TBHQ-Overview of Multiple Mechanisms against Oxidative Stress for Attenuating Methamphetamine-Induced Neurotoxicity.

Methamphetamine is a derivative of amphetamines, a highly addictive central stimulant with multiple systemic toxicity including the brain, heart, liver, lung, and spleen. It has adverse effects such as apoptosis and breakdown of the blood-brain barrier. Methamphetamine is a fatal and toxic chemical substance, and its lethal mechanism has been widely studied in recent years. The possible mechanism is that methamphetamine can cause cardiotoxicity and neurotoxicity mainly by inducing oxidative stress so as to generate heat, eliminate people's hunger and thirst, and maintain a state of excitement so that people can continue to exercise. According to many research, there is no doubt that methamphetamine triggers neurotoxicity by inducing reactive oxygen species (ROS) production and redox imbalance. This review summarized the mechanisms of methamphetamine-induced neurotoxicity including apoptosis and blood-brain barrier breakdown through oxidative stress and analyzed several possible antioxidative mechanisms of tert-butylhydroquinone (TBHQ) which is a kind of food additive with antioxidative effects. As a nuclear factor E2-related factor 2 (Nrf2) agonist, TBHQ may inhibit neurotoxicity caused by oxidative stress through the following three mechanisms: the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase system, the astrocytes activation, and the glutathione pathway. The mechanism about methamphetamine's toxic effects and its antioxidative therapeutic drugs would become a research hotspot in this field and has very important research significance.

Disposition of [14C]hydroquinone in Harlan Sprague-Dawley rats and B6C3F1/N mice: species and route comparison.

1. Hydroquinone (HQ) is present in some foods and has varied industrial, medical and consumer uses. These studies were undertaken to investigate the disposition of HQ in rats and mice following gavage, intravenous (IV) and dermal exposure. 2. [14 C]HQ administered (0.5, 5 or 50 mg/kg) by gavage or IV routes to male and female Harlan Sprague-Dawley (HSD) rats and B6C3F1/N mice was well absorbed and rapidly excreted primarily in urine. Radioactivity remaining in tissues at 72 h was <1% for both species at all dose levels and routes. No sex, species or route related differences in disposition were found. 3. With dermal application of 2, 10 or 20% [14 C]HQ, mice absorbed higher percentages of the dose than rats (37, 12, 12% versus 18.6, 4.43 and 1.79%, respectively). The HQ mass absorbed by mice increased with dose, while in rats it was more constant over the dose range. Absorbed HQ was rapidly excreted in urine of both species and urinary excretion indicated continued absorption over the exposure period. No sex differences in disposition were found. 4. The oral bioavailability of HQ at 5 mg/kg was low in both rats (1.6%) and mice (3.9%) demonstrating significant first pass metabolism. Dermal bioavailability in mice was 9.4% following application of 2% formulation. 5. Urinary metabolites for both species and all routes included the glucuronide and sulfate conjugates; no parent was found in urine.

Papel da exposição à Hidroquinona na artrite reumatoide experimental induzida pelo colágeno / Role of Hydroquinone exposure on experimental collagen-induced arthritis

