merck Animal Health (Summit, NJ: MSD Animal Health worldwide) had launched the flavored chew-able flea and tick treatment in parts of Europe a month previously.  According to Merck, its veterinary prescribed (isoxazoline-substituted benzamide derivative) weight-specific dose product provides single-dose protection for up to 3 months (species dependent), providing an advantage over monthly products, or use of “knock down” insecticides that consumers may not apply consistently.
 
The active substance of Bravecto® is (13.7%) fluralaner, a (synthetic) systemic, neuro-active ectoparasiticide (antiparasitic drugs used to kill the parasites that live on the body surface) that binds to proteins in plasma and thus circulates in the bloodstream to display efficacy: as with spot-on neonicotinoids, fleas and ticks must attach to the dog and commence feeding in order to be exposed to fluraner.  

The onset of effect is within 8 hours of attachment for fleas (C. felis) and 12 hours of attachment for ticks (Ixodes ricinus, Dermacentor reticulatus, D. variabilis and [US] ixodes scapularis).  Peak plasma level (Cmax) is reached 24 hours after administration, with mean half-life in blood 12 to 15 days.  Bioavailability is higher when fluralaner is administered with food.  Excretion occurs mainly in the form of unchanged parent molecule, primarily in the feces (~90% of the dose); with less than 0.01% of the dose found in urine, indicating that renal excretion occupies
a marginal role.

 ixodes scapularis

ixodes scapularis

But...
It doesn't prevent "Lyme Disease"?

As with other oral pesticides, consumers may mis-anticipate certain results: according to MSD Animal Health, because fleas and ticks must start feeding on the dog (ingest sufficient blood) in order to be killed by the insecticide, the risk of transmission of diseases with which they may be infected cannot be excluded (Merck defines as: unfavorable conditions”).  This is because the tick may regurgitate blood from the prior host just after boring a feeding hole and attaching (with anesthetic, to avoid detection) and commencing
its “blood meal.”

Merck positions Bravecto® more aggressively than its competitors, asserting that it can be used as part of a treatment strategy for the control of Flea Allergy Dermatits (FAD: an allergic reaction in dogs that are hypersensitive to “intermittent exposure to flea saliva” that is injected when a flea bites), since it “controls environmental flea populations” by killing current fleas that may lay eggs over time: “the flea life cycle is broken.

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The proportions of inactive ingredients in Bravecto®
(see discussion above) is not disclosed on both US and non-US packaging, and listed as “secret” in Australian data sheets.  This is “proprietary information” and only “hazardous” ingredients over 1% and/or “carcinogenic” ingredients in concentrations above .01% are listed in the chemical composition table.  Merck’s US Material Data Safety Sheet (MDSS: a technical document which provides detailed and comprehensive information on a “controlled” product) captions only “CPBI,” (carbamoyl benzamide phenyl isoxazolinesee: above) “starch,” [quotes added] “polyethylene glycol, sucrose, and gylcerine,” with total product proportions that vary from
54.64% to 74.64%.

However, The European Medicines Agency assessment report (CVMP: 2014) indicates the excipients sucrose, maize starch, sodium lauryl sulphate, magnesium stearate, aspartame, glycerol, soya bean oil (refined), macrogol 3350 (a pig liver commercial flavouring), and a novel excipient, disodium pamoate monohydrate (INN name: disodium embonate monohydrate).

New to the market, detailed information on the toxicity and the fate of fluralaner in the dog's body (absorption>> distribution>> metabolism>>, excretion) and in the environment is sparse —(AU Material Safety Data Sheet or “MSDS”: “The toxicological properties of the mixture(s) have not been fully characterized in humans or animals.”)—but users must contemplate that since it attaches to the protein in plasma and is slowly released and distributed to fatty tissues (where it becomes available to insects), it would concentrate in kidney, liver, and muscle tissues: as the dog’s metabolic and renal systems recognize it as a toxin, and attempt to cleanse and “repair” the blood. 

