Prescription, over-the-counter (OTC), herbal, and other treatments and preventive uses for COVID-19
- Details
- Category: Covid Research
- Created: Monday, 28 June 2021 19:45
- Written by Jaime A. Yáñez, Sun Ah Chung, Brenda Rojas Román, Palmer J. Hernández-Yépez, Franko O. Garcia-Solorzano, Shyla Del-Aguila-Arcentales, Fiorella Inga-Berrospi, Christian R. Mejia, and Aldo Alvarez-Risco
AbstractThe current COVID-19 pandemic has spread rapidly worldwide and has challenged fragile health care systems, vulnerable socioeconomic conditions, and population risk factors, and has led to an overwhelming tendency to misuse prescription drugs and self-medication with prescription drugs, over-the-counter (OTC) drugs, herbals products, and unproven chemicals as a desperate preventive or curative measure for COVID-19. In this chapter, we present the legislative differences between prescription drugs, OTC drugs, and herbals. Various approved and nonapproved prescription and OTC drugs as symptomatic treatment for COVID-19 are listed and evaluated based on their reported efficacy, safety, and toxicological profile. We also present the various herbal products that are currently studied and used as treatment and preventive for COVID-19.
The efficacy, toxicology profile, safety, and legal issues of some speculative preventive and treatment options against COVID-19, such as Miracle Mineral Solution (MMS), chlorine dioxide solution (CDS), colloidal silver, and hydrogen peroxide is presented. The chapter also emphasizes the specific strategies that need to be implemented to guide the population in the effective and safe use of prescribed medications, such as the Medication Therapy Management or Pharmaceutical Care process. Finally, this chapter aims to provide a deeper insight into the lack of health literacy in the population and the effect that drug utilization research (DUR) has in the decision making of health authorities and general public. We aim to provide the current information about the various treatment and preventive options used for COVID-19.
Since November 2019, a new type of coronavirus infected patients in China.1 , 2 This virus has spread rapidly to 213 countries and territories around the world causing a pandemic that at the time of writing (end of September 2020) has taken the lives of over 1 million people.3 The COVID-19 pandemic migrated from its initial epicenter in Asia to Europe and is currently causing a tremendous burden in Latin America. This situation has exposed fragile health care systems, vulnerable socioeconomic conditions,4 higher risk factors because of obesity and increasing rates of undernutrition,5 lack of procurement of medical supplies,6 and an inadequate reporting of COVID-19 cases and deaths.7 For instance, the Ministry of Health of Peru has recognized that its health care system was fragmented before the pandemic, and the current situation has made its fragility become more evident.8 It has been reported that Peru preferentially uses rapid serological tests (75%) to report active confirmed COVID-19 cases, which could lead to an overestimation of positive cases.9 Latin America has not implemented public policies to control self-medication that it is currently occurring at alarming rates as speculative preventive measures against COVID-19 start to flourish.10 This event has challenged many health care systems, causing the collapse of many hospitals around the globe.7 , 10, 11, 12, 13 It also impacted the global economy, leaving it vulnerable and probably prone to lose an estimated 2.4% of the GDP of the major economies.14 , 15 Unemployment rates have remarkably increased, leading to a possible recession.16 The COVID-19 pandemic was accompanied by conspiracy theories, rumors, and infodemic, aggravated because of the availability to access social media, and the development of mental health issues on the population due to the lockdown.17, 18, 19, 20, 21
Currently, with over six months of the outbreak of the pandemic, the COVID-19 crisis is expected to markedly affect people’s well-being and mental health as reported in China,22, 23, 24 Singapore,25 Iran,26 , 27 Italy,28 , 29 France,30 United Kingdom,31 Spain,32 , 33 Chile,34 Bolivia,35 , 36 Ecuador,36, 37, 38 Brazil,39, 40, 41 Peru,36 , 42 and indigenous populations.43 This disruption in people’s work and life has been accompanied by an unprecedented infodemic of fake news.44 This plethora of misinformation and false reports have spread faster because of social media.44 The entire world has been affected by this infodemic, and Latin America has been no exception. However, Peru was the only country in Latin America that took a different approach by implementing prison sentences to the creators and disseminators of fake news.17
The infodemic has been accompanied by a surge of unproven religious and herbal treatments for COVID-19 prevention.45 Herbal remedies or phytomedicinal self-medication use is common in developing countries46 , 47 and patients often do not properly report it to their physicians.48 , 49 It has been reported in a cross-sectional survey that patients do not disclose this information since they are afraid of their doctor’s disagreement or negative response because most of them followed advice from a nonmedical source (family, friend, internet, or social media).48 Other patients stated that their doctor did not ask them, while others considered that it was not necessary to inform their doctor.48 However, possible drug-herbal interactions are discussed in various reputable pharmacopeias that detail herbal use, efficacy and safety.50, 51, 52 Furthermore, drug-herbal interaction databases allow physicians to check possible interactions online.53 , 54 This is a confounding factor since people typically self-medicate regardless of the effort of regulatory agencies to educate the population.55 Unproven prescription drugs have been falsely promoted for COVID-19 prevention and treatment.56 Health literacy has been defined as the individuals’ capacity to obtain, process, and understand basic health information and services needed to make appropriate health decisions,57 and to address or solve a health-related problem.58 Latin America is a region with a low literacy rate that affects directly the drug utilization research (DUR), which encompasses the use, efficacy, and safety of medicines based on local research.59 This is primarily caused by the existence of a very limited generation of scientific publications by local investigators.59 , 60 On the available studies, data collection bias has been identified since they present methodological issues such as limited validation, small sample size, and unavailability of information and involvement of the public sector.60 All this causes a significant impact in the clinical and regulatory decisions that impact directly the public health decision making.61 In general, public health decisions in Latin America are adaptations of public health policies of other countries,11 rather than an actual country-based decision justified by local research.59 A clear example of this was the implementation of supervised walks for children and adolescents during the COVID-19 lockdown in Peru,11 which was based on the same measure that was implemented in Spain.62 However, this decision in Peru was implemented on May 18, 2020 when data from Spain already indicated that the number of COVID-19 cases increased in this age group,63 but importantly occurred at the time that the Multisystem Inflammatory Syndrome in Children (MIS-C) cases kept increasing in COVID-19 children around the world.64 This resulted in the report of the first case of concomitant MIS-C and COVID-19 in a three-year-old child in Peru, the first case in Latin America.11
