key: cord-0912111-96662usx
authors: Chandler May, Bruce; Holly Gallivan, Kathleen
title: Levocetirizine and Montelukast in the COVID-19 Treatment Paradigm
date: 2021-12-15
journal: Int Immunopharmacol
DOI: 10.1016/j.intimp.2021.108412
sha: 3db0335e34eb43958d7b8be0f65f145ebda96cd0
doc_id: 912111
cord_uid: 96662usx

Levocetirizine, a third-generation antihistamine, and montelukast, a leukotriene receptor antagonist, exhibit remarkable synergistic anti-inflammatory activity across a spectrum of signaling proteins, cell adhesion molecules, and leukocytes. By targeting cellular protein activity, they are uniquely positioned to treat the symptoms of COVID-19. Clinical data to date with an associated six-month follow-up, suggests the combination therapy may prevent the progression of the disease from mild to moderate to severe, as well as prevent / treat many of the aspects of ‘Long COVID,’ thereby cost effectively reducing both morbidity and mortality. To investigate patient outcomes, 53 consecutive COVID-19 test (+) cases (ages 3-90) from a well-established, single-center practice in Boston, Massachusetts, between March – November 2020, were treated with levocetirizine and montelukast in addition to then existing protocols [2]. The data set was retrospectively reviewed. Thirty-four cases were considered mild (64%), 17 moderate (32%), and 2 (4%) severe. Several patients presented with significant comorbidities (obesity: n=22, 41%; diabetes: n=10, 19%; hypertension: n=24, 45%). Among the cohort in the pilot study, there were no exclusions, no intubations, and no deaths. The pilot study in Massachusetts encompassed the first COVID-19 wave which peaked on April 23, 2020 as well as the ascending portion of the second wave in the fall. During this time the average weekly COVID-19 case mortality rate (confirmed deaths/confirmed cases) varied considerably between 1-7.5%[37]. FDA has approved a multicenter, randomized, placebo-controlled, Phase 2 design for a clinical trial, replete with electronic diaries and laboratory metrics to explore scientific questions not addressed herein.

The coronavirus 2019 (COVID-19) pandemic has been partially contained under a backdrop of substantial resources allocated by international parties to resolve the problem. Presently, definitive treatment for COVID-19 infection remains both limited and costly, particularly for patients with mild to moderate disease. The heterogenous clinical features of COVID-19 range from an asymptomatic presentation to acute respiratory distress syndrome (ARDS) and multi-organ system failure; untreated the disease can progress to pneumonia, ARDS, sepsis, shock, and death. The insidious progression is accompanied in some patients by an excessive inflammatory response underscored by an increase in proinflammatory cytokine levels 3, 4 termed 'cytokine storm.' The advent of the SARS-CoV-2 (COVID-19) pandemic presents a challenge in identifying a therapeutic that will derail viral replication / target cellular protein activity and effectively mitigate symptoms without causing concurrent host toxicity.

Coronaviruses are a large group of enveloped, positive sense (immediately translated by the host cell), single-stranded RNA viruses belonging to the order Nidovirales. SARS-CoV-2 has been designated within the order as the seventh discrete coronavirus species capable of causing human disease. The virus is characterized by a long incubation period between 5-14 days. Initial symptoms are varied, ranging from none to typical viral presentations including fever, cough, shortness of breath, fatigue, myalgia, headache, anosmia, and diarrhea 3, 5 . Contemporary and evolving COVID-19 research has identified the treatment of inflammation caused by the virus as a cornerstone of therapy 6 . The anti-inflammatory synergy between levocetirizine, a thirdgeneration antihistamine, and montelukast, a leukotriene receptor antagonist, was discovered by 