According to an FDA Freedom Of Information (FOI) summary, Plasma concentrations of fluralaner confirmed systemic and continuous exposure: “Measurements and Observations: All surviving pups and adult females were euthanized between Days 50 and 71 of lactation, and adult male dogs were euthanized 1 to 6 weeks after pups were born. Gross necropsy and organ weights were assessed in all dogs, and histopathological examination (the microscopic examination of tissue in order to study the manifestations of disease)was performed on selected tissues including reproductive organs and any tissues with gross lesions. Except for histopathological evaluation , measurements and observations were conducted masked to treatment.”

Merck's premarket clearance study used small groups of healthy dogs in a laboratory setting, along with at least one study on approximately 200 client-owned animals.  During those studies, side effects included vomiting, diarrhea, bloody or mucoid stools, inappetance, itching, dry skin, and seizures. These side effects were discounted as not clinically significant or not attributable to the medication by the researchers: “there were no serious adverse reactions.”  Merck's published list of possible side effects is: “vomiting, decreased appetite, diarrhea, lethargy, polydipsia (excessive thirst), and flatulence,” and this stands as the exclusionary list that veterinarians use
(see: above). 

Not required for regulatory approval, no study was undertaken regarding the potential for “chronic/long term effects” (more than 182 days) of fluralaner severally, or concerning the inactive ingredients as they might synergize and/or amplify it or each other; nor the issues of ordinarily unknown parameters for total immune response of any particular dog that could lead to central nervous system or hepatic injury.
 

 Leroy: a pause for wistful reflection...

Leroy: a pause for wistful reflection...

 

Hepatic injury?

 The liver (gastrointestinal system)

The liver (gastrointestinal system)

The Merck MSDS documents discusses that the liver, as “the main elimination organ of CBPI” would likely be the main target of injury, but that a 90-day repeat-dose toxicity study (on rats) did not indicate damage, and as such, any degenerative changes “are considered to represent reversible metabolic effects and hence are of non-adverse character.”  The liver is the singular organ in the body capable of regeneration.

Both anecdotal and officially submitted (FDA) reports include claims of liver and pancreatic injury; but as they are not among adverse effects identified by Merck's own testing, the company fiercely contests
any relationship. 

But the connection seems both reasonable and likely.  Part of the gastrointestinal (digestive) system, the liver produces and secretes bile into the intestine where the bile assists with the absorption and digestion of lipids (dietary fat).  The liver aids purification of the blood, by altering (metabolizing) what it perceives as potentially harmful chemicals into harmless ones, and then: either secretes them with the bile for elimination in the stool, or back into the blood, where they then are removed by the kidneys and eliminated in the urine. 

The typical non-specific symptoms of degenerative liver disease (loss of appetite, nausea/vomiting, lethargy, etc.) are common first “symptoms” of “adverse reaction” to Isoxazolines.
 
The dog’s pancreas (endocrine and digestive system) produces insulin hormones (regulates the flow of glucose/sugar) and enzymes that break down fat and proteins to aid in the digestion of foods.  When overburdened, the pancreas becomes inflamed (pancreatitis), and the flow of enzymes into the digestive tract is disrupted; the enzymes may be forced out of the pancreas and into the abdominal area.  Especially painful, these digestive enzymes will begin to break down fat and proteins in other organs (the body begins to digest itself).  Because of their function and proximity, the kidneys and liver are prime targets of this progression.  (See also: Enterohepatic Recirculation to understand how toxins are recycled through these organs, and the issue of chronic, systemic inflammation).

As consumer safety advocates had anticipated, less than two years later the FDA’s Center for Veterinary Medicine (CVM) had registered more than 5,300 complaints of adverse reactions to Bravecto®; more than half of which were submitted for a six month period through early January 2016; with a further 5,077 compiled by mid-October.  By August of 2017, the total had risen to 16,521.  On the latest 2017 report from the EMA (European Medicines Agency) there are now 3988 adverse event reports with 972 deaths associated with the
use of Bravecto®.

