bromochloroacetic-acid and azelaic-acid

The management of acne is a gratifying experience. Available treatments are effective, relatively nontoxic and generally safe. However, there is no quick fix. Antibiotics, hormone therapies and topical therapies are maintenance treatments. Isotretinoin can induce remission, as can some of the newer physical modalities of lights, lasers and radiofrequency devices. Effective management of acne often requires using a combination of treatments that act on different parts of the pathogenic process of acne development.

Topics: Acne Vulgaris; Administration, Oral; Administration, Topical; Adolescent; Adult; Androgens; Anti-Bacterial Agents; Benzoyl Peroxide; Child; Contraceptives, Oral; Dermatologic Agents; Dicarboxylic Acids; Drug Therapy, Combination; Female; Humans; Hydroxy Acids; Isotretinoin; Keratins; Keratolytic Agents; Male; Phototherapy; Retinoids; Sebum; Treatment Outcome

The effects of azelaic acid (AZA) on the epidermis of 47 individuals (12 with normal skin, 15 with seborrheic skin and 20 suffering from acne) and on in vitro cultured keratinocytes are reported. Topical application of a 20% AZA cream significantly improved the lesions of acne patients, but failed to induce clinically detectable changes in normal or seborrheic epidermis. Complementary investigations clearly showed that AZA treatment failed to induce specific changes in sebum composition, excretion rate, or in the size of sebaceous glands, but modified epidermal keratinization. Keratohyalin granules and tonofilament bundles were reduced in size and number, mitochondria were swollen and the rough endoplasmic reticulum of malpighian keratinocytes enlarged. The infundibular epidermis of acne individuals showed marked reduction of the horny layer thickness, widening of the horny cell cytoplasm, transitional corneal cells, normalization of filaggrin distribution, and the comedo contained few bacteria and spores. In vitro, AZA exerted marked time- and dose-dependent antiproliferative cytostatic effects on cultured keratinocytes, with a 50% inhibitory dose of 20 mM, decreased some keratinocyte proteins (highly soluble fractions S2, keratohyalin macroaggregate R2, and non-cross-linked fibrous protein S4) and a 95 kD and a 35 kD protein of the cytosolic fraction. Mitochondria were frequently damaged and the rough endoplasmic reticulum enlarged. Our results indicate that AZA is an antikeratinizing agent, displaying antiproliferative cytostatic effects on keratinocytes and modulating the early and terminal phases of epidermal differentiation.

Topics: Acne Vulgaris; Cell Differentiation; Cell Division; Cells, Cultured; Clinical Trials as Topic; Dermatitis, Seborrheic; Dicarboxylic Acids; Filaggrin Proteins; Humans; Keratins; Microscopy, Electron; Protein Synthesis Inhibitors; Random Allocation; Sebum; Skin; Skin Physiological Phenomena

The effects of topically applied 20% azelaic acid (AA) on normal human epidermis were investigated vs. placebo in a double blind study by electron microscopy in 15 volunteers. After 3 months of local application twice daily, the pattern of epidermal keratinization was found altered in skin treated with AA. In particular, the number and thickness of tonofilament bundles and the number of keratohyaline granules seemed decreased; the remaining granules were smaller, occasionally showing irregular electron densities. The perinuclear endoplasmic reticulum and the cytoplasmic cisternae were enlarged and swollen mitochondria were regularly observed in most malpighian keratinocytes. Thorough quantitative evaluation of the number and distribution of melanocytes by a MOP-videoplan computer system showed no differences between verum and placebo sites, although, the mean number of melanocytes had increased in both, as compared to the untreated controls taken before onset of therapy. No significant qualitative changes of the normal melanocytes were found. These findings indicate that azelaic acid may influence the differentiation of normal human keratinocytes by reducing the synthesis of keratin precursors and may, therefore, act as a mild antikeratinizing agent, whereas, the pigmentary system in normal human epidermis does not show any specific change after 3 months of treatment with AA.

Topics: Clinical Trials as Topic; Dicarboxylic Acids; Epidermal Cells; Epidermis; Humans; Keratins; Melanocytes; Microscopy, Electron; Placebos; Time Factors

The effects of azelaic acid (C9-dicarboxylic acid, AZA) on the proliferation and ultrastructure of neonatal NMRI mouse keratinocyte cultures were studied to clarify the mechanisms of AZA action on normal and diseased epidermis. The dose- and time-dependency of the drug effects on DNA synthesis was examined by 3H-thymidine incorporation into DNA and by autoradiography. Electron microscopy was used to detect the target cell organelles of the drug. Azelaic acid decreased DNA synthesis in a dose- and time-dependent manner with a 50% inhibitory concentration of 20 mM. The inhibition of DNA synthesis was already observed after 1 h of treatment, reached its maximum after 4 h, and was stable for 24 h. A complete reversibility of the inhibitory effects was observed within 2 h after discontinuation of the treatment, and, interestingly, a rebound effect occurred with a temporary increase of DNA synthesis. Furthermore, treatment with AZA reduced the RNA and protein synthesis of the cells. Electron microscopic evaluation of treated cultures showed early marked damage of the mitochondria, followed by dilation of the rough endoplasmic reticulum (RER). These alterations were completely reversible after discontinuation of the treatment. Our findings show that AZA exerts a dose- and time-dependent, reversible antiproliferative effect on keratinocytes, acting primarily on mitochondria and RER. The antiproliferative action of AZA could explain its beneficial effect in some skin disorders characterized by alteration of keratinocytic differentiation.

Topics: Animals; Cell Division; Cells, Cultured; Dicarboxylic Acids; DNA; Epidermal Cells; Epidermis; Keratins; Mice; Microscopy, Electron; Osmolar Concentration; Time Factors

Azelaic acid (AZA) has been reported to have an inhibitory effect on DNA synthesis of melanoma cell lines. In order to elucidate the mechanism(s) underlying this inhibitory effect, I elected to study the effects of AZA and, for control purposes, adipic acid (ADA) on DNA synthesis rate of nuclei isolated from melanoma cells and keratinocytes cultured in the presence of different concentrations of the dicarboxylic acids. Before doing so, I found, by autoradiography, that [3H]AZA is incorporated into the nuclei in a time-dependent manner. AZA, and to a lesser extent ADA, caused a dose-dependent inhibition of DNA synthesis, regardless of whether these substances were present in cell cultures before isolation of nuclei, or were incubated with already isolated nuclei. In searching for the target for this inhibitory effect on nuclear DNA synthesis, I found that AZA, and to a lesser extent ADA, is a potent inhibitor of both bacterial DNA polymerase and of multienzyme complexes isolated from cultured melanoma cells and keratinocytes. These data suggest that the inhibitory effect of the dicarboxylic acids AZA and ADA on DNA synthesis of several cell lines is due to the interference of these substances with the activation of enzymes (e.g. DNA polymerases) required for DNA synthesis.

Topics: Adipates; Animals; Cell Line; Cell Survival; Dicarboxylic Acids; DNA; Epidermal Cells; Epidermis; Humans; Keratins; Melanoma; Nucleic Acid Synthesis Inhibitors; Tumor Cells, Cultured