Monobenzyl Ether Research Articles

The Effect of Monobenzone Cream on Oxidative Stress and Its Relationship With Serum Levels of IL-1β and IL-18 in Vitiligo Patients.

Monobenzyl ether hydroquinone (MEBHQ) is a cream that promotes the spread and evenness of skin patches in vitiligo. Our aim was to investigate the oxidative and inflammatory effects of this cream on vitiligo patients consuming MEBHQ. A case-control study was conducted with three groups of 30 people from the control group, vitiligo patients before and after treatment. The percentage of vitiligo spots was determined by a specialist doctor. The levels of biochemical factors, oxidative stress profile and inflammatory factors were measured by enzymatic, colorimetric and ELISA methods, respectively. Vitiligo patients showed a high level of inflammation and oxidative stress compared to healthy people. Although after 3 months of using MBEHQ cream, the percentage of skin spots in vitiligo patients increased from an average of 63%-91% and the skin color became almost uniform, but it still increased the level of oxidative stress and inflammation in these patients. Although the level of oxidative stress increased significantly in these patients, there was no significant increase in the level of malondialdehyde. The lack of significant differences in the levels of biochemical factors between healthy people and vitiligo patients before and after using the treatment shows the absence of side effects. The use of MBEHQ increased the size of skin spots and uneven skin color in vitiligo patients. Although MBEHQ did not show side effects such as diabetes, liver and kidney diseases, it increased the levels of oxidative stress and inflammatory cytokines, which needs further study.

Efficacy and Safety of Diphenylcyclopropenone (DPCP) as a Depigmenting Therapy in Extensive Vitiligo

Abstract Background Patients with extensive vitiligo who have residual pigmentation affecting exposed areas especially acral sites or patients with vitiligo universalis often seek depigmentation. At present, there is no ideal depigmenting therapy available. Possible options include; monobenzyl ether of hydroquinone (MBEH) cream, phenol, cryotherapy and Q-switched lasers. Diphenylcyclopropenone (DPCP) has been reported to rarely cause vitiligo as a side effect during the treatment of alopecia areata. Aim The aim of the present work is to evaluate the efficacy and safety of DPCP as a depigmenting therapy in extensive Vitiligo. Patients and Methods This is a pilot single arm clinical trial study. Twenty patients with extensive vitiligo were recruited from the vitiligo outpatient clinic of Dermatology, Venereology and Andrology Department, Ain Shams University Hospitals. We used DPCP applied topically to residual pigmented patches (sensitization session then therapeutic sessions). Results Depigmentation occurred among 5 patients (25% of cases). Depigmentation occurred in different tested sites including the scalp, forearm and back. Itching and blister formation were the main side effects leading to intolerability to the DPCP treatment. Conclusion Cosmetic result of DPCP depigmentation was acceptable with no skin atrophy. Further studies could be done following other protocols using sensitization dose with less concentrations of DPCP to avoid patients' intolerance to the therapy.

Development and Validation of Stability indicating HPLC method for determination of related substances and assay of Monobenzone drug substance

Monobenzone, a mono benzyl ether of hydroquinone, is used as a topical drug for skin depigmentation. It increases the excretion of melanin from melanocytes. A novel stability-indicating high performance liquid chromatographic approach has been established in the current study to identify related compounds and assay of Monobenzone. The Agilent 1260 system was used for the HPLC analysis, and a gradient method using 0.1% orthophosphoric acid in water and acetonitrile as the eluent was used to separate Monobenzone from known contaminants and degradation products on a Zorbax SB-phenyl (250 mm x 4.6 mm) 5 μm column. The flow rate was set at 0.8 mL/min, the column oven temperature was 30 °C, and the detector wavelength was maintained at 215 nm. The relative retention times for Hydroquinone and Monobenzone dimer were around 0.35 and 1.86 respectively, while the Monobenzone retention time was approximately 10.4 min. The total run time was 30 min. For all known analytes spanning the concentration range from LOQ to 200% of the specification level, the calibration plot revealed a linear relationship (minimum r=0.999). All known analytes' LOD and LOQ were found to be within 0.06–0.10 μg/mL and 0.15–0.24 μg/mL, respectively. A recovery study determined the accuracy of the proposed method. For Hydroquinone and Monobenzone dimer, mean recovery was found to be in the range of 95.86%–99.89% and 93.02%–99.84% respectively. The repeatability study showed that the method is precise enough within acceptable limits. Studies on solution stability and robustness produced results that fell within acceptable bounds. The proposed method shows excellent linearity, accuracy, precision, specificity, robustness, LOD, LOQ and system suitability findings. Additionally, the forced degradation study showed that the approach was stability indicating in nature.

