In the 1970s it was noticed that Streptomyces avermitilis (bacteria) treated mice infested with intestinal roundworms attacking rodents. Isolation of Streptomyces avermitilis directed to the discovery of Ivermectin. Since that time Ivermectin for human use has been used to treat roundworms and other parasitic nematodes.
Abstract Ivermectin has been noticed to inhibit severe acute respiratory syndrome 2 or SARS-CoV-2 replication in vitro studies. It is not known whether this inhibition of SARS-CoV-2 replication correlates with better clinical outcomes.
Why Ivermectin Treatment is Prescribed?
Ivermectin for humans is a broadly used antiparasitic drug. World Health Organization has approved the use of Ivermectin in low and middle-income countries to treat worm infections, lice, and scabies. Ivermectin is considered safe for humans.
Ivermectin tablet is prescribed for various parasitic infections including threadworm infestation, roundworm infestation, whipworm infestation, elephantiasis (filariasis), loiasis, river blindness disease, and tropical eosinophilia. Apart from the antiparasitic activity of Ivermectin, it also possesses antiviral and anti-inflammatory properties.
Ivermectin Indications
Ivermectin medication is the drug of choice for Strongyloidiasis (threadworm infestation caused by Strongyloides stercoralis through contaminated soil) and Onchocerciasis also known as river blindness (a tropical disease caused by Onchocerca volvulus transmitted by blackflies bites).
Ivermectin is also used as an alternative drug for many other helminthic infections such as Ascariasis, Trichuriasis, Filariasis, Tropical eosinophilia, Loiasis, Scabies, and head lice infestation.
Ivermectin Mechanism of Action
Ivermectin tablets are speedily absorbed attaining maximum plasma concentrations with a broad tissue distribution around 4 hours after a 12 mg dose. It immobilizes infected organisms by persuading paralysis of the musculature of parasites by binding to the chloride ion channels of muscle or nerve cells.
Ivermectin for humans does not kill adult worms but prevents the release of microfilariae for some months after Ivermectin therapy. After a single standard dose, microfilariae in the skin reduce swiftly within 2-3 days.
The mechanism of action of Ivermectin is not very well comprehended however its is assumed that it binds to glutamate-gated chloride channels which are mostly available in nerve and muscle cells.
Recommendations for Taking Ivermectin Therapy
- Always follow the directions on the prescription label.
- Do not take Ivermectin in larger or smaller amounts or for longer periods than prescribed by the doctor.
- It is recommended to take Ivermectin on an empty stomach at least 1 or 2 hours before or after a meal.
- Usually, a single dose of Ivermectin is prescribed which should be taken with a full glass of water.
- In some cases, your doctor may prescribe various frequencies of Ivermectin severe months or a year after the first dose, particularly for patients with weak immune systems.
- Frequent stool samples should be examined to assess the effectiveness of Ivermectin treatment.
- Alcohol consumption can put you at risk of developing specific side effects of this drug.
- Very high doses than the prescribed doses can be harmful and may cause adverse reactions.
Ivermectin can Interact with Certain other Medications
An interaction means when the effectiveness of a medicine is altered by another drug or ingredient etc. The outcome of an interaction can be harmful (increase drug toxicity) or benedictive (synergetic increase in outcome).
Some common interactions of Ivermectin include:
Acenocoumarol: In is an anticoagulant medication that increases the time for the blood to clot when combined with Ivermectin.
Albendazole and Azithromycin: These two medications when combined with Ivermectin may lead to moderate alterations in the pharmacokinetics of these three drugs.
Levamisole: This anthelmintic drug when combined with Ivermectin, t can make the Ivermectin more potent.
Alcohol: Ivermectin in combination with alcohol can make the Ivermectin more potent.
Orange juice: When Ivermectin is combined with orange juice it can make Ivermectin less potent.
Ivermectin Side Effects
The common side effects of Ivermectin include dizziness, nausea, itchy skin, Abdominal pain, difficulty in passing stools, lethargy, and transient modifications in electroencephalography.
