A review of therapies for hyperpigmentation modulating the synthesis of eumelanin to pheomelanin.

There are significant psychosocial burdens in patients with hyperpigmentation, which emphasizes the importance of treatment. Current gold standard for treatment is hydroquinone; however, alternatives have been developed given the concern for side effects of hydroquinone. Melanogenesis is responsible for the production of eumelanin and pheomelanin; there are many factors that will determine whether eumelanin or pheomelanin will be produced. Eumelanin is known for its photoprotective qualities, while pheomelanin is implicated in photocarcinogenesis and photoaging. Multiple treatment modalities for hyperpigmentation that shift eumelanin to pheomelanin synthesis exist. Cysteamine, glutathione, kojic acid, and methyl sulfonyl methane are four agents used to treat hyperpigmentation by shifting the production of eumelanin to pheomelanin. It is critical to discuss photoprotection with patients to help reduce the potential impact of increased pheomelanin production and to expand research in this area.

The Use of Tranexamic Acid and Microneedling in the Treatment of Melasma: A Systematic Review.

Melasma is a chronic pigmentary disorder that results in hyperpigmented patches in sun-exposed areas. Tranexamic acid (TXA) and microneedling are potential treatment options for individuals with melasma. The objective of our systematic review was to review 12 randomized controlled trials and clinical trials on the use and efficacy of TXA with microneedling for melasma. The combination of TXA and microneedling was found to be more effective at improving melasma lesions than either treatment alone; TXA alone was equally effective at reducing melasma lesions vs the standard treatment of hydroquinone.

Cosmeceuticals in photoaging: A review.

BACKGROUND: Photoaging is a process of the architecture of normal skin damaged by ultraviolet radiation. Topical cosmeceuticals have been used to treat this condition. The authors aimed to understand the mechanism and level of evidence of different commonly used cosmeceuticals used to treat photodamaged skin. OBJECTIVE: A range of commonly used topical cosmeceuticals (botanicals, peptides, and hydroquinone) has been used in cosmetic medicine for many years to treat photodamaged skin. This review article compares their efficacy and level of evidence. MATERIAL AND METHODS: This study was a systematic review to evaluate the efficacy of different topical cosmeceuticals. Keywords including "Photoaging," "Azelaic acid," "Soy," "Green Tea," "Chamomile," "Ginkgo," "Tea Tree Oil," "Resveratrol," "Cucumber," "Ginseng," "Centella asiatica," "Licorice Root," "Aloe Vera," "Peptides," "Argireline," "Hydroquinone," were typed on OVID, PUBMED, MEDLINE for relevant studies published on photoaging treatment. RESULTS: Most of the evidence behind cosmeceuticals is of high-quality ranging from Level I to Level II. In particular, the evidence base behind peptides is the strongest with most studies achieving Level Ib status in the evidence hierarchy. CONCLUSION: Topical cosmeceuticals like botanicals, peptides and hydroquinone can effectively treat photodamaged skin.

Hyperpigmented Macules and Patches on the Face: Exogenous Ochronosis or Lichen Planus Pigmentosus?

We present a case of a patient with a 10-year history of blue-black macules and patches on the face and an associated history of skin-lightening cream usage. The skin lightening cream contained hydroquinone, which is often associated with exogenous ochronosis (EO). Interestingly, the biopsy did not show characteristic findings of ochronosis, confusing the final diagnosis, however discontinuing the skin-lightening creams halted the progression of the patient's skin lesions supporting a diagnosis of EO. EO presents as asymptomatic hyperpigmentation after using products containing hydroquinone. This condition is most common in Black populations, likely due to the increased use of skin care products and bleaching cream containing hydroquinone in these populations. Topical hydroquinone is FDA-approved to treat melasma, chloasma, freckles, senile lentigines, and hyperpigmentation and is available by prescription only in the US and Canada. However, with the increased use of skin-lightening creams in certain populations, it is important for dermatologists to accurately recognize the clinical features of exogenous ochronosis to differentiate it from similar dermatoses. An earlier diagnosis can prevent the progression to severe presentations with papules and nodules. We summarize the clinical presentations diagnostic features, and treatment pearls, concluding with a discussion of the differential diagnoses.  J Drugs Dermatol. 2024;23(7):567-568.     doi:10.36849/JDD.8248.

