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Published online 2022 Mar 30
The current global trend in vaccination drive indicates that 100% immunization is a distant reality. In view of the above facts, drug therapy should be considered as the mainstay for the treatment of this disease. Thus, the currently available drugs are being explored. Accordingly, many types of drugs, such as antiviral, anti-inflammatory, antimalarial, anti-cytokine, interferons, etc., have been tried against this deadly infection [2]. Hydroxychloroquine was used in the initial phase of the disease, but it was found that the drug was not efficacious [3]. Among the different types of drugs used in practice, antiviral drugs have been extensively studied for the management of this infection. Remdesivir, a broad-spectrum antiviral, was the first drug approved for emergency use in hospitalized patients with COVID. It is also one of the most widely used drugs for COVID-19. However, the cost factor, the limited effectiveness in cytokine storms, and the availability issues of remdesivir, particularly in the Indian market, have paved the way for the other repurposed drugs. The multi-character and multistep pathogenesis of the disease indicates that the use of only one category of drugs viz. antiviral, antimalarial, anti-inflammatory, or immunomodulatory, will not be worthwhile for the management of this deadly infection. Given the unique nature of the disease, combination therapy with an antiviral and immunomodulatory drug should be considered as the most effective and acceptable therapeutic regimen for the management of this disease. Ivermectin has been used as an antiparasitic drug for the last 30 years. Many in vitro studies have reported that the drug is effective against COVID-19 infection. Consequently, many clinical studies are in process to establish the efficacy and tolerability of the drug. The drug is well tolerated and is found to be safe [4], [5]. Doxycycline is an antibiotic and belongs to the tetracycline family. It has been used in therapeutics for more than five decades. Studies have confirmed the broad-spectrum antibacterial, antiviral, anti-inflammatory, and immunomodulatory potential of doxycycline. Many combinations have been tried and tested for the treatment of SARS-CoV-2 infection, but none is effective as yet. Thus, it was thought worthwhile to explore the potential of ivermectin and doxycycline as the effective and safe ‘combination therapy’ based on their unique multiple-step mechanism of action.
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The viral nucleocapsid protein (NCP) utilizes IMPα/β1 for initiating its action. Ivermectin acts by selectively inhibiting the α/β1 transporter, thus preventing the entry of NCP into the nucleus [21], [22], [23]. It is also considered that the drug selectively inhibits IMPα/β1 and does not affect other nuclear import pathways. Ivermectin has been reported to act by binding to IMPα/β1 through NLS binding pocket [11]. Furthermore, the formation of IMPα/β1 is also suppressed by the drug. It has also been hypothesized that two ivermectin molecules can interact to make it an ionophore [20].
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An important study was conducted on high-risk patients infected with SARS-CoV-2 who had suddenly developed clinical symptoms. These patients had at least one of the high-risk complications such as cardiac, lung, obesity, and diabetes. Doxycycline (100 mg orally or iv) was administered for 7 days in conjunction with a regular standard of care. It was observed that 85% of the patients were found to be recovered [30]. A report of various studies involving the use of Doxycycline against RNA viruses is reported in Table 2.
Combined therapy with ivermectin and doxycycline can effectively alleviate the cytokine storm of COVID-19 infection amid vaccination drive: A narrative review
An unprecedented global health crisis has developed due to the emergence of the mysterious coronavirus-2 of the severe acute respiratory syndrome, which has resulted in millions of deaths around the globe, as no therapy could control the ‘cytokine ...
