What Factors Affect a Sufficient Ivermectin Dose?

Ivermectin is a new type of broad-spectrum, high-efficiency, low-toxic antibiotic antiparasitic drug. It has a good killing effect on internal and external parasites, especially nematodes and arthropods. It is not effective against tapeworms, trematodes and protozoa. The macrolide antiparasitic drug's killing effect on nematodes and arthropods is to increase the release of the inhibitory transmitter -aminobutyric acid (GABA) of the worm and to open the Cl ion channel controlled by glutamic acid. Enhancing the permeability of the nerve membrane to Cl, thereby blocking the transmission of nerve signals, eventually paralyzing the nerves, causing the muscle cells to lose their ability to contract, leading to the death of the worm.

Drug Name: Ivermectin
Foreign name: Ivermectin
Whether prescription drugs: prescription

Main medication contraindications: Overdose can cause poisoning
Dosage form: White crystalline powder
Drug type: Antibiotic Parasitic Drugs

Ivermectin Basic Information

Chinese name

Chinese alias: 22,23-dihydroabametin; ivermectin

English name: Ivermectin

English alias: Ivermecti; mk933; 22,23-dihydroavermectin B1; Uvemec; Ivosint; Ivermectin; EQVALEN; IVOMEC;

CARDOMECmk-0933; Mectizan; Vermic;

CAS number: 70288-86-7

Molecular formula: C48H74O14

Molecular weight: 875.09300

Exact mass: 874.50800

PSA: 170.06000

LogP: 5.60140 ^[1]

Structural formula:

Ivermectin profile

Ivermectin

It is a derivative of avermectin. The discoverers of avermectin, William C. Campbell and Tomori Omura, won the 2015 Nobel Prize in Physiology and Medicine for their outstanding achievements in combating river blindness and elephantiasis with their derivatives, ivermectin ^[2] .

Ivermectin is a semi-synthetic macrolide antibiotic produced by the fermentation of streptomyces avermitilis. It mainly contains ivermectin B1 (Bla + B1b) not less than 93%, and Bla should not be less than 85%.

Ivermectin B1 is 22,23-dihydroavermectin B1.

Ivermectin physical and chemical properties

Properties: This product is white crystalline powder; tasteless. This product is easily soluble in methanol, ethanol, acetone, ethyl acetate, almost insoluble in water, and slightly hygroscopic. Ivermectin is a sixteen-membered macrolide antibiotic. Its basic structure is a large ester ring at carbon 16 and three main substituents, namely hexahydrophenylpropanyl at positions C2 to C8. Furans, disaccharides at C13, and ketones at C17 to C18. ^[3]

Storage conditions: 2-8ºC

Physical map

Ivermectin pharmacology

Ivermectin pharmacodynamics

Because trematodes and roundworms do not use GABA as a transmitter, and lack Cl channels controlled by glutamic acid, this class of drugs is not effective. The mammalian peripheral neurotransmitter is acetylcholine. Although GABA is distributed in the central nervous system, it is safer because it does not easily penetrate the blood-brain barrier and has minimal effect on it.

The mechanism by which this class of drugs affect the reproduction of parasites is not clear, but it can reduce the spawning of ticks, abnormal egg shape of ruminant nematodes, and sterility of filamentous nematodes (male and female).

Ivermectin pharmacokinetics

The pharmacokinetics of ivermectin vary significantly depending on the species, dosage form and route of administration. Taking plasma half-life as an example, 300 g / kg is injected intravenously into cattle and sheep. Although t1 / 2 is not significantly different (2.8 days and 2.7 days respectively), the lower plasma concentration of sheep is due to the apparent volume of distribution being greater than that of cattle. To. Ivermectin is excreted quickly in dogs (t1 / 2 = 1.6 to 1.8 days). The half-life of pigs is as long as 4 days.

Subcutaneous injection (200 g / kg) of a special commercial preparation in the United States was used. Due to the slow absorption from the injection, the half-life was prolonged (t1 / 2 = 8 days). The blood drug peaked at .48h. Performance is maintained for 2 weeks. The sheep's half-life after oral administration is 3 to 5 days, and the blood drug peak is reached after 24 hours.

Oral (100 g / kg) tablets for dogs, peak blood drug (40ng / mL) within 2 to 4 hours. The peak arrival time of pig blood drug is faster than oral administration (0.5 days) than subcutaneous injection (2 days), but the bioavailability of subcutaneous injection is much higher than that of oral administration.

The bioavailability when taken was only 41% of the injection method.

Ivermectin in two different dosage forms (paste and water-based microcellular dosage form) is orally administered to horses.

Not only is the aqueous microcellular preparation (4-5h) much faster than the paste (15h), but also the bioavailability is high. (The paste is only water-based

20% of cytokine).

