Assessing the Effectiveness of Stabilized Cysteamine 5% Cream Compared to Hydroquinone 4%/Ascorbic Acid 3% Combination Cream in Treating Acne-induced Post-inflammatory Hyperpigmentation: A Randomized, Controlled Study.

Objective: Postinflammatory hyperpigmentation (PIH) is a common sequela of acne vulgaris. Topical treatment with hydroquinone is the standard treatment, but may be associated with complications. Cysteamine is a relatively safe depigmenting agent with an observed depigmenting effect. We designed this study to assess the efficacy of a cysteamine 5% cream in treating acne-induced PIH. Methods: Twenty-eight out of 32 participants finalized this investigator-blind, randomized, and controlled trial (registered in Iranian Registry of Clinical Trials [IRCTID: IRCT20140212016557N5]). We randomized the patients to apply either cysteamine 5% or hydroquinone 4%/ascorbic acid 3% (HC) cream. Postacne hyperpigmentation index (PAHPI) and melanin index were the assessment measures after four months of treatment. We evaluated the quality of life by the Dermatology Life Quality Index (DLQI) questionnaire. Results: Both cysteamine and HC cream significantly decreased the PAHPI score and melanin index of acne-induced PIH patients (p<0.05). The decrease in PAHPI score and melanin index were not significantly different in treatment groups after four months (p>0.05). Quality of life ameliorated significantly only with cysteamine treatment. However, no significant change in quality of life was observed between groups. Limitations: Limitations of our study include the relatively small sample size and absence of follow-up. Conclusion: Cysteamine cream is an effective treatment of post-acne PIH, with similar efficacy to the accepted treatment of PIH, i.e., hydroquinone cream.

Topical isoniazid as a novel treatment for melasma: A randomized, double-blind, vehicle-controlled clinical trial.

INTRODUCTION: Melasma is a chronic hyperpigmentation disorder, and its treatment poses a challenge to dermatologists due to its chronicity and resistance to conventional therapies. Oral isoniazid is used for the treatment of tuberculosis. One of us had previously showed that topical isoniazid exerts a strong depigmenting action in animal models. In this clinical trial, we assessed the therapeutic effect of topical isoniazid on melasma. METHODS: Twenty female patients suffering from epidermal melasma were enrolled and divided equally into two groups. The treatment group received topical isoniazid 10%, and the control group received the cold cream vehicle as the placebo. All participants were advised to avoid sunlight and used SPF 50 sunscreen. Patients applied topical agents once daily at night for 3 months. The melanin and erythema indices were measured by colorimetric evaluations at baseline and after 4, 8, and 12 weeks of treatment. At these time points, the (mMASI) score was also determined, as was the subjective evaluation through Melasma Quality of Life Scale (MELASQOL) scores. Blood tests were performed to evaluate CBC and the liver enzymes. RESULTS: All patients completed the 12-week study. In the treatment group, a significant decrease in melanin index from 63.77 ± 6.27 at baseline to 55.92 ± 5.79 was recorded (p = 0.001). Very minimal clinical changes were also seen in the control group and melanin index was decreased from 62.65 ± 2.23 to 61.25 ± 2.34 (p = 0.004). Clinically significant differences were observed in the rate of changes between both groups. These findings indicate that topical isoniazid has significant depigmenting effects compared to the placebo (p = 0.001). The erythema index remained unchanged in both groups. In the treatment group, the mMASI score was 5.63 ± 3.28 at baseline and 2.13 ± 1.71 at the last follow-up, significantly reduced compared to the control group (p = 0.002). The MELASQOL score indicated a significant improvement in the quality of life in the treatment group. CONCLUSION: This clinical trial shows for the first time that topical isoniazid is effective in treating melasma. Further clinical trials are necessary to confirm the efficacy and tolerability of topical isoniazid in comparison with other skin-depigmenting compounds.

Successful treatment of solar lentigines by topical application of stabilized cysteamine: A vehicle-controlled, double-blind randomized study.

