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- Herausgeber: John Wiley & Sons
- Kategorie: Wissenschaft und neue Technologien
- Sprache: Englisch
CHEMISTRY AND BIOLOGICAL ACTIVITIES OF IVERMECTIN The book focuses on the biological activities of ivermectin as well as the significant global utility of IVM since it was first used about 35 years ago. Ivermectin (IVM) is a "wonder drug" containing a 16-membered macrocyclic lactone ring system in its structure and derived from the family of avermectins. It was isolated by the fermentation of the soil microorganism Streptomyces avermitilis by Satoshi Omura in 1960 and studied by William C. Campbell in 1981, which allowed for its treatment of onchocerciasis (River Blindness) in Africa. Both scientists subsequently received the 2015 Nobel Prize in Physiology or Medicine. It was approved by the FDA in 1997 for the treatment of Strongyloidiasis and crusted scabies in AIDS patients. After that, IVM has attracted the tremendous attention of the scientific community and has been used for diverse purposes, including as an inhibitor of the causative virus (SARS-CoV-2). The chief purpose of this volume is to focus on the chemistry and biological activities of ivermectin. The chapters have been arranged in a systematic manner, starting from the historical background and synthesis of IVM to the pharmacological and environmental aspects, followed by diverse applications. Although the usage of ivermectin for the treatment of COVID-19 remains under investigation and controversial, one of the chapters is dedicated to its use. The anti-parasitic, anti-malarial, anti-cancer, and anti-inflammatory activities of IVM are discussed in detail. The anthelminthic and insecticidal roles of IVM are briefly described and there are several cases of IVM in dermatology. Audience Researchers, scientists, and postgraduate students working in the fields of organic synthesis, medicinal chemistry, medical science, pharmacy, biotechnology and biomedical sciences.
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Table of Contents
Cover
Table of Contents
Series Page
Title Page
Copyright Page
Preface
1 Introduction to Ivermectin
1.1 Introduction
1.2 Sources and Synthesis
1.3 Pharmacological Potential of Ivermectin
1.4 Ivermectin’s Beneficial Role in Cattle
1.5 Ivermectin in the Treatment of COVID-19
1.6 Toxicity of Ivermectin
1.7 Conclusion
References
2 Historical Background of and Synthetic Approaches to Ivermectin (IVM) and its Homologues
2.1 Introduction
2.2 Synthetic Approaches Towards the Construction of IVM and Analogues
2.3 Biosynthesis
2.4 Chemical Synthetic Pathway
2.5 Crystal Structure
2.6 Conclusion and Outlook
Acknowledgements
References
3 Ivermectin as a Repurposed Drug for COVID-19
3.1 Introduction
3.2 Symptoms of COVID-19
3.3 Repurposing of the Drugs
3.4 Repurposed Drugs for COVID-19
3.5 Repurposing of Ivermectin for COVID-19
3.6 Proposed Possible Mechanism of Action
3.7 SARS COVID-19 Clinical Studies with Ivermectin
3.8 Conclusions
3.9 Acknowledgments
References
4 Ivermectin as an Anti-Parasitic Agent
Abbreviations
4.1 Introduction
4.2 Use of Ivermectin Against Various Human Parasitic Infections
4.3 Mode of Action Against Various Parasites
4.4 Conclusions
4.5 Acknowledgements
References
5 Emerging Paradigm of Ivermectin and its Hybrids in Elimination of Malaria
5.1 Introduction
5.2 Malaria
5.3 Life Cycle of Malaria
5.4 Drug Against Hepatic Malarial Stage
5.5 About Ivermectin
5.6 Designing and Synthesis of Ivermectin Inhibitors
5.7 Conclusions
5.8 Acknowledgments
References
6 Ivermectin: A Potential Repurposed Anti-Cancer Therapeutic
Abbreviations
6.1 Introduction
6.2 Mechanism of Anti-Carcinogenesis
6.3 Activation of Chloride Ion Channels
6.4 Anti-Mitotic Effect and Inhibition of Angiogenesis
6.5 Inhibition of Mitochondrial Respiration
6.6 Inhibitor of Cancer Stem Cells (CSCs)
6.7 Induction of Immunogenic Cell Death (ICD)
6.8 Epigenetic Modulator
6.9 Induction PAK1-Mediated Cytostatic Autophagy
6.10 Inhibition of P-glycoprotein (P-gp)
6.11 Inhibition of Yes-Associated Protein 1 (YAP1)
6.12 Inhibition of RNA Helicase
6.13 Caspase-Dependent Apoptosis
6.14 Activation of Transcription Factor E3 (TFE3)
6.15 Inhibition of Wnt-TCF Pathway Responses
6.16 Conclusions
References
7 Ivermectin as an Anti-Inflammatory Agent
7.1 Introduction
7.2 Ant-Inflammatory Action of Ivermectin
7.3 Conclusions
Acknowledgements
References
8 Ivermectin: An Anthelminthic and Insecticide
8.1 Introduction
8.2 Ivermectin as an Anthelmintic
8.3 Insecticidal Activity of Ivermectin
Conclusions
References
9 Potential Applications of Ivermectin (IVM) in Dermatology
9.1 Introduction
9.2 Mechanism of Action, Toxicity, and Side Effects of IVM
9.3 Motivational Approach of IVM in the Treatment of Skin
9.4 Role of IVM with Good Anti-Parasitic Properties Against the Infection of Skin
9.5 Importance of IVM as an Anti-Cancer or Anti-Tumor Agent in Curing the Skin
9.6 Social Value of IVM in the Medical Care of Red Scrotum Syndrome (RSS)
9.7 Utility of IVM as an Anti-Inflammatory Drug in the Treatment of Skin-Related Issues
9.8 Conclusions
Acknowledgements
References
10 Antiviral Uses of Ivermectin
10.1 Introduction
10.2 Mechanism of Action of Ivermectin
10.3 Anti-Viral Effects Against Various DNA and RNA Viruses
10.4 Conclusion
References
11 Toxicology, Safety, and Environmental Aspects of Ivermectin
11.1 Introduction
11.2 Ivermectin’s Antiparasitic Activity
11.3 Pharmacology
11.4 Adverse Effects in Humans and Animals
11.5 Ivermectin and Ectoparasites
11.6 Environmental Impact and Biodegradation of Ivermectin
11.7 Conclusion
References
Index
Also of Interest
End User License Agreement
List of Tables
Chapter 1
Table 1.1 Pharmacological applications of IVM and its mode of action.