Ivermectin is widely distributed in systemic tissues after absorption, with the highest concentrations in liver and adipose tissue. Ivermectin usually

It is oxidized to metabolites in the liver.

Ivermectin excreted by feces accounted for more than 90% in 5 to 6 days, and excreted by urine only accounted for 0.5% to 2%.

Ivermectin uses

Ivermectin is widely used in gastrointestinal nematodes, pulmonary nematodes, and parasitic arthropods of cattle, sheep, horses, and pigs, intestinal nematodes of dogs, ear mites, chigger mites, heartworms, and microfilariae, and poultry stomachs Gut nematodes and ectoparasites.

(L) Ivermectin of cattle and sheep is administered orally or subcutaneously to cattle and sheep at a dose of 0.2mg / kg, and is used to treat haematobium worm, austrian worm, cooper worm, and trichomonas (including Trichomonas escherichia) , Round nematodes, larvae, nematodes, hairy head nematodes, esophageal mouth nematodes, net tail nematodes, Sheep nematode adults and fourth stage larvae, the deworming rate is 97% to 100%. The above doses are also effective for arthropods: such as fly maggots (Lepidoptera, Gracilaria, Sheep Fly), mites (Bovine maggot mite, sheep itch mite), and lice (bovine bovine lice, bovine blood lice, and sheep ticks) Wait. Ivermectin is slightly less effective against chewing lice (Trichophyta) and sheep and flies.

Ivermectin is also extremely effective against ticks and flies propagating in feces. Although the drug does not immediately kill or dismember the ticks, it can affect

Reduces fertility by feeding, moulting and spawning. Subcutaneous injection of 0.2 mg / kg to animals at once or daily at low concentration

(0. 01mg / kg) 5 days after the drug, the above phenomenon was most obvious in ticks. One subcutaneous injection at a dose of 0.2mg / kg also has a certain control effect on the flies that breed in the feces. After 9 days of cattle treatment, the face flies and housefly larvae in the feces cannot develop into worms. After another 5 days, due to the abnormality of the pupae and The adult's maturation process is hindered and the breeding of flies is greatly reduced. The above dose is used for blood flies (blood flies), and the situation is similar after 4 weeks.

(2) Ma Ma oral administration of 0.2mg / kg ivermectin is highly effective on the following adults and fourth-stage larvae of large and small round nematodes (95% to 100%); such as large round nematodes (common round Nematodes, horse round nematodes, toothless round nematodes), tapeworm (horse parasitic worm), tapeworm (horse worm), stomach worms (Dracula nematodes, flexible nematodes), small intestinal nematodes (Eisenia Trichomonas trichoderma, Trichostrongylus wechneri), Pneumocystis nematodes (C. terrei), etc. For the three maggots of transition or gastric residence, the onchocerciasis microfilariae and the third stage larvae of the gastrointestinal worm that cause skin damage, although the amount of 0.2mg / kg is also limited at one time, but the best solution After one month, take the medicine in the above amount.

It is particularly significant that the recommended dose of ivermectin (0.2mg / kg) is about 99% for the treatment of mesenteric arterial damage caused by the early and fourth stage larvae of common round nematodes, and is usually used. 2 After a few days, the symptoms were significantly reduced, and the damage symptoms disappeared in about 28 days.

(3) Intramuscular injection of 0.3mg / kg ivermectin has a broad-spectrum insect repellent activity on pigs. For example, Ascaris suum, red roundworm, lanella roundworm, first hair nematode, esophageal mouth nematode, post-cylinder nematode, adult worms and immature worms, the rate of elimination is 94% to 100%. Trichinella (ineffective in muscle) is also extremely effective. The above-mentioned medication method also has a good control effect on swine blood lice and chigger mites.

(4) There are special dosage forms for dogs and cats [in the amount of 6-12 g / kg] for the prevention and treatment of canine heartworm microfilaria infection. In China, a 50g / kg oral administration can be used to treat heartworm microfilaria infection (adults). invalid). Clinical trials have confirmed that high-dose ivermectin is highly effective against a variety of dog parasites, such as 50 g / kg subcutaneous injection of H. canine, Brazilian H. elegans, European dog H. elegans, and 100 g / kg against W. canis , 200g / kg has excellent repellent effect on adult Toxocara canis and fourth stage larvae. For Toxocara gigas, at a dose of 200 g / kg, the effect of subcutaneous injection is only 69%, while oral administration is 95%. This product is injected subcutaneously to aerobic capillary nematodes (200 g / kg) and Osler's nematodes (400 g / kg) parasitic to the lungs of dogs.

It also has excellent repellent effect. Oral or subcutaneous injection of 200 g / kg, re-used after two weeks.