The U.S. Food and Drug Administration (FDA) declared that there are not any approved drugs or therapeutics to treat or prevent COVID-19 yet.65 That doesn’t mean that health professionals don’t know how to treat a patient with COVID-19, the management consists of symptomatic care and individualized treatment depending on the type of patient we have.65 However, this lack of knowledge has created a pathway leading to a growth in the tendency of self-medication, self-treatment, and self-care within the society.18 , 66 People put their health at risk due to peer pressure, medication availability, previous experience self-medicating, among other correlated factors.10 , 13 , 67 For example, a person can take dietary supplements such as silver instead of receiving professional care to treat or prevent coronavirus without any sustainable evidence of the effects of those substances against the SARS-CoV-2 or the adverse effects of those products just because someone recommended it on social media or TV.68
This chapter intends to present the safety, efficacy, and toxicology profiles of different products that were promoted by the people during the COVID-19 pandemic promising to treat or prevent the disease, such as prescription drugs, over-the-counter (OTC) drugs, herbal products, and unproven chemicals.13 , 69, 70, 71, 72 It also shows the need to implement strategies to guide the population and health care professionals in order to take safe and effective measures to fight against this virus.73 , 74 The COVID-19 pandemic has shown us that the population needs to be urgently correctly informed about the protocols, ways of prevention, unsafe medications and treatments for this disease, and what to do if a person suspects of having the disease.75
14.2. Health literacy and drug utilization
The Institute of Medicine76 defined health literacy as the individuals’ capacity to obtain, process, and understand basic health information and services needed to make appropriate health decisions. In this sense, Sorensen et al.77 reported that about 50% of people in eight European countries had limited knowledge of health. This could be explained because during formal education, given at elementary and high schools, health issues are not a fundamental component of the current curricula. This lack of proper health education would prevent people from taking wise decisions in health promotion for themselves and the ones surrounding them. Health literacy has a direct influence on the ability of people to filter the health information they receive. So, lack of proper health literacy is one of the reasons why people tend to receive and/or distribute news without proper verification.78
Digital health literacy not only requires the ability to navigate efficiently searching for trusted sources on the Internet; most importantly, it requires the ability to evaluate the quality of the information on the Internet to discern the true information from the wrong one. Digital health literacy also can be defined as the ability to search, find, understand, and evaluate health information from electronic sources and apply knowledge acquired to address or solve a health problem.58 Likewise, to be able to communicate efficiently with health professionals through the various technologies available for making health decisions.79 It needs to be realized that the COVID-19 global pandemic has showed us that in-person and face-to-face doctor consultations are not possible and that there are still gaps for us to understand and use the full potential of digital tools.80 However, this will require adequate training for health professionals and users, accompanied with more funding, research, and policy changes.80
The progress of the countries of the American continent81 in relation to digital health is varied. On the one hand, 61% of countries have a national digital health strategy, but several of them have yet to move from the phase of formulating digital health policies and strategies to the actual implementation of services to patients.81 Thus, it is reported that telehealth is still in the initial stages, which could explain that the population has serious limitations to access useful information through the Internet and that they can also filter the correct information.81 It has also reported that 52.6% have an electronic health information system but only 26.3% have legislation that supports its use in national systems, also explained by the lack of financing.81 Even though some initial efforts for digital health ecosystem for Latin America have been implemented, large-scale or nationwide coverage of digital health interventions to support health workforce development is still rarely reported in the literature.82, 83, 84 Because of the earlier onset of the COVID-19 pandemic in Europe, eHealth services were implemented earlier in countries such as Spain85 and were quickly replicated in the United States.86 As the pandemic moved toward Latin America, various countries implemented telemedicine systems with Peru,84 Brazil,87 and Mexico88 taking the lead in March, while Colombia89 implemented it in April, and Argentina90 in May 2020. However, other countries in the region have been more resilient in this aspect, such as Uruguay, which just approved telemedicine regulations,91 Paraguay that just launched its first official telemedicine app,92 and Bolivia started a telemedicine pilot test to evaluate its implementation.93
To provide high-quality eHealth services there are certain requirements that we consider need to be followed (Table 14.1 ). First, it is important to empower health care professionals for them to develop sufficient digital communication skills, which starts by acknowledging that the patient might perceive eHealth by a lower quality of clinical care.94 Second, patients need to be empowered by increasing their digital health literacy, which consists of the ability to search, find, understand, and evaluate health information from electronic sources and apply knowledge acquired to address or solve a health problem.58 Recently, a masterclass was published that exemplifies the actual wording to use for an eHealth consultation considering the critical components that need to be present such as greeting, introduction, courtesy, equipment check, establish remote experience, consent, signpost, preparation check, ID check, reason for call, agenda-setting, and key clinical questions.95
Table 14.1
Requirements to ensure the quality of eHealth programs.