The effectiveness and safety of 3% tranexamic acid cream vs. 4% hydroquinone cream for mixed-type melasma in skin of color: a double-blind, split-face, randomized controlled trial.

INTRODUCTION: Melasma, a chronic acquired skin pigmentation disorder, is characterized by the presence of irregular-edged brown to gray-brown patches with a symmetrical distribution, primarily on sun-exposed areas such as the face. Topical hydroquinone (HQ) is the gold standard for melasma treatment but has numerous side effects. This study assesses the effectiveness of topical tranexamic acid (TA) as an alternative for melasma treatment. METHODS: In a double-blind, split-face, randomized controlled trial involving 20 subjects, the effectiveness of 3% TA versus 4% HQ cream was evaluated over 8 weeks. The modified melasma area and severity index (mMASI), melanin index, erythema index, and side effects were assessed. Subjective improvement was measured using the patient global assessment (PtGA). RESULTS: A significant decline in the mMASI score was observed at weeks 4 and 8 in both groups compared to baseline. There were no statistically significant differences in PtGA scores between the 3% TA group and the 4% HQ group. CONCLUSIONS: Topical 3% TA is as effective and safe as 4% HQ for treating melasma in the Indonesian population, with potential advantages in terms of side-effect profiles.

The role of chitosan in mitigating tert-butylhydroquinone induced cognitive impairment and neurotoxicity in a rat model.

OBJECTIVE: This study aimed to investigate the impact of tert-butylhydroquinone (TBHQ), chitosan, and their combination on memory and neurobiochemical parameters in a rat model. The primary objectives were to assess the cognitive effects of TBHQ, explore the cognitive-enhancing properties of chitosan, and evaluate the combined effects of these substances. MATERIALS AND METHODS: A rat model was employed for behavioral tests, biochemical analyses, and histological examinations. Rats were exposed to TBHQ, chitosan, or a combination of both, and cognitive function was assessed through behavioral tests. Biochemical analyses focused on neurobiochemical parameters associated with memory and oxidative stress. Histological examinations were conducted to observe any structural changes in the brain. RESULTS: TBHQ exposure was associated with memory impairments and increased oxidative stress, indicating potential neurotoxic effects. Chitosan supplementation demonstrated cognitive-enhancing effects and showed promise in mitigating the memory impairments and oxidative stress induced by TBHQ. The combination of chitosan and TBHQ presented a potential protective effect on neurological health. CONCLUSIONS: Chitosan supplementation alongside TBHQ may mitigate memory impairments and oxidative stress associated with TBHQ exposure in a rat model. The study provides valuable insights into the cognitive effects of TBHQ and the neuroprotective potential of chitosan, highlighting the need for further research to elucidate molecular pathways and clinical implications. These findings contribute to understanding chitosan's role in safeguarding neurological health in conditions where TBHQ exposure is a concern, warranting further investigations for translational applications in human health.

Comparative study of melasma in patients before and after treatment based on lipomics.

BACKGROUND: Skin barrier alterations play a crucial function in melasma development. Past researches have demonstrated variations in lipid content between the epidermis of melasma lesions and normal tissues, along with the varied expression of lipid-related genes in melasma. This study aimed to analyze the lipidome profiles of skin surface lipids (SSL) in patients with melasma before and after treatment to understand associated abnormalities. METHODS: Melasma was treated with tranexamic acid orally and hydroquinone cream topically. Disease was assessed using the Melasma Area and Severity Index (MASI), and the impact to life was evaluated with Melasma Quality of Life (MELASQoL) score. Epidermal melanin particles were observed using reflection confocal microscopy (RCM), whereas epidermal pigment and blood vessel morphology were observed using dermoscopy, and SSL samples were collected. Specific information regarding alterations in lipid composition was obtained through multivariate analysis of the liquid chromatography-mass spectrometry data. RESULTS: After treatment, patients with melasma exhibited decreased MASI and MELASQoL scores (P < 0.001); RCM revealed reduced melanin content in the lesions, and dermoscopy revealed fewer blood vessels. Fifteen lipid subclasses and 382 lipid molecules were identified using lipidomic assays. The expression levels of total lipids, phosphatidylcholine, and phosphatidylethanolamine in the melasma lesions decreased after treatment (P < 0.05). CONCLUSION: This study revealed alterations in the SSL composition after effective melasma treatment, suggesting a compensatory role for lipids in melasma barrier function. The mechanism involving SSL and the lipid barrier, which influences melasma's occurrence, needs further elucidation.