Similar to other Isoxazolines: sickness extended across violent gastrointestinal, neurological, endocrine, and renal turmoil to multi-organ toxicity/failure, blindness, euthanasia and death.  Reports also include description of mydrasis (dilated pupils), nystagmus (uncontrollable eye movement), vestibular syndrome, seizures, broad behavioral changes: particularly irritability and defensive aggression (possibly fear-induced owing to hallucinations) may accompany as the toxin accumulates in the adrenal and thryroid glands and the central nervous system.  Observers caution that the CVM database is surely incomplete: as the FDA estimates that less than 10% of adverse experiences are actually reported. 

Some reports describe reactions manifesting several months into treatment... coincidentally, according to Merck’s New Animal Drug Application (NADA 141-426): “Dogs achieved steady-state fluralaner concentrations by the third treatment period.”  Other (un-compiled/non-reported) complaints include descriptions of consumers finding dead ticks attached to their dogs more than a year after discontinuing use, and questioning— with realization that there is no antidote for fluralaner poisoning: treatment consists in preventing further exposure together with supportive and symptomatic measures — how it can ever be flushed from the system.


An excessive adaptive response:

Immune-Mediated Hemolytic Anemia

 Immune-mediated hemolytic anemia

Immune-mediated hemolytic anemia


AE reports also included leucocytois (elevated white blood cells) and complaints asserting that administration of Bravecto® had triggered development of Immune-Mediated Hemolytic Anemia (IMHA), a complex disorder in which the dog's immune system destroys its own red blood cells.  In some cases, death had come swiftly.
 
A dog’s immune system comprises dedicated cells, proteins, tissues, and organs that represent his defense against infectious disease (fungal, parasitic, and viral infections) and foreign “toxins.”  Antibodies (secreted proteins) in that system bind to foreign substances (antigens), to destroy them. 

These white blood cells (WBCs or: leukocytes) are produced and derived from multi-potent (gene activation potential) cells in the bone marrow (hematopoietic stem cells).  Leukocytes are thus throughout the body, including the lymphatic system (circulatory and immune system: vessels that carry fluid toward the heart). 

The dog’s red blood cells (RBCs) serve the crucial function of carrying oxygen to the cells in the body and picking up carbon dioxide.  A diseased condition (anemia) arises when the body’s immune system mistakenly begins identifying its own RBCs as antigens— because the surface of those RBCs is modified by a disease process, drug, or toxin— then, recognizing them as “foreign,” binds to them to initiate their destruction. 

The annihilation of RBCs (hemolysis) results in the release of hemoglobin, which can lead to jaundice, and then to anemia when the body cannot produce enough new RBCs to replace the ones being destroyed.  The resulting disease is thus known as IMHA.

Merck is stern in its rebuke, that AE reports may be “anecdotes that are not substantiated by science and medical evidence.”  With the embedded limitation of the process of regulatory review, how can that barrier of terminology be challenged? 

Consumer Safety Advocates monitoring AE reporting remain frustrated with a professional veterinary community that is generally averse to engage any discussion that might explore a possible causative relationship between administration of the drug and IMHA diagnosis, links to pancreatic or liver injury,
or anything outside “common” or “… transient effects.”  Even cases that are reported as “likely resulting from reaction to a ‘toxin,’” there is no agreement—or guidance— on would constitute “proof.”

In 2016, as the public relations aspect of the controversy became more troublesome, Merck Animal Health (MAH) took the extraordinary step of posting a “Company Statement” on their website, with links to a surprisingly awkward (and edited) video featuring Merck’s Executive Director for its Technical Services division, adjoined to a “Bravecto®: Just the Facts” flyer for distribution to consumers… presumably from veterinarians.  Observers deemed it a public relations misfire: as aspects of the flyer in particular would seem to merely draw attention to the escalating debate, with its bold type and jarring admonishment to disregard media and AE reporting, including: “A report does not mean causation” and “Global safety surveillance of Bravecto use has provided additional compelling evidence of the safety of the product.”

