MECLODERM BN COMBINATION PRODUCT CREAM

Indications

• Suppression of inflammatory disorders
• Management of allergic conditions
• Congenital adrenal hyperplasia
• Inflammatory and allergic eye conditions

Dosage

Children: For children aged 1–11 months: Initially 1 mg, repeated up to 4 times in 24 hours according to response. Aged 1–5 years: Initially 2 mg, repeated up to 4 times in 24 hours according to response. Aged 6–11 years: Initially 4 mg, repeated up to 4 times in 24 hours according to response. Aged 12–17 years: 4–20 mg, repeated up to 4 times in 24 hours according to response.

Adults: Dosage varies based on condition; typically, initial doses are adjusted according to the patient's response and severity of condition.

Mechanism of action

Betamethasone exerts its effects by binding to glucocorticoid receptors, leading to modulation of gene expression and suppression of inflammatory cytokines and mediators.

Pharmacodynamics

Betamethasone reduces inflammation and immune response, which is beneficial in managing various inflammatory and allergic disorders.

Pharmacokinetics

Betamethasone is rapidly absorbed after administration, with a long half-life allowing for once-daily dosing in many cases. It is metabolized in the liver and excreted primarily in urine.

Adverse effects

• Hiccups
• Oedema
• Mood and behaviour changes
• Vision disorders
• Serious gastro-intestinal effects
• Musculoskeletal effects
• Ophthalmic effects
• Stevens-Johnson syndrome
• Myocardial rupture (following recent myocardial infarction)

Interactions

• Cobicistat + betamethasone: Unknown (increases exposure)
• Idelalisib + betamethasone: Unknown (increases exposure)
• Clarithromycin + betamethasone: Unknown (increases exposure)

Precautions

• Immunosuppression due to prolonged corticosteroid treatment
• Adrenal suppression if given for longer than 3 weeks
• Increased susceptibility to infections, including chickenpox and measles

Pregnancy

Readily crosses the placenta. Transient effect on fetal movements and heart rate.

Storage

Store at room temperature, protect from light.

Formulations

• Betamethasone sodium phosphate 4 mg per 1 ml solution for injection ampoules

Indications

• Vaginal candidiasis
• Vulval candidiasis
• Superficial fungal infections
• Otitis externa (as part of combination therapy)

Dosage

Adults: For vaginal candidiasis, 1 pessary of 500 mg can be inserted at night. Alternatively, for treatment with 1% cream, apply 2–3 times a day to the affected area for at least 14 days. For recurrent vulvovaginal candidiasis

Mechanism of action

Clotrimazole acts primarily by damaging the permeability barrier in the cell membrane of fungi. It inhibits ergosterol biosynthesis, which is essential for maintaining the integrity of fungal cell membranes. The inhibition of lanosterol 14-demethylase (CYP51) is a key mechanism behind its antifungal properties, leading to decreased ergosterol synthesis and resulting in cell membrane dysfunction. Clotrimazole also affects calcium homeostasis by inhibiting sarcoplasmic reticulum Ca2+-ATPase and blocking calcium-dependent potassium channels, contributing to its overall pharmacological effects.

Pharmacodynamics

Clotrimazole is considered a broad-spectrum antifungal that alters the permeability of fungal cell membranes, leading to inhibition of growth in pathogenic yeasts. At lower concentrations, it exhibits fungistatic properties, while at higher concentrations, it may be fungicidal against certain strains like Candida albicans. However, resistance to clotrimazole has become more common in recent years, limiting its efficacy in some populations.

Pharmacokinetics

Clotrimazole is primarily applied topically, and its absorption varies depending on the formulation and site of application. Following topical administration, systemic absorption is minimal, thereby reducing the risk of systemic side effects. The drug is metabolized in the liver and excreted via urine and feces. The pharmacokinetics may differ based on the dosing regimen and specific formulation used.

Contra-indications

• Hypersensitivity to clotrimazole or any excipients in the formulation
• Not recommended if trying to conceive due to potential damage to latex condoms and diaphragms

Adverse effects

• Skin reactions
• Vaginal burning
• Angioedema

Interactions

• Clotrimazole may increase the exposure of lomitapide, though the specific nature of this interaction is unknown

Precautions

• Avoid use in pregnancy without medical advice
• Use caution in patients with a history of hypersensitivity reactions

Pregnancy

Clotrimazole should be used during pregnancy only if clearly needed. Oral antifungal treatments should be avoided.