The downregulation of NF-kB is considered a key mechanism of action (MOA) for relief of COVID-19 symptoms and mitigation of inflammation as NF-kB plays a critical role in mediating responses to a remarkable diversity of external stimuli; providing at least in part, regulation of cytokine release triggered by infection. Equally if not more important, is recognition of the NF-kB family of transcription factors as pivotal across the spectrum of not only inflammation, but also immunity, cell proliferation, differentiation, cell survival, and cell death. NF-kB is expressed in 44.4%; parthenolide: 33.3%; combined treatment: 55.6% survival) and reduced proinflammatory cytokines in the lung. Viral titers in the lung homogenates were similar in both untreated and treated animals, suggesting that the reduction in proinflammatory cytokines after treatment with NF-kB inhibitors was not a consequence of reduced virus replication. One advantage of antivirals that target cellular protein activity rather than viral proteins lies in an effect is not likely to be negated by mutations in the virus genome. This research illustrated the activation of the NF-kB signaling pathway as a major contribution to inflammation after SARS-CoV-1 (2002) infection with the acknowledgement that NF-kB inhibitors have the potential as promising therapeutics in infections caused by SARS-CoV and other pathogenic coronaviruses 20 . Figure 1 depicts, in part, the mechanism of action associated with the combination levocetirizine and montelukast. 

Levocetirizine as a third-generation antihistamine, classically downregulates the H1 receptor on the surface of mast cells and basophils to block the IgE-mediated release of histamine. Histamine has been well characterized by its effects on the body, including in part, its function as a neurotransmitter, dilation of blood vessels which in turn increases permeability and lowers blood pressure, contraction of smooth muscle in the lung, uterus, and stomach, and as a source of sneezing, itching, and congestion. Levocetirizine is considered by pharmacologists an 'insurmountable' H1 receptor antagonist 23 . It has been objectively established as the most potent of the five modern generation antihistamines (levocetirizine, cetirizine, fexofenadine, loratadine, and desloratadine) through histamine wheal and flare data 10,24-27 .

Levocetirizine, given its low volume of distribution and high receptor occupancy, is also among a select group of H1 receptor antagonists which can inhibit NF-kB and activator protein-1 (AP-1) activity through H1 receptor-dependent and independent mechanisms 9, 21, 22 . Induction of such activity follows in a dose-dependent manner to decrease, inter alia, tumor necrosis factor-α induced production of the chemokine RANTES (Regulated upon activation, normal T cell expressed and presumably secreted). RANTES expression, mediated exclusively through NF-kB, attracts eosinophils, monocytes, mast cells and lymphocytes, activates basophils and induces histamine release from these cells. Montelukast functions at the CysLT1 receptor to inhibit the physiologic action of leukotriene D4 (LTD4). Leukotrienes are protein mediators of inflammation similar to histamine; however, 100-1000x more potent on a molar basis than histamine in the lung. LTD4 is the most potent cysteinyl leukotriene in contracting smooth muscle, thereby producing bronchoconstriction. Contemporary cell and animal science support the use of montelukast in patients with acute respiratory distress syndrome 28, 29 .

At the molecular level, distinct from CysLTR1 antagonism, montelukast has also been reported to 

An expanding body of molecular science favorably supports montelukast as a potential therapeutic for the treatment of COVID-19. Multiple in silico and in vitro studies have depicted the dual potential of montelukast to inhibit the SAR-CoV-2 main proteinase 3CL pro as well as viral entry into the host cell (Spike/ACE2). The anti-inflammatory drugs montelukast, ebastine, a secondgeneration antihistamine, and steroid, Solu-Medrol (methylprednisolone) exhibit remarkable affinities to 3CL pro . 3CL pro plays an essential role in processing polyproteins, the resultant products of which are subsequently utilized in the production of new virions. Additionally, there is a known clinical crossover between ebastine and levocetirizine, the latter considered more potent 27,30-34 .