Mostly, serious side effects are very rare. Serious side effects of Ivermectin include hepatitis, neurotoxicity, loss of vision, decreased heart rate, seizures, conjunctival hemorrhage, postural hypotension, toxic epidermal necrolysis, and Stevens-Johnson syndrome.
This is not the complete list of possible side effects. Make sure you discuss about the side effects of this drug before you start taking it. If you experience any serious side effects of this drug seek medical attention to avoid complications.
Extreme rare Ivermectin side effects on particular organs and systems
Cardiovascular: Ivermectin tablets may cause increased heart rate or low blood pressure while the patient is standing and sleeping, it may also cause postural hypotension.
Respiratory: the patients may experience bronchodilatation that significantly diminishes vital capacity after 24-30 hours. A few patients may experience transient cough and shortness of breath.
Nervous System: It may cause headache and vertigo. Some patients may experience a sudden behavior change.
Hematologic: patients who are getting Ivermectin treatment for onchocerciasis may experience prolonged prothrombin time.
Musculoskeletal: A few patients reported mild bone and joint pains and muscle pain.
Is Ivermectin Therapy Safe?
Ivermectin is considered very safe and well-tolerated by patients infected with parasitic infections. It is usually prescribed as a single or annual oral dose to treat various internal nematode infections (strongyloidiasis and onchocerciasis) as well as ectoparasitic infections (scabies and lice).
Various clinical trials have been performed to treat coronavirus disease with Ivermectin shows Ivermectin may be safely used for managing the disease as no significant increase in adverse reactions has been noticed.
Can Ivermectin Cause Blood Clots?
Ivermectin therapy has a very negligible effect on coagulation or clotting of blood. Ivermectin can be more likely to interfere with coagulation in fairly malnourished subjects in whom mild vitamin K deficiency may precede treatment. Patients taking blood thinners such as warfarin in combination with Ivermectin possess an increased risk of blood clotting disorders.
Can Ivermectin Cause Brain Damage?
Ivermectin use is not associated with brain damage in humans. Any chemical including avermectin requires to cross the blood-brain barrier to reach the brain. The blood-brain barrier is a combination of blood vessels and tissues that prevents harmful substances from reaching the brain. As Ivermectin can not cross the blood-brain barrier, it can not cause any damage to the brain.
How Long Do The Side Effects Last?
Usually, mild side effects of this medication can go away within a few days and you do not need a treatment for that. On the other hand severe side effects which are not very common, do not disappear so you need to consult a doctor.
Keep a record of your side effects while you are under Ivermectin treatment. It will help your healthcare provider assess whether the side effects are due to Ivermectin or any other reason.
A Mini Review Concerning The Pharmacokinetics and Interactions of Ivermectin in Humans
The antiparasitic drug Ivermectin possesses a broad spectrum of activity, great efficacy, and significant safety. This mini-review (open-access article) presents information concerning the pharmacokinetics and interactions of Ivermectin in humans. Awareness of these features could enhance the clinical effectiveness of Ivermectin.
Ivermectin is extremely potent with effective dosage levels that are usually low. For onchocerciasis treatment the optimal dose of Ivermectin is 150 μg/kg however the frequency of administration is still controversial starting from 150 μg/kg once to thrice yearly. The optimal duration of this treatment has not been established. In most patients with scabies, it is effective after a single oral dose of 200 μg/kg however often the regimen includes 2-3 repeated doses at an interval of one or two weeks.
Pharmacokinetics
For Ivermectin administration in humans, only the oral route is approved. Both one and two-compartment models have been employed to define Ivermectin kinetic behavior after its oral administration.
Absorption
In healthy and onchocerciasis people treated with 150 μg/kg, no substantial variances were noticed in the pharmacokinetic parameters calculated. After an initial reduction, both groups presented a propensity for a second rise in plasma levels (mostly happens within 6 to 12 hours after the dose) signifying an enterohepatic recycling of the drug.
It was also examined if reduced Ivermectin absorption could describe the fact that some harshly infected onchocerciasis patients experience comparatively few adverse effects of Ivermectin treatment, even though the incidence and scope of adverse reactions have been associated with infection intensity.
