Nasonex Mechanism of Action

Mometasone furoate is a topical glucocorticosteroid with local anti-inflammatory properties at doses that are not systemically active.
Clinical Pharmacology: Pharmacodynamics: In studies utilizing nasal antigen challenge, NASONEX Aqueous Nasal Spray has shown anti-inflammatory activity in both the early- and late-phase allergic responses. This has been demonstrated by decreases (vs placebo) in histamine and eosinophil activity and reductions (vs baseline) in eosinophils, neutrophils, and epithelial cell adhesion proteins.
In clinical trials with nasal polyposis, NASONEX Nasal Spray showed significant improvement when compared to placebo in the clinically relevant endpoints of congestion, nasal polyp size and loss of smell.
In two trials with 1954 patients 12 years of age and older, NASONEX Aqueous Nasal Spray 200 mcg twice daily was effective in significantly improving symptoms of rhinosinusitis compared to placebo as evaluated by the Major Symptom Score (MSS) composite of symptoms (facial pain/pressure/tenderness, sinus headache, rhinorrhea, post nasal drip, and nasal congestion/stuffiness) during the 15 day treatment period (P02683 p < 0.001; P02692 p = 0.038). A 500 mg three times a day amoxicillin arm was not significantly different from placebo in reducing the symptoms of rhinosinusitis as evaluated by the MSS. Fewer subjects treated with NASONEX Aqueous Nasal Spray 200 mcg twice daily were considered by the treating physician to be treatment failures than those with placebo (p=0.0074). In addition, during the post-treatment follow-up period, the number of recurrences seen with NASONEX was low and comparable to the amoxicillin and placebo treatment groups. Treatment duration beyond 15 days was not evaluated in acute rhinosinusitis.
Pharmacokinetics: Mometasone furoate, administered as a nasal spray, has a systemic bioavailability of <1% in plasma, using a sensitive assay with a lower quantitation limit (LLOQ) of 0.25 pg/ml. Mometasone furoate suspension is very poorly absorbed from the gastrointestinal tract, and the small amount that may be swallowed and absorbed undergoes extensive first-pass metabolism prior to excretion mostly as metabolites in the bile and to a limited extent in the urine.
Preclinical Pharmacology and Toxicology: Preclinical studies demonstrate that mometasone furoate is devoid of androgenic, antiandrogenic, estrogenic or antiestrogenic activity but, like other glucocorticoids, it possesses some antiuterotrophic activity and delays vaginal opening in animal models at high oral doses of 56 mg/kg/day and 280 mg/kg/day.
In cell culture, mometasone furoate was shown to be at least ten times more potent than other steroids, including beclomethasone dipropionate (BDP), betamethasone, hydrocortisone and dexamethasone, at inhibiting the synthesis/release of IL-1, IL-6, and TNFα. Mometasone furoate (IC₅₀=0.12 Nm) was also at least six times more potent than BDP and betamethasone at inhibiting IL-5 production. Also, in mixed leukocytes from atopic patients, mometasone was a more potent leukotriene production inhibitor than BDP.
In a preclinical model, the compound has been shown to reduce the accumulation of eosinophils markedly at the site of an allergic reaction. For example, in allergic mice with IgE-mediated allergy, inhaled mometasone furoate at doses as low as 13 micrograms/kg inhibited eosinophil infiltration into bronchoalveolar lavage fluid and the lung bronchi and bronchioles. Additionally, mometasone furoate reduced the number of lymphocytes and the levels of messenger RNA for the proallergic cytokines IL-4 and IL-5.
It is likely that much of the mechanism for the antiallergic and anti-inflammatory effects of mometasone furoate lies in its ability to inhibit the release of mediators of allergic reactions. Mometasone furoate significantly inhibits the release of leukotrienes from leukocytes of allergic patients. In addition, it is an extremely potent inhibitor of the production of the Th₂ cytokines IL-4 and IL-5 from human CD4⁺ T-cells.
Mometasone furoate was nonmutagenic in the mouse-lymphoma assay and the salmonella/mammalian-microsome bioassay. Mometasone furoate was negative in the mouse bone-marrow erythrocyte-micronucleus assay, the rat bone-marrow clastogenicity assay, the UDS assay in rat hepatocytes, the mouse mitotic male germ-cell clastogenicity assay, and the Chinese hamster lung-cell chromosomal-aberrations assay. At cytotoxic doses in Chinese hamster ovary cell cultures, mometasone furoate induced a dose-related increase in simple chromosome aberrations when continuously exposed (7.5 hours) in the nonactivation phase, but not in the presence of rat liver S9 fraction. This finding is not considered to be of significance in the risk assessment of mometasone furoate, since the S9 phase of the chromosomal-aberration assay and all in vivo assays were negative. Clastogenic responses without human health risk implications have been observed at cytotoxic doses with other corticosteroids, such as dexamethasone.
In subcutaneous Segment I and III studies, mometasone furoate was well tolerated at doses up to 7.5 micrograms/kg (2.6 times the human dose by inhalation). At 15 micrograms/kg prolonged gestation and prolonged and difficult labor occurred with a reduction in offspring survival and body weight or body weight gain. There was no effect on fertility.
Like other glucocorticoids, mometasone furoate is a teratogen in rodents and rabbits. Teratology studies were conducted in rats, mice and rabbits by the oral, topical (dermal) and/or subcutaneous routes. Umbilical hernia occurred in rats administered ≥600 micrograms/kg dermally, cleft palate in mice administered 180 micrograms/kg subcutaneously, and gallbladder agenesis, umbilical hernia, and flexed front paws in rabbits administered ≥ 150 micrograms/kg dermally. In these teratogenicity studies, there were also reductions in maternal body weight gains, effects on fetal growth (lower fetal body weight and/or delayed ossification) in rats, rabbits and mice, and reduced offspring survival in mice.
No toxicologic effects unique to mometasone furoate exposure were demonstrated. All observed effects are typical of this class of compounds and are related to the exaggerated pharmacologic effects of glucocorticoids.
The carcinogenicity potential of inhaled mometasone furoate (aerosol with CFC propellant and surfactant) at concentrations of 0.25 to 2.0 micrograms/l was investigated in 24-month studies in mice and rats. Typical glucocorticoid-related effects, including several non-neoplastic lesions, were observed. No statistically significant dose-response relationship was detected for any of the tumor types.