| Requirement 1: Empower health care professionals |
| Develop sufficient digital communication skills Acknowledge and circumvent the innate limitations of eHealth Provide information to patient ahead of time |
| Requirement 2: Empower patients |
| Increase their digital health literacy Adequate preparedness ahead of time |
Low levels of health literacy and specifically digital health literacy are the right field to start an apparently inexhaustible spread of false information. This lack of literacy is relevant because rumors had three times more share than verified stories.96 Furthermore, it has been reported that there is a lack of general knowledge about COVID-19 symptoms97 and lack of information on what drugs to take.98
Self-medication is more common in countries where health care systems tend to be less effective because of long waiting times in health care facilities, difficulty in obtaining physicians’ appointments, insufficient stock of essential medicines, delay in attention, and insufficient amount of available beds/space in health care facilities.99 This has resulted in the self-medication of various prescription drugs that have no confirmed clinical efficacy against SARS-CoV-2,100 which correlated with the Google trend data for web search query for the terms “hydroxychloroquine,”101 “ivermectin,”102 and “azithromycin”103 when potential COVID-19 related benefits were reported in the media (Fig. 14.1 ). Worldwide Google trend data has been reported previously for the term “self-medication,” “self-care,” and “self-administration.”70
Some of them include the antimalaria drug hydroxychloroquine,104 the antibiotic azithromycin,105 and the antiretrovirals lopinavir and ritonavir.106 Because of the lack of monitoring, these drugs could cause a shortage of these drugs for patients that need them for approved conditions,107 a direct impact in the price of these drugs,108 and jeopardize peoples’ health due to their known adverse events.100 , 109
This self-medication trend has been reported to have increased worldwide based on the number of Google searches since the pandemic started.70 This global trend has caused a tremendous medical challenge110 , 111 because the various prescription drugs currently approved for COVID-19 symptoms carry adverse drug reactions.72 Furthermore, there is high risk of incorrect dosage, improper route of administration, longer use than intended, improper storage, risk of dependency and abuse, and increased prevalence of pathogenic resistance to drugs.72 , 112 Even though self-medication intentions are common worldwide, it has only been reported in Saudi Arabia113 and Kenya,72 while actual statistics of prescription drug use has been reported in Peru.13
Regarding the consumption of the antibiotic azithromycin, an in vitro study assessed the combination of azithromycin and hydroxychloroquine showing a synergistic effect against SARS-CoV-2.114 , 115 The possible antiinflammatory properties of azithromycin, which could improve the disease progression, was also reported.114 , 115 However, its administration in combination therapy with hydroxychloroquine has been implicated in the elevation of the QT interval.116 Given the limited data available to ensure the efficacy of combination therapy, the American Society for Infectious Diseases recommends that the hydroxychloroquine/chloroquine plus azithromycin combination should be limited to clinical trials.116 , 117 Regarding the use of hydroxychloroquine in combination with azithromycin was publicly endorsed by President Trump, which caused self-medication causing several reports of severe poisoning in Nigeria and the United States.108 This public endorsement triggered various in vitro and in vivo studies that reported a decrease in viral load and mitigation in the cytokine storm in critically ill patients with SARS-CoV-2.118 Similarly, various studies reported the positive use of hydroxychloroquine and azithromycin for treatment in hospitalized COVID-19 patients.118, 119, 120, 121 However, the consumption of hydroxychloroquine with or without azithromycin caused an increase in cardiotoxic risk such as QT prolongation, torsades de pointes, and sudden death in hospitalized patients with COVID-19.116 , 122 , 123 Even though the literature alerts to the possible risks with the combination of azithromycin and hydroxychloroquine, it is recommended in Peru for moderate and severe COVID-19 cases in a clinical setting since May 2020.109 , 124 For mild COVID-19 patients, hydroxychloroquine is recommended at a dose of 400 mg orally every 12 h for the first day, and 200 mg orally every 12 h for 6 days.124 In the case of moderate-to-severe COVID-19 patients, hydroxychloroquine is recommended at a dose of 200 mg orally every 8 h for 7–10 days, or hydroxychloroquine + azithromycin at a dose regimen of 200 mg orally every 8 h for 7–10 days (hydroxychloroquine) + 500 mg orally on the first day and then 250 mg every 24 h for 5 days.124 A case report in Peru of a 13-year-old girl with encephalitis and COVID-19 serological diagnosis presented an unfavorable clinical evolution despite treatment with hydroxychloroquine, azithromycin, and corticosteroids, dying on the third day of hospitalization.125 This published case report accompanied by the observed lack of efficacy and increased risk triggered that ivermectin, hydroxychloroquine, and azithromycin were removed from the official COVID-19 treatment in Peru.126
Regarding the consumption of antiretrovirals in order to prevent a viral disease such as COVID-19 it is risky because liver damage has been observed in COVID-19 patients.127 Considering that antiretrovirals list liver damage as a common adverse effect,128 , 129 it would make them inappropriate for use in COVID-19 patients. Their use is relevant for other pathologies, but a recent review has determined that there is no clear evidence of the beneficial effects of antiretrovirals in the prevention of COVID-19.130 , 131 More research is still needed to determine the cost and benefit of antiretrovirals for COVID-19.
COVID-19 treatment has been a widely discussed aspect throughout 2020, with the appearance of various drugs that showed properties to control symptoms and even improve survival. As the weeks went by, these perspectives changed, leaving medicines aside, changing doses, and replacing medicines. First, it can be mentioned that there is no antiviral treatment and there is not yet a vaccine available, therefore the initial approach is based on symptom relief and oxygen therapy. In the case of patients with an oxygen saturation lower than 95%, they require high oxygen concentrations. Silent hypoxemia has been able to be detected with the use of an oximeter, which determines if the patient requires to be taken to the emergency services immediately.132 , 133 Corticosteroids gained an important role, as described in the recovery trial, which shown that dexamethasone reduced deaths by a third among critical COVID-19 patients.134 The lopinavir/ritonavir combination appeared as an alternative treatment,135 but then studies emerged that showed superior treatments such as arbidol.136 However, the lack of efficacy of lopinavir/ritonavir137 and both lopinavir/ritonavir and arbidol138 has been evidenced in COVID-19 patients. Chloroquine and hydroxychloroquine were proposed as immunomodulatory agents,139 including their concomitant use with azithromycin.140 The possible adverse event in the alteration of the QT interval was also reported due to concomitant use;122 however, such adverse events were later discarded.141 Furthermore, the use for chloroquine and hydroxychloroquine as a preventive drug for healthy and asymptomatic COVID-19 patients still needs a proper double-blind clinical trial.142 It is important to mention that each country has adapted different pharmaceutical treatment options that are constantly updated.
14.4. Over-the-counter (OTC) drugs
OTC drugs are medicines that can be sold without a prescription directly to the consumer according to the specific regulations of each country. In the context of the COVID-19 pandemic, OTC drugs can be used as symptomatic treatment for mild COVID-19 cases without the need for the patient to go to the hospital. It is important to notice that due to the ongoing situation regarding COVID-19 pandemic, hospitals regularly are saturated. As a consequence, patients who have mild symptoms of coronavirus can be treated at home. The mild symptoms of COVID-19 include fever, dry cough, and tiredness.143 , 144 It is important to note that loss of smell (anosmia) has been recognized as a prominent clinical symptom in COVID-19 patients without any other significant signs.145 , 146 Since there is no available treatment for COVID-19 related anosmia145 it is important to have a proper olfactory evaluation.147 , 148 Other symptoms that are less common but still considered mild are body aches, headache, sore throat, nasal congestion, and diarrhea.143 , 144 We present the OTC drugs that have been recommended for mild COVID-19 symptoms. Table 14.2 shows the OTC drugs that have been used for COVID-19 symptomatic treatment.