www.ncbi.nlm.nih.gov
Published online 2022 Mar 30
Combined therapy with ivermectin and doxycycline can effectively alleviate the cytokine storm of COVID-19 infection amid vaccination drive: A narrative review
Abstract
An unprecedented global health crisis has developed due to the emergence of the mysterious coronavirus-2 of the severe acute respiratory syndrome, which has resulted in millions of deaths around the globe, as no therapy could control the ‘cytokine storm’. Consequently, many vaccines have been developed and several others are being developed for this infection. Although most of the approved vaccines have been highly effective, many developing, and economically poor countries are still deprived of vaccination against SARS-CoV-2 due to the unequal distribution of vaccines worldwide. Furthermore, the uncertainty about the effectiveness of the available vaccines against the emerging mutants and variants also remains a matter of concern. Due to the multistep pathogenesis and unique features, combination therapy using safe immunomodulatory and antiviral drugs should be considered as the most effective and acceptable therapeutic regimen for this infection. Based on a thorough assessment of the literature, it was determined that it would be interesting to study the therapeutic potential of ivermectin and doxycycline, given their roles in several biological pathways involved in SARS CoV-2 pathogenesis. Following that, a comprehensive literature search was undertaken using Scopus, Web of Science, and Pubmed, depending on the inclusion and exclusion criteria. The present study provides a mechanism and comprehensive report, highlighting the role of combined therapy with ivermectin and doxycycline in alleviating the ‘cytokine storm’ of COVID-19 infection.Introduction
A mysterious deadly disease which has originated in the Wuhan city of China gripped the whole world in no time. This disease was later designated as COVID-19 and declared a pandemic. About 245 million people were affected by this pandemic till November 17, 2021. It has taken the lives of 4.97 million people across the globe. It has left scientists, government authorities, and the whole world community clueless and helpless. Since the emergence of this infection, many existing drugs are being used in therapeutics for the treatment of this deadly disease. ‘Cytokine storm’, the hallmark of this incurable illness, is the cause of disease severity and has resulted in millions of deaths due to this deadly disease, as no therapy could control the ‘cytokine storm’. Such was the devastation, damage, and intensity of this pandemic that it prompted researchers and government authorities across the globe to initiate the development process for the vaccines vigorously. Consequently, many vaccines have been developed, and others are in the development stage against this infection. Although most vaccines are highly effective, many of the developing and economically poor countries are still deprived of vaccination against SARS-CoV-2 due to the unequal distribution of vaccines worldwide. Furthermore, the uncertainty about the effectiveness of currently available vaccines against the emerging mutants and variants also remains a matter of concern [1].The current global trend in vaccination drive indicates that 100% immunization is a distant reality. In view of the above facts, drug therapy should be considered as the mainstay for the treatment of this disease. Thus, the currently available drugs are being explored. Accordingly, many types of drugs, such as antiviral, anti-inflammatory, antimalarial, anti-cytokine, interferons, etc., have been tried against this deadly infection [2]. Hydroxychloroquine was used in the initial phase of the disease, but it was found that the drug was not efficacious [3]. Among the different types of drugs used in practice, antiviral drugs have been extensively studied for the management of this infection. Remdesivir, a broad-spectrum antiviral, was the first drug approved for emergency use in hospitalized patients with COVID. It is also one of the most widely used drugs for COVID-19. However, the cost factor, the limited effectiveness in cytokine storms, and the availability issues of remdesivir, particularly in the Indian market, have paved the way for the other repurposed drugs. The multi-character and multistep pathogenesis of the disease indicates that the use of only one category of drugs viz. antiviral, antimalarial, anti-inflammatory, or immunomodulatory, will not be worthwhile for the management of this deadly infection. Given the unique nature of the disease, combination therapy with an antiviral and immunomodulatory drug should be considered as the most effective and acceptable therapeutic regimen for the management of this disease. Ivermectin has been used as an antiparasitic drug for the last 30 years. Many in vitro studies have reported that the drug is effective against COVID-19 infection. Consequently, many clinical studies are in process to establish the efficacy and tolerability of the drug. The drug is well tolerated and is found to be safe [4], [5]. Doxycycline is an antibiotic and belongs to the tetracycline family. It has been used in therapeutics for more than five decades. Studies have confirmed the broad-spectrum antibacterial, antiviral, anti-inflammatory, and immunomodulatory potential of doxycycline. Many combinations have been tried and tested for the treatment of SARS-CoV-2 infection, but none is effective as yet. Thus, it was thought worthwhile to explore the potential of ivermectin and doxycycline as the effective and safe ‘combination therapy’ based on their unique multiple-step mechanism of action.