Background: Solar lentigines are common hyperpigmented lesions typically appearing after 50 years of age and associated with negative psychological effects in affected individuals. Topical depigmenting products, such as hydroquinone and even the Kligman's formula, are usually ineffective for treating lentigines. Stabilized cysteamine has been recently shown to be as effective as the modified Kligman's formula for treating melasma. In this study, we evaluated the therapeutic effect of a stabilized cysteamine on solar lentigines. Methods: A vehicle-controlled, double-blind, and randomized study was performed on 30 patients with solar lentigines. Stabilized cysteamine or vehicle control creams were applied on solar lentigines on the dorsum of the hands daily for 12 weeks. Clinical measurements with colorimetry and visual analog scale were performed at baseline, 4, 8, and 12 weeks. Results: Statistically significant results were obtained in the cysteamine group versus the vehicle control group. Stabilized cysteamine provided a 40% reduction in colorimetric values (p < 0.002) versus a 2% reduction in the vehicle group (p < 0.405). Cysteamine also provided a 40% reduction in VAS (p < 0.001) versus a 2% reduction in the vehicle group (p < 0.245). Conclusion: Significant improvement of solar lentigines was observed after 12 weeks of application of stabilized cysteamine by all evaluation methods. Stabilized cysteamine represents a highly effective topical treatment for solar lentigines and can be considered as one of the first topical therapies effective on this hyperpigmentary disorder.

Comparison of the efficacy of cysteamine 5% cream and hydroquinone 4%/ascorbic acid 3% combination cream in the treatment of epidermal melasma.

BACKGROUND: Few safe and effective treatments are available for melasma. Cysteamine, a non-melanocytotoxic molecule is a safer alternative to hydroquinone and usable for long-term use. AIM: To evaluate the effect of cysteamine 5% cream in the treatment of melasma. METHODS: Sixty-five of 80 patients completed this single-blind, randomized, controlled trial. The patients received cysteamine 5% or hydroquinone 4%/ascorbic acid 3% (HC) cream. The therapeutic response was evaluated by modified MASI (mMASI) and melanin index (SkinColorCatch) after 2 and 4 months of treatment. The effect of treatment on the quality of life was also assessed. RESULTS: The decrease in mMASI score was from 6.69 ± 2.96 to 4.47 ± 2.16 in the cysteamine group and from 6.26 ± 3.25 to 3.87 ± 2.00 in the HC group after 4 months (p values < 0.001). The melanin index decreased from 37.72 ± 10.17 to 31.47 ± 11.90 in the cysteamine group and from 36.37 ± 10.80 to 23.16 ± 8.83 in the HC group after 4 months (p-value = 0.003 and <0.001, respectively). The difference between mMASI score at baseline and month 4 was not significant between both groups (p-value > 0.05). The difference between the melanin index at baseline and month 4 was significantly more pronounced in the HC group (p-value = 0.002). Quality of life improved in both groups (p-value < 0.05), but was not significantly different between groups (p-value > 0.05). CONCLUSION: Cysteamine was confirmed to be an effective treatment for melasma, with equivalent results to HC in reducing mMASI score and improving quality of life, despite lesser melanin index reduction observed. Cysteamine and HC efficacy was confirmed in patients recalcitrant to previous treatments, by a significant reduction of mMASI and melanin index.

Significant therapeutic response to cysteamine cream in a melasma patient resistant to Kligman's formula.

L-Cysteamine is a biological antioxidant produced during the coenzyme A metabolism cycle and is naturally present in all mammalian cells. The efficacy of topical cysteamine for the treatment of melasma has been recently shown in two double-blind, randomized, and placebo-controlled clinical trials. Herein, we report a 44-year-old patient with melasma resistant to Kligman's formula (Pigmanorm cream), who was successfully treated with topical cysteamine as a new depigmenting agent. Skin colorimetric measurements, MASI score determination, and standard photographies after 2 and 4 months of once daily application of cysteamine cream showed a marked improvement of the hyperpigmented lesions. Telangiectasia and perilesional hypopigmentation improved rapidly after the discontinuation of Kligman's formula and starting the treatment with topical cysteamine. After 4 months, the therapeutic results were maintained through a biweekly application regimen of cysteamine cream. The use of cysteamine cream was well tolerated and did not induce any side effects during the 3-year follow-up of the patient. Cysteamine is a natural molecule with an excellent safety profile and known antimutagenic, antimelanoma, and anticarcinogenic effects. Considering the high efficacy of cysteamine cream, it is possible that it could replace mutagenic and carcinogenic depigmenting agents such as hydroquinone in near future.

