2011-04-13

Amoxanox

Amlexanox

Amlexanox
Systematic (IUPAC) name
2-amino-7-isopropyl-5-oxo-5H-chromeno[2,3-b]pyridine-3-carboxylic acid
Identifiers
CAS number 68302-57-8
ATC code A01AD07
PubChem CID 2161
DrugBank APRD00795
ChemSpider 2076
UNII BRL1C2459K
KEGG D01828
ChEMBL CHEMBL1096
Chemical data
Formula C16H14N2O4
Mol. mass 298.293 g/mol
SMILES eMolecules & PubChem
Pharmacokinetic data
Half-life 3.5 hours
Excretion Renal (17%)
Therapeutic considerations
Pregnancy cat. ?
Legal status ?
Routes Topical
Yes(what is this?) (verify)

Amlexanox (trade name Aphthasol) is a medication with antiallergic and anti-inflammatory effects used in the treatment of aphthous ulcers (canker sores). Amlexanox is also available in Japan as oral tablets (trade name Solfa) for treatment of bronchial asthma, where it has been marketed by the Takeda Pharmaceutical Company since 1987, though Aphthtab by Egyptian Eva pharma also exist. In India it is available as Lexanox by

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Recurrent aphthous ulcer (RAU) is the most prevalent oral mucosal disease in humans, estimated to affect between 5% and 50% of the general population, although the actual prevalence may probably be greater [1-3] than the reported figures. This disorder is also commonly referred to as canker sores, recurrent aphthous stomatitis, recurrent oral ulcers and simple or complex aphthosis. RAUs are characterised by round, clearly defined, painful lesions covered by a fibromembranous slough [1,4] with an erythematous halo. It generally first presents in childhood or adolescence and then continues [5] into adulthood. Interestingly, cross-sectional studies indicate that females and individuals in higher [2] socioeconomic classes have a higher prevalence and severity of this disease. RAUs have been classified into three subtypes: minor aphthous ulcers, major aphthous ulcers and (2,6-10] herpetiform ulcers Minor RAU is the most common manifestation of the disorder, occurring in 75–80% of patients with RAU. This is characterised by shallow round or oval lesions of <10mm in diameter that are surrounded by a raised erythematous halo and covered by a grey-white pseudomembrane. These moderately painful ulcers generally appear on the non-keratinised oral mucosa (that is, the labial and buccal mucosa and the floor of the mouth) and resolve within 7–14 days without scarring. Patients generally notice a burning or tingling at the ulcer site as the lesion begins to develop. This is called as prodromal stage, which usually lasts for around 24 hours, the epithelium is infiltrated with mononuclear cells and oedema develops. The lesion then becomes increasingly painful as macules and papules with a surrounding erythematous halo develop. This is known as the pre-ulcerative stage and generally occurs in the first 18–72 hours of lesion development. The ulcerative stage itself may last for a number of days, while the pseudomembrane that covers the wound lessens the pain associated with the lesion. Finally, the ulcer is covered by [11] epithelium and wound healing occurs. . Classification of [7,8] recurrent aphthous ulcers (RAUs. Major RAU is a more severe form of RAU, affecting approximately 10% of patients with RAU. Lesions are generally deeper than those observed in minor RAU, often exceed 10mm in diameter and can be very painful. Major RAU lesions generally [2,6-8,10] take several weeks to heal and often leave a scar. Herpetiform ulcers, are multiple clusters of small lesions that occur throughout the oral cavity are not related to herpes simplex virus. Although the individual ulcers are between 2 and 3mm in diameter, these can cluster together to form large, irregular, plaqueform lesions that generally heal with scarring within 7–10 days. Approximately 10% of patients presenting [2,6-8,10] with RAU have the herpetiform manifestation. RAU can also be classified as simple aphthosis or complex aphthosis. The simple manifestation is characterised by shortlived episodes involving a few lesions that heal quickly with minimal pain. These are limited to the oral cavity. Conversely, complex aphthosis is a more disabling state, characterised by numerous and large lesions, continued ulceration and marked pain. Furthermore, lesions may occur in the genital or perianal [1,12] regions. The underlying aetiology of RAU is poorly understood, possibly because most patients with the condition are otherwise well. Pathogenesis is likely to be multifactorial, with potential predisposing factors including [13-17] [8] altered immunoregulatory balance, infection with bacteria or viruses such as herpes simplex, [17-20] [2,17,21] varicella zoster and Epstein-Barr, genetic disposition, haematological deficiencies in iron, folate, [17,22-25] [26] zinc or vitamin B, and food hypersensitivity and allergies. Trauma, including injections, sharp foods, tooth brushing and orthodontic treatment, may also play a precipitating role in the development of [27] [28,29] RAU as may emotional or environment stress. Interestingly, smoking appears to reduce the likelihood of RAU, with the condition sometimes occurring or recurring in individuals who have ceased [30] smoking. Several systemic diseases are also associated with an increase in the prevalence or severity of RAU. RAU- [31,32] [33-36] [37,38] like lesions are common in Behçet's disease, HIV infection, Crohn's disease and, to a lesser [39,40] extent, ulcerative colitis. Another gastrointestinal disease associated with RAU is coeliac disease (also [23,41,42] known as gluten-sensitive enteropathy), possibly due to malabsorption of B vitamins, folate and iron. Other systemic disorders with a potential link to RAU include mouth and genital ulcers with inflamed [1] [43,44] [45] cartilage (MAGIC) syndrome; periodic fever, aphthosis, cyclic neutropenia; and immunoglobulin A [46] (IgA) deficiency. Therapeutic Approaches to Recurrent Aphthous Ulcers (RAU) RAU lesions can be extremely painful, and may lead to difficulty in speaking or eating. Appropriate management of patients with this condition is largely symptomatic and should focus on reducing ulcer duration, relieving pain, ensuring adequate food and fluid intake, and preventing or reducing lesion [47] recurrence. . The first step towards effective management of RAU is to identify and appropriately treat any modifiable [4,22] predisposing factor (such as stress or nutritional deficiencies) or underlying systemic disease. Several medical approaches have been adopted for the symptomatic management of RAU. In general, topical therapies are recommended as a first-line approach to treatment, particularly in those patients who [48] are otherwise healthy. Pharmacological therapies that have been used have centered around topical drug and sometimes systemic therapy. Topical therapies include animicrobials, analgesic mouth rinses and gels, topical glucocorticosteroids, immunomodulators and hormones. The anti-inflammatory properties of topical corticosteroids mean that these agents are commonly used in the treatment of RAU; however, their efficacy has only been evaluated in small trials. These agents may [49-52] reduce symptoms of RAU; however, they appear to have little effect on the risk of ulcer recurrence and their extended use may be associated with overgrowth of oral Candida or hypothalamic-pituitary-adrenal axis suppression. Antiseptic and antibacterial mouth rinses are also often used to control microbial contamination in RAU and to reduce the likelihood of secondary infections. Reductions in oral mucosal flora may reduce the healing time for lesions, with small studies suggesting that antibacterial mouth rinses provide limited [53-59] symptomatic benefit, particularly with regard to ulcer duration and pain. Furthermore, the large placebo effect observed in several of these studies indicates that the beneficial effects of mouth rinses may also be mediated by improved oral care. [60-66] [67-69] Several systemic agents, including imidazothiazole antibiotics (levamisole), thalidomide, oral [4] [70] [71,72] corticosteroids, colchicines and pentoxifylline, have been evaluated in patients with RAU. In general, systemic agents should be reserved for patients who have failed topical therapy or who have a [48,73] serious associated systemic disease such as HIV infection or Behçet's disease.

