Description
Ivermectin(70288-86-7) is an antiparasitic agent effective in the treatment of onchocerciasis, or "river
blindness". Since ivermectin acts to prevent the adult worm from producing microfilariae,
it needs to be administered only once or twice a year.
History
The discovery of ivermectin was the result of a landmark collaboration in the 1970s between Merck & Co. and the Kitasato Institute in Japan. Microbiologist Satoshi Ōmura isolated a new Streptomyces species—Streptomyces avermitilis—from Japanese soil and sent its cultures to Merck. Merck scientist William C. Campbell then discovered ivermectins, a natural product with potent anthelmintic activity. To reduce its toxicity to mammals and optimize its efficacy, Merck chemists performed semi-synthetic modifications on ivermectin, hydrogenating it to obtain the derivative ivermectin. This optimization significantly improved the drug's safety, leading to its market launch as a highly effective veterinary drug in 1981. Its historic contribution lies in its application in human medicine: after demonstrating its remarkable efficacy against river blindness, Merck decided in 1987 to donate ivermectin (Mectizan®) indefinitely for the control and elimination of river blindness and lymphatic filariasis worldwide. This achievement ultimately earned Satoshi Ōmura and Campbell the 2015 Nobel Prize in Physiology or Medicine.
Definition
ChEBI:LSM-5397 is a milbemycin.
Preparation
The synthesis of ivermectin involves the hydrogenation
of the naturally occurring avermectin B1 (abamectin) at
the double bond linking C-22 and C-23. This results in a
mixture of two homologues, 22, 23-dihydroavermectin B1a
(H2B1a) and 22, 23-dihydroavermectin B1b (H2 B1b). The
a- and b- nomenclature refers to the presence on C-25, of
either a secondary butyl side chain or an isopropyl group,
respectively. The biological activities of H2B1a and H2B1b
are similar. Large-scale separation of the two homologues
is not practical, and, hence, ivermectin is marketed as a
mixture of H2 B1a (>80%) and H2 B1b (<20%).
Manufacturing Process
Avermectin is produced by biotechnological methods with the aid of
Streptomyces avermitilis.
Preparation of Catalyst I
Rhodium trichloride trihydrate (1.00 g, 3.80 mmol) was dissolved in water
(5.0 ml) with heating (70°C). A solution of triphenylphosphine (1.95 g, 7.43
mmol) in acetone (25.0 ml) was then added under a nitrogen atmosphere in
the course of 20 min. After 10 min hydrazine hydrate (1.90 ml; 39.09 mmol)
was added with stirring and the mixture was heated at reflux temperature for
3 hours, then kept at 45°C for a further 1 hour. The crystalline solid was
filtered off under nitrogen and washed with a little acetone and then with
diethyl ether. 1.05 g of an orange-coloured solid were obtained.
Hydrogenation with catalyst I
The catalyst (10 mg) was dissolved in toluene (25 ml) and added under argon
to the solution of a mixture (1.1 g) of avermectin B1a (96%) and avermectin
B1b (4%) and of 100 mg of triphenylphosphine in toluene (25 ml) in a
stainless steel autoclave. This starting material was then hydrogenated at
88°C under a hydrogen pressure of 20 bar with stirring of the solution. After
10 hours, HPLC analysis revealed a content of 86% dihydro-avermectin B1a
and of 4 % dihydroavermectin B1b, and also of 3% tetrahydroavermectin B1a.
Preparation of Catalyst II
Under an atmosphere of argon, a mixture of 7.5 mg of rhodium trichloride,
30.0 mg of tris-(hexylphenyl)-phosphine, 3 ml of acetone and 15 ml of
hydrazine hydrate is heated with stirring and reflux cooling for 4 hours.
Hydrogenation with catalyst II
The catalyst is added to a solution of 4.3 g of avermectin (B1a and B1b
mixture) in 25 ml of a mixture of acetone and cyclohexane in a ratio of 2:1.
After addition of 51.4 mg of tris-(mexylphenyl)phosphine, the hydrogenation
is carried out in a steel autoclave at a hydrogen pressure 5 bar and at 88°C.
After a hydrogenation time of 4 hours, 8.9% of starting material, 89.9% of
ivermectin (B1a and B1b mixture), tetrahydroavermectin content <0.1% was
obtained (according to HPLC analysis).