Technologies of Visibility

Technologies of Visibility

Effects of Monobenzyl ether of hydroquinone on 3T3 mouse fibroblast viability and ultrastructure

ABSTRACT Monobenzyl ether of hydroquinone (MBEH) is a topical depigmentation agent used by vitiligo patients to even the skin tone. We aimed to investigate the effects of MBEH on 3T3 mouse fibroblasts. Fibroblasts were treated with 250 µM, 500 µM, and 750 µM MBEH and vehicle (EtOH:DMSO) for 24 hours. Cell numbers of 250 µM, 500 µM, and 750 µM MBEH treated and vehicle groups decreased significantly compared to control group. TUNEL positive cell rate increased with MBEH concentration. In electron microscopic examination, control and vehicle groups showed active cells features, while mitochondrial swelling and cristae loss were seen in 250 µM MBEH-treated group. In cytoplasm of 500 µM MBEH-treated group, there were many multivesicular bodies and autophagic vacuoles. As an indication of apoptosis, cell membrane blebs and reduction in cell size were observed. In 750 μM MBEH-treated group, cells were completely degenerated. Our findings show that MBEH, which is used as a depigmentation agent to lighten the skin by destroying melanocytes, may also have dose-dependent negative effects on the viability of 3T3 mouse fibroblasts, and these may be mediated through autophagic and apoptotic cell death mechanisms.

Genome-wide association study identifies CDH13 as a susceptibility gene for rhododendrol-induced leukoderma.

Racemic RS-4-(4-hydroxyphenyl)-2-butanol (rhododendrol; trade name: Rhododenol [RD]), which is used in topical skin-lightening cosmetics, was unexpectedly reported in Japan to induce leukoderma or vitiligo called RD-induced leukoderma (RIL) after repeated application. To our knowledge, no studies have investigated chemical-induced vitiligo pathogenesis on a genome-wide scale. Here, we conducted a genome-wide association study (GWAS) for 147 cases and 112 controls. CDH13, encoding a glycosylphosphatidylinositol-anchored protein called T-cadherin (T-cad), was identified as the strongest RIL susceptibility gene. RD sensitivity was remarkably increased by T-cad knockdown in cultured normal human melanocytes. Furthermore, we confirmed tyrosinase upregulation and downregulation of the anti-apoptotic molecules (BCL-2 and BCL-XL), suggesting that T-cad is associated with RD via tyrosinase or apoptotic pathway regulation. Finally, monobenzyl ether of hydroquinone sensitivity also tended to increase with T-cad knockdown, suggesting that the T-cad could be a candidate susceptibility gene for RIL and other chemical-induced vitiligo forms. This is the first GWAS for chemical-induced vitiligo, and it could be a useful model for studying the disease's genetic aspects.

Chemical induced pathognomonic features observed in human vitiligo are mediated through miR-2909 RNomics pathway

BackgroundChemicals like Monobenzyl Ether of Hydroquinone (MBEH) and 4-Tertiary Butyl Phenol (4-TBP) have been widely recognized to induce clinical lesions that resemble vitiligo, but exact molecular pathway through which these chemicals initiate vitiligo is still far from clear. ObjectivesSince vitiligo is widely considered as an autoimmune disease, this study was an attempt to understand miR-2909 RNomics in vitiligo pathogenesis using MBEH treated primary melanocytes as an archetype cellular model because MBEH causes pathological features indistinguishable from clinical vitiligo. MethodsPrimary melanocytes were treated with MBEH and 4-TBP and the role of miR-2909 RNomics at transcriptional and translational level was explored through qRT-PCR, western blot analysis, flow cytometry, immunocytochemistry, immunohistochemistry and in silico binding affinities. 4 mm punch biopsies were also obtained from lesional sites of vitiligo patients to validate the results observed in cell culture experiments. ResultsMBEH induced miR-2909 RNomics led to downregulation of MITF, TYR, TYRP1, and TYRP2 leading to decreased melanin synthesis which in turn is a characteristic trait of vitiligo. On the other hand, 4-TBP increased TGF-β which also has the intrinsic capacity to downregulate MITF leading to decreased melanin synthesis and thereby initiation of vitiligo. ConclusionBased upon our results we propose a molecular pathway which has the inherent capacity to resolve the mechanism through which these chemicals may induce vitiligo. This mechanism was also found to be involved in the lesional biopsies of vitiligo patients. These results could be exploited in better understanding the pathogenesis as well as in treatment of vitiligo.