Table 14.2
OTC drugs as COVID-19 symptomatic treatment.
| Type of drug | Generic name | Symptom |
|---|---|---|
| Analgesic | Acetaminophen270 | Fever, mild pain |
| Antiinflammatory | Ibuprofen270 | Fever, moderate pain |
| Naproxen271 | ||
| Cough suppressant | Dextromethorphan272 | Cough |
| Antihistamines | Loratadine273 | Nasal congestion, Sneezing |
| Cetirizine273 | ||
| Sympathomimetic | Pseudoephedrine274a | |
| Phenylephrine275 | ||
| Opioid | Loperamide276 | Diarrhea |
14.4.1. Fever and body aches
In the management of fever due to COVID-19, and in general to any pathology, acetaminophen is recommended. The antipyretic effect and its safety at recommended doses make acetaminophen one of the most-used OTC drugs during the COVID-19 pandemic.10 , 149 However, the increasing use of acetaminophen for managing the COVID-19 associated fever is generating concern because patients can take high doses, which can lead to acute liver injury (ALI) or acute liver failure (ALF) due to overdose.150 Acetaminophen standard therapeutic oral dose is 0.5–1 g every 4–6 h to a maximum of 4 g/day, but more importantly it has a dose-dependent toxicity.151 Acetaminophen can cause hepatoxicity after major overdose,152 and severe liver damage has been observed with long-term use even at therapeutic doses in patients with alcoholic liver disease or viral infections.153 Furthermore, it has been reported that long-term consumption of acetaminophen carries a potential risk factor for chronic renal failure,154 cardiovascular and gastrointestinal diseases, and even mortality.151 This is corroborated in recent studies that have reported an increase in alanine aminotransferase, aspartate aminotransferase, bilirubin, and creatinine in patients with confirmed COVID-19.155 In addition, it has been reported that more than half of patients with ALI and ALF induced by acetaminophen have undetectable levels of acetaminophen, which is concerning.156 Therefore, clinicians should not rule out the possibility of acetaminophen toxicity and should pay attention to patients with a history of suspected acetaminophen poisoning or associated biochemical profile.156 This is important now with a potential significant increase in acetaminophen use due to the COVID-19 pandemic.149
Nonsteroidal antiinflammatory drugs (NSAIDs) play an important role in the treatment of fever and muscle aches. Ibuprofen is the most widely used OTC NSAID and has good properties for fever and pain. However, in the context of COVID-19 pandemic, it should be noted that the use of ibuprofen had a controversy due to statements in France, where it was stated that ibuprofen could worsen the clinical state in COVID-19 patients.157 , 158 Nevertheless, both the World Health Organization (WHO) and the European Medicines Agency (EMA) recommended not avoiding NSAIDs when clinically indicated due to lack of scientific evidence. Recent studies suggest that there are two phases in the immune response induced by the SARS-CoV-2.159 The first corresponds to the incubation and nonsevere stages, in which an immune response is required to eliminate the SARS-CoV-2 and prevent progression to severe stages of the disease.159 Thus, the defense mechanism in the initial stage might be blocked by NSAIDs. The second phase corresponds to the severe stage, in which lung damage appears to be related to a cytokine storm due to an acute immune reaction.159 It is in this second stage where the use of NSAIDs might be of more importance. In addition, the strong antipyretic efficacy of ibuprofen, which is more potent to reduce fever compared to acetaminophen, may be interfering with the benefits of a fever response.160 Nonetheless, there is no strong evidence that can support the worsening of COVID-19 symptoms due to ibuprofen, and more research is needed such as case-control studies, cohorts, and randomized clinical trials.161 , 162 Therefore, acetaminophen continues to be the first option in treating fever during the SARS-CoV-2 infection. NSAIDs are clinically recommended when the fever is high and the aches are really strong. In the case it is required to take an NSAID, although there is no significant evidence to remove ibuprofen from the list, people can opt for naproxen, which is also an OTC drug, and its effects last longer than ibuprofen. Likewise, it is important to keep in mind the presence of fever as a symptom in areas of prevalence of malaria and dengue, because it can be a factor that is confused with COVID-19 when in reality it denotes the possibility of contagion by these two diseases.163
14.4.2. Dry cough
In the treatment of dry cough, dextromethorphan has been widely used.164 In the context of COVID-19, it has been reported that dextromethorphan has a pro-viral activity because it stimulated the growth of the virus in monkey epithelial cells.165 A cellular stress coping process appears to be started by dextromethorphan, and this mechanism is also used by the SARS-CoV-2 for its replication.165 Consequently, its use should merit caution and further study in the context of COVID-19 treatment.165 In contrast, the TAS2R gene is believed to play an important role in host defense pathways, and has been reported that dextromethorphan is an agonist of this gene and could improve immunity especially in the treatment of dry cough.166 However, both studies are not conclusive enough to promote or restrict the use of dextromethorphan for the management of dry cough in SARS-CoV-2 infection.
14.4.3. Nasal congestion
Despite the fact that nasal congestion is a not-so-frequent symptom during COVID-19 infection, it is a symptom that should not be ignored. There are some OTC drugs for this symptom such as antihistamines, phenylephrine, and pseudoephedrine in combination with antihistamines: pseudoephedrine and loratadine, or dexbrompheniramine and pseudoephedrine. In an experimental study, it was reported that pseudoephedrine had a protective effect in mice infected with influenza A virus because it could mitigate the cytokine storm and improved lung pathological damage.167 However, a clinical study is still necessary to support its use in humans.