Amlexanox contains 5% amlexanox in an adhesive oral paste. Chemically, amlexanox is 2-amino-7- isopropyl-5-oxo-5H-[1]benzopyrano[2,3-b] pyridine-3-carboxylic acid. It has a molecular formula of C 16 H N O and has a molecular weight of 298.30. Amlexanox is odorless, white to yellowish-white 14 2 4 crystalline powder. Amlexanox is a novel anti-inflammatory, anti-allergic agent that has been used clinically in Japan for the treatment of patients with bronchial asthma (oral tablet), allergic rhinitis (nasal spray) and conjunctivitis (eye drops) for more than 15 years. Amlexanox as a 5% topical oral paste for the treatment of patients with RAU and is currently the only clinically proven product approved by the US FDA for the treatment of aphthous ulcers. The oral preparation has been specifically formulated to adhere to the oral mucosa, thus limiting the likelihood that [74] the drug will be rubbed away or rinsed away with saliva flow. Treatment should be initiated as soon as symptoms start, usually at the prodromal stage with application of the paste directly to the ulcers four [75] times daily until healing occurs. Mechanism of Action The mechanism of action by which amlexanox accelerates the healing of aphthous ulcers has not been clearly established. Amlexanox potently inhibits the release of histamine and leukotrienes from mast cells, basophils and neutrophils in in vitro settings, possibly through increasing intracellular cyclic AMP content [76] in inflammatory cells, a membrane-stabilising effect or inhibition of calcium influx. When given orally to animals, amlexanox has been shown to suppress both immediate and delayed-type hypersensitivity [75] reactions; however, the clinical relevance of these actions in RAU is not known. Clinical Trials Amlexanox for the treatment of aphthous ulcers has been evaluated in a numerous clinical trials that included a single-dose pharma-cokinetic study, a multiple-dose dose-ranging pharmacokinetic study, four vehicle-controlled efficacy trials, a dermal irritation study, a rigorous dermal sensitisation study, and a [77,78] 28-day safety study The pharmacokinetic profile of amlexanox was determined in two studies. In the single-dose study, 12 males received 100mg of 5% amlexanox paste, applied directly to the lesion. In the open-label, multipledose study, 18 subjects applied 5% amlexanox paste to their RAU lesions four times daily for 7 days. The efficacy of amlexanox was assessed in four randomised, double-blind, vehicle-controlled, parallel, [77] multicentre trials involving 1335 subjects. The participants were instructed to apply the paste onto their ulcers four times daily for the duration of the study or until the ulcers had healed. Ulcer number and size were measured by the investigator and pain was evaluated (using a visual analogue scale [VAS] or a categorical scale) by the subject before the first application of the paste and at each evaluation thereafter. A categorical scale was also used to describe erythema improvement and overall healing. When subjects presented with multiple ulcers, an average evaluation was used for all treated ulcers. The dermal effects of topical amlexanox were assessed in dermal irritation and dermal sensitisation [78] studies. In the irritation study, 25 subjects with clear, light-coloured, sensitive skin received 5% amlexanox paste, 1% amlexanox paste and vehicle applied under occlusive patches to the upper back. Patches remained in place for 24 hours, with irritation potential measured 10–15 minutes after patch removal and then 24 hours after the removal of the final patch. In the sensitisation study, 214 volunteers with healthy skin received 5% amlexanox paste or vehicle applied under occlusive patches to the upper back. Patches were applied three times per week for 3 weeks (induction period). A 2-week rest interval followed the induction period, after which subjects received the active drug or vehicle, again applied to the back, for two consecutive challenges of 48 hours (challenge period). Irritation and sensitisation potential were evaluated after the removal of the patches following the induction period and challenge period, respectively. Across all studies, adverse events were recorded during each study visit, with their severity and potential [78] relationship to study medications evaluated by the investigator. In the 28-day safety study, 100 subjects applied 5% amlexanox paste four times per day to lesions until they healed and then to the lesion site for the remainder of the study period (unless a new ulcer developed, in which case the new site was treated). Serum amlexanox levels and laboratory parameters were measured throughout the treatment period. Pharmacokinetics & Metabolism Following a single 100 mg dose of 5% amlexanox, the mean maximum serum concentration (C ; 120 ± max [78] 70 ng/mL) was achieved 2.4 ± 0.9h (t ) after application (figure 1). Most of the systemic absorption of max amlexanox is via the gastrointestinal tract, and the amount absorbed directly through the active ulcer is not a significant portion of the applied dose. The half-life for elimination was 3.5 +/- 1.1 hours in healthy individuals. Approximately 17% of the dose is eliminated into the urine as unchanged amlexanox, a hydroxylated metabolite, and their conjugates. With multiple applications four times daily, steady state levels were reached within one week, and no accumulation was observed with up to four weeks of usage Variability in area under the concentration time curve from time zero to 24 hours (AUC ) was large, ranging 24 from 30 to 973 ng·mL/h, with a mean of 360 ± 240 ng·mL/h. This intersubject variability is likely to be due to differences in absorption of the amlexanox paste between subjects and the difference in the amount of time each ulcer was exposed to the paste. The mean elimination half-life following a single amlexanox dose was 3.5 ± 1.1h. Within 24 hours of application, 17% ± 12% of the amlexanox dose had been excreted in the urine as amlexanox and its conjugates (7.8%), the amlexanox hydroxylated metabolite, M-1 (6.2%), and conjugates of M1 (3%).