Selective monobenzylation of 2,2-bis(hydroxymethyl)propionic acid (bis-MPA) to yield an AB linear monomer and analogous linear oligomers

The synthesis of a mono-benzylated AB monomer based on bis-MPA is explored and accomplished via a three-step synthesis without column chromatography. This optimized synthesis utilizes a generic acid-catalyzed esterification of bis-MPA to the ethyl ester. Subsequently, a selective mono-benzylation mediated by silver(I) oxide affords the monobenzyl ether of the ethyl ester. Finally, a simple base hydrolysis of monobenzyl ether ethyl ester yields 3-(benzyloxy)-2-(hydroxymethyl)-2-methylpropanoic acid, the AB monomer. This synthesis was utilized to generate gram quantities of the linear monomer (47% yield) and this monomer was used to produce a small amount of the linear polymer analogs. Although there are many branched analogs of bis-MPA, this is the first linear oligomer that has been confirmed.

Monobenzyl ether of hydroquinone 20 and 40% cream in depigmentation of patients with vitiligo: a randomized controlled trial

Background Depigmentation represents a final alternative for patients with widespread vitiligo, failing to attain satisfactory pigmentation and having a compromised quality of life. Monobenzyl ether of hydroquinone (MBEH) is the most widely used depigmenting agent, but little is known regarding specific features of its utilization.Objective To evaluate and compare two concentrations of MBEH cream (20 and 40%) regarding their effectiveness, tolerability, and effect on patients’ quality of life.Patients and methods In a double-blind randomized study, 40 patients indicated for depigmentation were equally divided into MBEH 20 and 40% groups. Patients’ responses were assessed bimonthly over 1 year or till complete depigmentation was attained through photography, point counting, and colorimetric assessment. Baseline and final evaluations by dermatology life quality index and visual analog scale were performed. Patients were followed up for 6 months. The study was registered under number ‘PACTR201808699550182.’Results A total of 39 patients completed the study. Significant color dilution, reduction of point counting and melanin indices, and improvement of dermatology life quality index and visual analog scale scores were obtained in both groups. The number of patients who achieved complete depigmentation and the degree of skin irritation was higher in MBEH 40% group, but no significant difference was found regarding the efficacy, adverse effects, or relapse between groups.Conclusion MBEH 20 and 40% concentrations proved to be effective in depigmentation; however, MBEH 20% is more suitable for face in terms of safety profile, whereas MBEH 40% can be employed for resistant cases as well as for hands and areas of thick skin.

Rapid repigmentation of vitiligo with tofacitinib plus low-dose narrowband ultraviolet B (nbUVB), even following depigmentation with monobenzyl ether of hydroquinone

Rapid repigmentation of vitiligo with tofacitinib plus low-dose narrowband ultraviolet B (nbUVB), even following depigmentation with monobenzyl ether of hydroquinone

Manejo despigmentante de vitiligo generalizado con monobenzil eter de hidroquinona

El vitiligo es una patología crónica, recidivante y difícil de tratar. El objetivo primario del tratamiento es inducir la repigmentación, sin embargo en casos extensos refractarios a tratamiento, se puede realizar despigmentación para corregir la discromía. Dentro de los tratamientos despigmentantes en vitiligo, a la fecha el único aprobado por la FDA es el Monobenzil éter de hidroquinona (monobenzona). Se expone el caso de una paciente con vitiligo extenso y refractario a tratamiento que fue manejado con monobenzona. El resultado fue exitoso durante tiempo prolongado, con recaída parcial al suspender el medicamento. La recaída remitió con el reinicio de la monobenzona. Sin nueva recaída actualmente con tratamiento de mantención 3v/semana. La monobenzona induce acromía secundaria a necrosis de los melanocitos. Se requiere su uso 1 a 2 veces al día por 6-12 meses para lograr la despigmentación. En pacientes adecuadamente seleccionados, es una alternativa válida para el manejo del vitiligo. Se presenta un caso exitoso de despigmentación con monobenzona. Actualmente, la paciente está muy satisfecha con los resultados.

Inhibition of germinal vesicle breakdown in Xenopus oocytes in vitro by a series of substituted glycol ethers.

