HIV-1; HSV-1; BoHV-1; SARS-CoV-2;
Ivermectin (MK-933) acts quickly and reversibly in the submicromolar range (EC50=250 nM), increasing the amplitude and delaying the deactivation of ATP-evoked P2X4 channel currents.Without altering the ion selectivity of P2X4 channels, ivermectin (MK-933) significantly boosts the potency of ATP and that of the typically low-potency agonist a,b-methylene-ATP in a use- and voltage-independent manner[1].
Ivermectin (MK-933) causes membrane hyperpolarization and muscular paralysis in the parasite by activating glutamate-gated chloride channels in its nerves and muscles[2].
The binding of Impα/β1 to NS5 is strongly inhibited by ivermectin (MK-933) (IC50=17 μM), but not the binding of Impβ1 by itself.Ivermectin (MK-933) exhibits strong antiviral activity against the dengue virus and HIV-1, which are both heavily dependent on importin α/β nuclear import with regard to the NS5 (non-structural protein 5) polymerase and HIV-1 integrase proteins, respectively[3].

Ivermectin (MK-933) acts quickly and reversibly in the submicromolar range (EC50=250 nM), increasing the amplitude and delaying the deactivation of ATP-evoked P2X4 channel currents.Without altering the ion selectivity of P2X4 channels, ivermectin (MK-933) significantly boosts the potency of ATP and that of the typically low-potency agonist a,b-methylene-ATP in a use- and voltage-independent manner[1].
Ivermectin (MK-933) causes membrane hyperpolarization and muscular paralysis in the parasite by activating glutamate-gated chloride channels in its nerves and muscles[2].
The binding of Impα/β1 to NS5 is strongly inhibited by ivermectin (MK-933) (IC50=17 μM), but not the binding of Impβ1 by itself.Ivermectin (MK-933) exhibits strong antiviral activity against the dengue virus and HIV-1, which are both heavily dependent on importin α/β nuclear import with regard to the NS5 (non-structural protein 5) polymerase and HIV-1 integrase proteins, respectively[3].

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Ivermectin acts as a specific positive allosteric modulator of heterologously expressed homomeric P2X4 receptor channels in Xenopus laevis oocytes. It does not significantly affect ATP-evoked currents mediated by P2X2, P2X3, P2X2/P2X3, or P2X7 channels. [1]
Ivermectin (≤10 µM) potentiates ATP-evoked currents at P2X4 channels in a rapid, reversible, and use-independent manner. It increases the peak current amplitude and dramatically slows the deactivation (decay) of the current. [1]
The potentiation by Ivermectin is concentration-dependent with an apparent EC50 of ~257 nM for currents evoked by 3 µM ATP. The equilibrium dissociation constant (Kd) derived from kinetic experiments was 278 nM. The effect did not reach a clear plateau at high concentrations (≥10 µM). [1]
Ivermectin (3 µM) increases the potency of ATP at P2X4 channels, decreasing the EC50 from 3 µM to 0.3 µM, and also increases the maximal current. [1]
Ivermectin (3 µM) converts the normally weak agonist α,β-methylene-ATP into a potent agonist at P2X4 channels, decreasing its EC50 from >300 µM to 19.8 µM. This provides direct evidence for an allosteric mechanism. [1]
The action of Ivermectin on P2X4 channels is largely voltage-independent, causing no shift in the reversal potential of ATP-evoked currents. The potentiation occurs at all tested membrane potentials (-120 to +60 mV), with a slightly weaker effect at voltages more negative than -60 mV. [1]
Ivermectin potentiates only the initial high-selectivity state (I1) of P2X4 channel currents during prolonged ATP application, not the secondary low-selectivity state (I2). The ion selectivity (NMDG+/Na+ permeability ratio) remains unchanged. [1]
The allosteric effect of Ivermectin on P2X4 channels is independent of the host cell system. Similar potentiation was observed in Xenopus oocytes, transfected HEK 293 cells, and transfected embryonic hippocampal neurons. [1]
Ivermectin (2-5 µM) did not significantly affect fast ATP-evoked inward currents in adult rat brain slice neurons from the trigeminal mesencephalic nucleus (TMN) or the majority of hippocampal CA1 pyramidal neurons, suggesting homomeric P2X4 channels are not the primary subtype in these native adult neurons. [1]
In embryonic hippocampal neurons transfected with P2X4, Ivermectin (3 µM) markedly augmented ATP-evoked currents, confirming its ability to modulate P2X4 channels in a neuronal context. [1]
In control experiments within hippocampal slices, Ivermectin (2 µM) rapidly and reversibly potentiated GABA-evoked currents at GABAA receptors, confirming its penetration into the tissue. [1]