Amlexanox serum levels following a single application of 5% amlexanox paste. Values are means ± SD [78] and were dose-normalised to 100mg of paste. In the multiple-dose pharmacokinetic study and efficacy studies, serum amlexanox levels were higher in subjects applying the paste to more than one ulcer than those with only one lesion, as would be [78] expected. Steady-state concentrations were reached within approximately 1 week, and no significant accumulation of amlexanox was observed over time. Furthermore, after 2 weeks of amlexanox exposure, the incremental increase in serum concentration at 2 hours after dosing was similar to that seen in subjects who had received a single dose. Efficacy Of the 1335 subjects included in the efficacy studies, 86% were white and 53% were women. Their mean [77] age was 28.6 ± 6.4 years, with 75% of subjects aged <30 years of age. The mean time between noticing symptoms and initiating treatment was approximately 24 hours. Over 80% of subjects presented 2 with a single ulcer of 1–72mm in area and, across the studies, mean ulcer size ranged from 4.7 to 2 7.8mm , with mean pain VAS scores varying between 4.1 and 4.7cm. No significant differences in ulcer size or pain were noted between treatment groups within each study. When the ulcers of subjects in the notreatment groups were evaluated, a large degree of variability was observed in time to healing: 10–15% of subjects had ulcers that healed within 2 days while 20% of subjects had ulcers that took longer than 10 [77] days to completely heal. Application of 5% amlexanox topical paste was shown to statistically accelerate complete ulcer healing and the time to resolution of pain across the four studies. Over the third, fourth and fifth days of treatment, amlexanox produced statistically superior reductions in ulcer size compared with no treatment (p < 0.001 for all comparisons) and with vehicle (p < 0.002 at day 3; p < 0.001 at days 4 and 5; figure 2). Furthermore, significantly more amlexanox recipients had completely healed ulcers from day 3