A 24 hour in vitro Xenopus oocyte maturation (germinal vesicle breakdown [GVBD]) assay developed by Pickford and Morris (Environmental Health Perspectives, 1999, 107, 285-292) was used to screen a series of substituted glycol ethers (GEs). Substituted GEs included: ethylene glycol monomethyl ether (EGME); EG monoethyl ether (EGEE); EG monopropyl ether (EGPE); EG monobutyl ether (EGBE); EG monohexyl ether (EGHE); diethylene glycol monomethyl ether (DGME); triethylene glycol monomethyl ether (TGME); ethylene glycol monophenyl ether (EGPhE); EG monobenzyl ether (EGBeE); EG diphenyl ether (EGDPhE); and propylene glycol monophenyl ether (PGPhE). The GEs inhibited progesterone- or androstenedione-induced GVBD with the following relative potency: EGPhE > PGPhE > EGME >> EGEE ≥ EGBeE > EGPE >> EGBE >EGHE > EGDPhE >> DGME ≥ TGME, or EGPhE >> PGPhE >> EGBeE > EGDPhE > EGEE > EGME > EGPE > EGBE, EGHE, DGME and TGME, respectively. Further, [3 H]progesterone or [3 H]androstenedione binding affinities to the oocyte plasma membrane progesterone receptor (OMPR) or classical androgen receptor (AR) were: EGME > EGPhE ≥ PGPhE ≥ EGEE > EGBeE >> EGPE >> EGBE ≥ EGHE > EGDPhE, TGME, and DGME, or EGPhE > PGPhE >> EGBeE > EGDPhE >> EGEE ≥ EGME >> EGPE, EGBE, and EGHE > DGME and TGME, respectively. Binary joint mixture studies with the GVBD model using flutamide (AR antagonist) and EGPhE indicated that flutamide/EGPhE mixture acted in a concentration additive manner. The effects of substituted GE series, however, may be mediated through the OMPR; the potency of EGPhE may be the result of bimodal inhibition of both the OMPR and AR pathways.

Preparation and unequivocal identification of the regioisomers of nitrocatechol monobenzyl ether

ABSTRACTThe four positional isomers of nitrocatechol monobenzyl ether were prepared as intermediates to nitrobenzodioxanes directly from 2-benzyloxyphenol or, through two-four steps, from catechol. These preparations addressed the issue of the certain identification of the nitration products prescinding from chemical correlation to the synthetic precursors because the positional isomers are very similar for some properties and analytical data available from the literature are largely incomplete and not conclusive. The here provided NMR, DSC, and acidity data unequivocally distinguish each nitrocatechol monobenzyl ether from its regioisomers.

Depigmentation Therapies for Vitiligo.

The general goals of medical management of vitiligo are to repigment vitiliginous areas of skin and to stabilize the progression of depigmentation. However, for some patients with vitiligo affecting extensive body surface areas who are unresponsive to repigmentation therapies, depigmentation of the remaining normal skin may be a better choice. Candidates for depigmentation therapy should be carefully screened and patient education is essential. Permanent topical therapies used for depigmentation include monobenzyl ether of hydroquinone, 4-methoxyphenol, and 88% phenol. Physical modalities, such as cryotherapy and lasers, are also being used successfully.

Targeting melanocyte and melanoma stem cells by 8-hydroxy-2-dipropylaminotetralin

Monobenzyl ether of hydroquinone (MBEH) is cytotoxic towards melanocytes. Its treatment efficacy is limited by an inability to eradicate stem cells. By contrast, 8-hydroxy-N,N-dipropyl-2-aminotetralin (8-DPAT) affects melanocyte stem cell survival. MBEH and 8-DPAT were added to melanocytes and melanoma cells to compare cytotoxicity. Stem cell content among viable cells was determined by fluorocytometry using markers CD34, Pax3, and CD271. Immunostaining was used to identify stem cells in skin explants treated with MBEH or 8-DPAT ex vivo. Mice were exposed to MBEH or 8-DPAT and scanned for depigmentation before harvesting skin. MBEH exposure prompted a relative increase in stem cells among cultured melanocytes and melanoma cells, as treatment preferentially eliminated differentiated cells and spared the stem cells. Viability of this remaining, enriched stem cell population was however rapidly reduced by exposure to 8-DPAT within melanocyte and melanoma cell cultures. In human skin explants, the abundance of melanocyte stem cells was also visibly reduced after 8-DPAT treatment, in contrast to tissue exposed to MBEH. Meanwhile, significant depigmentation of the mouse pelage and loss of differentiated melanocytes was observed in vivo in response to topical application of MBEH, but not 8-DPAT. Prolonged application of the latter agent instead appeared to effectively reduce the abundance of melanocyte stem cells in the dermis. This furthers the idea that MBEH and 8-DPAT target complementary cell populations. Results indicate that combination treatment may demonstrate superior therapeutic activity by eliminating both differentiated and tumor initiating populations.