An antioxidant and anti-ER stress combination therapy elevates phosphorylation of α-Syn at serine 129 and alleviates post-TBI PD-like pathology in a sex-specific manner in mice.

Clinical studies have shown that traumatic brain injury (TBI) increases the onset of Parkinson's disease (PD) in later life by >50%. Oxidative stress, endoplasmic reticulum (ER) stress, and inflammation are the major drivers of both TBI and PD pathologies. We presently evaluated if curtailing oxidative stress and ER stress concomitantly using a combination of apocynin and tert-butylhydroquinone and salubrinal during the acute stage after TBI in mice reduces the severity of late-onset PD-like pathology. The effect of multiple low doses of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) on post-TBI neurodegeneration was also evaluated. The combo therapy elevated the level of phosphorylation at serine 129 (pS129) of α-Syn in the pericontusional cortex of male mice at 72 h post-TBI. Motor and cognitive deficits induced by TBI lasted at least 3 months and the combo therapy curtailed these deficits in both sexes. At 3 months post-TBI, male mice given combo therapy exhibited significantly lesser α-Syn aggregates in the SN and higher TH+ cells in the SNpc, compared to vehicle control. However, the aggregate number was not significantly different between groups of female mice. Moreover, TBI-induced loss of TH+ cells was negligible in female mice irrespective of treatment. The MPTP treatment aggravated PD-like pathology in male mice but had a negligible effect on the loss of TH+ cells in female mice. Thus, the present study indicates that mitigation of TBI-induced oxidative stress and ER stress at the acute stage could potentially reduce the risk of post-TBI PD-like pathology at least in male mice, plausibly by elevating pS129-α-Syn level.

Sequential therapy with topical clobetasol for 14 days followed by hydroquinone versus hydroquinone alone in facial melasma treatment: a randomized, double-blind, controlled clinical trial.

BACKGROUND: Clobetasol has demonstrated remarkable results in treating melasma within a short time frame; however, its use is limited because of the risk of local side effects. To date, there is no controlled trial on sequential clobetasol/hydroquinone for melasma. This study aimed to investigate the tolerability and efficacy of 0.05% clobetasol followed by 4% hydroquinone (CLOB-HQ) in comparison to the isolated use of 4% hydroquinone (HQ). METHODS: A double-blinded, randomized clinical trial involving 50 women with facial melasma was performed. They were directed to apply 0.05% clobetasol every night for 14 days, followed by 4% hydroquinone for 46 days (CLOB-HQ group), or the use of hydroquinone for 60 days (HQ group). Evaluations were carried out at inclusion, and after 14 and 60 days of treatment, measuring modified Melasma Area and Severity Index (mMASI), Melasma Quality of Life scale (MELASQoL), and colorimetry. The Global Aesthetic Improvement Scale (GAIS) was assessed by a blinded evaluator. RESULTS: There was no difference in the main outcomes at D14 and D60 (P > 0.1). For CLOB-HQ, the mean (CI 95%) reduction in mMASI was 13.2% (5.1-21.3%) and 43.1% (32.2-54.0%) at D14 and D60, and for HQ, they were 10.6% (5.9-27.5%) and 44.8% (33.2-52.3%). The MELASQoL, colorimetric luminosity, and GAIS showed a progressive improvement for both groups despite no difference between them. No severe side effects were identified. No cases of telangiectasias, atrophy, or perioral dermatitis were associated with the use of CLOB. CONCLUSION: The sequential CLOB-HQ regimen was safe and well tolerated, even though its efficacy was not different from HQ after 14 or 60 days of treatment. Based on these findings, the use of clobetasol 14 days before hydroquinone is not advisable for the treatment of melasma.

