Ivermectin

5 Key excerpts on "Ivermectin"

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  Chemistry and Biological Activities of Ivermectin

  • Rashid Ali, Shahid Ul Islam, Shahid ul-Islam(Authors)
  • 2023(Publication Date)
  • Wiley-Scrivener

    (Publisher)

  1 Rashid Ali and Shahid ul-Islam (eds.) Chemistry and Biological Activities of Ivermectin, (1–22) © 2023 Scrivener Publishing LLC 1 Introduction to Ivermectin Aeyaz Ahmad Bhat 1 , Atif Khurshid Wani 2 , Tahir ul Gani Mir 2 * and Nahid Akther 2 1 School of Chemical Engineering and Physical Sciences, Lovely Professional University, Phagwara, Punjab, India 2 School of Bioengineering and Biosciences, Lovely Professional University, Phagwara, Punjab, India Abstract Ivermectin (IVM), an antiparasitic drug, has a wide range of biological applica- tions. Taking its spectrum of actions into consideration along with the significant safety and efficacy it was approved by USFDA in 2015 and made available as a generic medicine. In addition to cancer, it is used to treat number of bacterial and viral infections in humans. IVM takes part in several biological operations, mak- ing it a potential treatment option for a variety of viruses, including SARS-CoV-2. The antiviral activity of IVM has been studied in vitro and in vivo. The target sites of IVM in its actions against viruses and cancerous cells include viral replication and cell cycle progression respectively. This chapter provides an overview of the sources and synthetic scheme involved in IVM building besides elucidating its therapeutic potential. There have been very few reports on the toxic effects of IVM that have been published so far. However, some of the concerns related to its toxi- cology have been delineated in this chapter. Keywords: Ivermectin, pharmacology, antibacterial, anticancer, antiviral, COVID-19, toxicity 1.1 Introduction Ivermectin (IVR) belongs to the group of broad-spectrum antiparasitic agents which have a unique mode of action and is currently authorized to be *Corresponding author: [email protected] 2 Chemistry and Biological Activities of Ivermectin used for the treatment of onchocerciasis, lymphatic filariasis, strongyloidi- asis, scabies and head lice [1].

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  eBook - ePub

  Chemistry and Biological Activities of Ivermectin

  • Rashid Ali, Shahid Ul Islam, Shahid ul-Islam(Authors)
  • 2023(Publication Date)
  • Wiley-Scrivener

    (Publisher)

  [4] . We hope this chapter will for sure inspire to the newcomers as well as to those who are devoted their own research to the application part of IVM specifically in the dermatology, and can provide a new option with their useful information to the research community around the globe.

  Figure 9.2

  The chemical structures of the two components of Ivermectin (IVM), namely, 22,23-dihydroavermectin B1a and 22,23-dihydroavermectin B1b.