Chapter 3
Table 3.1 Symptoms of the people infected by COVID-19.
Table 3.2 The clinical results of the trial study of Shahbaznejad
et al.
[70]....
Table 3.3 Different reported results of the study of Lim
et a
l
. [73].
Chapter 4
Table 4.1 Use of Ivermectin in the treatment of parasitic infections in non-hu...
Table 4.2 List of other human-parasitic infections treated by Ivermectin.
Chapter 5
Table 5.1 Role of Ivermectin in different stages of Malaria.
Table 5.2 IC
50
value of hybrids
10-14
against the Erythrocytic stage of
P. fal
...
Table 5.3 IC
50
value of
10
,
11
,
12
,
13
and
14
against the Hepatic stage of
P.
...
Chapter 9
Table 9.1 The dosing schedule of IVM for a common dermatological conditions.
Chapter 11
Table 11.1 Reported Ivermectin dosage [39–41].
List of Illustrations
Chapter 1
Figure 1.1 Chemical structure of Ivermectin.
Scheme 1.1 Avermectin and IVR chemical structures.
Scheme 1.2 Synthesis of synthetically important synthon of IVM.
Figure 1.2 Antiviral properties of Ivermectin; figure adapted from [54].
Chapter 2
Figure 2.1 S. Ōmura collecting the historical soil sample comprising
S. averme
...
Figure 2.2 Steps in finding the
S. avermectinius
. (a) A soil sample; (b) Isola...
Figure 2.3 The chemical structures of IVM and other AVMs family members.
Figure 2.4 Photograph of the three Noble Prize winner of the year 2015 in the ...
Figure 2.5 IVM tablets packet consisting of 12 mg of the drug in each tablet....
Figure 2.6 The chemical structures of AVMs as well as IVM.
Scheme 2.1 Proposed route for the biosynthesis of AVMs from the
S. avermitilis
...
Scheme 2.2 Biosynthesis roadmap for the construction of AVMs (A1a and B1a).
Scheme 2.3 Direct biosynthetic reaction sequence from the AVM aglycone to AVM ...
Scheme 2.4 Preparation of the component 29 from the commercially available
D
-s...
Scheme 2.5 Synthesis of avermectim (B1
a
) aglycon
56
casting several crucial st...
Scheme 2.6 Final total synthesis of AVM (B1a) combining fragments prepared in ...
Scheme 2.7 Hydrogenation of AVM-B1, utilizing the Wilkinson’s catalyst – selec...
Scheme 2.8 The chemical structure of IVM (1), and synthesis of diverse IVM hyb...
Figure 2.7 (a-c) Extended scale contour plots of the 2D-COSY spectrum (500 MHz...
Scheme 2.9 Synthesis pathways for acylureas (83a-v) and acylthioureas (84a-v) ...
Scheme 2.10 Synthesis of moxidectin 4 starting from 85.
Scheme 2.11 Synthesis of moxidectin 4.
Scheme 2.12 Synthesis of moxidectin in four steps from 91.
Scheme 2.13 Schematic representation of the conversion of nemadectin into the ...
Figure 2.8 (a) ORTEP diagrams of the IVM molecules. (b) ORTEP diagram of two i...
Chapter 3
Figure 3.1 Model of SARS-CoV-2 life cycle (Adapted from [13] and licensed unde...
Figure 3.2 The two suggested routes of entry for SARS-CoV-2 virus, ACE2, and C...
Figure 3.3 Multiple organ failure and tropism in SARS-CoV-2 infection (Adapted...
Figure 3.4 Timeline for emergency approval of different repurposed drugs for C...
Figure 3.5 Key medications reused for in-patient COVID-19 treatment in clinica...
Figure 3.6 Probable proposed mechanism of action of IVM against SARS-CoV-2 (Ad...
Chapter 4
Figure 4.1 Ivermectin as an anticancer, antibacterial, antiviral and endecto-p...
Figure 4.2 A schematic mechanism of anti-parasitic action of Ivermectin on dif...
Chapter 5
Figure 5.1 Malaria parasite’s lifecycle in human and mosquito.
Figure 5.2 Therapeutic uses of ivermectin [5].
Figure 5.3 Avermectin (A
1a
, A
1b
, A
2a
, A
2b
, B
1a
, B
1b
, B
2a
, B
2b
) and Ivermectin....