Breast-feeding

Clotrimazole is excreted in breast milk; caution is advised when used in breastfeeding mothers.

Storage

Store in a cool, dry place, away from direct sunlight. Keep out of reach of children.

Formulations

• Clotrimazole 1% cream
• Clotrimazole 2% cream
• Clotrimazole 500 mg vaginal pessaries
• Clotrimazole 10% vaginal cream
• Clotrimazole 1% solution (ear drops)

Indications

• Bowel sterilization before surgery
• Hepatic coma
• Topical infections caused by susceptible organisms

Dosage

Children: Refer to the BNF for Children for appropriate dosing information.

Adults: By mouth: 1 g every 1 hour for 4 hours, then 1 g every 4 hours for 2–3 days. For hepatic coma: Up to 4 g daily in divided doses usually for 5–7 days.

Mechanism of action

Neomycin sulfate binds to the 30S ribosomal subunit of bacteria, leading to the misreading of mRNA and the inhibition of protein synthesis. This disrupts the production of essential proteins needed for bacterial growth and function, ultimately resulting in cell death.

Pharmacodynamics

Neomycin demonstrates bactericidal activity against susceptible bacteria. Its efficacy is enhanced in alkaline environments, which is why it is often used in combination with other agents for surgical prophylaxis. The drug is primarily effective against a range of gram-negative organisms, including Escherichia coli and Klebsiella species, but also has some activity against gram-positive organisms.

Pharmacokinetics

Neomycin is poorly absorbed from the gastrointestinal tract, and its systemic absorption is minimal when administered orally. In cases of systemic use, such as intramuscular or intravenous administration, neomycin is distributed widely in the body but is primarily excreted unchanged in the urine. The elimination half-life varies but is generally around 2 to 3 hours in individuals with normal renal function. Monitoring of serum concentrations is essential to prevent toxicity, especially in patients with renal impairment.

Adverse effects

• neurotoxicity
• ototoxicity
• nephrotoxicity
• allergic reactions
• skin rashes
• hearing loss

Interactions

• other nephrotoxic drugs
• loop diuretics
• neuromuscular blocking agents

Precautions

• monitor renal function
• use cautiously in patients with hearing impairment
• avoid concurrent use with other ototoxic medications
• ensure adequate hydration

Pregnancy

Safety in pregnancy has not been established. Use only if the potential benefit justifies the potential risk to the fetus.

Breast-feeding

Use caution; neomycin can be absorbed systemically and may affect the nursing infant.

Storage

Store at room temperature, away from light and moisture. Keep out of reach of children.

Formulations

• oral tablets
• topical ointments
• injectable solutions

Indications

• Eczema
• Psoriasis
• Contact dermatitis
• Seborrheic dermatitis
• Atopic dermatitis

Dosage

Children: Refer to the BNF for Children for appropriate dosing information.

Adults: Refer to relevant clinical guidelines or product information for specific dosing instructions.

Mechanism of action

Betamethasone dipropionate exerts its effects by binding to the glucocorticoid receptor, leading to the modulation of gene expression. This interaction results in the inhibition of pro-inflammatory cytokines, chemokines, and adhesion molecules, which reduces inflammation, suppresses the immune response, and promotes vasoconstriction in the affected tissues.

Pharmacodynamics

The pharmacodynamic effects of betamethasone dipropionate include a significant reduction in inflammation and immune response due to the inhibition of leukocyte infiltration at the site of inflammation. The drug also inhibits the release of arachidonic acid, subsequently decreasing the production of inflammatory mediators such as prostaglandins and leukotrienes. Its efficacy is enhanced by its high lipid solubility, allowing for better penetration through the skin layers.

Pharmacokinetics

Betamethasone dipropionate is well absorbed through the skin when applied topically. Its bioavailability is influenced by the formulation and the condition of the skin. The drug is metabolized primarily in the liver to inactive metabolites, which are excreted in the urine. The systemic absorption and effects are minimal when used as directed, but caution is advised in extensive applications or occlusive dressings, which may increase absorption.

Adverse effects

• Local skin atrophy
• Striae
• Telangiectasia
• Hypopigmentation
• Allergic contact dermatitis
• Systemic effects with prolonged use

Precautions

• Use with caution in patients with a history of diabetes mellitus
• Monitor for potential adrenal suppression with prolonged use
• Avoid application to infected areas unless treated

Pregnancy

Betamethasone dipropionate should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Limited data suggest that topical corticosteroids have low systemic absorption.