14.4.4. Diarrhea
Diarrhea is a not-so-frequent symptom in COVID-19 infection, but its management is important.168 It has been suggested that diarrhea may be related to the use of large amounts of either antibacterial or antiviral drugs and should be considered as an adverse reaction, and consequently the first option in those cases is to suspend the use of these drugs.169 Another proposed mechanism is that there is a direct infection of gastrointestinal cells by SARS-CoV-2, which uses ACE2 (angiotensin-converting enzyme 2) as receptor to enter the cells, and this enzyme plays an important role in regulating intestinal inflammation and diarrhea.169 Although loperamide, an OTC drug, is widely used for milder diarrhea, there is no evidence that can support the efficacy of this drug as well as other antidiarrheal drugs. Therefore, it is suggested that adequate rehydration and electrolytes monitoring should be performed as in all patients with diarrhea.170
14.5. Herbals
The lack of evidence to recommend a specific treatment for COVID-19 and the absence of an available vaccine to prevent this disease, lead us to consider the supportive care and the symptomatic treatment as good strategies to deal with COVID-19. Historically, herbal medicine has been used in several epidemics of acute respiratory infectious diseases, including severe acute respiratory syndrome (SARS) and influenza.171 This knowledge is valuable to inspire possible treatments for COVID-19.277 In this section, we present the use of several herbal medicines, especially Traditional Chinese Medicine (TCM), that have been evaluated in randomized controlled trials (RCT) and some other herbal compounds with an antiviral effect that have evaluated in preclinical studies.
14.5.1. Prevention
Several studies showed good experience using TCM for the prevention of SARS cases during the outbreak of 2003.172 Due to structural and genetic similarities between SARS-CoV and SARS-CoV-2, TCM is proving also to prevent COVID-19 cases currently. A prospective randomized study in 22,065 subjects, evaluated the use of Huoxiang Zhengqi oral liquid and Jinhao Jiere granules to prevent COVID-19; however, no suspected or confirmed COVID-19 case occurred in the control and intervention group, which did not make it possible to assess their effectiveness against COVID-19.173 There is a controversial study in Israel that reported that people with vitamin D deficiency in plasma was associated with a higher risk of COVID-19 infection,174 whereas other studies in the United Kingdom did not find any association between the Vitamin D plasma level and the risk of COVID-19 infection175 or severe COVID-19.176
14.5.2. Treatment
There is a large number of studies, and they were summarized in two systematic reviews and meta-analysis of RCTs by Xiong et al.177 and Wang et al.178 that compared the use of TCM plus standard care, in comparison with standard care only, in COVID-19 patients. For these studies, the standard care included antiviral drugs, antibiotics, corticosteroids, supportive oxygen, and others, whereas TCM included more than a 100 herbals. The top five most common were licorice root, baical skullcap root, pinellia rhizome, forsythia fruit, and bitter apricot seed. Potential positive benefits have been published, however, most of them have a high risk of bias and small sample size,177 , 178 which do not allow us to truly recommend its use in COVID-19 patients.
14.5.2.1. Clinical improvement
It has been reported that TCM reduce the length of hospitalization in terms of clinical symptoms score showing positive results for COVID-19 symptom improvement in patients that received TCM compared to standard care.177 , 178 Wang et al.178 included studies with different scales to assess this outcome and it may explain the high heterogeneity (I2 = 94%). However, in the Xiong et al.177 study this outcome was measured in just two studies not generating heterogeneity, and the pooled result maintained its direction and significance. It was also observed that TCM reduced the number of cases of cough and fatigue and the duration of fever and fatigue in COVID-19 patients.177 In terms of biomarkers, the C-reactive protein was reported to be significantly lower in the intervention group in the pooled result in both meta-analyses.177 , 178 However, no significant differences were found in white cell count and lymphocytes between the intervention and the control group. According to CT findings, COVID-19 patients who were treated with TCM plus standard care had significantly better improvement than the control group, in both meta-analyses.177 , 178
14.5.2.2. Mortality and adverse events
The overall result from the meta-analysis showed no significant differences in the number of deaths. No severe or moderate adverse effects were reported in any of the systematic reviews; no significant differences were found between intervention and control group. The most common type of adverse event was gastrointestinal, but the recovery was rapid.177 , 178
14.5.2.3. TCM in a guidelines of treatment for COVID-19
The sixth edition of the Guidelines of Diagnosis and Treatment for COVID-19 for China179 recommended the use of TCM according to the stage of the disease. For the patients in the medical observation period with fatigue with gastrointestinal discomfort: Huo Xiang Zheng Qi Shui, and for fatigue with fever: Lian Hua Qing Wen capsule, Shu Feng Jie Du capsule, and Jin Hua Qing Gan granule. For confirmed COVID-19 case with mild disease they recommend Qing Fei Pai Du Tang. For severe COVID-19 they recommended Xi Yan Ping injection, Xue Bi Jing injection, Re Du Ning injection, Tan Re Qing injection, Xing Nao Jing injection, and Qing Fei Pai Du Tang. For COVID-19 patients who required intense care they recommended Shen Fu injection, Sheng Mai injection, Shen Mai injection, Su He Xiang pill, and An Gong Niu Huang pill.
In July 2020, the number of the registered clinical trials for COVID-19 were 75, of them 26 aimed to evaluate TCM and only 19 aim to evaluate the combinations of TCM and Western medicine.180 Unfortunately, most of them have several limitations since the design protocol that may not permit to validate their results and conclusions.