Differential diagnosis and management of hyperpigmentation.

There is an increasing recognition of ethnic dermatology to reflect the increase in skin of colour (SOC) populations in the UK. Hyperpigmentary disorder is one of the commonest skin concerns in SOC but there has been limited training available in this field of dermatology. Variations in skin colour are genetically determined by the amount of melanin content, the eumelanin/pheomelanin ratio and the size of melanosomes, but is also influenced by other factors such as hormones and extrinsic factors such as ultraviolet radiation. Hyperpigmentation is a broad term to describe increased pigmentation in the skin, and making a correct diagnosis is an important first step in the successful management of hyperpigmentary disorders. A systematic approach based on the disease pathogenesis (e.g. reactive vs. nonreactive, increased melanin vs. increased number of cells or epidermal vs. dermal pigmentation) aided by a detailed history and clinical examination is the best way to diagnose a hyperpigmentary disorder. Based on its pathogenesis, management can be planned. For epidermal hyperpigmentation caused by increased melanin, topical skin-lightening agents targeting inhibition of tyrosinase or melanosome transfer and promotion of keratinocyte turnover can be used. Hydroquinone-containing cream is the gold-standard treatment for epidermal hyperpigmentation. Alternative treatments include laser toning or chemical peels. However, increased dermal pigmentation is more challenging to target with topical treatments. If hyperpigmentation is due to increased numbers of melanocytes or keratinocytes, high-fluence laser is the most appropriate treatment method.

The effect of Nrf2 activators tBHQ and 4-octyl itaconate on the nucleus pulposus cell degeneration.

OBJECTIVE: The present study aimed to investigate the impact of two Nrf2 agonists, tBHQ and 4-Octyl Itaconate, on nucleus pulposus (NP) degeneration and explore the underlying mechanism. PATIENTS AND METHODS: We isolated the NP cells from the disc tissue of disc herniation patients. NP cells were pretreated with an adequate dose of tBHQ, Itaconate, or the mixture of them, and then subjected to the Lipopolysaccharides (LPS) stimulation to induce degeneration. Besides, the Nrf2 gene silenced NP cells were also used as a comparison. Moreover, the LPS-treated NP cells were also cultured in the mix of tBHQ and Itaconate to determine whether the agonists affected reverse degeneration. RESULTS: LPS treatment suppressed Nrf2 expression and induced the NP cell degeneration with a decrease of cell viability and collagen II expression, an increase of reactive oxygen species (ROS) production, inflammatory cytokine accumulation (IL-1ß, TNF-α), and apoptosis (Caspase3, Caspase8). However, tBHQ or Itaconate pretreated NP cells contained a higher level of Nrf2 protein and alleviated the negative effect caused by LPS, which was abolished with the silencing of Nrf2. Additionally, tBHQ showed a better ability to suppress ROS than Itaconate. Meanwhile, Itaconate inhibited a higher amount of IL-1ß and TNF-α than tBHQ. Interestingly, when NP cells were pretreated with both tBHQ and Itaconate, the result indicated an excellent anti-ROS and anti-inflammatory peculiarity. Furthermore, when NP cells suffered from LPS first and then treated with the agonist, the anti-ROS and anti-inflammatory effects remained. However, the cell viability, collagen II, and apoptotic degree were not improved. CONCLUSIONS: Both tBHQ and Itaconate effectively prevent NP cells from degeneration through anti-ROS and anti-inflammation, and the combined use of them may have better effects. But in comparison, their impact on reversing NP cell degeneration has yet to be proven.

Oral Tranexemic Acid With Triple Combination Cream (Flucinolone+Hydroquinone+Tretinoin) Versus Triple Combination Cream Alone In Treatment Of Melasma.