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Methodology
A systematic search of PubMed, Google Scholar, Web of Science, and Science Direct was conducted from January 2020 to October 2021 for research on COVID-19 management using a combination of keywords, including "ivermectin + doxycycline + COVID-19," "ivermectin + doxycycline + SARS-CoV-2," and human studies, randomized controlled trials (RCT), prospective or retrospective cohort designs, case-control designs, case series, invitro studies, and case ports. Only studies that mentioned the combination of ivermectin and doxycycline to manage the cytokine storm of COVID-19 were included in this review article.Go to:
Ivermectin: a promising drug
Ivermectin is being used in therapeutics for more than three decades. Initially, it was considered an anthelmintic drug. The drug has been used effectively to treat lymphatic filariasis, head lice, strongyloidiasis, and river blindness [6], [7]. Many studies have shown its effectiveness against various RNA viruses [8]. The drug has already been approved in Peru and Bolivia for its use in mild cases of COVID-19 [4]. The first path-breaking in vitro study with ivermectin was conducted in Australia [9]. The usefulness of ivermectin against SARS-CoV-2 infected cells has been established in the above-mentioned work. The drug was found to inhibit viral replication with a dose of 5 µM. The viral load was found to be significantly reduced in the above study. A single dose controlled viral replication in this remarkable finding. Previously it has been established that the drug prevents HIV-1 replication by preventing the entry of integrase protein inside the nucleus [10]. Many RNA viruses depend upon their interaction with IMP α/β1 for their replication. Ivermectin acts as a broad-spectrum antibiotic by inhibiting the IMP α/β1, thereby suppressing the viral replication in all such infections, viz. influenza, chikungunya, and HIV [8], [11]. Studies have shown that SARS-CoV infection and viral replication are mediated through the transporter IMP α/β1. Ivermectin has been used very widely in a clinical setting, and no serious adverse effects have been reported so far.Go to:
Efficacy of ivermectin in viral infections
Ivermectin has been widely used in therapeutics as an antiparasitic drug. It has also produced promising results against RNA and DNA viruses [8], [11]. According to recent reports, the drug (1–2 μM) also suppresses the Zika virus [12]. The drug also significantly inhibited the dengue virus and was found to be safe at the concentrations used [8], [9]. Leon Caley and his team conducted the first study on the use of ivermectin in COVID-19 infection. This was an in vitro study that reported a highly significant reduction in viral load. The researchers in this study have found that no toxicity with ivermectin was observed. The remarkable findings of the above study paved the way for the conduction of clinical trials on ivermectin. Currently, many studies are in process to find out the effectiveness of the drug alone or with other drugs. The encouraging results of the in vitro study prompted the researchers to conduct clinical studies to establish the therapeutic utility of the drug in the in vivo studies. A matched case-controlled study (186 matched pairs) conducted in AIIMS, Bhuvaneshwar, has reported a 73% reduction in COVID-19 with two doses (300 µg at 72 h apart), suggesting its significant prophylactic activity. However, the single dose of ivermectin could not produce any significant prophylactic activity [13]. A retrospective cohort study (n = 280) conducted in the USA showed that ivermectin produced significantly lower mortality in patients hospitalized in four Florida Hospitals [14]. Another observational study was conducted in the USA involving 1970 COVID-19 positive critically ill hospitalized patients from 169 hospitals. The study reported a marked improvement in the survival rate [15], [16]. A random control clinical trial on COVID patients was conducted in Bangladesh in two groups. Patients in group A were treated with ivermectin and doxycycline, while the Group B patients were treated with hydroxychloroquine and azithromycin. After comparing the above groups with two different combinations, it was found that the results were better in group A. Furthermore, the adverse events were 31.67% in group A as compared to 46.43% in group B [6]. Reports of various studies involving the use of ivermectin against viral infections are presented in Table 1.Table 1
Report of various studies involving the use of doxycycline against viral infections.Type of study | Type of infection | Results/Remarks |
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In vitro | Dengue virus | Significant inhibition of infection. The drug inhibited serine protease enzymes and viral entry[26]. |