"Special Precaution: ..."

In 2017, noting the potential for neurological effects, the Committee for Veterinary Medicinal Products (CVMP) of the European Medicines Agency (the government authority that approves drugs for veterinary use in the United Kingdom) advised Merck MSD that Bravecto® must have a label warning: “Special Precaution: Use with caution in dogs with pre-existing epilepsy” (The Veterinary Record, Sept. 2017, p.340).  The US version, however, does not carry this caution, even though its new “spot-on” version of fluralaner (see below) does. 

Merck: “The most frequently reported adverse reactions include vomiting or diarrhea. Other side effects that may be seen include decreased appetite, lethargy, increased thirst, and flatulance.(sic).”

 

 
reverse chemistry time.jpg



Back to the future?

 

Reverse Engineering an oral pesticide

In March of 2016, the CVMP granted marketing approval for Intervet/Merck's “spot-on” version of Bravecto® (although Merck eschews that too-common title for “topical”) in 5 weight-designated doses; with the US FDA following, in July.  Five months earlier, based on a benefit vs. risk analysis, the CVMP had rejected Intervet International B.V.’s (Merck) latest version (EMA/CVMP/750172/2015), which added a new target species (cats), because: “the data on user safety were unacceptable.”  
 

 Carpeting makes it home?

Carpeting makes it home?

CVMP determined that Intervet’s target animal study (TAS) “Household Simulation Model”—which used a fipronil (a different classification of pesticide) spot-on as a “surrogate” for fluralaner—was in-exact and irrelevant. 

Merck had postured that this methodology demonstrated “no concern to the user” regarding quantifying the potential for indirect environmental exposure of fluralaner to the consumer. 

Merck had offered its own TAS: in which dogs had been held in individual cages with carpeting as “bedding,” to simulate the home environment.  According to CVMP: “This is a concern as plasma concentrations of fluralaner were measured in all control animals - which were housed separately - in the pivotal TAS study in dogs at up to 740 ng/ml which is considered high.”  The CVMP noted that “a plasma level under 25 ng/ml is still proven to be efficacious for the indications of the product,” and that as such, “These results indicate that the [risk] exposure via the direct environment
can be significant.”

A strip of carpeting
as bedding
in a Laboratory cage to
simulate a
"home environment"

“In the absence of fluralaner-specific information on exposure via the direct environment under normal conditions of use,” the CVMP estimated a dermal exposure level based on the main plasma levels in Intervet’s TAS, leading to a margin of exposure “insufficient to protect the user.” 

The CVMP also considered the issues of transmission to children via “hand-to-mouth contact” (petting/playing) with the dog, or “ingestion of house dust… a well-known scavenger for hydrophobic substances” (that repel water); and that the formulation, with an “elimination half-life of 21 days in the [dog]” was “hence not easily cleaned from the environment.”  As the “cause of contamination of control animals in the TAS studies” was unclear and “not single study site specific or target animal specific,” the CVMP calculated a margin of error (MOE) of only 40 (not: 100), discussing that “the applicant did not perform specific studies to investigate the extent of environmental (household) contamination using fluralaner under
field conditions.”

Immediately appealing the decision, Merck argued that “Generic/surrogate exposure modelling is an appropriate tool, and the chosen fipronil spot-on solution was an appropriate surrogate.”  CVMP ultimately agreed with Intervet’s contention that “…risk of indirect exposure via cross-contamination is usually not addressed for [regulatory approval of] topically applied antiparasitic spot-on formulations,” and that “harmonizing” was therefore appropriate.  CVMP accepted Merck's conclusion that “contamination of untreated control animals in the dog TAS study is considered most likely due to a single direct exposure to the active substance (cross-contamination) at or around the time of treatment [of the subject dogs].”  That is: Intervet employees conducting the TAS failed to control for
cross-contamination.