  9.2 Mechanism of Action, Toxicity, and Side Effects of IVM

  Basically, IVM drug selectively binds to the glutamate-gated chloride channels in the invertebrates. This type of medication works very well by interfering with invertebrate’s muscle cells and the nerve cells. In general sense, IVM’s mode of action involves the binding to glutamate chloride ion channels preferentially, and that condition is able to increase cell permeability to the chloride ions. In consequence, the condition facilitates the hyperpolarization of the muscle as well as nerve cells – leading finally to the parasitic death instantly. It encourages the secretion of inhibitory neurotransmitter such as γ-aminobutyric acid (GABA) from the presynaptic nerve terminals and supports its binding to the postsynaptic receptors too. Which in turn, increases the permeability subtly to the chloride ions influx, and hence resulting hyperpolarization of the muscle, and nerve cells will ultimately causes the parasite’s paralysis and death. It acts pleasantly on the both endoparasites as well as ectoparasites by inhibiting the conduction process of nerve impulse in intermediary neurons and in nerve-muscle synapses, respectively. Alternately, we can say that the inhibitory neurotransmitter (GABA) is released, cause for the hyperpolarization of postsynaptic membrane and the prolonged hyperpolarization ultimately leads to the paralysis and death. The GABA blocks neurotransmission from interneurons to motor neurons in nematodes, while it blocks from motor neurons to muscle cells in arthropods. Due to the IVM’s limited blood-brain barrier (BBB) penetration, most mammals do not experience the GABA-agonist effects of IVM. The IVM is considered relatively safe, as no genotoxicity was observed; but at a very high dose, it exhibited embryotoxicity in animals. Despite being uncommon, drug overdose, either acute or chronic, can cause the toxicity. The toxicity of IVM manifests with a lot of symptoms such as diarrhea, muscle fasciculation, drooping of lips, breathing difficulty, increased salivation, bilateral mydriasis, ataxia, absent menace reflex and rarely encephalopathy recumbency, depression, reduced pupillary reflex and death. Typically, within the first 36 h following injection, clinical symptoms usually progress. In cases of dermatological conditions, the side effects are exceptionally minimal for the IVM drug when it is taken in a form of therapeutic doses, like nausea, muscle aches, dizziness, abdominal pain, headache, tremors, edema, sleepiness, dizziness, and malaise etc. These types of side effects are nearly uncommon with topical IVM but may include a burning sensation, dandruff, and dry skin as well. It is important to seek medical assistance right immediately if the side effects are severe or observed persistently [5] . On the basis of past accomplishment, the few important dosing schedule of IVM drug for a common dermatological conditions are tabulated in the Table 9.1

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  Insect Pharmacology

  Channels, Receptors, Toxins and Enzymes

  • Lawrence I. Gilbert, Sarjeet S. Gill(Authors)
  • 2010(Publication Date)
  • Academic Press

    (Publisher)

  In these compounds, the replacement of the hydroxy group on the distal sugar with an epimethylamino group resulted in a marked increase in potency against a variety of lepidopterans and reduced activity against mites. 3.3. Mode of Action 3.3.1. Biochemical and Molecular Action Avermectins are potent endectocides. Ivermectin, the first and most commercially important member of this class, is the world’s most successful animal health drug of all time (Raymond and Sattelle, 2002). While the molecular mode of action of avermectins initially proved difficult to define Figure 3 Chemical structure of emamectin. Figure 4 Chemical structure of doramectin. 3: The Insecticidal Macrocyclic Lactones 71 (Jackson, 1989), more recent evidence indicates that they act primarily on glutamate-gated chloride chan-nels of helminths and insects, with additional effects (especially at high concentrations) on g -aminobutyric acid (GABA) receptors. Early evidence for GABA receptors as a site of action came from studies performed mostly on insects (Sattelle, 1990). Dihydroavermectin B 1a -sensitive GABA-binding sites were identified in the cock-roach Periplaneta americana using [ 3 H]GABA binding (Lummis and Sattelle, 1985). Furthermore, avermectins were shown to act as a partial agonist at a GABA-binding site in honeybees ( Apis melli-fera ) defined by [ 3 H]muscimol binding (Abalis and Eldefrawi, 1986). Deng and Casida (1992) exam-ined the interactions of radiolabeled avermectin with nerve membranes from housefly ( Musca domestica ) heads and hypothesized that avermectins may either have multiple binding sites at each chlo-ride channel, or may bind to GABA-gated chan-nels at low concentrations and at other chloride channels at higher concentrations. Evidence from vertebrate studies also pointed to GABA receptors as a site of action. Administered to rats, Ivermectin acts as a GABA-ergic anxiolytic drug (Spinosa et al ., 2002).