Efficacy of cysteamine cream in the treatment of epidermal melasma, evaluating by Dermacatch as a new measurement method: a randomized double blind placebo controlled study.

BACKGROUND: Melasma is a difficult-to-treat hyperpigmentary disorder. Very few studies have been performed regarding the efficacy of cysteamine in the treatment of melasma. OBJECTIVE: To determine the efficacy of cysteamine cream in the treatment of patients with epidermal melasma using Dermacatch® as a more accurate skin colorimetric measurement tool. METHODS: Participating patients (n = 40) received either placebo (n = 20) or cysteamine cream (n = 20) in a double-blind placebo controlled study. Cysteamine cream or placebo was applied on the lesions once a day at bedtime throughout the four-month study period. Treatment efficacy was determined through Dermacatch® and Mexameter® skin colorimetry, MASI scores, Investigator Global Assessments (IGAs), and patient questionnaires, all performed at baseline, 2-month, and 4-month examinations. RESULTS: Prior to the start of the protocol, the mean difference between pigmented and normal skin was calculated for cysteamine and placebo groups using both Dermacatch® (72.3 ± 27.8 and 52.9 ± 16.4, respectively) and Mexameter® (93.6 ± 42.6 and 65.4 ± 22.6, respectively). At 2 months, the mean differences were 38.1 ± 15.3 (Dermacatch®) and 49.9 ± 19 (Mexameter®) in the cysteamine group and 64.9 ± 25.3 (Dermacatch®) and 68 ± 26.2 (Mexameter®) in the placebo group. At 4 months, the mean differences were 23.8 ± 12.9 (Dermacatch®) and 35.5 ± 16.1 (Mexameter®) in the cysteamine group, and 50 ± 18 (Dermacatch®) and 51.2 ± 16.8 (Mexameter®) in the placebo group. Statistically significant differences were found between the cysteamine and placebo group outcomes at both time points (p = .01, p = .02). At the end of the treatment period, MASI scores were significantly lower in the cysteamine group versus placebo (8.03 ± 5.2 vs. 12.2 ± 7.4, p = .04). IGA scores and patient viewpoints indicated significant efficacy of cysteamine cream versus placebo. CONCLUSION: Cysteamine cream showed significant efficacy in decreasing melanin content of the lesions, as established by Dermacatch® as a new measuring method.

Correlation between protoporphyrin IX fluorescence intensity, photobleaching, pain and clinical outcome of actinic keratosis treated by photodynamic therapy.

BACKGROUND: Photodynamic therapy (PDT) with Metvix® is a good therapeutic option to treat actinic keratosis, but it presents drawbacks (pain, lesion recurrences, heterogeneous outcome), emphasizing the possible need to individualize treatment. OBJECTIVE: We assessed whether PDT clinical outcome and pain during treatment were correlated with protoporphyrin IX fluorescence intensity and photobleaching. METHODS: 25 patients were treated by Metvix PDT. The outcome was evaluated after 1.3 (±0.4), 7.6 (±1.8), 13.2 (±1.2) and 33.6 (±3.0) months. After administration of Metvix, red light (632 ± 10 nm) was delivered with a light-emitting diode panel device. The outcome was assessed on a cosmetoclinical scale. RESULTS: All patients who showed a fluorescence level before PDT treatment above a certain threshold had a complete recovery at 33.6 (±3.0) months. CONCLUSION: Our approach could be used to individualize PDT treatment based on the pretreatment fluorescence level, and to predict its long-term outcome.

Ebselen is a new skin depigmenting agent that inhibits melanin biosynthesis and melanosomal transfer.