Rendering to this study, there was no noticeable association between the plasma concentration after a single oral dose of 150 μg/kg and the incidence of adverse reactions. Neither parasite load nor Ivermectin concentrations influenced the incidence of adverse reactions in the whole group of patients.
The capability to attain satisfactory levels of Ivermectin after oral administration in patients with disseminated strongyloidiasis may be messed up, causing the requirement for alternative routes of administration in these patients. Thus, Ivermectin levels, in patients with disseminated strongyloidiasis, were below the average of those noticed by others following oral administration.
This was followed by the administration of three subcutaneous doses of 200 μg/kg, injected every 2 days, increasing Ivermectin levels at 1 week after the last dose, with evidence of additional metabolite accumulation and also a continued antiparasitic outcome. Thus, in patients, who are incapable of absorbing oral medication, parenteral Ivermectin could be a better option.
In another report, a male patient with disseminated strongyloidiasis, severe hypoalbuminemia, and paralytic ileus, was given oral Ivermectin. Three hours after the third daily dose, the serum Ivermectin concentration was normal it increased 16 hours after the first subcutaneous dose. Over the next 15 days, subcutaneous Ivermectin produced serum Ivermectin levels between 11.4 and 17.2 ng·ml−1 with no substantial accumulation.
Distribution
As Ivermectin carries high lipid solubility, this compound is extensively distributed inside the body. Ivermectin strongly binds to plasma proteins in healthy subjects. It was also high in patients with onchocerciasis with a particular binding for serum albumin. Two binding sites were observed there, with a connotation constant of 2 × 108 mol−1 at the prime site.
This type of keen binding assumes great significance as the medication is administered in world regions where hypoalbuminemia and malnutrition are common. So in such patients, a reduction in plasma proteins and subsequently an increased free fraction of Ivermectin could be expected. Yet, acetylsalicylic acid does not affect Ivermectin binding.
Ivermectin was not spotted in the cerebrospinal fluid of a patient with disseminated strongyloidiasis, severe hypoalbuminemia, and paralytic ileus, after five subcutaneous doses of Ivermectin, when the serum level was 12.1 ng·ml−1.
Elimination
Studies concerning the metabolism of Ivermectin in humans are rare. It is expansively metabolized by human liver microsomes by cytochrome P450. The major isoform responsible for the biotransformation of this compound in the liver of humans is cytochrome P-4503A4, adapting the drug to at least 10 metabolites, which are mostly hydroxylated and demethylated derivatives. In plasma, radioactive metabolites were informed after the oral administration of Ivermectin in healthy volunteers.
After oral administration and metabolization of Ivermectin in the liver, the peak concentration of ivermectin is around 4 hours after the dosing. Less than 1% of the administered dose is eliminated in the urine.
In the elimination half-life, no variances were observed among healthy and onchocerciasis subjects. It was also proposed that the kinetics of Ivermectin were somewhat disengaged from its pharmacodynamics. Concerning excretion pathways, Ivermectin and its metabolites were eliminated majorly in feces and just 1% in urine.
Interactions
Several studies have been performed to determine the effect of Ivermectin in combination with other drugs to manage helminths. The combination of Ivermectin and doxycycline is extremely effective in interrupting the transmission of onchocerciasis in humans.
The administration of anthelmintic and antibacterial medication daily for 6 weeks kept the microfilaremia levels low as compared to Ivermectin alone. Doxycycline encouraged Ivermectin-induced conquest of microfilaremia as it sterilized adult female worms for a few months by reducing the symbiotic endobacteria of filariae.
Some other studies revealed that to manage onchocerciasis, the combination of Ivermectin with other medications has no advantage as compared to Ivermectin alone. So in infected patients, the administration of Ivermectin did not affect the kinetics of an oral dose of Albendazole. Albendazole did not transform the kinetic behavior of a single dose of oral Ivermectin.
The combination of Ivermectin and Levamisole was neither macrofilaricidal nor more effective against the microfilariae and adult worms as compared to the administration of Ivermectin alone. Even though Levamisole enhances Ivermectin plasma bioavailability in these patients.
