Of huge importance now is to provide a fast, cost-effective, safe, and immediately available pharmaceutical solution to curb the rapid global spread of SARS-CoV-2. Recent publications on SARS-CoV-2 have brought attention to the possible benefit of chloroquine in the treatment of patients infected by SARS-CoV-2. Whether chloroquine can treat SARS-CoV-2 alone and also work as a prophylactic is doubtful. An effective prophylactic medication to prevent viral entry has to contain, at least, either a protease inhibitor or a competitive virus ACE2-binding inhibitor. Using bromhexine at a dosage that selectively inhibits TMPRSS2 and, in so doing, inhibits TMPRSS2-specific viral entry is likely to be effective against SARS-CoV-2. We propose the use of bromhexine as a prophylactic and treatment. We encourage the scientific community to assess bromhexine clinically as a prophylactic and curative treatment. If proven to be effective, this would allow a rapid, accessible, and cost-effective application worldwide.
Is there an ideal drug for a pandemic like COVID-19?
A prophylaxis strategy and a suitable treatment for the emerging SARS-CoV-2 are crucial for reducing the mortality and morbidity of this disease, but developing and obtaining regulatory approval for new drugs can take years and are discordant with the urgent need for a therapy. Drug repurposing is an attractive alternative drug discovery strategy, because it eliminates many steps usually required at the early phase of drug development. There is the advantage of ease of access, decreased cost of development as they have established manufacturing arrangements, and the possibility to provide a wide array of options for combination studies. The background pharmacological knowledge available for such compounds may also reduce concerns regarding adverse effects in patients as they have gone through rigorous safety and risk testing and are already approved as safe for human use.
It is feasible to address this problem from a theoretical perspective. Theoretically, the ideal drug candidate (or combination) has to be specific, effective, already has regulatory approval (for any indication) ideally globally, but at a minimum in multiple countries. It should be widely available, inexpensive, and most important, has a long history of safe use with minimal side effects. Such a drug candidate could be applied immediately off-label and in so doing break the spreading chain or at least decrease the speed of spreading of the disease. Such a drug candidate, if even only partially effective, could have a huge epidemiological impact. Looking at a global perspective, it could mean the difference between a moderate and severe course of the disease, and/or between life and death. A reduction in the replication of the virus and of the total initial viral load in the host cells, especially in young and healthy individuals, could prevent the critical threshold of becoming infected or transmitting the virus from being reached.
Bromhexine or bromhexine hydrochloride (N-cyclo-N-methyl-(2-amino-3,5-dibromo-benzyl) amine hydrochloride) is derived from Vasicin, a plant-derived ingredient and alkaloid that was developed from the Indian lung herb, Adhatoda vasica, and is a brominated aniline and benzylamine derivative. Bromhexine hydrochloride acts as a mucolytic (breaks down mucus and helps clear chest congestion) and is approved in many countries as an OTC drug. It is characterized by low side effects and a low purchase price. Bromhexine is structurally related to ambroxol, an active demethylated metabolite of bromhexine, that is also a known medicine in the market. The available data suggest further that ambroxol is a potent inducer of surfactant synthesis in AT2 cells. Its lung protective properties have been discussed in infants and severely ill adult patients as well as the potential as an adjuvant in anti-infective therapy. Thus, bromhexine also provides indirect protective effects. Bromhexine hydrochloride is sold under a few brand names, such as, Bisolvon®, Broncholyte Elixir, Paxirasol, and Bisolex amongst others. According to the package inserts (information for use), the medicinal products containing bromhexine hydrochloride are usually administered three times a day (8–16 mg per dose for adults). It shows a quick and almost complete absorption in the intestine. Lung-tissue concentrations 2 h post dose are 1.5–4.5 times higher in bronchiolo-bronchial tissues and between 2.4 and 5.9 times higher in pulmonary parenchyma compared to plasma concentrations. Unchanged bromhexine is bound to plasma proteins by 95%.