Breast-feeding

Caution is advised when using betamethasone dipropionate during breastfeeding, as it is unknown whether it is excreted in breast milk. Topical corticosteroids should be applied sparingly and avoided on the breast area to minimize ingestion by the infant.

Storage

Store at room temperature, away from light and moisture. Keep out of reach of children.

Formulations

• Topical cream
• Topical ointment
• Topical lotion

Indications

• Bacterial infections caused by aerobic organisms
• Topical treatment of skin infections

Mechanism of action

Neomycin binds to specific proteins and 16S rRNA within the 30S ribosomal subunit of susceptible bacteria. This binding interferes with the decoding site, causing misreading of mRNA and leading to the incorporation of incorrect amino acids into polypeptides. As a result, nonfunctional or toxic peptides are produced, and polysomes are disrupted into nonfunctional monosomes. Neomycin's bactericidal action is characterized by its ability to irreversibly bind to the 30S ribosomal subunit, thereby inhibiting bacterial protein synthesis.

Pharmacodynamics

Neomycin is primarily active against aerobic bacteria and is not effective against fungi, viruses, or most anaerobic bacteria. It mediates its bactericidal effects by inhibiting protein synthesis, which suppresses bacterial growth and survival. Following oral administration, neomycin exhibits a duration of bactericidal activity lasting between 48 to 72 hours. It is particularly useful in treating infections caused by strains of E. coli and Klebsiella, and it also acts to reduce colonic bacterial populations in patients with hepatic coma.

Pharmacokinetics

Neomycin is poorly absorbed from the gastrointestinal tract when taken orally, which limits its systemic availability and enhances its utility in targeting colonic bacteria. It is generally not used parenterally due to its potential for nephrotoxicity and ototoxicity. The duration of action following oral administration can last from 48 to 72 hours, and it is primarily excreted unchanged in the urine. Caution should be exercised when using neomycin in patients with renal impairment, as the risk of toxicity increases.

Adverse effects

• Nephrotoxicity
• Ototoxicity
• Allergic reactions
• Diarrhea
• Nausea
• Vomiting

Interactions

• neomycin+digoxin: Unknown (decreases absorption)
• neomycin+sorafenib: Unknown (decreases exposure)

Precautions

• Use with caution in patients with renal impairment
• Monitor renal function during therapy
• Evaluate hearing function in long-term use

Pregnancy

Neomycin is classified as category D; it should be used only if the potential benefit justifies the potential risk to the fetus.

Breast-feeding

Neomycin is excreted in breast milk; caution should be exercised when administered to nursing mothers.

Storage

Store in a cool, dry place away from light. Keep out of reach of children.