BACKGROUND: Melasma is an acquired cutaneous disorder characterized by hyperpigmentation of the face predominantly affecting the areas exposed to direct sun light. The triple combination cream, i.e., a mid-potency corticosteroid (Fluocinolone acetonide 0.01%), a retinoid (Tretinoin 0.05%), and Hydroquinone 4% is one of the widely used topical medicament for melasma treatment world over. Tranexamic acid is another agent found to be effective in melasma treatment when used topically, intra-lesionally or orally. This study has been conducted to compare mean decrease in Melasma Area Severity Index (MASI) score when tranexamic acid is combined with triple combination cream versus triple combination cream alone for melasma treatment. METHODS: A randomized controlled trial was conducted in a tertiary care hospital of Pakistan. Sixty-three patients of melasma who met the inclusion criteria and gave written informed consent for the study were enrolled. These patients were randomly divided into 2 treatment groups. Group A was given triple combination cream and oral tranxemic acid while Group B was given triple combination cream for duration of 8 weeks. Severity of melasma was assessed by MASI, which was calculated at baseline and at the end of week 8. Mean decrease in MASI score was calculated in both groups and statistically analysed employing SPSS 20. RESULTS: Sixty patients, 30 in both groups, completed the study. Study participants were predominantly female (81.67%), with mean age of 30.46±6.24 years in group A while 31.90±4.53 in group B. No statistically significant difference was noted in both treatment groups for mean decrease in the MASI score (6.4933±4.38358 in group A compared to 5.7833±5.04251 in the group B; p-value 0.56). CONCLUSIONS: The addition of oral tranexamic acid did not contribute significantly in decrease in MASI score when used in combination with topical triple regimen. It may have a role as an adjuvant to topical triple combination cream.

Antioxidant Combo Therapy Protects White Matter After Traumatic Brain Injury.

Following traumatic brain injury (TBI), increased production of reactive oxygen species (ROS) and the ensuing oxidative stress promotes the secondary brain damage that encompasses both grey matter and white matter. As this contributes to the long-term neurological deficits, decreasing oxidative stress during the acute period of TBI is beneficial. While NADPH oxidase (NOX2) is the major producer of ROS, transcription factor Nrf2 that induces antioxidant enzymes promotes efficient ROS disposal. We recently showed that treatment with an antioxidant drug combo of apocynin (NOX2 inhibitor) and TBHQ (Nrf2 activator) protects the grey matter in adult mice subjected to TBI. We currently show that this antioxidant combo therapy given at 2 h and 24 h after TBI also protects white matter in mouse brain. Thus, the better functional outcomes after TBI in the combo therapy treated mice might be due to a combination of sparing both grey matter and white matter. Hence, the antioxidant combo we tested is a potent therapeutic option for translation in future.

Hydroquinone: myths and reality.

Hydroquinone has pharmacological uses in disorders of pigmentation because of its ability to competitively inhibit the enzyme tyrosinase. Our contemporary review presents the strongest evidence supporting the use of hydroquinone with the most effective and tolerable formulations combining hydroquinone, retinoid and corticosteroid (modified Kligman formula or 'triple combination cream'). The risk of exogenous ochronosis is low if prescribed concentrations of ≤ 5 for a limited period with regular monitoring. Dermatologists should reassure patients that with controlled use, hydroquinone can be well-tolerated and safe for a range of hyperpigmentary conditions.

Randomized, Double-Blinded, Split-Face Study Comparing the Efficacy and Tolerability of Two Topical Products for Melasma.

BACKGROUND: Melasma is a common disorder of hyperpigmentation that disproportionately affects individuals with skin of color. There is a paucity of studies evaluating non-hydroquinone (HQ) topical therapies for the treatment of melasma in darker skin types. OBJECTIVE: To compare the safety, efficacy, and tolerability of a HQ-free, retinol-free cosmetic topical brightener (CTB) and HQ 4% in the treatment of moderate symmetric facial melasma in patients with Fitzpatrick skin types (FST) III–VI. Methods & Materials: This was a randomized, double-blinded, split-face clinical trial. Eighteen adult patients with facial melasma were treated with CTB and HQ 4%, each to a different side of the face, twice daily for 12 weeks. Clinical assessments included half-face Melasma Area Severity Index (MASI), Overall Hyperpigmentation scale, and Melasma Severity Rating Scale (MSRS). Patients completed a Melasma Quality of Life (MelasQoL) questionnaire and clinical photographs were taken at each visit. RESULTS: CTB and HQ 4% demonstrated statistically significant improvements in half-face MASI, Overall Hyperpigmentation, MSRS and MelasQol compared to baseline. HQ 4% showed statistically significant improvements in MSRS at week 12 compared to CTB, but was non-superior for all other clinical endpoints. CONCLUSION: HQ-free, retinol-free CTB and HQ 4% both are effective and well-tolerated in the treatment of moderate facial melasma in FST III–VI. J Drugs Dermatol. 2020;19(9):822-827. doi:10.36849/JDD.2020.5353.