In vivo (RCT) | Dengue virus | A significant reduction in mortality from dengue hemorrhagic fever was observed. 11.2% mortality was found in doxycycline treated group (13/116) as compared to 20.9% mortality in untreated group (24/115)[33]. |
In vivo (Clinical study) | SARS-CoV- 2 | Administration of the drug resulted in marked reduction in all symptoms of COVID-19[28]. |
In vitro study | SARS-CoV-2 | Doxycycline inhibited infection. The results are comparable to those of other drugs[25]. |
In vitro study | Vesicular stomatitis virus | The drug significantly inhibited the virus[57]. |
In vitro | Chikungunia virus | Doxycycline significantly inhibited the virus[27]. |
In vivo (Clinical study) | Dengue virus | Suppression of cytokines[33]. |
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The probable mechanism of action of ivermectin
Transport of proteins across the nuclear membrane is essential for carrying out important physiological processes such as cell division, differentiation, and multiplication. IMPα/β1 is a type of transporter that transports various proteins from the cytoplasm to the nucleus. This process is accomplished with the help of nuclear localization signal and nuclear pore complex. It has been reported that MPα/β1 is involved in the infectivity of SARS-CoV [17]. Thus, it can be considered that IMPα/β1 may be involved in the etiology of SARS-CoV-2 [10], [12], [18], [19], [20].The viral nucleocapsid protein (NCP) utilizes IMPα/β1 for initiating its action. Ivermectin acts by selectively inhibiting the α/β1 transporter, thus preventing the entry of NCP into the nucleus [21], [22], [23]. It is also considered that the drug selectively inhibits IMPα/β1 and does not affect other nuclear import pathways. Ivermectin has been reported to act by binding to IMPα/β1 through NLS binding pocket [11]. Furthermore, the formation of IMPα/β1 is also suppressed by the drug. It has also been hypothesized that two ivermectin molecules can interact to make it an ionophore [20].
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Doxycycline: a multifaced medication
Doxycycline is a derivative of tetracycline, which is widely used in infections caused by Mycoplasma pneumonia, Streptococcus pneumonia, Haemophilus influenza, Chlamydia psittaci, Klebsiella species, and acinetobacter. The drug has also been used to treat other infections such as rickettsia infections, plague, and cholera [24]. The pharmacokinetic pattern of the drug is very.impressive. The drug attains maximum plasma level within 2 h after drug administration. Literature survey has revealed that the drug does not produce any serious adverse effect during the ordinary course of therapy. Unlike other antibiotics, doxycycline does not produce diarrhea. Doxycycline acts by blocking/modifying the signaling pathways involved in viral infection in multiple steps.Efficacy of doxycycline in viral infections
Doxycycline (4.5 μM) has been reported to produce a significant reduction in viral load in SARS-CoV-2 infected cell lines [25]. The inhibitory activity was comparable with that produced by other drugs such as hydroxychloroquine, lopinavir, and azithromycin. This important study has also reported that doxycycline produced the above effect by the two-step mechanism, i.e., by preventing the viral entry and also by inhibiting the viral replication. It has also been found that the drug utilizes the same mechanism in suppressing the chikungunya virus, as mentioned above [26]. The drug has also been shown to inhibit dengue virus replication as well as its entry into the cells by inhibiting the dengue virus serine protease and also by suppressing the E2 envelope, respectively [27]. The case report of four high-risk patients with an associated pulmonary disease has shown that doxycycline treatment (100–200 mg daily) for 5–14 days had revealed a remarkable improvement in all symptoms of COVID-19 [28]. This was the first report of its kind on SARS-CoV-2 infected symptomatic patients. Studies have also reported that doxycycline prophylaxis was effective in preventing acute lung injury in experimentally induced H3N2 virulence in mice [29].An important study was conducted on high-risk patients infected with SARS-CoV-2 who had suddenly developed clinical symptoms. These patients had at least one of the high-risk complications such as cardiac, lung, obesity, and diabetes. Doxycycline (100 mg orally or iv) was administered for 7 days in conjunction with a regular standard of care. It was observed that 85% of the patients were found to be recovered [30]. A report of various studies involving the use of Doxycycline against RNA viruses is reported in Table 2.
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