Consumer safety advocates already frustrated by reports of adverse effects to the chew remain alarmed by Merck's desire to backward-engineer their novel product to an existing platform.  More perplexing was the firm’s embrace of common interpretation that “the physicochemical properties of the active substance” are similar to ordinary US off-patent (non-prescription) antiparasitics: which had—at that precise moment—emerged as contentious with a rapidly growing US-based social media group monitoring the phamacovigilance process.

reverse chemistry3.jpg

toxic excipents?

Also of concern were excipients (solvents/humectants/stabilizers) that are, however, specific to Bravecto® as fluralaner “topical,” such as dimethylacetamide (DMA), a category 4 acute toxicity (H332; harmful if inhaled and H312; harmful in contact with skin) and category 1B reproductive toxicity (H360D at concentration >5%, may damage the unborn child).  For that reason, a “risk characterization” for DMA would be provided in the user safety evaluation, owing to the possibility of dermal exposure to the consumer as the product is applied to the dog. 

A further risk characterisation (adverse systemic effects: acute oral exposure) for (14%; US: 13.2%) N,N-diethyl-m-toluamide (DEET) would be also be included: “A NOAEL of 75 mg/kg bw/day was reported. This NOAEL was derived from an oral capsule study in dogs terminated on day 5 due to severe (neuro)toxicity.”  Used as a topical insect repellent, DEET is a known percutaneous (through the skin) penetration enhancer.  In dogs, metabolism (oxidation) of DEET occurs in the liver, with toxicosis primarily involving the gastrointestinal tract and the central nervous system. 

A pivotal one-generation study in rats was submitted to address issues of reproductive toxicity, (in rats and rabbits) for developmental toxicity, and the assessment of the initial application for Bravecto® chewable by the CVMP was extrapolated regarding genotoxic potential and generalized safety characteritics.


Same drug...
different warnings?

exposure assessment.png

Most surprisingly, Intervet/Merck’s labeling for the spot-on version of fluralaner differs, warning: “Use with caution in dogs with a history of seizures.  Seizures have been reported in dogs receiving fluralaner, even in dogs without a history of seizures.”  Consumer safety advocates are sharply critical that absent is information as to why this caution has not been extended to the already in-use chew product.

There is no antidote for fluralaner poisoning. Treatment consists in preventing further exposure together with supportive and symptomatic measures.


Ever heard the term: 
“Conscious proprioception”?

 

sarolaner

 

A 30-day treatment that lasts 90 days?

 Canine neuromuscular degeneration 

Canine neuromuscular degeneration 

In Novermber of 2015, the European Medicines Agency (CVMP) approved Simparica™ (advertised as: “persistent protection”) for use in dogs and horses in the European Union, as a killer of four common European ticks and two types of fleas.  Zoetis Animal Health (Florahm Park, NJ) promotes the chewable insecticide as faster working (8 hours for ticks) than Merial's Nexgard®, citing a comparative study.  The US FDA granted approval for the American market in February of 2016, indicated for use against adult fleas, flea home infestations (killing before they can reproduce) and the Lone Star (Amblyomma americanum), Gulf Coast (Amblyomma maculatum), and American “brown dog tick” (Rhipicephalus sanguineus).

Whereas Merial’s and Merck AH’s active ingredients are licensed from other companies, sarolaner was discovered and developed by its patent holder, Zoetis. 

Zoetis maintains that the active ingredient sarolaner (classification: Isoxazoline; see above), available in six (spray dried pork liver powder beef-flavor) weight-appropriate dosages, maintains its efficacy 96% consistently for (US version) 35 days, vs., for example Nexgard®'s 76% kill at 28 days; thereby offering protection if the user is a “a few days late.”  This is significant, as “spot-ons” by definition are heavy/overdose on application; then trailing off in effectiveness: a perpetual overdose-to-under-protected cycle (which, in turn, explains the acute-to-sub-acute adverse reaction in many dogs).