Artrite reumatoide (AR) é uma doença autoimune, que causa inflamação crônica nas membranas sinoviais de diversas articulações. O modelo experimenal de artrite induzida pelo colágeno (AIC) é empregado para investigar os mecanismos da AR e para identificar potenciais agentes terapêuticos. Embora a etiologia da AR ainda seja desconhecida, há evidências que a AR se desenvolve em indivíduos predispostos geneticamente, após exposição a fatores ambientais, como o tabagismo, que se destaca como maior fator de risco para indução da AR e para o agravamento em pacientes com AR já estabelecida. Porém, o mecanismo efetivo da ação dos diversos componentes do cigarros ainda precisa ser elucidado. A Hidroquinona (HQ) é um composto fenólico, encontrada em concentração elevada no cigarro, com maior ativade pró-oxidativa, além de ser produto da biotransformação do benzeno, também encontrado no cigarro. Neste caso, a HQ é responsável pela imunotoxicidade e mielotoxicidade do benzeno. Devido a alta exposição de fumantes à HQ e a associação do tabagismo com a AR, investigamos se a exposição à HQ teria participação no desenvolvimento da AIC em ratos Wistar. Para tanto, animais foram expostos à HQ em diferentes protocolos experimentais, a saber: A - por 35 dias consecutivos, durante fase de indução e desenvolvimento da artrite; B - por 14 dias consecutivos, até a segunda injeção de colágeno, na fase de sensibilização e indução da AIC; C - por 7 dias consecutivos, do 29º ao 35º dia, na fase posterior ao desenvolvimento da AIC. Os resultados obtidos mostraram que a HQ agravou a AR nos 3 grupos experimentais, aumentando os parâmetros clínicos, o número de células no líquido sinovial, a inflamação nas sinóvias, caracterizada por maior influxo de neutrófilos, proliferação de sinoviócitos (histologia por HE e imunohistoquímica), aumento nos níveis de IL-6 e IL-1ß (ELISA) no líquido sinovial e rearranjo do colágeno na sinóvia (microscopia por segundo harmônico). No entanto, os efeitos mais acentuados foram observados em animais dos grupos A e C, que também tiveram perda de peso significativa. Ademais, exposição à HQ, nos 3 grupos experimentais, causou expressão aumentada do receptor aril hidrocarboneto (AhR), um receptor ativado por xenobióticos durante a AR, e aumento nos níveis do fator de transcrição ROR e de IL-17 na sinóvia. Como AhR/ROR/IL-17 em linfócitos e neutrófilos é uma via importante na gênese da AR, ensaios in vitro foram realizados para elucidar o papel da HQ nesta via. A incubação com HQ in vitro de esplenócitos de animais naive elevou a expressão de AhR e de secreção de IL-17 (por citometria de fluxo), as quais foram bloqueadas pelo antagonista de AhR (α-naftoflavona). Em conjunto, os resultados obtidos nos permitem concluir que a HQ, como um importante componente do cigarro agrava a CIA em ratos, e a ativação via AhR/IL-17 é um possível mecanismo da patogênese da artrite

Rheumatoid arthritis (RA) is an autoimmune disease that causes chronic inflammation in the joint synovial membranes. The experimental model of collagen-induced arthritis (CIA) is used to investigate the involved mechanisms in RA and to identify novel therapeutic agents. The genesis of RA is multifactorial, involving interplay of genetic and environmental factors and smoking is the trigger factor in the development or RA and worsens the pre-existing RA but the mechanisms undlerlying are yet to be elucidated. Hydroquinone (HQ) is a phenolic compound, found in high concentrations in cigarette, where HQ is the major oxidative component. Moreover, HQ is benzene metabolite, which is also found in cigarette smoke, being responsible for the myelotoxicity and immunotoxicity detected during benzene exposure. Due to this association, we aimed to investigate the role of HQ exposure on CIA development in Wistar rats and the involved mechanisms. Animals were exposed to HQ according to different protocols: A - during 35 consecutive days, during the sensitization and devolpment phases of the disease; B - during 14 consecutive days, until the second injection of collagen, during the sensitization phase; C - during 7 consecutive days, from day 29 to 35, after the development phase of CIA. The results showed that HQ worsened the RA in the 3 experimental protocols, HQ elevated the clinical parameters of CIA development, increased inflammation in the synovial membrane, characterized by increased influx of neutrophis, synoviocytes proliferation (visualized by Immunohistochemistry and Histology analysis), augmented the levels of IL-6 and IL-1ß in the synovial fluid (ELISA assay) and led to intense collagen deposition on the synovia. The most pronounced effects where observed in animals from groups A and C, which also had weight body loss. In addition, in the 3 protocols, HQ exposure also increased the expression of AhR receptor, a receptor activated by xenobiotics during RA, and increased the expression of ROR and levels of IL-17 secretion in the synovial membranes. As AhR/ROR/IL-17 in lymphocytes and neutrophils is an important pathway involved in the genesis of RA, in vitro studies have been performed to elucidate the role of HQ exposure in this pathway. The HQ in vitro treatment augmented the expression of AhR and secretion of IL-17 by splenocytes (FACS assay) and the administration of an AhR antagonist (α-naphtoflavone) blocked these effects. Taken together, the results obtained here allow us to conclude that HQ, as an important cigarette component, aggravates CIA in rats, and the activation of AhR/IL-17 pathway is a possible mechanism involved in the RA pathogenesis

Risk assessment of skin lightening cosmetics containing hydroquinone.