Lucas et al. , as mentioned above, showed a decrease in the frequency of metastases and a slowdown of the spread of metastases in mice with prostate cancer using TMPRSS2 inhibitors. The extent of metastasis reduction with bromhexine was slightly lower in the wild-type mice than in the genetic TMPRSS2− mice. This is most likely due to an incomplete pharmacological blockage of the protease activity by the applied bromhexine, presumably due to the dosage and the long dosage intervals in the study (72 h). The terminal half-life of bromhexine in an oral application of 8 mg per single dose is an average of 6.6 h. Bromhexine is orally readily bioavailable, and thus, a more frequent and higher oral dose could have a stronger and longer term inactivation of the TMPRSS2 enzyme. Endonasal, sublingual, buccal application, or inhalation might also be good alternatives as this could circumvent the first pass effect. Laporte and Naesens reported that bromhexine did not show any significant cell entry or replication inhibition effect in vitro in influenza viruses. However, the authors showed that influenza viruses utilize, contrary to SARS-CoV-2, a different extracellular host protease for priming. Thus, these results are not representative for SARS-CoV-2.
In theory, bromhexine is an attractive drug against COVID-19, because it is an OTC drug that is available globally, affordable, with proven safety, and in so doing fulfills all criteria hypothesized above for a global and immediate off-label use. The IC90 (inhibitory concentration) for TMPRSS2 inhibition using bromhexine is favorable at 1 μmol compared to 10 μmol for camostat mesilate. However, the first pass effect for bromhexine is much higher than for camostat mesilate (75–80% versus 33–40%). The currently recommended oral dose for camostat mesilate is 300–600 mg per day which would translate into an oral dose of about 68–136 mg and a parenteral dose of 17–32 mg per day. These are only estimations and dose finding has to be done to identify the ideal dose.
A clinical trial (registration number NCT04273763), carried out by WEPON Pharmaceutical Group Co. Ltd., is the first human body-based preliminary exploratory randomized-controlled clinical study on treating COVID-19 with bromhexine hydrochloride tablets (BHT). The clinical study evaluated the efficacy and safety of oral intake of 96 mg (32 mg tid) BHT combined with standard treatment (experimental group) compared to standard treatment alone (control group) in suspected patients and confirmed patients with mild or common COVID-19. The study results showed the signs of efficacy from multiple angles using BHT (WEPON Pharmaceutical Group Co Ltd. communication. Appendix 3. Exploratory Study on First Use of BHT for Prevention and Cure of COVID-19. 2020). Treatment with BHT alleviated lung injury to a certain extent, as we have proposed, and no severe adverse effects were experienced. The experimental group compared to the control group required less oxygen inhalation days (2 days on average for the experimental group and 4 days on average for the control group), had lower proportion of patients requiring oxygen inhalation (16.67% for the experimental group and 33.33% for the control group), and had smaller incidence of adverse events of liver injury which is expected (25% for the experimental group and 66.67% for the control group). Bromhexine and ambroxol appear to have a liver protective effect. Comparatively, liver toxicity when given chloroquine/HCQ and liver damage in COVID-19 is a high risk. The exploratory results of the study support our proposal that bromhexine hydrochloride may have a good effect on the treatment of COVID-19.
Recent publications on COVID-19 have brought attention to the possible benefit of chloroquine in the treatment of patients infected by SARS-CoV-2. Whether chloroquine can treat COVID-19 alone and also work as a prophylactic is doubtful. This needs to be further investigated before masses of people start to take this relatively toxic drug as a preventive measure. People have been poisoned and one death has occurred due to overdose using chloroquine. The FDA does say that studies are under way to see if chloroquine can be effective in the treatment of COVID-19. Chloroquine had been approved for “compassionate use” where patients are in a life-threatening condition. Past research on chloroquine has shown in vitro activity against many different viruses, but no benefit in animal models. Chloroquine in almost all animal models of different viral infections only partially worked or did not work. Treatment with chloroquine did not prevent influenza infection in a randomized, double-blind, placebo-controlled clinical trial. Conversely, it worked very well in vitro. This could indicate that the main mechanism of action of chloroquine, in vivo, is via interference with the non-specific endosomal pathway and not with the ACE2 receptor directly.