Although it is intended for monthly application, the CVMP assessment notes that “Simparica was as effective as fipronil in reducing tick counts for up to 90 days
after treatment.”

In its “Summary of Product Characteristics,” Zoetis states (as a product benefit): “C-sarolaner-related residues were widely distributed [through blood plasma] to the tissues” (bracketed text added).  In its safety information warning, Zoetis does caution that “Simparica may cause abnormal neurologic signs such as tremors, unsteadiness, and/or seizures.” 

No cause for the sudden increase in sarolaner plasma concentrations was identified.
The dog was not treated,
and was ultimately euthanized.”
— Zoetis, Inc. (Summary of Product Characteristics)

The document also discusses a “separate exploratory pharmacokinetic study” in which adverse reactions included (subsequent to an abrupt 2.5-fold rise in “plasma concentrations” after the 3rd monthly dose): vomiting/diarrhea, lethargy, anorexia, and abnormal neurological signs including ataxia (loss of muscle coordination, particularly in the extremities), tremors, disorientation, hypersalivation, diminished conscious proprioception (the ability to sense non-vision realized stimuli regarding position, motion, and equilibrium: a neuro-muscular disorder; which may be categorized as acute or chronic), and absent menace response (one form of “blink reflex”: reflexive blinking and body posture that occur in response to the rapid approach of an object, which may indicate damage to the cortical nerve).
 
The description continues: “This rise resulted ing in a Cmax (peak serum concentration) more than 7-fold higher than the mean Cmax at the maximum recommended use dose.  No cause for the sudden increase in sarolaner plasma concentrations was identified.  The dog was not treated, and was ultimately euthanized.”  There is essentially no knowledge on tolerance related to breed, age, or specific health circumstances.  Officially reported adverse effects include bloody vomiting, ataxia, convulsions and seizures, and death.

As with other Isoxazoline class ectoparasitides, ticks need to start feeding on the host (consuming sufficient blood) to become exposed to sarolaner; therefore, the transmission of infectious parasite-borne diseases cannot be excluded.  There is no antidote for Sarolaner poisoning. Treatment consists in preventing further exposure together with supportive and symptomatic measures.

Little to nothing has been published yet regarding the environmental toxicity of sarolaner.

 Phoenix: author of a crimson sky?

Phoenix: author of a crimson sky?

 

Lotilaner

 

As is common with “spot-on” type pesticides: a continual overdose declining
to under-dose administration.

The US FDA approved Elanco Animal Health’s (Eli Lilly and Co.: Indianapolis, IN) Credelio® in January of 2018.  The active ingredient in the once-monthly chew is lotilaner, (classification: isoxazoline; see above) for which Elanco holds a patent.  Credelio® kills the lone star tick (Amblyomma americanum), American dog tick (Dermacentor variabilis), black-legged tick (Ixodes scapularis) and brown dog tick (Rhipicephalus sanguineus), as well as fleas (Ctenocephalides felis).  Elanco advertises the beef-flavored (pork) chew as “tasty” and well accepted by dogs, displaying efficacy against fleas in as little as 4 hours.

Elanco’s evaluation of safety was completed over segments of a 90-day period, with 12 laboratory-set studies on beagles, who were killed pursuant to “organ weight determination” by day 225. 

Peak serum plasma concentration (Cmax) for lotilaner occurs between 2-6 hours after administration, with half-life in adult dogs estimated to be 30.7 days.  This means that only 50% of the potency of lotilaner is available at the end of the dosing period; but also: that the next dose, if given according to instructions, would impart a 150% potency for a period of time.  This perpetual over-to-under dose scenario may account for the seemingly transitory appearance of acute (observable) adverse effects.  Bioavailability is higher (82%) when administered with food.  The major route of elimination (unchanged lotilaner) is fecal (via biliary excretion), with renal excretion (see below) less than 10% of the dose.  From Elanco’s tests, highest tissue levels were recorded in body fat and liver, followed by kidney.

