So I decided to take the histamine / #SARSCOV2 / #COVID19 literature for a ride after the astelazine nasal spray randomized trial that showed that application of the spray for 3 times a day may cut the risk of COVID19 PCR confirmed infection by 71% jamanetwork.com
In this single center, double blind placebo controlled trial), COVID19 infections were assessed in a high quality manner: testing with a rapid antigen test *irrespective* of symptoms 2x/week, and all positive tests were confirmed via #PCR. This eliminate the numerous biases of symptom driven testing To judge the plausibility of the results, two questions in addition to the quality of the clinical trial are relevant: first, is there is a mechanistic explanation for the results? second, do the pharmacokinetics check out, i.e. can the drug reach sufficient amounts in the human body to do so? Let's consider the first question, that of biological plausibility. Enter this paper published in 2024: journals.asm.org . Using a clever staged screening approach, the investigators showed that the histamine (the "allergy molecule") serves as an alternative receptor for SARSCOV2 I like to draw attention to: > Figure 1E, which shows how well various antihistamines, both first and second generation can block the virus in a dish when present at various concentrations. > Figure 2F/H which show that the drugs have to be present before the cells see the virus to block the virus
Let's zoom at the inhibition curves by azelastine (Astelin/Astepro) and loratadine (Claritine). The two azelastine nasal products have distinct pharmacokinetics with *systemic* Cmax (peak concentration) and AUC (area under the curve) in the 00s pg/ml & 000s pg*h/ml respectively
I could not find tissue concentrations after nasal spray, but we know that these systemic (blood) concentrations are due to the 40% of the drug that is absorbed in the blood. This means that the remaining 60% of the drug remains in a rather small area in the tissue cavity, and it would reasonable .. to provide a VERY conservative lower bound of the the concentration of azelastine in the nasal epithelium by dividing the amount not absorbed by the volume of the nasal cavity (=15 ml). For the 2 formulations in the US, this leads to Cmax of 5.48 ug/l & 8ug/ml respectively. Time for some high school chemistry now, to put these Cmax into estimates of viral inhibition based on the paper journals.asm.org The MW of azelastine is 388 g/mol, so the nasal concentrations map to 14 & 20 uM, or somewhere between 1.2 to 1.3 log 10 scale. Viral entry inhibition saturates over 1.1 log10 uM at around 80%. Obviously the concentration in the nose does not stay at this level for ever, but at *very crude* first order approximation (have I mentioned I love Fermi calculations?), the result checks out *if* the virus enters through the nose.
This appears to be the case using various ex vivo models of infection (these are key papers from 5 years ago) pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov What about the systemic effects of the absorbed azelastine? Based on pharmacokinetics they appear to be ZERO. (00s pg/ml map to nanomolar concentrations, 1000 times less than the IC50 of the virus inhibition curve). In summary, if azelastine works, it works in the nose and the kinetics check out. Having examined azelastine, I decided to carry out a *thought* experiment about loratadine. I cannot emphasize enough that the material in the next couple of posts are theoretical calculations that suggest, but do not prove that oral versions of these drugs may not as good options Loratadine's pharmacokinetics are well described in the literature, and there are a gazillion papers about how the various forms are absorbed and metabolized/ The reference studies pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov and the PK parameters are shown in the table below
Both loratadine and it's active metabolite desloratadine (aka Aerius/Clarinex/Neoclaritin) achieve systemic concentrations ~ 20-30 ng/ml after a 40mg dose and a half life of around 14-18 hours. The sister study suggests that the concentration is proportional to the dose, i.e. 10mg -> 1/4 drug level
Plugging the molecular weights of loratadine (382 g/mol) & desloratadine (310 g/mol) shows that 40 mg of loratadine would achieve a maximum concentration that is rough ly20-30x lower than the IC50 effectively ruling out the viability of this route of administration for a SARSCOV2 prophylactic.
In summary, assuming that most virus enters through the nose (and it seems that the newer variants exhibit such tropism even more than the original) & one sticks with nasal antihistamine sprays prophylactically, one may achieve sufficient levels to block viral entry The biological data suggest that these drugs may not work if given after exposure ie they will not block the virus that is inside the cells, though one must remember that in actual infection not all cells are exposed at the same time and thus ... one could expect a smaller (but not zero) effect the closer one starts using the drugs to the time of infection. This is a hypothesis, in need of verification via a clinical trial: if you get infected please stick with proven therapeutics such as paxlovid/remdesivir !