Pharmacological properties of the drug Methylprednisolone aceponate
GCS for external use. Has anti-inflammatory and anti-allergic effects. It has virtually no systemic GCS or mineralocorticoid effect. Suppresses the skin inflammatory reaction, reduces vascular permeability. Systemic absorption does not exceed 2.5%. Possessing high lipophilicity, it quickly penetrates through the stratum corneum of the skin into the dermis, where it undergoes hydrolysis with the formation of active metabolites - 17-propionate and free methylprednisolone. Both derivatives have greater affinity for steroid receptors than the parent compound. After entering the systemic circulation, it is quickly conjugated with glucuronic acid and inactivated. It is excreted mainly by the kidneys in the form of metabolites. The half-life is about 16 hours. It does not accumulate in the body.
Currently, atopic dermatitis (AD) is considered a chronic recurrent allergic skin disease that occurs mainly in early childhood in individuals with a hereditary predisposition. The disease has age-related features of the localization and morphology of inflammation foci, is characterized by skin itching and is caused by hypersensitivity to both allergens and nonspecific irritants [1–3].
In clinical practice, the term “atopy” has been used since the 1920s, and later the term “atopic dermatitis” was used, characterized by an unusual response of the skin to common irritants [4]. In 1980, JM Hanifin and G. Rajka [5] proposed the currently generally accepted criteria for diagnosing AD; over 37 years of use, the criteria have been modified.
According to modern concepts, the most effective approach to the treatment of AD is complex therapy. In children, a necessary component is a hypoallergenic diet and the elimination of risk factors in everyday life. In clinical practice, antihistamines can be used for the treatment of AD; according to indications, sodium thiosulfate, magnesium sulfate, pro- and prebiotics, vitamins A, E [1, 6].
The leading role in the complex treatment of AD is played by external therapy, the purpose of which is to suppress skin inflammation, hydrate the skin, prevent and eliminate secondary infection, and improve the barrier functions of the skin. The choice of external agents for treatment is determined by the age of the child, the phase of the disease, and the presence of complications [1, 6, 7]. The use of such traditional means as tar, sulfur, naphthalan, ichthyol, antiseptic - Dorogov stimulant (ASD) (3rd fraction), menthol, anesthesin, is limited by their sharp specific odor, which can lead to exacerbation of both the skin and respiratory processes syndrome that can be observed in AD. In modern medical practice, the main role in the treatment of exacerbations of AD is given to topical glucocorticosteroids (GCS) due to their high efficiency. The drugs are recognized as first-line treatment for AD, while topical calcineurin inhibitors, recommended in some publications, are classified [8] as second-line due to unproven safety. In addition, a pilot study demonstrated the benefits of using methylprednisolone aceponate compared to pimecrolimus [9]. The benefits of methylprednisolone aceponate compared to tacrolimus were also shown [10]. Topical corticosteroids are the optimal means for relieving exacerbation of AD from the standpoint of evidence-based medicine [11].
The first use of the topical corticosteroid hydrocortisone in 1950 revolutionized dermatology. In the 1960s–1970s. more effective agents were synthesized, the potential of which increased due to either halogenation or methylation of the main molecule of the steroid framework [11].
For use in pediatric practice, topical corticosteroids are subject to particularly strict criteria: such a drug must have a strong anti-inflammatory effect, low systemic bioavailability, rapid onset of action and minimal local side effects [6, 7, 11].
Halogenated topicals are widely used in dermatological practice.
In the Russian Federation, a lot of halogenated GCS is used [12]. When prescribing them, it is necessary to take into account that such drugs are genotoxic in vitro, and chromosomal aberrations of peripheral blood are indicated [13]. The use of halogenated steroid drugs leads to a decrease in the synthesis of fibroblasts, collagen, glycosaminoglycans, a slowdown in the rate of cell division of the epidermis and dermis, which predisposes to the development of skin atrophy, as well as side effects such as perioral dermatitis, stretch marks, hypertrichosis, acneiform folliculitis, and pigmentation disorders. Long-term circulation of halogenated drugs in the blood determines the suppression of the production and disruption of the circadian rhythm of endogenous cortisol [14].