Following reports on potential risks of hydroquinone (HQ), HQ for skin lightening has been banned or restricted in Europe and the US. In contrast, HQ is not listed as a prohibited or limited ingredient for cosmetic use in Japan, and many HQ cosmetics are sold without restriction. To assess the risk of systemic effects of HQ, we examined the rat skin permeation rates of four HQ (0.3%, 1.0%, 2.6%, and 3.3%) cosmetics. The permeation coefficients ranged from 1.2 × 10-9 to 3.1 × 10-7 cm/s, with the highest value superior than the HQ aqueous solution (1.6 × 10-7 cm/s). After dermal application of the HQ cosmetics to rats, HQ in plasma was detected only in the treatment by highest coefficient cosmetic. Absorbed HQ levels treated with this highest coefficient cosmetic in humans were estimated by numerical methods, and we calculated the margin of exposure (MOE) for the estimated dose (0.017 mg/kg-bw/day in proper use) to a benchmark dose for rat renal tubule adenomas. The MOE of 559 is judged to be in a range safe for the consumer. However, further consideration may be required for regulation of cosmetic ingredients.

Effects of soap-water wash on human epidermal penetration.

Skin decontamination is a primary interventional method used to decrease dermal absorption of hazardous contaminants, including chemical warfare agents, pesticides and industrial pollutants. Soap and water wash, the most common and readily available decontamination system, may enhance percutaneous absorption through the "wash-in effect." To understand better the effect of soap-water wash on percutaneous penetration, and provide insight to improving skin decontamination methods, in vitro human epidermal penetration rates of four C(14) -labeled model chemicals (hydroquinone, clonidine, benzoic acid and paraoxon) were assayed using flow-through diffusion cells. Stratum corneum (SC) absorption rates of these chemicals at various hydration levels (0-295% of the dry SC weights) were determined and compared with the results of the epidermal penetration study to clarify the effect of SC hydration on skin permeability. Results showed accelerated penetration curves of benzoic acid and paraoxon after surface wash at 30 min postdosing. Thirty minutes after washing (60 min postdosing), penetration rates of hydroquinone and benzoic acid decreased due to reduced amounts of chemical on the skin surface and in the SC. At the end of the experiment (90 min postdosing), a soap-water wash resulted in lower hydroquinone penetration, greater paraoxon penetration and similar levels of benzoic acid and clonidine penetration compared to penetration levels in the non-wash groups. The observed wash-in effect agrees with the enhancement effect of SC hydration on the SC chemical absorption rate. These results suggest SC hydration derived from surface wash to be one cause of the wash-in effect. Further, the occurrence of a wash-in effect is dependent on chemical identity and elapsed time between exposure and onset of decontamination. By reducing chemical residue quantity on skin surface and in the SC reservoir, the soap-water wash may decrease the total quantity of chemical absorbed in the long term; however, the more immediate accelerated absorption of chemical toxins, particularly chemical warfare agents, may be lethal. Copyright © 2015 John Wiley & Sons, Ltd.

In vitro Dermal Absorption of Hydroquinone: Protocol Validation and Applicability on Illegal Skin-Whitening Cosmetics.

In Europe, hydroquinone is a forbidden cosmetic ingredient. It is, however, still abundantly used because of its effective skin-whitening properties. The question arises as to whether the quantities of hydroquinone used become systemically available and may cause damage to human health. Dermal absorption studies can provide this information. In the EU, dermal absorption has to be assessed in vitro since the Cosmetic Regulation 1223/2009/EC forbids the use of animals. To obtain human-relevant data, a Franz diffusion cell protocol was validated using human skin. The results obtained were comparable to those from a multicentre validation study. The protocol was applied to hydroquinone and the dermal absorption ranged between 31 and 44%, which is within the range of published in vivo human values. This shows that a well-validated in vitro dermal absorption study using human skin provides relevant human data. The validated protocol was used to determine the dermal absorption of illegal skin-whitening cosmetics containing hydroquinone. All samples gave high dermal absorption values, rendering them all unsafe for human health. These results add to our knowledge of illegal cosmetics on the EU market, namely that they exhibit a negative toxicological profile and are likely to induce health problems.

Single and multiple dose pharmacokinetics and tolerability of HX-1171, a novel antioxidant, in healthy volunteers.

BACKGROUND: HX-1171 (1-O-hexyl-2,3,5-trimethylhydroquinone) is a promising antioxidant with therapeutic potential for hepatic fibrosis. The aim of this study was to investigate the tolerability and pharmacokinetics of HX-1171 in healthy volunteers. METHODS: A randomized, single-blind, placebo-controlled, dose escalation study was conducted in 83 subjects. In the single ascending dose study, 20, 40, 80, 160, 300, 600, 1,200, 1,500 or 2,000 mg of HX-1171 was administered to 67 subjects. In the multiple ascending dose study, 500 or 1,000 mg was administered to 16 subjects for 14 days. The plasma and urine concentrations of HX-1171 were determined by using a validated liquid chromatography-mass spectrometry method. Pharmacokinetic parameters were obtained by non-compartmental analysis. Tolerability was assessed based on physical examinations, vital signs, clinical laboratory tests, and electrocardiograms. RESULTS: Adverse events reported in the study were all mild in intensity and resolved without any sequelae. HX-1171 was rapidly and minimally absorbed with a median time at maximal concentration of 0.63-1.50 hours and slowly eliminated with a terminal half-life of 21.12-40.96 hours. Accumulation index ranged from 2.0 to 2.2 after repeated dosing for 14 days. For both the single and multiple doses administrations, urinary concentrations indicated that less than 0.01% of the HX-1171 administered was excreted in urine. CONCLUSION: HX-1171 was well tolerated and minimally absorbed in healthy volunteers. The pharmacokinetic profile of HX-1171 was consistent with once-a-day dosing.