Formulations

• Topical ointment
• Cream
• Eye drops
• Oral tablets

Mechanism of action

Glucocorticoids inhibit neutrophil apoptosis and demargination, and inhibit NF-Kappa B and other inflammatory transcription factors. They also inhibit phospholipase A2, leading to decreased formation of arachidonic acid derivatives. In addition, glucocorticoids promote anti-inflammatory genes like interleukin-10. Corticosteroids like betamethasone can act through nongenomic and genomic pathways. The genomic pathway is slower and occurs when glucocorticoids activate glucocorticoid receptors and initiate downstream effects that promote transcription of anti-inflammatory genes including phosphoenolpyruvate carboxykinase (PEPCK), IL-1-receptor antagonist, and tyrosine amino transferase (TAT). On the other hand, the nongenomic pathway is able to elicit a quicker response by modulating T-cell, platelet and monocyte activity through the use of existing membrane-bound receptors and second messengers. Corticosteroids interact with specific receptor proteins in target tissues to regulate the expression of corticosteroid responsive genes, thereby changing the levels and array of proteins synthesized by the various target tissues. As a consequence of the time required for changes in gene expression and protein synthesis, most effects of corticosteroids are not immediate, but become apparent after several hours. ... Although corticosteroids predominantly act to increase expression of target genes, there are well documented examples where glucocorticoids decrease transcription of target genes ... In contrast to these genomic effects, recent studies have raised the possibility that some actions of corticosteroids are immediate and are mediated by membrane-bound receptors. /Adrenocorticosteroids/ The mechanisms by which glucocorticoids inhibit glucose utilization in peripheral tissues are not fully understood. Glucocorticoids decrease glucose uptake in adipose tissue, skin, fibroblasts, thymocytes, and polymorphonuclear leukocytes; these effects are postulated to result from translocation of the glucose transporters from the plasma membrane to an intracellular location. These peripheral effects are associated with a number of catabolic actions, including atrophy of lymphoid tissue, decreased muscle mass, negative nitrogen balance, and thinning of the skin. /Adrenocorticalsteroids/ The mechanisms by which the glucocorticoids promote gluconeogenesis are not fully defined. Amino acids mobilized from a number of tissues in response to glucocorticoids reach the liver and provide substrate for the production of glucose and glycogen. In the liver, glucocorticoids induce the transcription of a number of enzymes involved in gluconeogenesis and amino acid metabolism, including phosphoenolpyruvate carboxykinase, glucose-6-phosphatase, and fructose-2,6-bisphosphatase. Analyses of the molecular basis for regulation of phosphoenolpyruvate carboxykinase gene expression have identified complex regulatory influences involving an interplay among glucocorticoids, insulin, glucagon, and catecholamine. The effects of these hormones and amines on phosphoenolpyruvate carboxykinase gene expression mirror the complex regulation of gluconeogenesis in the intact organism. /Adrenocorticalsteroids/ ... /A/ major action of corticosteroids on the cardiovascular system is to enhance vascular reactivity to other vasoactive substances. Hypoadrenalism generally is associated with hypotension and reduced response to vasoconstrictors such as norepinephrine and angiotensin II. This diminished pressor response is explained partly by recent studies in experimental systems showing that glucocorticoids increase expression of adrenergic receptors in the vascular wall. Conversely, hypertension is seen in patients with excessive glucocorticoid secretion, occurring in most patients with Cushing's syndrome and in a subset of patients treated with synthetic glucocorticoids (even those lacking any significant mineralocorticoid action). /Adrenocorticosteroids/ For more Mechanism of Action (

Pharmacodynamics

Corticosteroids bind to the glucocorticoid receptor inhibiting pro-inflammatory signals, while promoting anti-inflammatory signals. Corticosteroids have a wide therapeutic window as patients may require doses that are multiples of what the body naturally produces. Patients who require long-term treatment with a corticosteroid should be counselled regarding the risk of hypothalamic-pituitary-adrenal axis suppression and increased susceptibility to infections.

Mechanism of action

Clotrimazole acts primarily by damaging the permeability barrier in the cell membrane of fungi. Clotrimazole causes inhibition of ergosterol biosynthesis, an essential constituent of fungal cell membranes. If ergosterol synthesis is either completely or partially inhibited, the cell is no longer able to construct an intact and functional cell membrane,. Because ergosterol directly promotes the growth of fungal cells in a hormone‐like fashion, rapid onset of the above events leads to dose-dependent inhibition of fungal growth. Though decreased ergosterol, due to the inhibition of lanosterol 14-demethylase (also known as _CYP51_) is accepted to be primarily responsible for the antimycotic properties of clotrimazole, this drug also shows other pharmacological effects. These include the inhibition of sarcoplasmic reticulum Ca2+‐ATPase, depletion of intracellular calcium, and blocking of calcium‐dependent potassium channels and voltage‐dependent calcium channels. The action of clotrimazole on these targets accounts for other effects of this drug that are separate from its antimycotic activities. Clotrimazole exerts its antifungal activity by altering cell membrane permeability, apparently by binding with phospholipids in the fungal cell membrane. In contrast to polyene antibiotics (eg, amphotericin B), the action of clotrimazole is less dependent on the sterol content of the cell membrane. As a result of alteration of permeability, the cell membrane is unable to function as a selective barrier, and potassium and other cellular constituents are lost.

Pharmacodynamics

Clotrimazole is a broad-spectrum antifungal agent that inhibits the growth of pathogenic yeasts by changing the permeability of cell membranes. The action of clotrimazole is fungistatic at concentrations of drug up to 20 mcg/mL and may be fungicidal _in vitro_ against Candida albicans and other species of the genus Candida at higher concentrations. Unfortunately, resistance to clotrimazole, which was rare in the past, is now common in various patient populations. Clotrimazole is generally considered to be a fungistatic, and not a fungicidal drug, although this contrast is not absolute, as clotrimazole shows fungicidal properties at higher concentrations.