In pediatric practice, it is preferable to use non-halogenated topical agents. These include methylprednisolone aceponate, which has high anti-inflammatory activity [11], lipophilicity, and improved pharmacokinetics compared to previously created drugs [4].
The purpose of this work was to evaluate data on the effectiveness and safety of the use of methylprednisolone aceponate (Advantan, BAYER) in the complex therapy of children suffering from AD.
Material and methods
The work used data presented in MEDLINE/PubMed for the query “methylprednisolone aceponate atopic dermatitis”. Inclusion criteria: compliance with the search query, publication in English. The exclusion criterion was inconsistency with the publication of the drug and/or nosological form. 26 publications were found, 17 of them are considered in the review. In addition, 9 publications containing the necessary definitions are presented [1–6, 12–14].
results
Methylprednisolone aceponate belongs to the second class of topical corticosteroids, i.e. 100–150 times more effective than hydrocortisone. Advantan's active metabolite, 6α-methylprednisolone-17-propionate, binds to intracellular glucocorticoid receptors. The steroid receptor complex interacts with specific sections of DNA, thereby causing a series of biological effects. In particular, this leads to the induction of the synthesis of the lipocortin-1 protein, which suppresses the activity of the key enzyme of the arachidonic acid cascade, phospholipase A2, as a result of which the synthesis of pro-inflammatory prostaglandins and leukotrienes is disrupted. Other mechanisms of the anti-inflammatory effect of GCS have been established: inhibition of the formation and all functions of macrophages, inhibition of the synthesis of proinflammatory cytokines, enhancement of the vasoconstrictor effect of adrenaline, etc. [7, 10]. Topical use of methylprednisolone aceponate leads to the suppression of inflammatory and allergic skin reactions, as well as reactions associated with increased proliferation, which leads to a reduction in objective symptoms (such as erythema, swelling, lichenification) and subjective sensations (itching, irritation, pain). When methylprednisolone aceponate is used externally in an effective dosage (0.1%), systemic exposure is minimal. After repeated application of the drug to large surfaces (40–60% of the skin surface), as well as use under an occlusive dressing, no dysfunction of the adrenal glands is observed, the level of cortisol in plasma and its circadian rhythm remain within normal limits, and there is no decrease in the level of cortisol in daily urine [ 6, 11].
When it enters the systemic circulation, 6α-methylprednisolone-17-propionate quickly and completely binds to the transport protein transcortin, and then undergoes conjugation with glucuronic acid in the liver and is excreted in a conjugated form by the kidneys [7, 11].
The effectiveness of therapy largely depends on the correct choice of dosage form. When choosing it, it is necessary to take into account such morphofunctional features of the skin in children as constant anatomical and physiological development, rapid change of layers of the epidermis, loose arrangement of keratinizing cells, intense mitosis not only in the basal, but also in the spinous and granular layers, increased sensitivity of the skin to external influences, abundant vascularization of the skin, one layer of endothelial cells near the vessels [6].
The choice of external agents for treatment is determined by the age of the child, the phase of the disease, and the presence of complications [15–17]. Methylprednisolone aceponate is approved for use in children starting from 4 months of age [12]. The undoubted advantages of the drug include the possibility of its use on vulnerable areas of the skin, in particular on the face. The use of 0.1% methylprednisolone aceponate allows you to choose the optimal dosage form for the appropriate age group. For children of the first year of life, an emulsion based on 67.5% water is preferred; for children under 3 years of age, an emulsion and cream based on 60% water is preferred. From the age of three, ointment can be used on foci of chronic inflammation, and fatty ointment can be used on foci of persistent chronic inflammation, especially in areas with a pronounced stratum corneum [6, 7, 11].
Studies on the properties of methylprednisolone aceponate have been conducted in different countries. Thus, domestic practice has accumulated experience in the effective use of methylprednisolone aceponate in pediatric practice [6]. Reliable clinical evidence of the high effectiveness of methylprednisolone aceponate when used in children of the first year of life has been obtained [16, 17]. The drug has a pronounced antipruritic effect in chronic itching, the leading symptom of AD [17].
Numerous evidence has been presented regarding the advisability of using methylprednisolone aceponate in preschool children [6, 18–20]. The use of the drug in adolescents is justified [7, 10, 21].