Removing of the catalyst system
The crude product after distillative removal of the solvent mixture, dissolved
in a mixture of 35 ml of methanol and 20 ml of water and this solution is
extracted with 25 ml of cyclohexane in a separating funnel. The phases are
separated and concentrated under reduced pressure. The extraction is
repeated twice in the same manner.
Brand name
Stromectol (Merck);Mectizan.
Therapeutic Function
Antiprotozoal
Antimicrobial activity
It is also active against O. volvulus and other filarial
worms, but the effect is chiefly directed against the larval
forms (microfilariae). Uniquely among anthelmintic agents
it exhibits activity against some ectoparasites, including
Sarcoptes scabiei.
General Description
Pharmaceutical secondary standards for application in quality control, provide pharma laboratories and manufacturers with a convenient and cost-effective alternative to the preparation of in-house working standards.
Ivermectin is a derivative of avermectin B1 that is used against both endo- and ectoparasites in veterinary applications. It has also been indicated as a potential drug for the management of Onchocerca volvulus, identified as the cause of ′river blindness′ in humans.
Pharmaceutical Applications
A mixture of two closely related semisynthetic derivatives of avermectins, a complex of macrocyclic lactone antibiotics produced by Streptomyces avermitilis. In commercial preparations the ratio of the two components, dihydroavermectin B1a and dihydroavermectin B1b, are present within the limits 80–90% and 10–20%, respectively.
Biological Activity
Positive allosteric modulator of the α 7 neuronal nicotinic acetylcholine receptor and the purinergic P2X 4 receptor. Antihelmintic. Also modulates glutamate- and GABA-activated chloride channels. Potentiates glycine-gated currents at low concentrations (30 nM).
Mechanism of action
Two mechanisms of action are thought to be involved in the action of IVM. The first is an
indirect action in which motility of microfalaria is reduced, which in turn allows cytotoxic cells of
the host to adhere to the parasite, resulting in elimination from the host. This action may occur by
virtue of the ability of IVM to act either as a γ-aminobutyric acid (GABA) agonist or as an inducer of
chloride ion influx, leading to hyperpolarization and muscle paralysis. The chloride ion influx
appears to be the more plausible mechanism. Recently, it has been shown that IVM binds
irreversibly to the glutamate-gated chloride channel of the nematode Haemonchus contortus,
whereas the channel is in an open conformation. The binding then remains locked in the open
conformation, allowing ions to cross the membrane, leading to the paralytic action of IVM. The
result of this action is a rapid decrease in microfilarial concentrations.
A second action of IVM leads to the degeneration of microfilariae in utero. This action would result
in fewer microfilariae being released from the female worms, and it occurs over a longer period of
time. The presence of degenerated microfilariae in utero prevents further fertilization and
production of microfilariae.
Pharmacokinetics
Oral absorption: c. 60%
Cmax 12 mg oral: c. 30–47 ng/mL after 4 h
Plasma half-life: c. 12 h
Volume of distribution: 46.9 L
Plasma protein binding: 93%
It is rapidly metabolized in the liver and the metabolites are
excreted in the feces over about 12 days with minimal (<1%)
urinary excretion. Highest concentrations occur in the liver
and fat. Extremely small amounts are found in the brain.
Clinical Use
Ivermectin (Cardomec, Eqvalan, Ivomec,70288-86-7) is a mixtureof 22,23-dihydro derivatives of avermectins B1a and B1bprepared by catalytic hydrogenation. Avermectins aremembers of a family of structurally complex antibioticsproduced by fermentation with a strain of Streptomycesavermitilis. Their discovery resulted from an intensivescreening of cultures for anthelmintic agents from naturalsources. Ivermectin is active in low dosage against awide variety of nematodes and arthropods that parasitizeanimals.
Ivermectin has achieved widespread use in veterinarypractice in the United States and many countries throughoutthe world for the control of endoparasites and ectoparasitesin domestic animals. It has been found effective forthe treatment of onchocerciasis (“river blindness”) in humans, an important disease caused by the roundwormOncocerca volvulus, prevalent in West and Central Africa,the Middle East, and South and Central America.Ivermectin destroys the microfilariae, immature forms ofthe nematode, which create the skin and tissue nodules thatare characteristic of the infestation and can lead to blindness.It also inhibits the release of microfilariae by theadult worms living in the host. Studies on the mechanismof action of ivermectin indicate that it blocks interneuron–motor neuron transmission in nematodes by stimulatingthe release of the inhibitory neurotransmitter GABA.The drug has been made available by the manufacturer ona humanitarian basis to qualified treatment programsthrough the World Health Organization.