14.5.3. Potential candidates for clinical trials
Several herbal isolated compounds have been proved in preclinical studies as a potential inhibitor for SARS-CoV-2. Several phytochemicals were assessed in silico using molecular docking that showed that oleanolic acid extracted from Allium cepa was a superior inhibitor for SARS-CoV-2 than remdesivir, whereas Moringa olifera did not show any antiviral effect.181 However, these findings need to be assessed in in vitro and in vivo future studies. Regarding TCM, baicalin and baicalein extracted from Shuanghuanglian were described as potent antiviral agents against SARS-CoV-2 in an in vitro study.182
14.5.4. Dietary supplements
14.5.4.1. Zinc
Zinc has proved its effectiveness against common flu and immunological prevention among some risk patients like older adults.183 For instance, high oral dose of zinc salts has been reported to improve clinical indicators such as oxygen saturation and fever in COVID-19 adult patients.183 However, this study was performed only in four (4) patients and further investigation in a larger group of patients is necessary. Currently, four registered clinical trials are being performed to evaluate the comparative effectiveness of zinc supplements against vitamin C and usual care for the treatment of mild-to-moderate symptoms of SARS-CoV-2 community acquired.184
14.5.4.2. Vitamin C
For many years, the administration of ascorbic acid has been prescribed to enhance the immune system in patients who are susceptible to viral diseases such as common flu.185 Thus, a study performed in mice showed that vitamin C (ascorbic acid) combined with red ginseng juice enhanced T-cell immune response and stimulated NK cells.186 In the same study, the interruption of the influenza A viral lytic cycle was observed accompanied with an improved toleration to lung inflammation.186 A systematic review of ongoing randomized clinical trials related to the use of vitamin C in COVID-19 patients identified that a high dose of vitamin C improved biomarker levels such as ferritin and D-dimer, and caused a trend to decrease oxygen requirement after the infusion of vitamin C.187 Similarly, a case report illustrated the clinical improvement of a patient after five days of infusion with vitamin C.187 Thus, vitamin C has been proposed a prophylactic and adjunctive medical treatment for COVID-19.188
14.5.4.3. Omega-3
A Cochrane meta-analysis of 10 studies examined the effects of omega-3 fatty acids, γ-linolenic acid and antioxidants in acute respiratory distress syndrome (ARDS) patients.189 Quality of evidence was identified exhibiting no benefits in mortality and uncertain effects in reducing intensive care unit (ICU) length of stay, ventilator days, or oxygenation.189
14.6. Unproven chemicals
The COVID-19 pandemic has caused the disruption in people’s work and life, which has been accompanied by an unprecedented infodemic of fake news.44 This plethora of misinformation and false reports have spread faster because of social media.44 The infodemic has been matched with a low health literacy condition across the world. Health literacy has been defined as the individuals’ capacity to obtain, process, and understand basic health information and services needed to make appropriate health decisions,57 and to address or solve a health-related problem.58 All this has caused a surge and revamping of unproven chemicals that has been promoted as preventives and even miracle cures for COVID-19.45 In this section we present the reported efficacy, safety, and toxicology profile of some of these speculative preventive and treatment options against COVID-19 such as Miracle Mineral Solution (MMS),190 chlorine dioxide solution (CDS),191 colloidal silver,192 and hydrogen peroxide,193 which is summarized in Table 14.3 .
Table 14.3
Summary of the efficacy, safety, and toxicology profile of unproven chemicals used as speculative preventive and treatment options against COVID-19.
| Unproven chemical | Efficacy | Safety | Toxicology profile | References |
|---|---|---|---|---|
| Chlorine dioxide solution (CDS) | NEEa | NEEa | Nausea, vomiting, diarrhea, severe dehydration, anuria, unconsciousness, cyanosis and chocolate brown serum. | 194, 195, 196, 197, 198, 199, 200, 201, 202, 203 |
| Miracle Mineral solution (MMS) | NEEa | NEEa | Nausea, vomiting, diarrhea, severe dehydration, fever, chills or rigors, tachycardia, and dry cough | 194, 195, 196, 197, 198, 199, 200, 201, 202, 203 |
| Colloidal silver | NEEa | NEEa | Argyria or jaundice, dehydration, fever, confusion, hypotension, hypoxia, lethargy, slurred speech, organ damage, profound disfiguration, hypochloremia, hyponatremia, cell apoptosis or necrosis, oxidative stress, and cholelithiasis | 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221 |
| Hydrogen peroxide | NEEa | Not safe | Vomiting, gastric injury, skin burning or mechanical pressure injury, oxygen embolism, unconsciousness, and respiratory paralysis | 193,222, 223, 224, 225 |
14.6.1. Chlorine dioxide solution (CDS) and Miracle Mineral Solution (MMS)
CDS is a chemical that has previously been portrayed as a miracle cure for multiple diseases,226 and has been revamped in the current pandemic as an unproven cure and preventive for COVID-19.191 Multiple health and sanitary regulatory agencies around the world do not support nor recommend the prophylactic use of chlorine dioxide and its chemical predecessor Miracle Mineral Solution (MMS) in humans.194 The CDS defenders cite the unpublished research work of its most representative promoter Andreas Ludwig Kalcker and his pending patent applications.227, 228, 229 They also cite the unpublished online testimonies, misinterpreted research animal and human studies, and its presumed safety based on its use in water treatment and blood transfusion bags.190 , 230 CDS supporters have drafted 25 protocols to use CDS (alone or in combination with dimethyl sulfoxide [DMSO]) via the oral, intravenous, rectal, vaginal, topical, and ocular route in adults and children.230 These protocols do not have efficacy nor safety data nor regulatory agency approval anywhere in the world. The FDA first warned consumers about the dangers of MMS and CDS in 2010,194 however, people are still ingesting it, and their numbers appear on the rise, especially since the COVID-19 pandemic.
14.6.1.1. Efficacy
The promoters of CDS and MMS are making false and dangerous claims by presenting them as a remedy for autism, cancer, HIV/AIDS, hepatitis, flu, and recently, COVID-19.194 , 231 Their promoters declare that vomiting and diarrhea are evidence that CDS or MMS is working; however, this lacks any scientific evidence that supports its safety or efficacy.194 , 197 , 199
14.6.1.2. Toxicology profile
This chemical can cause nausea, vomiting, diarrhea, and symptoms of severe dehydration.195, 196, 197 There is a case report of life-threatening complications from poisoning with sodium chlorite, where a 55-year-old man arrived to the ICU in a cyanotic state with lowered consciousness displaying anuria and chocolate brown serum.200 The patient required renal replacement therapy, treatment with methylene blue, and red blood cells transfusion.200 Another case report indicated that a 41-year-old woman developed Kikuchi-Fujimoto disease (KFD)201 after consuming MMS, which resulted in fever spiked to 40°C, chills, tachycardia, rigors, and dry cough.202 She recovered after 16 days of treatment for her symptoms and continuous follow-up.202 The use of these unproven chemicals is dangerous, and extreme caution needs to be implemented.203
14.6.2. Colloidal silver
Colloidal silver is a substance that consists of silver nanoparticles suspended on a liquid in very low quantities, similar as in homeopathy.192 In humans, silver is absorbed through inhalation, parenteral route, ingestion, or topically, and most of it is metabolized by binding with other proteins in the liver and kidneys.232
14.6.2.1. Efficacy
Researchers have found that colloidal silver nanoparticles have antifungal, antibacterial, and antiviral activity.205, 206, 207 , 232 Negatively charged silver nanoparticles showed a significantly higher antibacterial activity than regular colloidal silver.208 It has been reported that silver can inhibit the replication of the following viruses: HIV-1, Hepatitis B virus, Tacaribe virus, recombinant respiratory syncytial virus, Influenza A/H1N1 virus, monkey pox virus, herpes simplex virus-1, human parainfluenza virus, vaccinia virus, murine norovirus-1,209 , 210 and H3N2 Influenza virus.211 However, further research must be performed to assess the effect of colloidal silver against SARS-CoV-2.