Experience with the use of Advantan has shown that the elimination of itching and inflammation under the influence of the drug leads to an improvement in the general condition, in particular, eliminates sleep disorders in various age groups, which plays a very significant role in the treatment of children suffering from AD [16, 17, 22].
Methylprednisolone aceponate in the form of one of four dosage forms (emulsion, cream, ointment, fatty ointment) is recommended for use once a day [23]. A single use of a drug with a high level of effectiveness and safety significantly increases adherence to therapy [23].
Currently, methods for the treatment of AD have been developed that involve the use of methylprednisolone aceponate in alternation with moisturizers [24, 25].
Significant advantages of using methylprednisolone aceponate compared with mometasone furoate have been shown [26], completely refuting an earlier report of their comparable anti-inflammatory activity [27].
Methylprednisolone aceponate is well tolerated by patients of various age groups [6, 7, 11, 15–25]. We found the only description of the development of contact sensitization to the drug in a patient previously sensitized with 17-hydrocortisone butyrate [28].
Thus, the vast majority of studies conducted indicate the high effectiveness and safety of external use of methylprednisolone aceponate (Advantan, BAYER) in various age groups of children. Choosing the optimal dosage form of the drug depending on age and clinical characteristics will increase the therapeutic effect.
Advantan emuls 0.1% 20g
Registration Certificate Holder
LEO Pharma (Denmark)
Dosage form
Medicine - Advantan® (Advantan®)
Description
Emulsion for external use 0.1%
white, opaque.
1 g
methylprednisolone aceponate 1 mg
Excipients
: medium chain triglycerides - 150 mg, softizan 378 - 50 mg, polyoxyethylene-2-steryl alcohol - 40 mg, polyoxyethylene-21-steryl alcohol - 40 mg, glycerol 85% - 30 mg, disodium edetate - 1 mg, benzyl alcohol - 12.5 mg, purified water - 675.5 mg.
20 g - laminated aluminum tubes (1) - cardboard packs.
Indications
Ointment, cream, greasy ointment
Inflammatory skin diseases sensitive to therapy with topical corticosteroids:
- atopic dermatitis, neurodermatitis, childhood eczema;
- true eczema;
- microbial eczema;
- occupational eczema;
- dyshidrotic eczema;
- simple contact dermatitis;
- allergic (contact) dermatitis.
Emulsion
Inflammatory skin diseases sensitive to therapy with topical corticosteroids:
- atopic dermatitis, neurodermatitis, childhood eczema;
- simple contact dermatitis;
- allergic (contact) dermatitis;
- true eczema;
- seborrheic dermatitis/eczema;
- microbial eczema;
- photodermatitis, sunburn.
Contraindications for use
- tuberculous or syphilitic processes in the area of application of the drug;
- viral diseases in the area where the drug is applied (for example, chickenpox, herpes zoster);
- rosacea, perioral dermatitis in the area of application of the drug;
- areas of skin with signs of reaction to vaccination;
- children up to 4 months;
- hypersensitivity to the components of the drug.
pharmachologic effect
When applied externally, Advantan® suppresses inflammatory and allergic skin reactions, as well as reactions associated with increased proliferation, which leads to a reduction in objective symptoms of inflammation (including erythema, swelling, weeping, etc.) and subjective sensations ( including itching, irritation, pain, etc.).
When methylprednisolone aceponate is used externally at the recommended dose, the systemic effect is minimal in both humans and animals. After repeated application of Advantan to large surfaces (40-60% of the skin surface), as well as when applied under an occlusive dressing, no dysfunction of the adrenal glands is observed: the level of cortisol in the blood plasma and its circadian rhythm remain within normal limits, and there is no decrease in the level of cortisol in daily urine is happening.
During clinical studies, the use of Advantan for up to 12 weeks in adults and up to 4 weeks in children (including young children) did not reveal the development of skin atrophy, telangiectasia, stretch marks and acne-like rashes.
Methylprednisolone aceponate (especially its main metabolite, 6α-methylprednisolone-17-propionate) binds to intracellular glucocorticoid receptors. The steroid receptor complex binds to specific regions of the DNA of immune response cells, thereby causing a series of biological effects.
In particular, the binding of the steroid receptor complex to the DNA of immune response cells leads to the induction of macrocortin synthesis. Macrocortin inhibits the release of arachidonic acid and, thereby, the formation of inflammatory mediators such as prostaglandins and leukotrienes.