We assessed the ability of ebselen, a glutathione peroxidase mimic, to reduce pigmentation in various models. In murine B16 melanocytes, 25 µm ebselen inhibited melanogenesis and induced a depolymerisation of actin filaments. In co-cultures of B16 melanocytes with BDVII keratinocytes, a pretreatment of melanocytes with ebselen resulted in a strong inhibition of melanosome transfer to keratinocytes, as shown under optical and electron microscopy. In reconstructed epidermis, topical 0.5% ebselen led to a twofold decrease of melanin without affecting the density of active melanocytes. A similar result was obtained with topical 0.5% ebselen in black guinea pig ears. Ebselen induced a decrease of epidermal melanin parallel to a localisation of melanin and melanosomes in the basal layer. Ebselen appears as a new depigmenting compound that inhibits melanin synthesis and melanosome transfer to keratinocytes.

D-penicillamine, a potent melanogenesis inhibitor, lacks any depigmenting effect on black guinea pig skin: the first randomized, evaluator-blinded, vehicle-controlled, in vivo study.

D-penicillamine is a melanogenesis inhibitor. This in vivo study on ten black guinea pigs using a 5% D-penicillamine ointment showed its lack of any skin-lightening effect. The potential reasons for this ineffectiveness are discussed in the paper, which could be very helpful for researchers exploring new skin-lightening agents.

A new spectrophotometric method for simple quantification of melanosomal transfer from melanocytes to keratinocytes.

Three major difficulties must be overcome to establish a quantitative method for melanosomal transfer analysis: (i) establishing a three-dimensional co-culture reassuring direct melanocyte to keratinocyte transfer, (ii) separation of melanocytes and keratinocytes following co-culture and (iii) melanosome quantification in each cell population. Melanocytes and keratinocytes are cultured on the opposite sides of the porous membrane of hanging cell inserts (1µm pores, 2×10(6) pores/cm(2) ). Cell separation is performed after 3days of co-culture by simple trypsinisation. Melanosome quantification in separated cell populations was accomplished by an ELISA-like method using gp-100 as the antigen. Melanocytes and keratinocytes come into 'direct' contact through the pores, and melanosomal transfer is accomplished without cell passage through the membrane. Cell separation by simple trypsinisation results in pure melanocyte and keratinocyte populations. Melanosome quantification by the ELISA-like method proved to be sensitive and specific to distinguish the known inhibitors and inducers of melanosomal transfer.

Porokeratosis of Mibelli with mutilation: a case report.

Porokeratosis is a rare keratinization disorder of the skin characterized by annular plaques with an atrophic center surrounded by a raised keratotic wall that spreads centrifugally. We report a case of porokeratosis of Mibelli with mutilation. A 30-year-old woman presented with atrophic plaques on the index fingers of both hands with a keratotic ridge in some margins of the plaques. There was loss of the distal phalanx of the left index finger. In the right hand, shortening of the right distal phalanx and flexion contracture of the distal interphalangeal joint were noted in the index finger.

Topical captopril as a novel agent against hypertrophic scar formation in new zealand white rabbit skin.

Collagen constitutes the majority of extracellular matrix in tissues such as bone, cartilage, and especially the skin. Over production and/or decreased degradation of collagen fibers could lead to an abnormal wound healing response resulting in hypertrophic scarring or keloid formation. Recently, angiotensin II has been shown to be present in several cutaneous cells and that it stimulates fibroblast proliferation, collagen synthesis, and suppresses matrix metalloproteinase activity. The following study examines the effect of topical captopril, an inhibitor of angiotensin II production, against hypertrophic scar formation in New Zealand white rabbits.Two dermal wounds were made over the ventral surface of the ears of each rabbit (n = 6). In each animal, separate wounds were treated once per day with either topical 5% captopril or the vehicle alone (70% ethanol and 30% propylene glycol) for 7 consecutive days. Wounds were harvested at postoperative day 28, and the scar elevation index (SEI) as well as collagen organization was evaluated. SEI was reduced from 3.06 in the vehicle-treated group to 1.94 in the captopril treated wounds (P < 0.05). However, an increase in collagen organization was achieved by captopril, while an 8.50% decrease in collagen organization scale was derived by captopril compared to the vehicle. Results of this study show, for the first time, the efficacy of topical captopril as a new agent for the prevention of hypertrophic scar formation in an animal model. Thus, captopril might represent the first angiotensin converting enzyme inhibitor with a novel pharmacologic application in dermatology.