Except for the third stage larva), the effective rate is 95% ~ 100%.

Ivermectin is also effective for some arthropod infections in dogs and cats. The dogs and cats were injected subcutaneously at a dose of 200 g / kg for two weeks.

Use it again to rule out ear mite, chigger mite, and dog lung mite infections. 300g / kg, twice in a row (interval of 2 weeks)

It is also very effective against selenium mites infection. It is best to treat canine mites in dogs with a subcutaneous injection of 600 g / kg at intervals of 7 days. Use 5 times.

(5) Poultry is highly effective for poultry nematodes such as chicken roundworms and closed capillaries and arthropods for poultry parasites, such as knee mites (mutant knee mites). However, this product is not effective against Heterodes galliformis.

(6) Reindeer infects Oedemagena tarandi, and it can be injected subcutaneously according to the amount of bovine (200 g / kg).

Ivermectin drug interactions

Different adjuvants contained in ivermectin commercial preparations can affect the effect of the drug. For example, sheep's oral preparation containing Tween-80 as an adjuvant, it is still safe when the amount of ivermectin reaches 4000 g / kg, but if Propylene glycol as adjuvant caused ataxia and hemoglobinuria in sheep for 3 days. Ivermectin injection containing Tween-80 as an adjuvant in the United States is a commercial preparation for equine animals, but it cannot be used in dogs, otherwise it is extremely unsafe.

Ivermectin function indications

This product is a derivative of avermectin, and belongs to a semi-synthetic oral broad-spectrum antiparasitic drug. This product has an effect on most nematodes (but not all nematodes) in various life cycles; it is effective on microfilariae of onchocerciasis, but it is not effective on adults; it is also effective on roundworms that are only in the intestine. This product has a selective inhibitory effect. By combining with the high affinity of chloride channels of glutamic acid as a valve in spinal nerve cells and muscle cells, it leads to an increase in the permeability of cell membranes to chloride ions, causing nerve cells or muscles. Cells are hyperpolarized, paralyzing or dying. This product can also interact with chloride channels of other ligand valves such as the neurotransmitter g-aminobutyric acid (GABA). The selectivity of this product is because some mammals do not have glutamic acid-chloride ion channels, and avermectin has only low affinity for mammalian ligand-chloride ion channels. This product cannot penetrate human blood-brain barrier. Onchocerciasis and roundworm-like disease and hookworm, tapeworm, whipworm, and roundworm infections.

Ivermectin clinical study

[Efficacy Indications] Applicable to onchocerciasis and roundworm-like disease and hookworm, tapeworm, whipworm, tapeworm infection.

[Chemical composition] The main ingredients of this product are ivermectin B1a and ivermectin B1b. The chemical name of ivermectin B1a is (5-O-desmethyl-22,23-dihydroavermectin A1a ); The chemical name of ivermectin B1b is (5-O-desmethyl-25-des (1-methylpropyl) -22,23-dihydro.

[Pharmacological action] 1. Pharmacological action This product is a derivative of avermectin, which belongs to an oral semi-synthetic broad-spectrum antiparasitic drug. This product has an effect on most nematodes (but not all nematodes) in various life cycles; it is effective on microfilariae of onchocerciasis, but not on adults; it is also effective on roundworms only in the intestine. This product has a selective inhibitory effect. By combining with the high affinity of chloride channels of glutamic acid as a valve in spinal nerve cells and muscle cells, it leads to an increase in the permeability of cell membranes to chloride ions, causing nerve cells or muscles. Cells are hyperpolarized, paralyzing or dying. This product can also interact with chloride channels of other ligand valves, such as the neurotransmitter -aminobutyric acid (GABA). The selectivity of this product is because some mammals do not have glutamate-chloride channels, and avermectin has only a low affinity for mammalian ligand-chloride channels. This product cannot penetrate human blood-brain barrier. 2. Toxicological studies of genotoxicity: only in vitro mutagenicity tests were performed, and no genotoxicity was found in this product. Reproductive toxicity: When the repeated dose of the rat reaches 3 times the maximum human clinical recommended dose (in terms of body surface area), no effect on animal fertility has been seen. Repeated doses of mice, rats, and rabbits reached 0.2, 8.1, and 4.5 times (based on body surface area) the maximum human clinical recommended doses, indicating that this product has teratogenic effects. Cleft palate appeared in both animals, and the rabbit also had clubbing forepaws. These effects occur at close to maternal toxic doses. Therefore, this product is obviously not selective fetal toxicity. However, there is no sufficient and strict research data on pregnant women to confirm the safety of using this product in pregnancy, so it should not be used during pregnancy.

[Drug interaction] It is not clear.