Figure 5.4 Ivermectin based anti-malarial hybrids.
Figure 5.5 Ivermectin based anti-malarial hybrids.
Chapter 6
Figure 6.1 Structure of avermectins (AVM), IVM & other derivatives such as dor...
Figure 6.2 Anticancer potential of IVM: IVM exerts its effect (
in vitro
or
in
...
Figure 6.3 Mechanism of anti-carcinogenesis: (
1
) IVM serves as an ionophore, a...
Chapter 7
Figure 7.1 Pathway for the formation of PGE2 and other metabolites responsible...
Figure 7.2 Representation of the metabolism of arachidonic acid through cycloo...
Figure 7.3 Structures of ivermectin having the mixture of avermectin B
1a
and B
Figure 7.4 Involvement of NF-κB in the development and progression of inflamma...
Chapter 8
Figure 8.1 Life cycle of the filarial worm,
Onchocerca volvulus.
Source: https...
Figure 8.2 Phases in the elimination of human onchocerciasis [14].
Figure 8.3 Life cycle of the parasitic worms
Wuchereria bancrofti.
Source: htt...
Figure 8.4 Life cycle of parasitic worms
Strongyloides stercoralis.
Source: CD...
Figure 8.5 Ivermectin (22,23-dihydroavermectin B1). Source:
DrugBank Accession
...
Chapter 9
Figure 9.1 Systematic representation of diverse potential applications of iver...
Figure 9.2 The chemical structures of the two components of ivermectin (IVM), ...
Chapter 10
Figure 10.1 Potential mechanisms of Ivermectin against viruses [61].
Chapter 11
Figure 11.1 Structure of Ivermectin.
Figure 11.2 Adult worms of
D. immitis
in the heart of Dog. Picture credit: Fer...
Figure 11.3 Onchocerca volvulus filarial parasite. Picture credit: Higazi, Tar...
Figure 11.4 Reported predicted targets of ivermectin (IVM) [27–38].
Figure 11.5 General pharmacokinetics.
Figure 11.6 A child suffering from Scabies, Picture credit: RML Hospital, New ...
Guide
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Table of Contents
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Title Page
Copyright
Preface
Begin Reading
Index
Also of Interest
End User License Agreement
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Emerging Trends in Medicinal and Pharmaceutical Chemistry
Series Editor: Shahid-ul-Islam
Scope: The Emerging Trends in Medicinal Chemistry and Pharmacology Series is intended to provide recent trends, the state-of-the-art, and advancements particularly in the rapidly growing fields of drug design and synthesis, medicinal natural products, phytochemistry, pharmacology and applications. With a focus on generating means to combat different human diseases, the series addresses novel strategies and advanced methodology to circumvent the invasion from microbial infections and to ameliorate the effects caused by dreadful diseases.
Chemistry and Biological Activities of Ivermectin
Edited by
Rashid Ali
Department of Chemistry at Jamia Millia Islamia New Delhi, India
and
Shahid ul-Islam
Department of Textile & Fiber Engineering, Indian Institute of Technology Delhi, India
This edition first published 2023 by John Wiley & Sons, Inc., 111 River Street, Hoboken, NJ 07030, USA and Scrivener Publishing LLC, 100 Cummings Center, Suite 541J, Beverly, MA 01915, USA© 2023 Scrivener Publishing LLCFor more information about Scrivener publications please visit www.scrivenerpublishing.com.
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Library of Congress Cataloging-in-Publication Data
ISBN 978-1-394-16654-1
Cover image: Pixabay.ComCover design by Russell Richardson
Preface
The Nobel Prize-winning Ivermectin (IVM), dubbed “the wonder drug,” is a 16-membered macrolide that belongs to the family of avermectins (AVMs). Because of its widespread pharmaceutical applications, it has piqued the interest of scientists all over the world in recent years. Notably, initially, it was isolated by the fermentation of the soil microorganism Streptomyces avermitilis by S. Omura in Japan. Remarkably, it was approved by the FDA in 1997 for the treatment of Strongyliasis and crusted scabies, in patients with AIDS. After that, this wonder drug has played a significant role in diverse diseases, including its recent usage in COVID-19. Hence, taking into consideration the usefulness of the IVM, herewith we disclose the chemistry and biological activities of the IVM. With this particular book, our main intent is to spread a clear message to the readers about what has yet been known about IVM since its inception to date and where this emerging field might go in many years to come.
The first chapter of this book deals with the introduction, followed by a brief historical background and detailed chemistry about IVM in the second chapter. Though the treatment of the IVM for COVID-19 remains controversial and investigational, chapter 3 will be the heart of this book. The anti-parasitic and anti-malarial activities of the IVM drug will be discussed in detail in chapters 4 and 5. On the other hand, chapter 6 describes the anti-cancer activity, while the subsequent chapter 7 details the anti-inflammatory activity of IVM. The anthelminthic and insecticidal roles of IVM have been briefly described in Chapter 8. The chapter has exposed several cases of IVM in dermatology. Finally, chapters 10 and 11 close this volume of the book with anti-viral uses and safety, toxicology, and environmental aspects of IVM, respectively.
We are highly thankful to all the contributors for crafting their valuable knowledge and expertise and making it available in the form of their chapter(s)—helpful to those who really want to enjoy this subject and to those who are willing to enter into this research field.
