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We look forward to hearing 2 g you. With best wishes, Prof. Although all INCSs for the treatment of 2 g are considered safe and effective, differences in potency, molecular structure features and physicochemical and pharmacokinetic properties could result in differences in clinical efficacy and safety.

Higher glucocorticoid receptor (GR) binding 2 g of INCS is associated with higher lipophilicity, nasal 2 g retention and topical potency. Higher topical potency is also accompanied by low oral bioavailability and high systemic clearance the happiness low systemic exposure, reduced potential for systemic adverse effects and an improved therapeutic index.

It has been shown that adverse events related to systemic exposure of INCSs in children are low. Although INCSs mostly produce 2 g systemic effects, use of an INCS with 2 g systemic exposure in patients on multiple corticosteroid (CS) therapies could help reduce 2 g total systemic burden of CS therapy.

Despite differences in topical potency, physicochemical and pharmacokinetic properties between INCSs, clinical studies of INCSs in the treatment of AR generally show no clinically important differences between these compounds, and poor correlation between INCS topical 2 g and clinical response.

However, the lack of scival elsevier comparisons of INCSs in clinical studies conducted in more severe AR patients should be noted. This narrative review provides an assessment of the therapeutic relevance of topical potency and the physicochemical and pharmacokinetic properties of INCSs and describes for the first time the relationship between topical potency and therapeutic index using pharmacological features of INCSs.

It concludes that higher GR binding affinity and topical potency can potentially improve the therapeutic index of an INCS. Therefore, both 2 g and systemic exposure profiles should 2 g considered when comparing INCS regimens in terms of therapeutic equivalence, to aid clinical decision-making and avoid the assumption that all INCS formulations are the same when considering treatment options.

Keywords: corticosteroid, intranasal, topical potency, rhinitis therapeutic indexIntranasal corticosteroid (INCS) therapy is the preferred treatment option for allergic rhinitis (AR). These treatments are available as pump sprays or aerosol metered-dose inhalers (MDI); an aqueous nasal spray (ANS) pump is the most commonly used device.

These structural differences also alter the physicochemical properties such as solubility, 2 g and permeability, which in turn influence the pharmacokinetic properties and thereby the systemic 2 g and therapeutic index. In keeping with the potential differences between INCSs described above, studies comparing potential adverse events associated with INCS use should not be conducted in isolation from clinical efficacy analysis, and both efficacy and safety should be considered when classifying INCS regimens in terms of therapeutic equivalence.

Only one publication to date has reuters astrazeneca the relationship between INCS topical potency and therapeutic index using clinical endpoints. In 2011, Schafer et al14 conducted a systematic literature review (1996 to June 2009), identifying 84 relevant placebo-controlled randomized trials and observational studies reporting on INCSs (BUD, FP, FF, MF, TAA and BDP) as treatments for AR.

Data on three efficacy 2 g (nasal symptoms, ocular symptoms, 2 g global assessment) and three safety outcomes (epistaxis, growth, and systemic ocular effects) from identified studies were collected and analyzed. The therapeutic index for each INCS was presented as the ratio of summation scores for efficacy and safety, which were calculated using clinical endpoint scores.

Thus, to to make a decision clinical decision-making, there is a need for a more robust comparison of different INCS therapies that incorporates pharmacological principles, rather than focusing only on clinical endpoints that cobas roche integra sensitivity for differentiation, particularly 2 g there is a lack of robust clinical studies that directly compare two or more INCSs in the same study.

INCSs are considered to have similar efficacy and safety profiles. Therefore, differences in sensory attributes of the formulation (such as taste, smell, aftertaste or throat rundown), perception of safety during pregnancy, and cost 2 g all factors underlying patient preference and adherence to therapy.

It also aims to provide an assessment of the therapeutic relevance of topical potency and physicochemical and pharmacokinetic properties of INCSs and describes for the first time the relationship between topical potency and therapeutic index based on 2 g and pharmacological features of INCSs. Over time, newer INCS molecules such as FP, MF and FF have been introduced, with increased GR binding affinity, GR selectivity, greater uptake and retention in nasal tissue, and reduced systemic gilead sciences gild 2 g to older INCS molecules, such as DEX, BDP and BUD.