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  Natural Products Isolation

  Separation Methods for Antimicrobials, Antivirals and Enzyme Inhibitors

  • G.H. Wagman, R. Cooper(Authors)
  • 1988(Publication Date)
  • Elsevier Science

    (Publisher)

  3 ' avermectin being active against at least one stage of the life cycle of nematodes. Species of the phylum, Platyhelminthes (cestodes and trematodes) are not susceptible to the avermectins presumably because they lack the GABA regulatory system. Parasites which have developed resistance to other parasitic This mechanism of action is consistent with The avermectins are neutral, solvent extractable, macrocylic compounds shown in Figure 1-17 methylation at the C-5 hydroxyl. between C-22 and C-23 are designated with a subscript 1 and compounds containing a 23-hydroxyl are designated subscript 2. The A components vary from the B components by The compounds which contain a double bond The subscripts a and b :349 refer to compounds containing a sec-butyl or an iSOpKOpy1, respectively, at the C-25 position, with the most active anthelmintic compounds being the disaccharide compound, glycosylated with a-L-oleandrosyl-a-L-oleandrose. Other components have been reported and will be discussed in section 5. RZ H Avermectin R, 9. C2H5 CH3 %b a 3 a 3 A2 a OH C2H5 CH, %b OH CH, CH, Bl (I C2H5 Bl b CH, H '2 b OH CH, H B2 a OH C2H, H Where R, is absent, a double bond is present. a-L-oleandrose. Both sugars are Figure 1-1: Structures of the avermectins The potency of the avermectins is quite remarkable. Estimated field dosages for Control of nematode parasites make them two to three orders of magnitude more potent then presently available anthelmintic agents, such as fenbendazole, levamisole and thiabendazole.6 Bla/lb has been chosen for animal use; the natural product, avermectin B,, has been selected for agricultural applications. Ivermectin, 22,23-dihydro

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  Antiparasitic and Antibacterial Drug Discovery

  From Molecular Targets to Drug Candidates

  • Paul M. Selzer(Author)
  • 2009(Publication Date)
  • Wiley-Blackwell

    (Publisher)

  Parasitology , 134, 1123–1132. 63 Eng, J.K.L., Blackhall, W.J., Osei-Atweneboana, M.Y., Bourguinat, C., Galazzo, D., Beech, R.N., Unnasch, T.R. et al. (2006) Ivermectin selection on [beta]-tubulin: Evidence in Onchocerca volvulus and Haemonchus contortus. Molecular and Biochemical Parasitology , 150, 229–235. 64 Robertson, A.P., Bjorn, H.E. and Martin, R.J. (1999) Resistance to levamisole resolved at the single-channel level. The FASEB Journal, 13, 749–760. 65 Precious, W.Y. and Barrett, J. (1989) The possible absence of cytochrome P-450 linked xenobiotic metabolism in helminths. Biochimica et Biophysica Acta, 992, 215–222. 66 Pouliot, J.F., L heureux, F., Liu, Z., Prichard, R.K. and Georges, E. (1997) Ivermectin: Reversal of P-glycoprotein- associated multidrug resistance by Ivermectin. Biochemical Pharmacology , 53, 17–25. 67 Xu, M., Molento, M., Blackhall, W.J., Ribeiro, P., Beech, R. and Prichard, R.K. (1998) Ivermectin resistance in nematodes may be caused by alteration of P- glycoprotein homolog. Molecular and Biochemical Parasitology , 91, 327–335. 68 Molento, M.B. and Prichard, R.K. (1999) The effects of the multidrug-resistance- reversing agent verapamil and CL347,099 on the efficacy of Ivermectin or moxidectin against unselected and drug-selected strains of Haemonchus contortus in jirds (Meriones unguiculatus). Parasitology Research, 85, 1007–1011. 69 Jones, P.M. and George, A.M. (2005) Multidrug resistance in parasites: ABC transporters, P-glycoproteins and molecular modelling. International Journal for Parasitology , 35, 555–566. 70 Hong, H., Lu, Y., Ji, Z.N. and Liu, G.Q. (2006) Up-regulation of P-glycoprotein expression by glutathione depletion- induced oxidative stress in rat brain microvessel endothelial cells. Journal of Neurochemistry , 98, 1465–1473. 71 Eng, J.K.L. and Prichard, R.K. (2005) A comparison of genetic polymorphism in populations of Onchocerca volvulus from untreated- and Ivermectin-treated patients.

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