Mechanism of action

Framycetin binds to specific 30S-subunit proteins and 16S rRNA, four nucleotides of 16S rRNA and a single amino acid of protein S12. This interferes with decoding site in the vicinity of nucleotide 1400 in 16S rRNA of 30S subunit. This region interacts with the wobble base in the anticodon of tRNA. This leads to interference with the initiation complex, misreading of mRNA so incorrect amino acids are inserted into the polypeptide leading to nonfunctional or toxic peptides and the breakup of polysomes into nonfunctional monosomes. Like other aminoglycoside antibiotic drugs, neomycin inhibits bacterial ribosomes by binding to the 30S ribosomal subunit of susceptible bacteria and disrupting the translational machinery of bacterial protein synthesis. Bacterial translation is normally initiated by the mRNA binding to the 30S ribosomal subunit and subsequent binding with 50S subunit for elongation. Aminoglycosides are usually bactericidal in action. Although the exact mechanism of action has not been fully elucidated, the drugs appear to inhibit protein synthesis in susceptible bacteria by irreversibly binding to 30S ribosomal subunits. /Aminoglycosides/ A class of angiogenesis inhibitor has emerged from our mechanistic study of the action of angiogenin, a potent angiogenic factor. Neomycin, an aminoglycoside antibiotic, inhibits nuclear translocation of human angiogenin in human endothelial cells, an essential step for angiogenin-induced angiogenesis. The phospholipase C-inhibiting activity of neomycin appears to be involved, because U-73122, another phospholipase C inhibitor, has a similar effect. In contrast, genistein, oxophenylarsine, and staurosporine, inhibitors of tyrosine kinase, phosphotyrosine phosphatase, and protein kinase C, respectively, do not inhibit nuclear translocation of angiogenin. Neomycin inhibits angiogenin-induced proliferation of human endothelial cells in a dose-dependent manner. At 50 microM, neomycin abolishes angiogenin-induced proliferation but does not affect the basal level of proliferation and cell viability. Other aminoglycoside antibiotics, including gentamicin, streptomycin, kanamycin, amikacin, and paromomycin, have no effect on angiogenin-induced cell proliferation. Most importantly, neomycin completely inhibits angiogenin-induced angiogenesis in the chicken chorioallantoic membrane at a dose as low as 20 ng per egg. These results suggest that neomycin and its analogs are a class of agents that may be developed for anti-angiogenin therapy. ... Aminoglycosides are aminocyclitols that kill bacteria by inhibiting protein synthesis as they bind to the 16S rRNA and by disrupting the integrity of bacterial cell membrane. Aminoglycoside resistance mechanisms include: (a) the deactivation of aminoglycosides by N-acetylation, adenylylation or O-phosphorylation, (b) the reduction of the intracellular concentration of aminoglycosides by changes in outer membrane permeability, decreased inner membrane transport, active efflux, and drug trapping, (c) the alteration of the 30S ribosomal subunit target by mutation, and (d) methylation of the aminoglycoside binding site. ... /Aminoglycosides/

Pharmacodynamics

Framycetin is used for the treatment of bacterial eye infections such as conjunctivitis. Framycetin is an antibiotic. It is not active against fungi, viruses and most kinds of anaerobic bacteria. Framycetin works by binding to the bacterial 30S ribosomal subunit, causing misreading of t-RNA, leaving the bacterium unable to synthesize proteins vital to its growth. Framycetin is useful primarily in infections involving aerobic bacteria bacteria. Neomycin mediates its bactericidal action by inhibiting bacterial protein synthesis, thereby suppressing the growth and survival of susceptible bacteria. Following oral administration, the duration of bactericidal activity of neomycin ranged from 48 to 72 hours. By decreasing colonic bacteria that produce ammonia, neomycin was shown to be effective as an adjunctive therapy in hepatic coma to improve neurologic symptoms. Neomycin is active against both gram positive and gram negative organisms, including the major _E. coli_ species resident in the colon as well as the enteropathogenic forms of _E. coli_. It is also active against _Klebsiella_-_Enterobacter_ group. Resistant strains of _E. coli_, _Klebsiella_ and _Proteus spp_. may emerge from neomycin therapy. Neomycin has no antifungal activity and has some activity against some protozoa.