Study of oral tranexamic acid, topical tranexamic acid, and modified Kligman's regimen in treatment of melasma.

BACKGROUND: Melasma is a pigmentary disorder affecting mainly face . Various treatment modalities available as topicals, superficial chemical peels and lasers but none till date gives promising results, until date quest for the best treatment modality is on. AIM: To study the effect of oral and topical Tranexamic acid (TXA) and modified Kligman's regimen in treatment of melasma. METHOD: Patients having melasma were enrolled after consent for voluntary participation. A detailed history and clinical examination was done. Total 60 patients were enrolled and randomized in three groups, 20 received oral TXA 250 mg twice daily, 20 topical TXA and 20 received modified Kligman's regimen for 8 weeks along with sunscreen MASI(Melasma area severity index) was calculated at baseline, at end of 4 & 8 weeks. MASI score was compared with that at the end of the study. Based on reduction in mean MASI the therapeutic response was graded. Pre and post treatment photographs was also compared. Statistical analysis done by using student square T test , ANOVA And TUKEY test. RESULTS: Reduction in MASI score was observed in all the groups but greater reduction in MASI score with modified Kligman's regimen by 30% followed with oral TXA by 25% reduction and least with topical TXA by 5%. CONCLUSION: Although modified Kligman's regimen is comparatively more efficient but due to its side effects in long term usage oral tranexamic acid could be a promising therapeutic approach for melasma.

Microneedling with Drug Delivery (Hydroquinone 4% Serum) as an Adjuvant Therapy for Recalcitrant Melasma.

A 42-year-old woman with phototype V, presented a 9-year history of refractory centrofacial melasma to topical bleaching agents and peelings, untreated for the last 90 days. One session of microneedling with 1.5 mm needles was performed with hydroquinone 4% sterile serum drug delivery; after 3 days, modified Kligman's formula (hydroquinone 4% + fluocinolone acetonide 0.01% + tretinoin 0.05%) and broad-spectrum sunscreen SPF 70 were introduced for daily use. After 30 days, a significant improvement was observed in the clinical outcome (Figure 1) and the quality of life of the patient. These parameters were measured using Melasma Area and Severity Index (MASI) scale, with an 82.5% decrease, and Melasma Quality of Life Scale - Brazilian Population (MELASQoL-BP), with a 60% decrease. Dermatoscopic analysis (polarized videodermatoscopy x20) of the glabellar region revealed lighting of the pseudoreticular pigment network, diffuse light to dark brown background, and reduction in vascularity and telangiectasias (Figure 2). At the 5-month follow-up, there had been no relapse. The patient continued to use a broad-spectrum sunscreen along with the topical regiment.

Efficacy of 577 nm pro-yellow laser in the treatment of melasma: a prospective split-face study.

We aimed to study the effectiveness of 577 nm pro-yellow laser in the treatment of melasma. A total of 82 patients with melasma were included in this comparative study. A detailed medical history, examination, and calculation of Melasma Area and Severity Index were done for all patients. All participants were treated with topical sunscreen and hydroquinone 4% cream on both sides of the face. In addition, the left side of the face was subjected to a single pass of 577-nm pro-yellow laser at a monthly interval for three sessions. Follow up was done by comparing the Melasma area and severity index at 0, 3 and 6 months. At baseline, there is no significant difference in the Melasma area and severity index score between both sides of the face. At 3 months, MASI score was statistically significantly decreased on both sides of the face compared to pretreatment (P < .05). At 6 months, the mean MASI score at the laser-treated side was statistically significantly decreased compared to the non-laser-treated side (P < .05). we concluded that the addition of 577 nm pro-yellow laser in the treatment of melasma leads to maintain the improvement and reduction of the recurrence rate.