Editors
1Introduction to Ivermectin
Aeyaz Ahmad Bhat1, Atif Khurshid Wani2, Tahir ul Gani Mir2* and Nahid Akther2
1School of Chemical Engineering and Physical Sciences, Lovely Professional University, Phagwara, Punjab, India
2School of Bioengineering and Biosciences, Lovely Professional University, Phagwara, Punjab, India
Abstract
Ivermectin (IVM), an antiparasitic drug, has a wide range of biological applications. 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, making 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 toxicology 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 used for the treatment of onchocerciasis, lymphatic filariasis, strongyloidiasis, scabies and head lice [1]. Recently, it has been shown that IVR can also exhibits a lot of new interesting activities such as antibacterial, antiviral and anticancer. IVR acts as a positive allosteric regulator of several channels including the glutamate-gated chloride channel (GluCl), γ-aminobutyric acid type-A receptor, glycine receptor, neuronal α7-nicotinic receptor, and purinergic P2X4 receptor. In most of the IVR-sensitive channels, the effects of IVR include the potentiation of agonist-induced currents at low concentrations and channel opening at higher concentrations [2]. In vertebrates, IVR also functions as a positive allosteric regulator of a number of ligandgated ion channels. Glycine receptor (GlyR), γ-aminobutyric acid type-A receptor (GABAAR) and neuronal 7-nicotinic receptor are all activated or modulated by submicromolar concentrations of IVR (nAChR). The specific binding and high affinity of this compound to the GluCl channels found in the nerve and muscle cells of invertebrate animals is strictly related to its anti-parasitic activity. This causes the nerve or muscle cell to become hyperpolarized, increasing the permeability of the cell membrane to chloride ions, which causes the parasite to become paralyzed and die. Because some mammals lack GluCl channels, IVR has a very low affinity for mammalian GluCl channels and does not bind to them; these three facts serve as the foundation for its activity.
IVR appears to be safe for use in humans, but there have been reports linking the drug to parasympathetic disturbances (salivation, dilation of pupils) [3–5]. Along with its well-known anti-parasitic properties, IVR has also recently been shown to have strong anti-cancer properties, suggesting that it may be useful in the treatment of a number of cancers [6]. IVR exhibits anti-cancer properties due to its capacity to block the Wnt/TCF pathway, AKT/mTOR, and MDR (multidrug resistance) proteins (transcription factor of T-cells). One of the main oncogenic kinases, PAK-1 (p21-activated kinase), is degraded as a result of IVR [7]. By blocking Wnt-TCF, it is effective in treating lung, skin, and colon cancer as well as glioma multiforme, melanoma, and glioma [8]. IVR causes autophagy, a self-destructive effect in breast cancer, as demonstrated by Dou et al. studies using breast cancer cell lines, animal models, and 20 patient breast cancers have shown that reduced autophagy of breast cancer cells is associated with decreased expression of PAK-1 because of ubiquitin-mediated degradation. Inhibiting PAK-1 prevented Akt from becoming phosphorylated, which blocked the Akt/mTOR signaling pathway and slowed the growth of tumors [9].
1.2 Sources and Synthesis
Ivermectin (IVR) is a 22,23-dihydro derivative of avermectin B1 formed by the Streptomyces avermitilis bacterium from macrocyclic lactone (Figure 1.1). Besides IVR the other was approved for human use in the year 1987 by FDA [5, 10]. The general synthetic route is achievable by performing selective catalytic hydrogenation at C22–C23 as highlighted in Scheme 1.1.
IVR is a nonhygroscopic, crystalline powder that ranges in color from white to yellow-white and has a melting point of about 155°C. The respective empirical formulas are C48H74O10 and C47H72O14, with the molecular weights of 875.10 and 861.07.
Ivermectin B1a and B1b have very similar chemical structures; Ivermectin B1a has an ethyl group at the C-26 position, while B1b has a methyl group.
Figure 1.1 Chemical structure of Ivermectin.
Scheme 1.1 Avermectin and IVR chemical structures.
Scheme 1.2 Synthesis of synthetically important synthon of IVM.
IVR is made up of at least 80% B1a and no more than 20% B1b. A very important structural moiety or a “synthon” of the important drug IVM can be synthesized in lab by adopting the following synthetic procedure as depicted in Scheme 1.2. The mild thermally induced cycloaddition of two aromatic compounds, 3,4-bis(benzyloxy)furan (1) and 2-(himethylsilyl) ethyl coumalate (2) is a crucial constructive step in the synthesis of the synthon (11) and results in an 88% yield of the chromatographically separable endo and exo adducts (3,4). Although the isomerization at C-24 may present challenges, the conversion of the endo adduct 4 to 11 is initially investigated despite the fact that both adducts are potentially useful intermediates for the synthesis of the synthon. The synthesis was further carried out by the reaction of the derivative (5) which was reduced to derivative (6). Derivative (6) was further bought under the well-known concept of Witting reaction to yield the compound (7). Reaction with base and further oxidation of the derivative (7) generated derivative (10) that was finally reduced in the last step of the reaction to generate the synthetically importantly synthon (11) in good yield.