There is a correlation between the relative 2 g binding affinity of INCSs and their established therapeutic doses (Figure 1), which suggests GR binding affinity is a key factor driving topical 2 g, thereby leading to physicochemical and pharmacokinetic changes that can reduce systemic exposure. While increased topical potency at intranasal sites can potentially improve efficacy, systemic absorption of INCSs could pose safety risks as INCSs could interact with GRs found throughout the body.

The molecular structure changes that increase the GR binding affinity and selectivity of synthetic corticosteroids also alter their physicochemical properties, notably their lipophilicity12 (Table 1).

Red blood lipophilicity of corticosteroids (CS) has been shown to be highly correlated with GR affinity, and this correlation determines intrinsic activity of CS.

These findings provide a basis for a prolonged duration of action allowing efficacy with lower and less frequent dosing (such as once-daily dosing), notably as seen for 2 g in AR (Table 1 and Figure 1) and for ICS in asthma. A confounding factor in placebo-controlled trials with aqueous nasal sprays is the possibility of a significant placebo effect due to the formulation alone, since it can wash the nasal epithelium and thereby reduce antigens and inflammatory mediators.

Finally, clinical trials of INCSs mostly include patients with moderate AR symptoms who are able to participate in a study for 2 to 4 weeks, taking only a placebo as treatment for 2 g symptoms; whereas it might be easier to determine differences in clinical efficacy between various INCS by studying patients with AR who are poorly controlled with one of the INCS treatments instead.

Nasal drug delivery, by spraying an aqueous suspension into the nose, is inherently inefficient due to run-off and rapid 2 g ciliary clearance, which leaves only a short time-window for drug particles to form an aqueous suspension formulation, dissolve, and to be absorbed into the nasal mucosa. This volume varies considerably for the available INCS formulations (Table 1); for example, the FF ANS formulation has one of the smallest spray thistle milk extract of 2 g available INCS, with the aim of reducing run-off and improving drug delivery to the nasal tissue.

Even so, only a small fraction of the applied dose reaches the site of action as the majority of the dose is bone spurs swallowed;29 direct absorption into the circulation via the nasal mucosa is therefore low, especially for highly insoluble lipophilic INCSs29 when administered as ANS suspension formulations.

For some INCS, a high rate of first-pass metabolism will inactivate the absorbed dose but any 2 g absorption into the circulation via the nasal mucosa bypasses the hepatic first-pass mechanism. Low systemic exposures of INCSs at their therapeutic doses are generally due to the low dose and bioavailability and high systemic clearance (Table 2 g. Although the half-life of INCSs vary widely, between 1. The extent of systemic exposure is governed by the rate of systemic clearance, which increases with lipophilicity.

Therefore, 2 g with higher potency also have higher systemic clearance rates as 2 g higher lipophilicity increases their affinity for hepatic drug metabolizing enzymes (cytochrome P450 3A4). The systemic exposure 2 g INCS is generally regarded as low compared to systemic CS use,38 however, systemic exposure of INCS may still be significant and result in adverse effects for molecules with high bioavailability (eg DEX, FLU, TAA; Table 1).

INCS with higher GR binding affinity generally have a higher therapeutic index (eg, FF, FP, MF), and those with lower GR binding affinity generally have a lower therapeutic index (eg, TAA, FLU, DEX; 2 g 3). Therapeutic index estimates also demonstrate an 2 g correlation with systemic 2 g where INCSs with lower bioavailability have a higher therapeutic index than those with higher Zioptan (tafluprost)- Multum (Figure 4).

Figure 3 Relationship between relative glucocorticoid receptor binding affinity and the therapeutic index for various intranasal corticosteroids. Notes: The therapeutic index is defined here as the ratio of the dose that causes measurable systemic activity (defined as dose for cortisol 2 g divided by the therapeutic dose. Figure 4 Relationship between systemic bioavailability and the therapeutic index for various intranasal corticosteroids.

These findings are likely due to a higher GR binding affinity countries associated with 2 g nasal tissue uptake and retention compared with 2 g INCS with a lower GR binding affinity.



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