Furthermore, prolonged prothrombin ratios were noticed in 148 subjects (Ivermectin group) when Ivermectin was administered orally. However, no patients suffered bleeding complications, suggesting interference with vitamin K metabolism.
When is comes to Ivermectin and coagulation abnormalities, Ivermectin has a minimal effect on coagulation, and concern regarding mass treatment for this particular reason appears to be unjustified. Moreover, a patient who had been on long-term oral anticoagulant therapy with acenocoumarol demonstrated a tenacious, extreme hypo coagulability while using Ivermectin and metidation without protection to treat trees. So it should be noted that this kind of interaction may happen and can cause hemorrhagic complications.
Evidence concerning the influence of foods on the pharmacokinetics of Ivermectin is rare. Information about the influence of alcohol on Ivermectin kinetic behavior is rare. However, combining alcoholic drinks is not recommended as Ivermectin is associated with GABA receptors and the impact of alcohol on the central nervous system.
Lastly, Ivermectin was administered to 16 individuals with water or orange juice. Orange juice reduced AUC and C max perhaps because fruit juices and constituents are potent inhibitors of certain drug transporters.
Conclusion
Even though the effectiveness of Ivermectin has been conventional in humans against several parasitic diseases, the pharmacokinetic characteristics of this compound are not well known in humans as compared to animals. Potential drug-drug interactions and drug-food interactions occur for Ivermectin that need to be considered during the therapeutic use of this medication.
Computational Estimation of The Interaction of Ivermectin with Fibrinogen
Ivermectin is an orally bioavailable drug that belongs to avermectins, a group of macrocyclic lactones. Some studies stated that Ivermectin has anti-inflammatory properties and for that reason, this medicine was widely used in the initial stages of the COVID-19 pandemic.
Hypercoagulability and the development of extensive and tough-to-lyse microclots are hallmarks of both acute and long-term COVID-19. When fibrinogen is converted to fibrin, is responsible for clot formation but abnormal structural and mechanical clot properties can cause pathologic thrombosis.
Current experimental evidence states that the spike protein from severe acute respiratory syndrome SARS-CoV-2 may straight bind to the blood coagulation factor fibrinogen and tempt structurally abnormal blood clots with sharp proinflammatory activity.
As per this study, molecular docking and molecular dynamics simulations have been used to discover the probable activity of the antiparasitic drug Ivermectin to avert the binding of SARS-CoV 2 spike protein to fibrinogen and lessen the occurrence of microclots.
The computational results of this study show that Ivermectin may bind with high affinity to many sites on the fibrinogen peptide with more common binding in the central, E region, and the coiled-coil region as opposed to the globular D region.
The silico outcomes show that Ivermectin may interfere with spike protein fibrinogen binding and may decrease the development of fibrin clots resistant to degradation. Further in vitro studies are necessary to authenticate whether Ivermectin binding to fibrinogen is adequately stable to avoid interaction with spike protein and may reduce its thrombo-inflammatory effect in vivo.
A Prospective Study to Assess The Safety and Efficacy of Ivermectin in Covid 19 patients
Ivermectin has been noticed to constrain severe acute respiratory syndrome SARS-CoV-2 replication in vitro. It is not clear that this inhibition correlates with enhanced clinical outcomes. To evaluate the safety and efficacy of Ivermectin in hospitalized patients infected with covid 19 286 patients were included in the study.
Univariate investigation of primary mortality outcomes and comparisons between treatment groups were determined. Logistic regression and propensity score matching were employed to adjust for confounders.
Patients in the Ivermectin group got 2 doses of Ivermectin 200 μg/kg along with common clinical care. The Ivermectin group patients had a pointedly higher length of hospital stay than the control group. However, this significance is not maintained on multivariable logistic regression analysis.
The duration of intensive care unit stay and mechanical ventilation were longer in the control group. However, the mortality advantage was not observed with Ivermectin treatment before and after propensity score matching.
ICU admission and intubation rates were not considerably different between both groups. No differences were observed between groups concerning the duration of hospital stay, ICU admission, intubation rate, and in-hospital mortality.