Retinoic acid synergistically enhances the melanocytotoxic and depigmenting effects of monobenzylether of hydroquinone in black guinea pig skin.

Monobenzylether of hydroquinone (MBEH) has long been utilized for the depigmentation therapy of patients with extensive vitiligo. In this approach, the normally pigmented areas surrounding vitiligo lesions are depigmented to achieve a uniform skin tone. One of the important disadvantages of MBEH therapy, however, is the resistance of a considerable number of vitiligo patients against the depigmenting effect of this agent. We have previously proposed that the glutathione-dependent cytoprotection of melanocytes can be impaired through the inhibition of the enzyme glutathione S-transferase by retinoic acid (RA). The combination of RA with melanocytotoxic agents could thus lead to increased susceptibility of melanocytes to such compounds. In this study we have shown, for the first time, that the melanocytotoxic and depigmenting effects of MBEH are synergistically enhanced when it is combined with RA. The treatment of black guinea pig skin with RA (0.025%) alone induced no significant changes in the number of epidermal melanocytes and no skin depigmentation. On the other hand, MBEH (10%) produced mild to moderate skin depigmentation and reduced the average number of melanocytes from 76 (+/-5)/field (magnification: x 40) in control sites, to 42 (+/-6)/field in the depigmented skin. The RA (0.025%)-MBEH (10%) combination, however, produced a complete degree of depigmentation in the majority of treated sites after 10 days of application and reduced the average number of melanocytes to only 6 (+/-6)/field. RA-MBEH combination serves as a very potent skin depigmenting formula and now awaits future assessments of its potential use for the treatment of extensive vitiligo.

Topical methimazole as a new treatment for postinflammatory hyperpigmentation: report of the first case.

We have previously shown that the peroxidase inhibitor methimazole (1-methyl-2-mercapto imidazole; MMI) is a noncytotoxic inhibitor of melanin production in cultured B16 melanocytes. It was further demonstrated that the topical application of 5% MMI on brown guinea pig skin for 6 weeks causes a significant reduction in the amount of epidermal melanin, resulting in visually recognizable cutaneous depigmentation. Herein, we report a 27-year-old male with postinflammatory hyperpigmentation (due to acid burn), successfully treated with topical MMI as a new skin depigmenting agent. Topical 5% MMI caused a moderate to marked improvement of the hyperpigmented lesions within 6 weeks of once-daily application. Topical MMI was well tolerated by the patient and did not affect the level of serum thyroid hormones (free thyroxin, free triiodothyronine and the thyroid-stimulating hormone). Unlike most known depigmenting agents, such as hydroquinone and kojic acid, MMI is a noncytotoxic, nonmutagenic compound, and it is possible that MMI could serve as a novel agent for the treatment of hyperpigmentary disorders in human.

Pharmacology of RALGA, a mixture of retinaldehyde and glycolic acid.