The article mentions that the in vivo antiviral potential of ivermectin has been reported against West Nile virus and Newcastle disease virus, as well as against pseudorabies virus and parvoviruses, based on cited studies.[5]
It also notes that ivermectin was ineffective at preventing lethal Zika virus infection in a murine model (Ifnar1-knockout mice), citing another study.[5]

An AlphaScreen-based binding assay was used to assess the interaction between biotinylated importin α/β1 and His-tagged dengue virus NS5 protein. The assay was performed in 384-well plates using serial dilutions of importin proteins and ivermectin. The signal was quantified using a plate reader, and titration curves were plotted to determine IC₅₀ values.[3]
The same assay was also used to evaluate the binding of importin β1 alone to NS5 in the presence of ivermectin.[3]

Two-electrode voltage-clamp recording in Xenopus oocytes: Wild-type P2X receptor cRNAs were injected into Xenopus laevis oocytes. Electrophysiological recordings were performed 1-4 days after injection using a two-electrode voltage-clamp setup. Oocytes were superfused with a recording solution. ATP and other drugs were applied via a solenoid-operated solution switcher. Ivermectin (≤10 µM, dissolved in DMSO) was applied in the superfusate. Currents were recorded, filtered, and digitized for analysis. [1]
Whole-cell patch-clamp recording in HEK 293 cells: HEK 293 cells were transfected with P2X4 channel cDNA. Recordings were made 24-48 hours later using the whole-cell patch-clamp configuration. Cells were voltage-clamped, and drugs were applied externally. The effect of Ivermectin (3 µM) on ATP-evoked currents was tested. [1]
Whole-cell patch-clamp recording in embryonic hippocampal neurons: Embryonic hippocampal neurons were transfected with P2X4 and EGFP plasmids using a gene gun. Recordings were made 24-48 hours post-transfection from EGFP-positive neurons using the whole-cell patch-clamp configuration. A U-tube concentration clamp system was used to apply ATP and Ivermectin (3 µM). [1]
Whole-cell patch-clamp recording in adult rat brain slices: Coronal slices of hippocampus and brainstem were prepared from young rats. Neurons (e.g., trigeminal mesencephalic nucleus neurons, CA1 pyramidal cells) were visually identified. Whole-cell recordings were made with patch pipettes. ATP was applied via pressure microejection from a pipette positioned near the cell body. Ivermectin (2-5 µM) was added to the superfusion system from a concentrated stock solution. [1]

Absorption, Distribution and Excretion
Absorption is good. High-fat meals can improve absorption. Ivermectin is metabolized in the liver, and almost all of it and its metabolites are excreted in the feces, expected to be completed within 12 days. Less than 1% of the administered dose is excreted in the urine. The volume of distribution is 3–3.5 L/kg. It does not cross the blood-brain barrier. Metabolism/Metabolites Primarily metabolized in the liver. Ivermectin and its metabolites are almost entirely excreted in the feces, expected to be completed within 12 days. Less than 1% of the administered dose is excreted in the urine. Biological Half-Life After oral administration, the half-life of ivermectin is approximately 18 hours.

Hepatotoxicity
Single-dose ivermectin treatment was associated with a low incidence of elevated serum transaminases. One case of clinically significant liver injury following ivermectin treatment has been reported (Case 1). This injury occurred one month after a single dose and was characterized by hepatocellular elevations of serum enzymes, but without jaundice. The patient recovered rapidly and completely. Elevated serum transaminases were not uncommon in trials of ivermectin for the prevention of SARS-CoV-2 infection and for improving the course of early and severe COVID-19, but the incidence was not significantly different between patients treated with ivermectin and those treated with placebo or control drugs.
Probability score: D (Possibly a rare cause of mild, clinically significant liver injury).

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Protein binding
93%

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The LD₅₀ of ivermectin after 24 hours of incubation in 50% confluence HeLa cells was 150 μM, as determined by a cytotoxicity assay. [3]

[1]. Allosteric control of gating and kinetics at P2X(4) receptor channels. J Neurosci. 1999 Sep 1;19(17):7289-99.

[2]. Mechanism of ivermectin facilitation of human P2X4 receptor channels. J Gen Physiol. 2004 Mar;123(3):281-93.