Another study done with the transmissible gastroenteritis virus (TGEV, a type of coronavirus) has shown that pure silver nanoparticles and silver nanowires do have inhibitory action against TGEV coronavirus, but colloidal silver does not.212 Colloidal silver as people consumed today (orally and topically), might not help to prevent or treat COVID-19, but inhaling 3–7 nm colloidal silver particles could have an effect against bacteria and viruses (such as the SARS-CoV-2) without the risk of developing drug resistance in the lungs.213 , 214 It has been reported that silver could help in the treatment of different types of cancer, such as breast cancer, leukemia, lung carcinoma, and skin carcinoma, among others.209 However, the results are inconclusive and more studies are necessary.
14.6.2.2. Safety
Contradictory literature is found about the use of silver and its interaction within the organism. Some researchers say that silver nanoparticles are safe to use, and that is why many products used today contain silver, such as creams for burned skin and dressings for open wounds.215 , 233 Other researchers discourage the use of this substance, claiming that it can cause leukocytoclastic vasculitis, argyria, neurological symptoms, and problems in different organs after long-term consumption.216 , 217
14.6.2.3. Toxicological profile
In high concentrations or long-term ingestion, silver can cause argyria, an irreversible brown-black pigmentation on tissues caused by the accumulation of silver granules, which seems to not be harmful to the patient.204 , 233 Other scientists reference silver’s toxicity because in high quantity or over a prolonged time, it can cause neurological problems (confusion), hypochloremia, hyponatremia, profound disfiguration, damage to mitochondria reducing the cellular ATP content, and increases the generation of reactive oxygen species (hydrogen peroxide and superoxide production) leading to oxidative stress.209 , 218, 219, 220 Furthermore, it can cause damage in the DNA-promoting apoptosis, recruitment of E-cadherin to the junction between cultured keratinocytes, irregularities in the cycle of mitosis or changes in the chromosomal structure, changes in the structure of the cellular cytoskeleton and increase in cell migration in cultured keratinocytes.209 , 218, 219, 220 This could cause hypotension, jaundice, obscure fingers, dry mucous membranes, cholelithiasis, lethargy, fever, hypoxia, slurred speech, and accumulation of silver in different organs (liver, spleen, lungs, colon, and kidneys) that can lead to long-term damage.209 , 218, 219, 220 Another study reported that silver nanoparticles are four times less toxic than silver ions, but they still cause an increase in the levels of apoptosis and necrosis in THP-1 monocytic cells as the concentration and time increase.234 It also needs to be mentioned that silver nitrate causes damage, inhibits metabolic activity, and reduces or suppresses the proliferation activity in keratinocytes, diminishes fibroblasts activity, and attacks feeder cells of keratinocytes.221
14.6.2.4. Legal issues
During the COVID-19 pandemic, many businesses, politicians, and antivaccination groups have taken advantage of the misinformation and desperation of the people to take unacceptable measures, such as selling unauthorized products like colloidal silver to treat and prevent coronavirus.69 , 235 Due to this, the FDA’s Office of Criminal Investigators and the Department of Justice of the United States of America have taken legal actions against companies, such as My Doctor Suggests LLC and GP Silver LLC, that were accused of promoting and selling silver-based products to cure and prevent COVID-19.236, 237, 238
14.6.3. Hydrogen peroxide
Intentional ingestion of high concentration hydrogen peroxide for health purposes has gained popularity in certain patient populations, purported benefits are due to the increased oxygen released into the bloodstream.193 Hydrogen peroxide is also known as oxydol or dihydrogen dioxide, which is a chemical that appears as a colorless liquid, used in the production of inorganic and organic chemicals.239 , 240 It is also used in a wide range of cleaning and personal care products, including surgical disinfectant, toothpaste and mouthwashes, bathroom cleaners and laundry stain removers, hair dyes, and bleaches.239 , 240 Hydrogen peroxide can also be found in OTC first-aid antiseptics; it is used as a bleaching agent in some food products, and it has other consumer and industrial uses as well including water treatment.239 , 240 Hydrogen peroxide is available in dilute form (3%–10%) for household use and OTC and in concentrated form (greater than 30%) for industrial use.222
Hydrogen peroxide injected into the bloodstream is considered an alternative treatment that claims to cure cancer, called hyperoxygenation therapy. This theory is based on the erroneous concept that cancer is caused by oxygen deficiency and can be cured by exposing cancer cells to more oxygen than they can tolerate. There is no evidence that this treatment can cure any serious disease, and it has been reported to be potentially harmful.223 At the same time, there is also no evidence that gargling diluted hydrogen peroxide eliminates SARS-CoV-2, which was another theory that hydrogen peroxide can help prevent COVID-19.224
14.6.3.1. Efficacy
The SARS-CoV-2 can be persistent on inanimate surfaces, and this is why there is a list of biocidal chemicals such as hydrogen peroxide. This product is known to clean areas that might be contaminated with virus such as SARS-CoV-2. The efficacy of this chemical with a concentration of 0.5% is effective within 1 min.241 However, its use is limited to inanimate surfaces, while no evidence exists for oral ingestion.