1.3 Pharmacological Potential of Ivermectin
1.3.1 Ivermectin in the Treatment of Cancer
1.3.1.1 Ovarian Cancer
The fifth most common cause of cancer-related death in women is epithelial ovarian cancer. The therapeutic options for epithelial ovarian cancer have remained largely unchanged for more than 30 years, despite improvements in the treatment of many malignancies. Patients with ovarian cancer frequently receive platinum-based chemotherapy, such as cisplatin, but these treatments have a poor prognosis. This is probably because there is significant intra and inter tumor heterogeneity at the molecular and epigenetic levels [11, 12]. Sequencing has shown that TP53 mutations are frequently found in epithelial ovarian tumors, and that low-frequency mutations in the genes NF1, BRCA1, BRCA2 and RB1 are also present [13]. For better clinical management of ovarian cancer, new therapeutic approaches or agents are required. Let us start the pharmacological profile of the Ivermectin with the most important breakthrough which was provided by Zhang et al. The studies were carried out and it was found that by inhibiting Akt/mTOR signaling, Ivermectin improves the in-vitro and in-vivo effectiveness of cisplatin in treating epithelial ovarian cancer. In spite of specific cellular and molecular variations, Ivermectin inhibited growth in the G2/M phase and induced caspase-dependent apoptosis in ovarian cancer. The inhibitory effect of cisplatin on ovarian cancer cells was dramatically enhanced by Ivermectin in a dose-dependent manner. Ivermectin inhibited, in ovarian cancer cells, the phosphorylation of essential molecules in the Akt/mTOR signaling pathway. In addition, Ivermectin-induced inhibition of Akt/ mTOR, growth arrest, and apoptosis were restored by overexpressing constitutively active Akt. Ivermectin alone significantly slowed tumor growth in a mouse model of ovarian cancer xenograft. Tumor growth was completely stopped when combined with cisplatin throughout the course of treatment without any side effects. Additionally, the Ivermectin concentrations used in our study are pharmacologically feasible.
1.3.1.2 Renal Cell Cancer
The proximal tubules of nephrons give rise to the epithelial tumor known as renal cell carcinoma (RCC), which is resistant to radiotherapy and chemotherapy [14, 15]. Patients with metastatic RCC still experience relapses as the disease worsens, despite the fact that targeted therapy significantly improved their clinical outcomes [16]. Therefore, patients who experience post-operative relapse or who have RCC that has spread to other organs require novel and potent therapeutic approaches. Recent research has shown that many cancers depend heavily on oxidative phosphorylation to meet their energy needs for survival and growth [17, 18]. Tumor stem cells are more reliant on mitochondrial metabolism than glycolysis when compared to differentiated tumor cells [19]. All of which imply that the special reliance on mitochondrial metabolism that cancer cells have can be utilized therapeutically. Zhu et al. reported that Ivermectin, an antibiotic, targets renal cancer with preference by causing mitochondrial dysfunction and oxidative damage. In numerous RCC cell lines that represent various histological subtypes and mutation statuses, Ivermectin significantly reduces proliferation and induces apoptosis. Importantly, Ivermectin is significantly less or completely ineffective in normal kidney cells than it is in RCC cells, proving that it is more toxic to RCC. Additionally significantly reducing RCC tumor growth in vivo is Ivermectin. Ivermectin causes mitochondrial dysfunction by reducing the potential of the mitochondrial membrane, the rate of respiration, and the production of ATP. Ivermectin-treated RCC cells and the xenograft mouse model exhibit oxidative stress and damage as a result of mitochondrial dysfunction. Ivermectin is confirmed to be targeting mitochondria in RCC cells by the rescue of Ivermectin’s effect by acetyl-L-Carnitine (ALCAR, a mitochondrial fuel), or by the antioxidant N-acetyl-L-cysteine (NAC). Ivermectin may be more toxic to RCC than normal kidney cells because RCC cells have higher mitochondrial mass, respiration, and ATP production. This research suggests that Ivermectin is a promising treatment option for RCC and that targeting mitochondrial metabolism is an additional RCC treatment option.
1.3.2 Ivermectin Against Viruses
Ivermectin (IVM), an FDA approved drug, has shown great potential against viruses of different genetic nature (Figure 1.2). The mice infected with pseudorabies virus and piglets carrying circovirus infection have shown significant improvement in the survival rate upon treatment with IVM [20, 21]. Alphaviruses are dangerous viruses capable of causing neuroinvasive and arthralgia disease. IVM acts as a potential anti-alpha viral drug inhibiting chikungunya, sindbis, semliki forest, and flavivirus viruses. West Nile virus is also inhibited by IVM at low (μM) concentrations [22]. Zika virus, a positive sense RNA virus transmitted via mosquito, is inhibited by the IVM action during in vitro analysis [23]. Recently, IVM was found to be effective against SARS-CoV-2 when it was applied on engineered kidney cell of Vero/hSLAM [24]. Viral replication is one of the highly targeted molecular sites by drugs. Bovine herpesvirus 1 is inhibited by IVM treatment by targeting subunits of DNA polymerase [25]. Homosexuals infected with human immunodeficiency virus harboring strongyloides were given continuous IVM dosage. The patients showed significant parasitological and clinical improvement after receiving multiple IVM doses. Thus, results indicated effectiveness of IVM in strongyloidiasis in AIDS patients [26]. IVM is generally used for treating parasitosis, but off late it has also shown efficiency in inhibiting importin protein which is essential for the replication of viruses with RNA genome like HIV and dengue virus [27]. Because of the approved status of IVM, it is imperative to explore its mechanistic details in target the dangerous pathogens to prevent pandemics like SARS-CoV-2.
Figure 1.2 Antiviral properties of Ivermectin; figure adapted from [54].