BACKGROUND: Retinoids and alpha-hydroxy acids (AHAs) are major compounds in topical therapy. They exert distinct but potentially complementary activities. However, their association is limited by their respective irritating potential. Recently, the first association between a retinoid and an AHA has been achieved; this formulation (RALGA) associates retinaldehyde (RAL)--a precursor of retinoic acid (RA)--and glycolic acid (GA)--an AHA. OBJECTIVE: To study the pharmacological properties of RALGA. METHODS: The bioavailability of RAL into the skin after topical RALGA was studied by HPLC, and its bioconversion to RA was analysed by measuring the enzyme activity of retinaldehyde dehydrogenase and the RA content in the epidermis and dermis. The retinoid activity of RALGA was studied on the modulation of Hhb4 keratin mRNA on the tail of C57BL/6 mice, and its comedolytic properties on the size and density of dermal cysts and the morphology of sebaceous glands in hairless mice. RESULTS: Epidermal and dermal concentrations of RAL and RA were higher after RALGA treatment, as compared to both RAL 0.1% alone and RA 0.05% alone; this indicates that the presence of GA favours the bioavailability and biotransformation of RAL into RA. The retinoid activity of RALGA (suppression of Hhb4 mRNA keratin) was similar to that of RAL alone, indicating that the presence of GA does not interfere with specific retinoid activity; GA alone had no effect in this test, which confirms the specificity of Hhb4 mRNA keratin modulation for retinoid activity. The diameter and the density of dermal cysts as well as the size of sebaceous glands were significantly decreased by RALGA. CONCLUSION: These observations indicate that the addition of an AHA such as GA to a retinoid such as RAL results in a better bioavailability of the retinoid, thus a higher delivery of RA, which potentiates the biological activities of the retinoid. This combination allows a delivery of high amounts of RA in the skin while preventing the side-effects usually observed with high concentrations of topical RA.

Enhancement of the depigmenting effect of hydroquinone and 4-hydroxyanisole by all-trans-retinoic acid (tretinoin): the impairment of glutathione-dependent cytoprotection?

Many of the well-known depigmenting agents such as hydroquinone and 4-hydroxyanisole are, in fact, melanocytotoxic chemicals which are oxidized in melanocytes to produce highly toxic compounds such as quinones. These cytotoxic compounds are responsible for the destruction of pigment cells, which results in skin depigmentation. However, cells are capable of protecting themselves against cytotoxic agents by intracellular glutathione (GSH). This protection takes place under the enzymatic action of the detoxification enzyme glutathione S-transferase (GST), which is responsible for the conjugation of toxic species to GSH. The depigmenting effect of hydroquinone is shown to be potentiated by buthionine sulfoximine (BSO) and cystamine as the result of the reduction of intracellular levels of GSH by these two agents. Additionally, BSO and cystamine are shown to inhibit the activity of GST. The combination of all-trans-retinoic acid (tretinoin, TRA) with hydroquinone or 4-hydroxyanisole is also known to produce synergetic skin depigmentation. TRA serves as a potent inhibitor of mammalian GSTs and is known to make cells more susceptible to the cytotoxic effect of chemicals by inhibiting the activity of this enzyme. This agent is also shown to reduce the level of intracellular GSH in certain cells. We have proposed that the mechanism of action of TRA to synergistically enhance the melanocytotoxic effect of chemicals involves the inhibition of GST and the impairment of glutathione-dependent cytoprotection against melanocytotoxic agents.

Peroxidase-mediated mechanisms are involved in the melanocytotoxic and melanogenesis-inhibiting effects of chemical agents.

Melanogenesis is based on the enzymatic conversion of the amino acid tyrosine, through a series of intermediates, to melanin pigments. The nature of the enzymes involved in the different steps of melanogenesis has been intensely debated. However, it is now believed that tyrosinase is responsible for the conversion of tyrosine to dopa and of dopa to dopaquinone, and that peroxidase accomplishes the oxidative polymerization of the eventually formed indoles to eumelanin pigments. Some very few investigators have also considered a main role for peroxidase in initiating melanogenesis. At present, most different hypotheses are focused on tyrosinase-mediated mechanisms to elucidate the melanocytotoxic and depigmenting activities of chemicals. However, many properties of these agents cannot be explained by such mechanisms. Most of the melanocytotoxic agents (e.g. hydroquinone, catechols, butylated hydroxyanisole) can be converted to cytotoxic species, such as quinones, by the peroxidase-H(2)O(2) system. On the other hand, many of the melanogenesis inhibitors which are not known to inhibit tyrosinase (e.g. glucocorticoids, ascorbic acid, indomethacin) have the capacity to strongly inhibit peroxidase activity. We have proposed that peroxidase-mediated mechanisms, in addition to or in several instances rather than tyrosinase-mediated mechanisms, can explain the melanocytotoxic and depigmenting properties of such agents.