Cumulative proportion of subjects with complete pain resolution over time with (a) 5% amlexanox vs no [59,61] treatment (studies 106 and 108) and (b) 5% amlexanox vs vehicle (studies 106, 107 and 108). * p < 0.05. In addition to accelerating the healing of aphthous ulcers, 5% amlexanox has also been shown to prevent [80] ulceration at the prodromal stage. Patients with prodromal symptoms that were validated by thermography were randomised to receive either 5% amlexanox or no treatment. After 3 days, 35% of the amlexanox recipients had developed an ulcer, compared with 97% of patients in the no-treatment group. Amlexanox reduced the maximum ulcer size score by 84% (p < 0.01), ulceration by 88% (p < 0.01), the maximum pain score by 69% and the extent of pain by 85% (p < 0.01) compared with no treatment. Taken together, the medium improvement in healing of approximately 1.5 days (based on either ulcer size or pain resolution) with amlexanox compared with no treatment, as well as the prevention of pain and ulceration when amlexanox was applied in the prodromal stage of the condition, are of significant clinical relevance. This is particularly true given that current management of RAU is symptomatic rather than prophylactic. Safety [78] Treatment with amlexanox was well tolerated across the oral and dermal studies. In the oral application studies, effects that were considered by investigators to be potentially related to the study treatment occurred in 2.1%, 2.5% and 2.4% of vehicle, 1% amlexanox and 5% amlexanox recipients, respectively. These effects were all classed as mild to moderate in severity, with the exception of one case of severe stinging in the vehicle treatment group. Most effects were local and, other than the transient stinging or burning that was reported in 1.3% of subjects, no single adverse effect occurred in >1% of the study population. No adverse effects were reported in the dermal irritation study and, likewise, no adverse effects considered to be potentially related to the study treatments were reported in the dermal sensitisation [78] study. Carcinogenesis, Mutagenesis, Impairment of Fertility : Amlexanox was not carcinogenic when administered orally to rats for two years and to mice for 18 months. In vitro (Ames) and in vivo (mouse micronucleus) mutagenicity tests of amlexanox were negative. Amlexanox at doses up to two 2 hundred times the projected human daily dose, on a mg/m basis, did not significantly affect fertility or general reproductive performance in rats. Pregnancy Category B : Teratology studies were performed with rats and rabbits at doses up to two 2 hundred and six hundred times, respectively, the projected human daily dose, on a mg/m basis. No adverse fetal effects were observed. At doses up to two hundred times the projected human daily dose, on 2 a mg/m basis, amlexanox did not have significant effect on peri- and postnatal development of rat fetuses. There are no adequate and well-controlled studies in pregnant women. Nursing Mothers : Amlexanox was found in the milk of lactating rats; therefore, caution should be exercised when administering amlexanox oral paste, 5%, to a nursing woman. Pediatric Use : Safety and effectiveness of amlexanox oral paste, 5%, in pediatric patients have not been established Geriatric Use : Clinical studies of Lexanox did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy How to apply : The paste should be applied as soon as possible after noticing the symptoms of an aphthous ulcer, four times daily, preferably following oral hygiene after breakfast, lunch, dinner, and at bedtime. The paste should be applied after drying the ulcer(s) by gently patting it with a soft, clean cloth. On a clean finger tip approximately 1/4 inch (0.5 cm) should be squeezed out of the tube and applied to the site of mouth ulcer. How supplied : Amlexanox oral paste, 5%, is supplied in 5 gram tubes. Amlexanox oral paste, 5%, should be stored at controlled room temperature, 15°-30°C (59°-86°F)

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