14.6.3.2. Safety
The growing naturopathic health industry has promoted the use of hydrogen peroxide in treating a wide variety of medical conditions. Ingestion of hydrogen peroxide can cause poisoning and results in morbidity through three main mechanisms: direct caustic injury, oxygen gas formation, and lipid peroxidation. Severe toxicity has resulted from the use of hydrogen peroxide solutions to irrigate wounds within closed body cavities or under pressure as oxygen gas has resulted in embolism.193 , 225
14.6.3.3. Toxicological profile
Hydrogen peroxide ingestion, inhalation, or contact with skin and eyes can be toxic. The severity of the effect depends on the concentration. Low concentrations can cause vomiting, mild gastrointestinal irritation, and gastric distension. Higher concentrations (>35%) can burn the exposed skin entering the adjacent tissues and blood vessels, consequently causing mechanical pressure injury and causing gastrointestinal erosion, oxygen embolism, and loss of consciousness followed by respiratory paralysis.193 , 222 , 224
14.7. Medication therapy management
In the health care system, a series of steps are established to ensure that patients who attend health care centers can achieve medical attention to their ailments. So, when it comes to chronic diseases, patients manage to get medical diagnosis and receive a prescription. However, the medical literature shows different results in relation to the control of diseases, which is directly related to the level of health literacy of patients.242 In this way, it has been possible to recognize problems in adherence to drug treatment, especially in chronic diseases as diabetes,243 tuberculosis,244 glaucoma,245 hypertension,246 and others. Nonadherence is a drug-related problem.
14.7.1. Drug-related problem
Pharmaceutical Care Network Europe (PCNE) stablished the definition for drug-related problem (DRP) as an event or circumstance involving drug therapy that actually or potentially interferes with desired health outcomes.247 DRPs have been reported in different types of patients such as ischemic stroke,248 epilepsy,249 rheumatoid arthritis,250 and other illnesses.
14.7.2. Medication therapy management/pharmaceutical care
To identify, solve, and prevent DRPs, a clear methodology is required, and for this there is the medication therapy management, also known as pharmaceutical care, which seeks to contribute to achieving therapeutic goals as in the case of patients with diabetes,251, 252, 253 hypertension,254 , 255 and other diseases. However, some barriers to provide pharmaceutical care have been detected.256 , 257 It seeks to reduce the discrepancies between what is indicated by the doctor and the drugs that are finally used by the patient. In this way, it is possible to reduce DRPs, which achieves three specific impacts: reduction of workload, reduction of morbidity and mortality, and reduction of (re)hospitalizations (Fig. 14.2 ).278, 279
Impact of reduction of discrepancies in the use of medication.
14.7.3. Pharmaceutical care during the COVID-19 pandemic
COVID-19 is an infectious disease of pandemic proportions, with more than 34 million cases and over 1 million deaths reported worldwide (at the time of writing).3 The current pandemic has generated many problems with the use of drugs for prevention and treatment, influenced by fake news17 and other aspects. During COVID-19, people have needed to receive pharmaceutical care and it has been shown that pharmacists have been able to provide different services to patients. The care of patients with COVID-19 within hospital settings presented different limitations that has generated negative impact in the mental health and job satisfaction of health care professionals.12 , 26 , 35 , 37 , 258 Despite this, it has been possible to report clinical interventions to optimize the use of medications and avoid self-medication. There is a need for health professionals to guide patients and their families to take the necessary actions to prevent further infections, especially the most vulnerable.9 , 11 , 259, 260, 261 Thus, Cadogan and Hughes262 recognized that pharmaceutical care can contribute to the following actions:
-
Provide objective and reliable information on the disease and associated symptoms.
- Educate the public about infection control and preventive measures to reduce transmission (e.g., hand hygiene, social distancing, and self-isolation).
- Implement infection control measures (e.g., cleaning and disinfection of the pharmacy environment, limiting public access to the pharmacy).
- Maintain continuity of pharmacy services, including supplies of essential medications and other products (e.g., hand sanitizers, protective masks).
- Facilitate continued supply of OTC and prescription medications to patients (including emergency supply of repeat medications where necessary).
Likewise, Li et al.263 were able to recognize innovative strategies to deal with COVID-19 such as establish evidence-based drug evaluation and guidelines; remote inpatient order review and dispensing telepharmaceutical care, telehealth counseling, and patient education; and multimedia health education. At the hospital level, Song et al.264 has also evidenced the contribution in medical rounds of pharmacists to optimize pharmacotherapy. Many community pharmacies have been on the frontline of health service to fight against COVID-19, dispensing products, and providing counseling about drugs to patients,265 and fighting against misinformation.266 Specifically, there is evidence from Germany that shows that pharmaceutical care in the pharmacy, telephone, and video call was provided from community pharmacies with 44.2% of pharmacies that conducted medication reviews during the COVID-19 epidemic. The contribution from the rural pharmacy in actions against COVID-19 has even been described.267 In China expert teams were created to focus on issues related to pharmaceuticals, pharmacokinetics, and pharmacotherapy, as well as treatment alternatives due to drug shortages.268 Finally, it has been reported that telepharmacy services have continued to guide patients.269
Fig. 14.3 shows that medication therapy management/pharmaceutical care must consider the different kind of information that the patients receive to work closely with them to make good health decisions to prevent adverse events and the patient can reach the therapeutic goals during COVID-19 care.
Information sources for health decision making.
Health care systems need to empower health professionals who have direct access to the population as in the case of community pharmacists, whom the population had available to make consultations during the COVID-19 pandemic. Community pharmacists have served as source of information for the general public280, 281 to clearly understand the messages from the authorities and prescribers, to avoid self-medication and to report adverse reactions by the use of prescription and OTC drugs, herbals, and unproven chemicals for the treatment of COVID-19.
14.8. Conclusion
COVID-19 is a new disease and we are still understanding its pathophysiology and symptomatology, and are in the process of producing an effective and safe vaccine and specific treatments. Currently, various prescription and OTC drugs, herbal products, and unproven chemicals have been used in an effort to manage the COVID-19-related symptoms. The efficacy, safety, and toxicology of these has been presented, and caution needs to be taken with all of them. Medication therapy management or pharmaceutical care is critical as well as consultation with community pharmacists. The sense of urgency and desperation against a pandemic is evident, but the caution against the preventive and COVID-19-related symptom treatment is warranted. Future studies and therapeutic strategies will continue to be produced in order to counter a pandemic that has affected so many people and lives across the globe.References
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