1.3.3 Ivermectin in the Treatment of Bacterial Infections
Microorganisms dwell in everywhere environment owing to their adaptable nature. They adapt to extreme environments by regulating their different set of genes for survival [28]. The property of adapting to different environments is one of the major factors that allow pathogens to infect plants, humans, animals, and livestock. Several strategies have been developed to counteract bacterial and fungal infections. One of such drugs is the IVM which has been found to be effective against several pathogenic strains of both bacterial and fungal origin. IVM was tested for anti-staphylococcal activity that were isolated from bovine milk and it was found to be effective at 6.24 and 12.5 μg/ml [29]. One of the prime concerns over the years has been the development of antimicrobial resistance. This makes the treatment of both fungal and fungal infections complicated and difficult. IVM has shown significant inhibitory actions against various mycobacterial species that includes drug-resistant strains [30]. The methicillin resistant S. aureus was inhibited by IVM at 20 μg/ml concentration by targeting its cell wall, cell membrane and genetic material [31]. The effectiveness of IVM has been reported against Chlamydia trachomatis also [32].
1.4 Ivermectin’s Beneficial Role in Cattle
Anthelmintic combinations have become an effective pharmaceutical strategy to control gastrointestinal nematodes in grazing systems of livestock production in the face of nematodicidal resistance. Using a pharmacokinetic/pharmacodynamic (PK/PD) approach, potential drug-drug interactions were investigated after the coadministration of two macrocyclic lactones (ML), Ivermectin (IVM), and abamectin (ABM) to parasitized cattle. The therapeutic response of the combination was assessed under various resistance scenarios and the kinetic behavior of the two drugs administered either alone or in combination was evaluated. Calves were given a single subcutaneous (s.c.) injection of IVM (100 µg/kg), a single s.c. injection of ABM (100 µg/kg), or a combination of IVM+ABM (50 µg/kg each) to achieve a final ML dose of 100 µg/kg (Farm 1). Up to 20 days after the treatment, plasma samples were taken from those animals. The plasma concentrations of IVM and ABM were measured using HPLC. In Farm 2, experimental animals were given IVM (200 µg/kg), ABM (200 µg/kg), or IVM+ABM (100 µg/kg each), while Farms 3 and 4 used IVM+ABM (200 µg/kg each). The fecal egg count reduction test (FECRT) was used to determine the anthelmintic effectiveness. Similar trends for IVM kinetic behavior following coadministration with ABM were revealed by PK analysis. In contrast, the presence of IVM increased the systemic exposure during the elimination phase and prolonged the half-life of ABM elimination. Despite the fact that IVM alone was ineffective at controlling Cooperia spp., IVM+ABM was the only treatment to have an efficacy of more than 95% against these organisms across all farms.
1.5 Ivermectin in the Treatment of COVID-19
Ivermectin, a widely used anti-parasitic drug, inhibits SARS-CoV-2 replication by preventing viral proteins from entering the host cell nucleus [Figure 1.2] [24]. Doxycycline was recently identified as a potential inhibitor of SARS-CoV-2 papain-like protease in a virtual drug screening [43]. An observational study combining a single dose of Ivermectin with a multidose of doxycycline for the treatment of COVID-19 found that symptoms and viral response improved significantly [44]. A recent retrospective study discovered that hospitalized patients who received Ivermectin in combination with other treatments (e.g., azithromycin and hydroxychloroquine) had lower mortality than those who did not receive Ivermectin [44]. More research is needed to clarify these findings. The observations that SARS-CoV-2 rapidly multiplies in the respiratory tract, as well as evidence from animal models showing 3-fold higher levels of Ivermectin in pulmonary tissue than in plasma one week after oral dosing, highlight the importance of this need [1].
Methods: Patients were examined physically for COVID-19-related symptoms and vital signs (e.g., temperature, blood pressure, pulse rate, oxygen saturation, and respiratory rate) were taken. On the day of enrollment, as well as on days 3, 7, and 14, nasopharyngeal swabs were obtained to confirm the presence of SARS-CoV-2 using rRT-PCR. Patients were followed up on a weekly basis after day 14 until the test was found to be negative.
1.5.1 Mode of Action
IVM is quickly absorbed through the mouth, highly liposoluble, widely distributed throughout the body, metabolized in the liver (cytochrome P450 system) and almost entirely eliminated in feces [45]. It reaches peak plasma levels after a typical oral dose in healthy humans at 3.4–5 h and the plasma half-life has been reported to be 12-66 h [46]. There are not many studies on the pharmacokinetics of Ivermectin in humans, despite its widespread use [47]. In healthy subjects, Ivermectin binds to plasma proteins with a high affinity (93.2 %) [48]. When given in nations where malnutrition and hypoalbuminemia are prevalent, such a “avid binding” can be helpful because it increases the availability of “free fraction” of Ivermectin [45]. In patients with COVID-19, hypoalbuminemia is a common symptom that also seems to be related to the severity of lung injury [49]. Ivermectin may therefore have adequate bioavailability in this situation. Ivermectin’s mode of action seems to be influenced by how it affects the ion channels in cell membranes. In particular, it results in an influx of negatively charged ions, which hyperpolarizes the affected cells and paralyses them. The neurotransmitter gamma-amino butyric acid (GABA) was initially believed to be its primary target because there is a wealth of evidence showing that Ivermectin opens GABA-regulated Cl- channels in a variety of in vitro preparations of invertebrate and, particularly, vertebrate membranes. Ivermectin, however, has recently been demonstrated to cause an influx of Cl- through channels that are not controlled by GABA. In fact, compared to other types of channel, GABA-linked Cl channels in the cell membranes of the parasitic nematode Ascaris suum are less sensitive to Ivermectin [50]. In both mammalian brain tissue and the free-living nematode worm Caenorhabditis elegans, specific Ivermectin binding sites have been found. However, Ivermectin’s affinity for the nematode site is roughly 100 times greater than it is for the mammalian brain site [51]. It appears that the GABA and Ivermectin receptors are very different because GABA was unable to compete with Ivermectin for binding to the C. elegans receptor protein [52]. Ivermectin is toxic to both nematodes and arthropods and photoaffinity labeling has revealed specific Ivermectin binding proteins in the cell membranes of the fruit fly Drosophila melanogaster and the worm C. elegans[53].