The Use of Cellulose Nanocrystals for Potential Application in Topical Delivery of Hydroquinone.

Nanotechnology-based drug delivery systems can enhance drug permeation through the skin and improve the drug stability. The biodegradability and biocompatibility of cellulose nanocrystals have made these nanoparticles good candidates to use in biomedical applications. The hyperpigmentation is a common skin disorder that could be caused by number of reasons such as sun exposure and pregnancy. Hydroquinone could inhibit the production of melanin and eliminate the discolorations of skin. This study is aimed at introducing cellulose nanocrystals as suitable carriers for drug delivery to skin. Prepared cellulose nanocrystals were characterized by dynamic light scattering and atomic force microscopy. The size of cellulose nanocrystals determined using dynamic light scattering was 301 ± 10 nm. Hydroquinone-cellulose nanocrystal complex was prepared by incubating of hydroquinone solution in cellulose nanocrystals suspension. The size of hydroquinone-cellulose nanocrystal complex determined using dynamic light scattering was 310 ± 10 nm. The hydroquinone content of the hydroquinone-cellulose complex was determined using UV/vis spectroscopy. Hydroquinone was bound to cellulose nanocrystals representing 79.3 ± 2% maximum binding efficiency when 1.1 mg hydroquinone was added to 1 mL of cellulose nanocrystals suspension (2 mg cellulose nanocrystal). The hydroquinone-cellulose nanocrystal complex showed an approximately sustained release profile of hydroquinone. Approximately, 80% of bound hydroquinone released in 4 h.

Hydroquinone-salicylic acid conjugates as novel anti-melasma actives show superior skin targeting compared to the parent drugs.

BACKGROUND: Hydroquinone (HQ) and salicylic acid (SA) are drugs for treating melasma through the mechanisms of tyrosinase inhibition and chemical peeling, respectively. Their high frequency of causing skin irritation has led to limited use of both drugs. OBJECTIVES: We designed the new conjugates obtained by joining HQ and SA by the co-drug concept for evaluating cutaneous absorption capability. METHODS: Monoester (4-hydroxyphenyl 2-hydroxybenzoate, HPH) and diester (1,4-phenylene bis(2-hydroxybenzoate), PBH) forms of the conjugates were synthesized and physicochemically characterized. The enzymatic hydrolysis to the parent drugs was examined. Both an equimolar dose and a saturated solubility were utilized as the applied dose for testing cutaneous absorption via pig and nude mouse skins. RESULTS: The conjugates had higher lipophilicity, less aqueous solubility, and a lower melting point/crystallinity than the parent drugs. Both conjugates showed a quick conversion into the parent drugs in esterases and skin homogenates, with PBH showing the greater hydrolysis. The hydrolysis level in skin after topical application was less as compared to that in esterases and homogenates. The tyrosinase inhibition (%) and molecular docking demonstrated that the conjugates possessed skin-lightening capability (3% for HPH and 7% for PBH) although this activity was lower than that of HQ (23%). The conjugates showed an increased skin deposition compared to the respective parent drugs. Total absorption of HPH and PBH led to a 13- and 19-fold enhancement in cutaneous retention compared to HQ alone. A similar increment of skin deposition was shown for the conjugates when compared to SA. Contrary to skin reservoir retention, transdermal transport across the skin was decreased by the conjugates, especially for PBH. This indicates the maximization of cutaneous targeting by the conjugates. CONCLUSIONS: Topically applied HPH and PBH can be the new candidates for treating melasma due to efficient skin absorption and acceptable skin tolerance.

The risk of hydroquinone and sunscreen over-absorption via photodamaged skin is not greater in senescent skin as compared to young skin: nude mouse as an animal model.