Gastrointestinal impact and renal failure

kidneys2.jpg

The noted (clinically observable) adverse reactions included: weight loss, polyuria (abnormally large volume of dilute urine), diarrhea, elevated blood urea nitrogen (BUN: an indication that the kidneys are unable to remove urea from the blood normally); elevated creatinine (an indication of impaired kidney function or kidney disease); elevated potassium (symptomatic of hyperkalemia, related to kidney failure); elevated phosphorus (an electrolyte disturbance, hyperphosphatemia, indicative of kidney failure); dyspnea (labored breathing/shortness of breath); and polyphagia (excessive appetite). 

Polyphagia is suggestive of impact to the gastrointestinal system (where 80% of the dog’s immune system resides), manifest by inflammatory bowel syndrome, insulin deficiencies (the body is unable to assimilate its blood sugar, and the resulting low blood sugar levels may impact appetite) or insulin-resistant intestinal cancers. 

As with other Isoxazoline class ectoparasitides, ticks need to start feeding on the host (consuming sufficient blood) to become exposed to lotilaner; therefore, the transmission of infectious parasite-borne diseases cannot be excluded.  There is no antidote for lotilaner poisoning. Treatment consists in preventing further exposure together with supportive and symptomatic measures.


 
The profit motive and the adversarial and bio-fascist attitude of corporations and of segments of society toward other living beings and the natural world will be the ultimate undoing,
the nemesis of this bioindustrial epoch in human evolution,
to the extinction of this mode of being and state of mind,
if not of Homo sapiens itself.”
— Michael W. Fox, BVetMed, PHD, DsC, MRCVS
 
 Paco: "They can't really SEE me... right?"

Paco: "They can't really SEE me... right?"

" ...The tried and true knowledge and use of herbal products by indigenous peoples have developed over millennia to safely and effectively repel, control and kill noxious insects.  Furthermore, these products cannot be patented and are far less costly than those of the multinational drug companies... that also sell to the chemical-toxic agribusiness industry. To suggest that people should use their product[s]... totally disregards the impact on beneficial insects and the birds, reptiles, bats and other wildlife who consume them.

Government legislators and municipal authorities should move to ban the sale of these kinds of products in stores across their jurisdictions. If we chose to be deaf to reason and common sense, then we will not notice or care about the silencing of this living world. Many already notice the absence of the butterflies in their yards and gardens and of once a myriad kinds of insects around night lights everywhere.

But will they understand that when the diversity of beneficial insects and insectivores is gone they will be more vulnerable to ever more insect-borne diseases?

This is in part because the most “noxious” insects—those species in part aided in their proliferation because of our ecological interferences—develop resistance to our armament of chemical warfare against them. This causes collateral damage to other harmless and beneficial species. Great economic losses for farmers ( already being experienced by almond and citrus crop growers), and famines will come when there are no bees and other pollinators for the plants, and no plant-pest killing parasitic wasps who indirectly sustain us, our economy and those diminishing other species who can barely endure the planetary infestation
and mindless onslaught of our species?

I never imagined that I would come live in a world where multinational corporations would exploit not only nature’s resources for pure profit regardless of the social and ecological costs and harmful consequences but garner the findings of the biological sciences to produce crops that manufacture their own insecticides and have resistance to herbicides, all products they sell along with their patented, genetically engineered seeds. 

But all to what end? The profit motive and the adversarial and bio-fascist attitude of corporations and of segments of society toward other living beings and the natural world will be the ultimate undoing, the nemesis of this bio-industrial epoch in human evolution, leading to the extinction of this mode of being and state of mind,
if not of Homo sapiens itself”

— Michael W. Fox, BVetMed, PHD, DsC, MRCVS; The Rachel Carson Council: 
Bayer & Merck Anti-Flea & Tick Products for Pets: Animal Health & Environmental Risks