GCS inhibition of the synthesis of vasodilating prostaglandins and potentiation of the vasoconstrictor effect of adrenaline leads to a vasoconstrictor effect.
Drug interactions
No drug interactions have been identified with Advantan®.
Dosage regimen
Externally.
Adults and children from 4 months
The drug is applied once a day in a thin layer to the affected areas of the skin.
Continuous daily use of Advantan in the form of cream, ointment or greasy ointment should not exceed for adults
12 weeks, for
children
– 4 weeks. The course of treatment with Advantan in the form of an emulsion should usually not exceed 2 weeks.
Cream
is a dosage form with a low fat content and high water content, therefore it is recommended for
subacute and acute inflammation without significant weeping.
The cream eliminates the inflammatory process both on smooth skin and on the scalp, incl. on skin prone to oily skin.
Ointment
is a dosage form with a balanced ratio of fat and water, therefore it is recommended for
subacute or chronic inflammatory skin diseases that are not accompanied by weeping.
The ointment has a therapeutic effect, also helping to eliminate dry skin and restore its normal oil content.
Fatty ointment
is an anhydrous dosage form, therefore it is recommended for
the treatment of long-term chronic inflammatory skin processes with very dry skin
. The occlusive effect of the fatty ointment provides a pronounced therapeutic effect even with significant lichenification and infiltration.
Emulsion
Apply a thin layer to the affected areas of the skin, rubbing lightly. For sunburn, the emulsion is used 1-2 times a day. If the skin becomes excessively dry when using the emulsion, it is necessary to switch to a dosage form of Advantan® with a higher fat content (ointment or fatty ointment).
Overdose
When studying the acute toxicity of methylprednisolone aceponate, no risk of acute intoxication was identified with excessive single external use (applying the drug over a large area under conditions favorable for absorption) or unintentional ingestion.
Symptoms:
with excessively long and/or intensive local use of GCS, skin atrophy (thinning of the skin, telangiectasia, striae) may develop.
If atrophy occurs, the drug must be discontinued.
Side effect
The drug is usually well tolerated.
Very rarely
(in less than 0.01% of cases) local reactions may be observed, such as itching, burning, erythema, and the formation of a vesicular rash. If the drug is used for more than 4 weeks and/or on an area of 10% or more of the body surface, the following reactions may occur: skin atrophy, telangiectasia, striae, acneiform skin changes, systemic effects due to corticosteroid absorption. During clinical studies, none of the above side effects were noted when using Advantan® for up to 12 weeks in adults and up to 4 weeks in children.
In rare cases
(0.01-0.1%) folliculitis, hypertrichosis, perioral dermatitis, skin depigmentation, allergic reactions to one of the components of the drug may be observed.
special instructions
In the presence of bacterial complications and/or dermatomycosis, in addition to therapy with Advantan®, it is necessary to carry out specific antibacterial or antifungal treatment.
Avoid contact of the drug with the eyes.
As with the use of systemic corticosteroids, glaucoma may develop after topical use of corticosteroids (for example, when using large doses or very long-term use of occlusive dressings or application to the skin around the eyes).
Effect on the ability to drive vehicles and operate machinery
. Not identified.
Storage conditions
Ointment, cream and emulsion should be stored at a temperature not exceeding 25°C.
Best before date
Shelf life – 3 years.
Oily ointment should be stored at a temperature not exceeding 30°C. Shelf life – 5 years.
The drug should be stored out of the reach of children.
Use during pregnancy and breastfeeding
Restrictions during pregnancy - With caution. Restrictions when breastfeeding - With caution.
If it is necessary to use the drug Advantan® during pregnancy and lactation, you should carefully weigh the potential risk to the fetus and the expected benefits of therapy for the mother. During these periods, long-term use of the drug on large areas of the skin is not recommended.
Nursing mothers should not apply the drug to the mammary glands.
Use in children
Restrictions for children - With caution.
Continuous daily use of Advantan in the form of a cream, ointment or fatty ointment is for adults
no more than 12 weeks, for
children
– no more than 4 weeks.
Contraindicated in children under 4 months of age.
Terms of sale
The drug is approved for use as a means of OTC.