1.6 Toxicity of Ivermectin
The toxicity associated with use of Ivermectin is relatively low [55]. It has been subjected to in vitro mutagenesis experiments in both microorganisms and mammalian cells. Studies on the acute oral toxicity of Ivermectin in mice, dogs, and monkeys reveal species-specific variations in susceptibility. Human beings, like all other primates, are obviously less sensitive than rodents, especially mice [56]. Toxic effects of the medication are higher in newborn rats than in young adult rats. The treatment of animals with very high doses of Ivermectin resulted in embryotoxicity [57]. Off-label use has been linked to sporadic cases of toxicity in collies and other herding breeds. Ataxia, tremors, mydriasis, depression, and even coma and death might be among the side effects. Old English sheepdogs, Shetland sheepdogs, and Australian sheepdogs should not be given Ivermectin since it is toxic to them [58]. Animals should be clear of Dirofilaria immitis (heartworm) microfilaria before receiving large dosages of Ivermectin [59].
Oral administration of Ivermectin has been and continues to be the standard method of dosing [60]. Topical route is also one of the common routes of administration [61, 62]. Occasionally, the rectal route is used in humans, but the subcutaneous route is more common in cattle and the intravenous route in experimental veterinary medicine [63, 64]. Ivermectin is used to treat a wide range of parasite illnesses, and is usually given in a single dosage of 150–200 g/kg. Dosing may be repeated once or twice a few days or three to six months following the last oral dosage. Recommended dosing for individuals with crusted scabies, according to the Centers for Disease Control and Prevention [65] is 150 g/kg orally on days 1, 2, 8, 9, 15, 22, and 29. Several clinical studies and human studies have been completed or are now underway to assess Ivermectin’s preventative or curative efficacy in COVID-19 . Most studies had been using a dosage of 0.2 mg/kg for 1 day and 0.6 mg/kg for 5 days [44, 66, 67]. Using a randomized, controlled design, researchers are testing the effects of giving healthy human volunteers Ivermectin every day for 28 days at doses of up to 100 micrograms per kilogram. As the study’s end date drew closer, no safety concerns had been. However, there is a lack of clinical evidence on whether or not Ivermectin pharmacokinetics is affected by diet. Most of an oral dosage of Ivermectin is excreted intact in the feces (between 98 and 99 percent in most animal species) due to its low biotransformation. Biotransformation of Ivermectin is mostly done by CYP3A4, followed by CYP2E1 and CYP2D6 to a much smaller degree [68]. The significance of these newly reported findings in regards to Ivermectin’s efficacy and safety must be validated, and the function, if any, of these metabolites must be explored further.
1.6.1 Acute Toxicity
Studies of acute (single dose) toxicity have been performed on mice, rats, rabbits, dogs, and monkeys. Tremors, bradypnea, ptosis, ataxia, and lack of the righting reflex were symptoms of Ivermectin’s acute toxicity in rats. Ivermectin was shown to have caused these clinical symptoms due to its direct action on the central nervous system. It was observed that newborn rats were more vulnerable than young adults, and it was hypothesized that this was because the blood-brain barrier in rats only fully developed after birth. Mydriasis has been found most reliable sign of toxicity in Beagle dogs. Preceding deaths were characterized by prolonged comas. Vomiting was the most reliable sign of toxicity in Rhesus monkeys [69, 70]. When compared to rats, monkeys did not exhibit a high dose-response curve. Repeated doses of Ivermectin over three-month oral studies in mice, fourweek dermal studies in Sprague Dawley rats, three- and nine-month oral studies in Beagle dogs, 2-week dermal studies in minipigs, and 2-week oral studies in rhesus monkeys have been conducted [69, 71]. Mortality was seen at a dosage 9 mg/kg/day when Ivermectin was orally administered to rats for 13 weeks. Death preceded by neurotoxic symptoms was detected exclusively in rats given the maximum daily dosage of 12 mg/kg after being fed 1, 3, or 12 mg/kg orally for 27 weeks. Mortality was highest among females and occurred mostly during the first two weeks of treatment. Dermally administering 20 mg/kg of Ivermectin to rats once daily for four weeks resulted in no observed toxicity. Excessive salivation and a loss in body weight were seen in Beagle dogs given Ivermectin by oral gavage at doses of 0.1, 0.25, 0.5, and 1.5 mg/kg/day for 14 weeks. In another research, 14 weeks of oral treatment with 0.5, 1, or 2 mg/kg/day resulted in neurotoxicity and poor health for four of the eight dogs in the high dosage group. Beagle dogs given Ivermectin orally at doses of 0.1, 0.5, or 1.5 mg/kg per day for 39 weeks showed no signs of death or serious side effects. After 2 weeks of once-daily Ivermectin treatments, rhesus monkeys showed no signs of toxicity. Finally, mice and minipigs administered daily through the dermal route with up to 13 and 20 mg/kg/day Ivermectin, respectively, showed no observable adverse effects (for 13 weeks in mice and up to 39 weeks in minipigs) [69, 70].