Enhanced bleaching treatment: opportunities for immune-assisted melanocyte suicide in vitiligo.

Depigmentation in vitiligo occurs by progressive loss of melanocytes from the basal layer of the skin, and can be psychologically devastating to patients. T cell-mediated autoimmunity explains the progressive nature of this disease. Rather than being confronted with periods of rapid depigmentation and bouts of repigmentation, patients with long-standing, treatment-resistant vitiligo can undergo depigmentation treatment. The objective is to remove residual pigmentation to achieve a cosmetically acceptable result--that of skin with a uniform appearance. In the United States, only the use of mono-benzyl ether of hydroquinone (MBEH) is approved for this purpose. However, satisfactory results can take time to appear, and there is a risk of repigmentation. MBEH induces necrotic melanocyte death followed by a cytotoxic T-cell response to remaining, distant melanocytes. As cytotoxic T-cell responses are instrumental to depigmentation, we propose that combining MBEH with immune adjuvant therapies will accelerate immune-mediated melanocyte destruction to achieve faster, more definitive depigmentation than with MBEH alone. As Toll-like Receptor (TLR) agonists--imiquimod, CpG, and Heat Shock Protein 70 (HSP 70)--all support powerful Th1 responses, we propose that using MBEH in combination with these agents can achieve superior depigmentation results for vitiligo patients.

Green Polymer Chemistry VIII: Synthesis of Halo‐ester‐Functionalized Poly(ethylene glycol)s via Enzymatic Catalysis

Halo-ester-functionalized poly(ethylene glycol)s (PEGs) are successfully prepared by the transesterification of alkyl halo-esters with PEGs using Candida antarctica lipase B (CALB) as a biocatalyst under the solventless conditions. Transesterifications of chlorine, bromine, and iodine esters with tetraethylene glycol monobenzyl ether (BzTEG) are quantitative in less than 2.5 h. The transesterification of halo-esters with PEGs are complete in 4 h. (1) H and (13) C NMR spectroscopy with MALDI-ToF and ESI mass spectrometry confirm the structure and purity of the products. This method provides a convenient and "green" process to effectively produce halo-ester PEGs.

Study on Synthesis of 2,2-Dimethyl-3-Hydroxy-7-Octynoic Acid

Pitipeptolide A can be disconnected across the amide bind to afford t-Boc-glycine, the linear depsipeptide and the Dhoya fragment. 2,2-dimethyl-3-hydroxy-7-octynoic acid unit was prepared in eight steps from 1,5-pentanediol monobenzyl ether. including oxidation, TBS protection, deprotection and Saponification with (1M) sodium hydroxide solution gave the Dhoya unit (8) in 75% overall yield.

Effect of monobenzyl ether of hydroquinone for advanced vitiligo patients

Background: Vitiligo is a common depigmentation disorder occurring in about 1% of the population worldwide. The disease causes the appearance of white patches on the skin. If vitiligo involves most of the body, it might be easier to depigment the normal remaining skin rather than to attempt repigmentation. For depigmentation therapy, monobenzyl ether of hydroquinone (MBEH) remains the only drug that the Food and Drug Administration approved for depigmentation therapy within the United States. The mechanism of toxicity of MBEH has remained little understood.

Vitiligo-Inducing Phenols Activate the Unfolded Protein Response in Melanocytes Resulting in Upregulation of IL6 and IL8

Vitiligo is characterized by depigmented skin patches due to loss of epidermal melanocytes. Oxidative stress may play a role in vitiligo onset, while autoimmunity contributes to disease progression. In this study we sought to identify mechanisms that link disease triggers and spreading of lesions. A hallmark of melanocytes at the periphery of vitiligo lesions is dilation of the endoplasmic reticulum (ER). We hypothesized that oxidative stress results in redox disruptions that extend to the ER, causing accumulation of misfolded peptides, which activates the unfolded protein response (UPR). We used 4-tertiary butyl phenol (4-TBP) and monobenzyl ether of hydroquinone (MBEH), known triggers of vitiligo. We show that expression of key UPR components, including the transcription factor X-box binding protein 1 (XBP1), are increased following exposure of melanocytes to phenols. XBP1 activation increases production of immune mediators interleukin-6 (IL6) and IL8. Co-treatment with XBP1 inhibitors reduced IL6 and IL8 production induced by phenols, while over-expression of XBP1 alone increased their expression. Thus, melanocytes themselves produce cytokines associated with activation of an immune response following exposure to chemical triggers of vitiligo. These results expand our understanding of the mechanisms underlying melanocyte loss in vitiligo and pathways linking environmental stressors and autoimmunity.