[3]. Ivermectin is a specific inhibitor of importin α/β-mediated nuclear import able to inhibit replication of HIV-1 and dengue virus. Biochem J. 2012 May 1;443(3):851-6.

[4]. Ivermectin Inhibits Bovine Herpesvirus 1 DNA Polymerase Nuclear Import and Interferes with Viral Replication. Microorganisms. 2020 Mar 13;8(3). pii: E409.

[5]. Ivermectin, a New Candidate Therapeutic Against SARS-CoV-2/COVID-19. Ann Clin Microbiol Antimicrob. 2020 May 30;19(1):23.

LSM-5397 is a milbemycin. Ivermectin is a semi-synthetic antiparasitic drug derived from avermectin compounds. Avermectin compounds are a class of highly effective, broad-spectrum antiparasitic drugs isolated from the fermentation products of Streptomyces avermitosa. Ivermectin itself is a mixture of two avermectins, containing approximately 90% 5-O-demethyl-22,23-dihydroavermectin A1a (22,23-dihydroavermectin B1a) and 10% 5-O-demethyl-25-de(1-methylpropyl)-22,23-dihydro-25-(1-methylethyl)avermectin A1a (22,23-dihydroavermectin B1b). Ivermectin is primarily used to treat onchocerciasis in humans, but may also be effective against other worm infections such as strongyloidiasis, ascariasis, whipworm infection, and pinworm infection. When used topically, it can be used to treat head lice infections. With the outbreak of the COVID-19 pandemic in 2020, ivermectin gained attention for its off-label use in the prevention and treatment of COVID-19. Although research is ongoing, most of the current evidence regarding ivermectin for COVID-19 treatment relies on preprint data from in vitro experiments, the clinical value of which remains unclear. Due to various factors—such as relatively small patient numbers per trial and the rapid pace of trials—studies on ivermectin for COVID-19 are rife with statistical errors and plagiarism allegations. Furthermore, the use of pooled patient data (rather than individual patient data (IPD)) in large-scale meta-analyses has been shown to mask otherwise obvious data errors, such as extreme last-digit bias and duplication of patient record blocks. Until high-quality, peer-reviewed data on the safety and efficacy of ivermectin in humans for COVID-19 are available, ivermectin should be avoided for this purpose; well-validated therapies (such as COVID-19 vaccines, like [Comirnay](https://go.drugbank.com/drugs/DB15696)) should be chosen instead. Ivermectin is an anti-infective drug effective against various parasitic nematodes and scabies, and is the first-line treatment for onchocerciasis (river blindness). It is usually administered orally in one to two doses. Ivermectin treatment is associated with mild, self-limiting elevations in serum transaminases, and in rare cases, clinically significant liver damage may occur. Ivermectin B1a has been reported in Streptomyces avermitilis, and relevant data are available. Ivermectin is a highly bioavailable cyclic lactone compound derived from Streptomyces, possessing antiparasitic and potential antiviral activity. After administration, ivermectin exerts its anthelmintic effect by binding to and activating glutamate-gated chloride channels (GluCls) expressed on nematode neurons and pharyngeal muscle cells. This leads to increased chloride permeability, causing a hyperpolarized state, ultimately resulting in paralysis and death of the parasite. Ivermectin may exert its antiviral activity by binding to the nuclear importation protein (IMP) α/β1 heterodimer, including its potential activity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). This heterodimer is responsible for the nuclear importation of viral proteins, such as integrase (IN) proteins. This binding inhibits the nuclear importation of both host and viral proteins and may inhibit viral replication. Ivermectin is a mixture of avermectin H2B1a (RN 71827-03-7) and a small amount of avermectin H2B1b (RN 70209-81-3), both macrolide antibiotics derived from Streptomyces avermitilis. It binds to glutamate-gated chloride channels, leading to increased permeability and hyperpolarization in nerve and muscle cells. It can also interact with other chloride channels. It is a broad-spectrum antiparasitic drug, effective against microfilariae of Onchocerca salina, but ineffective against adult worms. See also: Ivermectin (note moved to).