Montelukast has been safely and extensively used throughout the world since 1998. In certain patient populations, particularly children, are reports of an increase incidence of neuropsychiatric events (NAE). As such, FDA issued a black box warning in the Spring of 2020 pertaining to use in allergic rhinitis. However, observational studies, including the FDA's own Sentinel study which examined asthma patients 6 years and older 30 The two molecules are titratable, i.e., levocetirizine from 5 mg -20 mg / day and montelukast from 10 mg to 40 mg / day and are underscored by millions of days of patient use. In the United States, both are considered Pregnancy Category B (dosed once daily -levocetirizine 5 mg; montelukast 10 mg). In the context of treating a potentially life-threatening infectious disease, COVD-19, the combination appears remarkably suited as a therapeutic in the treatment paradigm.

Machelle 

A descriptive analysis of 53 COVID-19 (+) patients from a well-established single-center otolaryngology and allergy practice is presented in The 73-year-old male diagnosed in March 2020, improved in 10 days although continued to exhibit a dry cough for months. The 80-year male, post subdural hematoma with a neurological deficit, was diagnosed in the hospital on day 3; however, did well and also recovered from the virus on combination therapy. Importantly, most patients treated with co-administration of levocetirizine and montelukast had symptom resolution within 7 days. Subjects with symptom resolution after 7 days typically had comorbidities that required a longer treatment period.

Notably, there were no comorbidity exclusions, no intubations, no deaths, and no reported treatment-related safety findings. In addition, no one in the study exhibited 'Long COVID' symptoms greater than three months. Combination: Anti-inflammatory synergy between levocetirizine and montelukast in the downregulation of IL-4, IL-6, IL-8, TNF-alpha, GM-CSF, NF-kB, ICAM-1/sICAM-1, VCAM-1, and neutrophil/eosinophil quantity and migration [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] 

To investigate patient outcomes, 53 consecutive COVID-19 test (+) cases (ages 3-90) from a well-established, single-center practice in Boston, Massachusetts, between March -November 2020, were treated with levocetirizine and montelukast in addition to then existing protocols 2 . In review, thirty-four patients (64%) were considered mild, 17 (32%) moderate, and 2 (4%) severe. 

The current study utilized commercially available products and the respective adult doses for the treatment of allergy and asthma, i.e., levocetirizine 5 mg and montelukast 10 mg orally, once a day. In general, therapy was continued for 14 days. The three-year-old pediatric patient was treated with levocetirizine 1.25 mg and montelukast 4 mg daily, also for 14 days. Patients with significant comorbidity were treated for thirty days or longer, depending upon their underlying disease (e.g., asthma, allergy, nasal polyps, etc.). Clinical experience with the treatment of COVID-19 outside the pilot study as well as treatment of multiple other inflammatory disease states (e.g., sepsis, traumatic brain injury, traumatic lung injury, vasculitis) over the past 10 years, suggests a potentially higher, yet safe dosing regimen may foreshorten the nature and extent of the COVID-19 presentation, particularly if therapy is initiated early (within 5 days of the onset of symptoms / diagnosis). Such patients are less likely to progress to pneumonia or require hospitalization, parameters which have been defined in the Phase 2 trial design.

Levocetirizine and montelukast are characterized in part by different metabolic pathways which significantly decreases the potential for a drug-drug interaction. The extent of metabolism of levocetirizine in humans is less than 14% with 77% excreted unchanged through the kidney. The minimal biotransformation of levocetirizine in the liver is low and likely of no clinical relevance 51 . As such, differences resulting from genetic polymorphisms or the concomitant intake of hepatic drug metabolizing enzyme inhibitors are expected to be negligible 41 . Separately, montelukast is predominantly metabolized through the relatively minor CYP450 2C8 pathway and excreted in the bile 46 . Metabolic interaction of levocetirizine with montelukast or other extensively transformed drugs is unlikely.

Limitations of the pilot study include the absence of a placebo arm, respectfully considered within the ethical constraints of the underlying disease. Regarding statistics, data was collected from

March -November 2020, a period in time when there was insufficient testing, potentially inflating the treatment effect. Without controls, the extent of this effect is difficult to quantify. Further study is warranted.