Clinical Use
Ivermectin(70288-86-7) has broad-spectrum activity in that it can
affect nematodes, insects, and acarine parasites. It is the
drug of choice in onchocerciasis and is quite useful in
the treatment of other forms of filariasis, strongyloidiasis,
ascariasis, loiasis, and cutaneous larva migrans. It is
also highly active against various mites. It is the drug of
choice in treating humans infected with Onchocerca
volvulus, acting as a microfilaricidal drug against the
skin-dwelling larvae (microfilaria). Annual treatment
can prevent blindness from ocular onchocerciasis.
Ivermectin is clearly more effective than diethylcarbamazine
in bancroftian filariasis, and it reduces microfilaremia
to near zero levels. In brugian filariasis diethylcarbamazine-
induced clearance may be superior. It also
is used to treat cutaneous larva migrans and disseminated
strongyloidiasis. Its safe use in pregnancy has not
been fully established.
Clinical Use
Onchocerciasis
Non-disseminated strongyloidiasis
Lymphatic filariasis (in combination with albendazole)
Scabies
If the patient is harboring Asc. lumbricoides, the worms will be passed in the feces. Head lice will also be killed, which is very much welcomed by the treated patients. Ivermectin has been widely used in the veterinary field, where use is also made of its effect on ectoparasites.
Veterinary Drugs and Treatments
Ivermectin is approved in horses for the control of: large strongyles
(adult) (Strongylus vulgaris, S. edentatus, S. equinus, Triodontophorus
spp.), small strongyles, pinworms (adults and 4th stage larva), ascarids
(adults), hairworms (adults), large-mouth stomach worms
(adults), neck threadworms (microfilaria), bots (oral and gastric
stages), lungworms (adults and 4th stage larva), intestinal threadworms
(adults), and summer sores (cutaneous 3rd stage larva) secondary
to Hebronema or Draschia Spp.
In cattle, ivermectin is approved for use in the control of gastrointestinal
roundworms (adults and 4th stage larva), lungworms
(adults and 4th stage larva), cattle grubs (parasitic stages), sucking
lice, and mites (scabies). For a listing of individual species covered,
refer to the product information.
In swine, ivermectin is approved for use to treat GI roundworms,
lungworms, lice, and mange mites. For a listing of individual species
covered, refer to the product information.
In reindeer, ivermectin is approved for use in the control of
warbles.
In American Bison, ivermectin is approved for use in the control
of grubs.
In dogs and cats, ivermectin is approved only for use as a preventative
for heartworm. It has also been used as a microfilaricide,
slow-kill adulticide, ectoparasiticide, and endoparasiticide.
Metabolism
Ivermectin is rapidly absorbed, is bound to a great extent to plasma protein, and is excreted in the
urine or feces either unchanged or as the 3′-O-demethyl-22,23-dihydroavermectin B1α or as the
dihydroavermectin B1α monosaccharide. The absorption of IVM is significantly affected by the
presence of alcohol. Administration of IVM as an alcoholic solution may result in as much as a
100% increase in absorption.
Toxicity evaluation
Ivermectin toxicity has been reported in collie dogs
and may be due to increased penetration of drug
across the blood-brain barrier to the central nervous
system (91) and/or the release of γ -aminobutyric acid
in the central nervous system (92). Vomiting, salivation,
diarrhea, melena, and death have resulted when
dogs with Dirofilaria immitis microfilariae were treated
with ivermectin (93,94). Adverse reactions in horses
with Onchocerca cervicalis microfilariae at the time of
therapy may manifest as transient, ventral, subcutaneous
edema (95).
References
References/Citations
1) Wagstaff?et al.?(2012),?Ivermectin is a specific inhibitor of importin α/β-mediated nuclear import able to inhibit replication of HIV-1 and dengue virus; Biochem. J.,?443?851
2) Caly?et al.?(2020),?The FDA-approved drug ivermectin inhibits the replication of SARS-CoV-2 in vitro; Antiviral Res.,?178?104787
3) Ottesen and Campbell (1994),?Ivermectin in human medicine; J. Antimicrob. Chemother.,?34?195