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Drug Indications
Topical ivermectin cream is indicated for the treatment of inflammatory skin lesions associated with rosacea. An over-the-counter ivermectin lotion is available for the treatment of head lice infestations in patients 6 months or older. Oral ivermectin is a broad-spectrum antiparasitic drug indicated for the treatment of intestinal strongyloidiasis caused by Strongyloides stercoralis and onchocerciasis caused by Onchocerca filariasis. Systemic ivermectin therapy is used internationally to treat a variety of tropical diseases, including filariasis, cutaneous larval migration, and loa filariasis.
FDA Label
Treatment of Rosacea
Mechanism of Action
Ivermectin selectively and with high affinity binds to glutamate-gated chloride channels in the muscle and nerve cells of microfilariae, invertebrates. This binding leads to increased cell membrane permeability to chloride ions and causes cell hyperpolarization, ultimately resulting in paralysis and death of the parasite. Ivermectin is also thought to act as an agonist of the neurotransmitter γ-aminobutyric acid (GABA), thereby disrupting GABA-mediated synaptic transmission in the central nervous system (CNS). Ivermectin may also impair O. Ivermectin inhibits microfilariae of Onchocerca volvulus and may inhibit their release from the uterus of female adults.

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Ivermectin is used clinically to treat river blindness (onchocerciasis) caused by Onchocerca volvulus. Its antiparasitic mechanism involves acting as an agonist of glutamate-gated chloride channels in invertebrates. [1]
This study identified ivermectin as a novel and specific pharmacological tool for probing P2X4 receptor channels and distinguishing them from other P2X receptor subtypes (P2X2, P2X3, P2X7). [1]
Ivermectin's effect on P2X4 channels is considered allosteric because it enhances the potency and titer of agonists (ATP and α,β-methylene-ATP) without acting as an agonist itself (maintaining no change in current) or altering ion selectivity. [1]
Based on the lack of effect of ivermectin, this study concludes that homologous P2X4 channels are unlikely to be the main subtype mediating the rapid ATP response in the trigeminal nucleus and hippocampal CA1 neurons of adult rats. [1]

C48H74O14

875.1

874.508

70288-86-7

6321424

White to off-white solid powder

155 °C

5.601

3

14

8

62

1680

20

CC[C@H](C)[C@@H]1[C@H](CC[C@@]2(O1)C[C@@H]3C[C@H](O2)C/C=C(/[C@H]([C@H](/C=C/C=C/4\CO[C@H]5[C@@]4([C@@H](C=C([C@H]5O)C)C(=O)O3)O)C)O[C@H]6C[C@@H]([C@H]([C@@H](O6)C)O[C@H]7C[C@@H]([C@H]([C@@H](O7)C)O)OC)OC)\C)C

AZSNMRSAGSSBNP-ZGXOMDHGSA-N

InChI=1S/C48H74O14/c1-11-25(2)43-28(5)17-18-47(62-43)23-34-20-33(61-47)16-15-27(4)42(26(3)13-12-14-32-24-55-45-40(49)29(6)19-35(46(51)58-34)48(32,45)52)59-39-22-37(54-10)44(31(8)57-39)60-38-21-36(53-9)41(50)30(7)56-38/h12-15,19,25-26,28,30-31,33-45,49-50,52H,11,16-18,20-24H2,1-10H3/b13-12+,27-15+,32-14+/t25-,26+,28+,30+,31+,33-,34+,35+,36+,37+,38+,39+,40-,41+,42+,43-,44+,45-,47-,48-/m1/s1

(1R,4S,5'S,6R,6'R,8R,10E,12S,13S,14E,16E,20R,21R,24S)-6'-[(2R)-butan-2-yl]-21,24-dihydroxy-12-[(2R,4S,5S,6S)-5-[(2S,4S,5S,6S)-5-hydroxy-4-methoxy-6-methyloxan-2-yl]oxy-4-methoxy-6-methyloxan-2-yl]oxy-5',11,13,22-tetramethylspiro[3,7,19-trioxatetracyclo[15.6.1.14,8.020,24]pentacosa-10,14,16,22-tetraene-6,2'-oxane]-2-one

MK-933; L-64047; MK 933; L64047; MK-0933; Noromectin; MK 933; Mectizan; MK 0933; Ivermectin; Ivomec; L 64047; Pandex.

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : 100~250 mg/mL ( 114.27~285.68 mM )
Ethanol : ~100 mg/mL
H2O : < 0.1 mg/mL

Solubility in Formulation 1: ≥ 2.5 mg/mL (2.86 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.08 mg/mL (2.38 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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Solubility in Formulation 3: 10% DMSO+40% PEG300+5% Tween-80+45% Saline: ≥ 2.5 mg/mL (2.86 mM)

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 (Please use freshly prepared in vivo formulations for optimal results.)