Strengths include the mitigation of symptoms, particularly given the intrinsic mechanism of action of montelukast, inter alia, its ability to improve breathing. Moreover, treatment was offered to all patients regardless of age, comorbidities, and time from presentation of symptoms to time to the initiation of therapy. FDA accepted the initial data as positive proof of concept, suggested, and subsequently approved a multicenter, randomized, placebo-controlled, Phase 2 study design for a clinical trial, replete with electronic diaries and laboratory metrics to explore scientific questions not addressed herein. As new COVID variants evolve in a global environment, one of many attributes of the repurposed combination lies in the ability to target cellular protein activity rather than viral proteins, an effect not likely to be negated by mutations in the virus genome. Levocetirizine and montelukast appear to offer a significant addition to the treatment of COVID-19, effectively mitigating symptoms without creating concurrent host toxicity. Cumulative data to date suggests the uniquely synergistic combination may reduce the progression and duration as well as prevent/treat many of the aspects of 'Long COVID,' thereby cost-effectively reducing both the morbidity and mortality associated with the disease. 

moderate severe) (Y/N) (Y/N) (Y/N) (Y/N) (Y/N) (Y/N) (Y/N) (Y/N) M 54 CURE MOD Y Y Y N N Y N Y M 69 CURE MILD Y Y Y N Y N N N M 58 CURE MOD Y N Y N N N N Y M 63 CURE MOD Y Y Y N Y N Y M 62 CURE MOD Y N Y N Y N Y F 47 CURE MILD N N Y Y N N N N F 24 CURE MILD Y N N N Y N N N F 40 CURE MILD N N N N Y N N N F 56 CURE MILD Y Y Y N Y N N N F 73 FATIGUE MILD Y N Y Y Y N N N M 31 CURE MILD N N N Y N N N N M 44 CURE MOD Y N N N N N N N M 40 PARTIAL SMELL MOD Y Y Y Y Y Y N N M 61 CURE MILD Y N Y Y N Y N Y F 52 CURE MILD N N N Y N N N N M 87 CURE MOD Y N Y N N Y F 51 CURE MILD N Y Y N N N N N F 60 CURE MILD Y N Y N N N N N F 64 CURE MILD Y Y Y N Y Y N N M 70 CURE MILD Y Y Y N N Y Y Y F 18 CURE MILD Y N N N N N N N M 80 CURE MOD Y N Y N Y Y N Y M 83 CURE MILD N N N N N Y Y Y M 47 CURE MILD N N N Y N N N N F 41 CURE MILD N N N Y N N N N M 71 CURE MOD Y Y Y N Y Y N Y F 80 FATIGUE MOD Y N y N Y Y Y Y F 17 CURE MILD N N N N N N N N F 50 CURE MILD Y Y N Y N N N N M 32 CURE MOD Y Y Y N Y Y Y Y F 55 CURE SEVERE Y Y Y N N Y N Y F 66 CURE MILD Y Y Y N N N N N F 73 CURE MILD Y N Y N Y Y Y Y F 70 CURE MILD Y N Y N N Y Y Y M 23 CURE MOD Y Y Y N Y N N N F 75 CURE MOD Y Y Y Y Y Y N Y F 75 CURE MOD Y Y Y N Y Y N Y M 89 CURE MOD Y N Y N Y N Y Y M 21 CURE MILD Y N Y N Y Y N N F 69 CURE SEVERE Y Y Y N Y Y Y Y F 67 CURE MILD N N N Y N N Y Y M 55 CURE MILD Y N N N Y Y Y Y M 58 POLYPS MOD Y Y Y Y Y N N Y F 22 CURE MILD N N N Y Y Y N N F 21 CURE MILD Y N Y Y Y N N N F 55 CURE MILD Y Y N Y N N N N F 26 CURE MILD Y Y N N N N N N F 56 CURE MILD N N N N N N N N F 90 CURE MOD Y Y Y N Y Y N Y F 83 CURE MILD Y N Y N N N N Y F 29 CURE MILD Y N Y N N N N N F 23 CURE MILD Y N Y N Y N N N F 3 CURE MILD N N N N Y N N N

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