The extracellular concentration of the orally applied chloroquine, especially in lung tissue, in vivo, may not be high enough to inhibit virus binding via the discussed glycosylation of the binding pocket. After the viral infection has spread in the body and due to the incredibly high viral loads, the non-specific endocytotic pathway is mainly used for further virus replication. This may explain the recent success reported with chloroquine to assist in the curing of the virus. In already infected individuals, we believe that it is essential to combine HCQ with a TMPRSS2 inhibitor, like bromhexine, to block complete entry of the virus into host cells. In the case of prophylaxis, the inhibition of the TMPRSS2 is essential and the non-specific endosomal entry is negligible. An effective prophylactic medication to prevent viral entry has to contain, at least, either a TMPRSS2 inhibitor, e.g., bromhexine or a competitive virus ACE2-binding inhibitor, e.g., a peptide inhibitor. This will prevent further spreading of the virus through the host’s body. Furthermore, a combination with the lesser toxic chloroquine derivate, HCQ sulfate, that is (amongst other functions) an effective endosomal protease inhibitor, inhibiting cathepsin B/L, could be a favorable combination for the treatment of moderate-to-severe COVID-19 cases. The addition of the 3CLpro inhibitor, quercetin, is also a favorable addition. This combination would block virus-host cell entry completely by blocking the specific receptor-mediated entry (via bromhexine) and non-specific endocytotic virus entry (via HCQ sulfate and quercetin) as well as viral replication (quercetin).
The recommended dose of HCQ sulfate for prophylaxis is 400 mg per week and for a curative treatment a loading dose of 800 mg (twice daily 400 mg) for the first day and 400 mg (twice daily 200 mg) for the following 4 days. The toxic dosage range of chloroquine and HCQ is close to the therapeutic range. Especially, since chloroquine derivatives are quite toxic, a combination with bromhexine and a lower dose of HCQ could be applicable. A combination of airway protease inhibitors with other antiviral drugs is known to obtain a synergistic effect or reduce the risk of resistance. An example shows that a combination of oseltamivir with the serine protease inhibitor BAPA (benzylsulfonyl-D-Arg-Pro-4-amidino-benzylamide) is able to suppress influenza virus replication in human airway epithelial cells at remarkably lower concentrations compared to a treatment with each inhibitor alone. One can deduce that the same could be applicable for the herein proposed drug application. Bromhexine would be a valuable addition in combination with antivirals such as remdesivir. The beneficial role of flavonoid supplements like quercetin to contribute to an inhibition of the viral entry and replication must also be considered as additional support to current and also our proposed treatment scheme (Fig. 3)
Summary and perspectives
A rationale was put forward for the repurposing of existing drugs namely bromhexine in combination with HCQ and/or quercetin as an immediately available and affordable treatment option or prophylactic use in response to the COVID-19 pandemic. It appears the fight against COVID-19 is just beginning. Globally, the economic cost of the pandemic has been estimated at $1 trillion in 2020 (UN’s trade and development agency, UNCTAD). There is, at the time of this writing, still no sign of the COVID-19 pandemic slowing down, and with over 2,000,000 recorded infections, it is time to take unprecedented global actions . It is still in the early stages of the outbreak and we have limited knowledge about the transmission and mutation rate of this virus. As the virus continues to spread to more individuals, more mutations may arise which can potentially make the virus even more virulent and difficult to eradicate. As specific functions of the viral proteins and the pathogenicity of the virus become clearer and the sharing of information on variants and clinical information becomes more accessible, we can plan that therapeutic treatments are near in our future.
Neutralizing antibodies and vaccines will play significant roles in controlling this SARS‐CoV‐2 outbreak, but will realistically only become available once it is too late. A fast and immediate prophylactic option to prevent or potent drug to treat the disease progression in these urgent times is the repurposing of an already existing approved drug to be used for off-label usage. Bromhexine or preferably in combination with HCQ could be such an ideal candidate or candidate combination. A further combination with quercetin could be beneficial, as well. First, the combination could be utilized for prophylactic applications, specifically for the more vulnerable individuals such as the elderly, diabetics, those with coronary diseases, and immune-compromised individuals. Here, quercetin could possibly replace HCQ. Second, this combination can be used to lower the viral burden in newly infected individuals, limiting their capacity to transfer the virus and in so doing also prevent them from developing a severe or even critical manifestation of the disease. We encourage the scientific community to test bromhexine and the suggested combinations and to follow our recommended approach to also identify further ideal repurposing candidates according to the herein proposed criteria.
Reference & Source information: https://link.springer.com/
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