1.6.2 Developmental and Reproduction Toxicity
Repeated administration of Ivermectin at doses of 0.2, 8.1, and 4.5 times the maximum recommended human dosage was shown to be teratogenic in mice, rats, and rabbits, respectively [69]. There have been a number of studies spanning many generations. Teratogenicity was not seen in rats [72], but there was significant toxicity to both parents and offspring. It was suggested that the blood-brain barrier in young rats had a role. Dogs given 600 g/kg once a month for eight months and mated to untreated female dogs showed no reproductive toxicity [71].
1.6.3 General and Safety Pharmacology
In 1987, when Ivermectin was initially licensed as a human drug, general pharmacology was considered “optional” and not governed by formal regulations. There was no electrocardiogram (EKG) abnormality in dogs given Ivermectin orally at doses up to 1.5 mg/kg/day for 39 weeks. Marked hypotension during nonclinical toxicity testing was only found in moribund animals treated with Ivermectin. In 32 older Liberian males, treated with Ivermectin, EKG recording were done twice daily pretreatment and on five times post-treatment. Twenty of the subjects had aberrant heart rhythms before therapy. Neither substantial modifications nor new abnormalities were identified [73] Respiratory abnormalities were only seen in moribund animals which were given Ivermectin. No direct impact of Ivermectin on the respiratory system has yet been proven or proposed [74]. As was previously indicated, the most often reported adverse symptoms during preclinical tests with Ivermectin were neurotoxic consequences. A Serbian research team performed pharmacological tests to better describe the central and peripheral effects in rats dosed with Ivermectin. Although a single intravenous administration of 2.5, 5.0, or 7.5 mg/kg generated no obvious CNS depression however, drowsiness and stumbling were noticed between 10 to 40 min following a dosage of 10 mg/kg Ivermectin, and substantial CNS depression resulting to death in half of the animals treated with 15 mg/kg. Consistent with its GABAergic properties 14, Ivermectin was shown to prolong the time it took to fall asleep after being given thiopentone [75]. Furthermore, Ivermectin prevented convulsions generated by lidocaine and strychnine [76]. Anticonvulsive dosages in both cases were much less than the Ivermectin LD50 that was determined by calculations (18.2 mg/kg). Ivermectin generates diverse inhibitory effects in the CNS of animals through GABA-sensitive and GABA-insensitive pathways; moreover, flumazenil antagonized the effects of Ivermectin solely against lidocaine-induced convulsions. Safety and toxicity to the immune system Ivermectin was licensed for human use years before the first recommendations relating to immunotoxicity assessment were released by EM(E)A (2000), the US FDA (2002) and ICH (2005). No substantial investigation of Ivermectin immunological safety has so far been undertaken utilizing state-of-the-art technologies in line with current strategies. In male CD-1 mice, Ivermectin effects on T-dependent and T-independent antibody responses were evaluated after a single subcutaneous injection of either 0.2 or 20 mg/kg [77]. This study was an early example of the types of immunotoxicity studies commonly performed at the turn of the millennium. A statistically substantial augmentation of T-dependent antibody response was observed.
1.7 Conclusion
IVM has been proven effective in humans against a number of parasite diseases, but when compared to animals the pharmacokinetic characteristics of this drug are less acknowledged in people. IVM has potential food and drug interactions, which should be taken into account when using the medication for therapeutic purposes. IVM has shown promise in the treatment of a variety of bacterial, viral, and even fungal infections with activity frequently found to be satisfactory in these cases. Recently, the use of IVM has been expanded to encompass the treatment of COVID-19 and different cancers, together with the treatment of livestock grazing systems. Table 1.1 lists the medical conditions and infections for which this medication is used along with the critical concentration and mode of action. However, research is still needed to confirm and fully examine the drug’s promising human applications, while also taking into account its pivotal toxicity and marking on well-established earlier reports.
Table 1.1 Pharmacological applications of IVM and its mode of action.
Pharmacological application
Concentration
Mechanisms of action
References
Wound healing
0.03-1 %
Decrease in exudation, edge edema, granulation, and hyperemia
[33]
Anti-inflammation
32mg/kg/24h
Blocks NF-kB pathway for lipopolysaccharide production
[34]
Antioxidant
1mg/kg
Increase in plasma nitric oxide and decrease in total antioxidant capacity
[35]
Cytotoxic
2.5–15 μM
Promotion of cellular apoptosis
[36]
Anti-fungal
210.0 mg/L
Reduction in the population growth by targeting replication
[37]
Anti-viral
2 mM
Inhibition of viral replication by targeting NS3 helicase enzyme
[38]
Anti-ovarian cancer
5 µM
Regulation of lncRNA-EIF
4
A
3
-mRNA
[39]
Ant-colorectal cancer
2.5 and 5 µM
Cell cycle arrest
[40]
Anti-malaria
300 μg/kg/day
Reduction in prevalence and incidence
[41]
Anti-dengue
400 µg/kg/day
Inhibition of viral replication
[42]
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