[Adverse reactions] Systemic reactions: including weakness, weakness, abdominal pain, fever; gastrointestinal reactions: including anorexia, constipation, diarrhea, nausea, vomiting; nervous system reactions: including dizziness, drowsiness, dizziness, tremor; skin: including itching , Rash, pimples, rubella, small pustules; ophthalmology: The following ophthalmic adverse reactions are caused by the disease itself, but they have also been reported after treatment with ivermectin. These adverse reactions include visual abnormalities, eyelid edema, anterior uveitis, conjunctivitis, Limbitis, keratitis, chorioretinitis, or choroiditis. The above symptoms are generally mild symptoms that do not cause blindness, and generally can be relieved without corticosteroid treatment. Others: Including arthralgia, synovitis, axillary lymph node enlargement and tenderness, cervical lymph node enlargement and tenderness, inguinal lymph node enlargement and tenderness, lymph node enlargement and tenderness in other parts, facial edema, peripheral edema, standing Hypotension, tachycardia, drug-induced headaches, and abnormal laboratory tests of myalgia: include increased ALT and / or AST, decreased white blood cells, increased eosinophils, and increased hemoglobin.

[Contraindications] Those with severe liver, kidney, and heart dysfunction, allergies to this product, and mental disorders are prohibited.

Ivermectin dosage

The recommended dose of roundworm-like disease is a single oral dose of 200 g / kg, taken with water. No increase is usually required, but follow-up is required to ensure cure. The usual doses are as follows: for 15-24 kg, the dose is half a tablet (about 3 mg); for 25-34 kg, the dose is 1 tablet (about 6 mg); for 35-50 kg, the dose is 1 and a half (about 9 mg) ); 51-65 kg, 2 tablets (about 12 mg); 66-79 kg, 2 and a half tablets (about 15 mg); 200 g / kg or more. The recommended dose for onchocerciasis is a single oral dose of 150 g / kg, taken with water. The usual doses are as follows: 15-24 g, a half-tablet (about 3 mg); 25-44 kg, a 1-tablet (about 6 mg); 45-64 kg, a half-tablet (about 9 mg) ); 65-84 kg, 2 tablets (approximately 12 mg); 150 g / kg more than 80 kg. Hookworm infections over 14 years of age take 12 mg (equivalent to 0.2 mg / kg) orally; those under 14 years of age take 6 mg orally. Ascaris lumbricoides infection is a single oral administration of 6 mg (equivalent to 0.1 mg / kg) for persons over 14 years of age, and a single oral administration of 3 mg for persons under 14 years of age. Whipworm infections over 14 years of age give a single oral administration of 12 mg (equivalent to 0.2 mg / kg); those under 14 years of age take a single oral administration of 6 mg. Ascaris lumbricoides infection is a single oral administration of 12 mg (equivalent to 0.2 mg / kg) for persons over 14 years of age; a single oral administration of 6 mg for persons under 14 years of age. Overdose: symptoms This product should be used at the prescribed dose. Excessive use may include ataxia, slow breathing, tremor, drooping eyelids, reduced activity, vomiting, and dilated pupils. In case of overdose, you should induce vomiting and gastric lavage as soon as possible. If necessary, you can give laxatives and other conventional anti-drug treatment. In case of accidental poisoning, supportive therapy (including supplementation of body fluids and electrolytes, oxygen or mechanical ventilation) can be performed as needed. Booster drugs should be given if clinically significant hypotension occurs.

Ivermectin adverse reactions

Overdose can cause poisoning without specific antidote. Intramuscular injection can cause severe local reactions.

Ivermectin considerations

Relevant historical data indicate that anti-filariasis drugs [such as acetaminozine citrate (DEC-C)] can cause severe allergic reactions (Mazzotti response) and ophthalmic reactions to the skin and / or whole body of patients with onchocerciasis larvae. . These reactions may be due to allergic and inflammatory reactions caused by dead microfilament larvae. These reactions may occur clinically in patients treated with ivermectin on filaria larvae, which may or may be related to the drug itself. After treatment with microfilaria drugs, patients with allergic onchocercia dermatitis are more likely to have serious adverse reactions, especially edema and onchocercia dermatitis which exacerbate carcinogenicity, mutagenicity and reproductive toxicity. When using this product, patients with roundworm disease must repeat the fecal test to ensure that the roundworm infection has been cleared. This product cannot kill adult onchocerciasis. Therefore, continuous treatment is needed when using this product to treat onchocerciasis. Roundworm disease in immunodeficiency hosts: Patients with immunodeficiency (including HIV infection) may require repeated treatment for gut roundworm disease. For such patients, no clinical trials have been conducted to determine alternative dosing regimens, and suppression treatments (such as once a month) may be useful.