Intrinsic aging and photoaging modify skin structure and components, which subsequently change percutaneous absorption of topically applied permeants. The purpose of this study was to systematically evaluate drug/sunscreen permeation via young and senescent skin irradiated by ultraviolet (UV) light. Both young and senescent nude mice were subjected to UVA (10 J/cm(2)) and/or UVB radiation (175 mJ/cm(2)). Physiological parameters, immunohistology, and immunoblotting were employed to examine the aged skin. Hydroquinone and sunscreen permeation was determined by in vitro Franz cell. In vivo skin absorption was documented using a hydrophilic dye, rhodamine 123 (log P=-0.4), as a permeant. UVA exposure induced cyclooxygenase (COX)-2 and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) upregulation. Epidermal tight junction (TJ) were degraded by UVA. UVB increased transepidermal water loss (TEWL) from 13 to 24 g/m(2)/h. Hyperplasia and inflammation, but not loss of TJ, were also observed in UVB-treated skin. UVA+UVB- and UVA-irradiated skin demonstrated similar changes in histology and biomarkers. UVA+UVB or UVA exposure increased hydroquinone flux five-fold. A negligible alteration of hydroquinone permeation was shown with UVB exposure. Hydroquinone exhibited a lower penetration through senescent skin than young skin. Both UVA and UVB produced enhancement of oxybenzone flux and skin uptake. However, the amount of increase was less than that of hydroquinone delivery. Photoaging did not augment skin absorption of sunscreens with higher lipophilicity, including avobenzone and ZnO. Exposure to UVA generally increased follicular entrance of these permeants, which showed two- to three-fold greater follicular uptake compared to the untreated group. Photoaging had less impact on drug/sunscreen absorption with more lipophilic permeants. Percutaneous absorption did not increase in skin subjected to both intrinsic and extrinsic aging.

Application of physiologically-based toxicokinetic modelling in oral-to-dermal extrapolation of threshold doses of cosmetic ingredients.

The application of physiologically based toxicokinetic (PBTK) modelling in route-to-route (RtR) extrapolation of three cosmetic ingredients: coumarin, hydroquinone and caffeine is shown in this study. In particular, the oral no-observed-adverse-effect-level (NOAEL) doses of these chemicals are extrapolated to their corresponding dermal values by comparing the internal concentrations resulting from oral and dermal exposure scenarios. The PBTK model structure has been constructed to give a good simulation performance of biochemical processes within the human body. The model parameters are calibrated based on oral and dermal experimental data for the Caucasian population available in the literature. Particular attention is given to modelling the absorption stage (skin and gastrointestinal tract) in the form of several sub-compartments. This gives better model prediction results when compared to those of a PBTK model with a simpler structure of the absorption barrier. In addition, the role of quantitative structure-property relationships (QSPRs) in predicting skin penetration is evaluated for the three substances with a view to incorporating QSPR-predicted penetration parameters in the PBTK model when experimental values are lacking. Finally, PBTK modelling is used, first to extrapolate oral NOAEL doses derived from rat studies to humans, and then to simulate internal systemic/liver concentrations - Area Under Curve (AUC) and peak concentration - resulting from specified dermal and oral exposure conditions. Based on these simulations, AUC-based dermal thresholds for the three case study compounds are derived and compared with the experimentally obtained oral threshold (NOAEL) values.

Risk assessment of free hydroquinone derived from Arctostaphylos Uva-ursi folium herbal preparations.

Uva-ursi folium (bearberry leaf) has been traditionally used to treat symptoms of lower urinary tract infections. The most representative constituent of this herbal drug is arbutin that is rapidly absorbed in the small intestine and undergoes hepatic conjugation to form hydroquinone (HQ) conjugates. As free HQ is crucial for the safety of the herbal preparation, we reviewed published and unpublished experimental and human studies to clarify some outdated assumptions and to support the safety of therapeutic daily doses of Uva-ursi folium extract. Specifically, data on pharmacokinetics and the human exposure of arbutin and HQ were reviewed. A therapeutic recommended human daily dose of bearberry leaf extract (420 mg hydroquinone derivatives calculated as anhydrous arbutin) liberates free HQ in urine at a maximum exposure level of 11 µg/kg body weight (bw)/d. By means of an experimental no observed effect level value, a permitted daily exposure dose below which there is a negligible risk to human health was estimated for free HQ (100 µg/kg bw/d). Dietary sources of arbutin/HQ that are regularly consumed long term by humans generate comparable free HQ exposure levels. There is no direct evidence, regarding human data, supporting the fact that free HQ causes convulsion, hepatotoxicity, nephrotoxicity, or promotion of tumors in humans. Free HQ had no activity promoting pancreatic, bladder, stomach, or liver carcinogenesis. In conclusion, under the recommended use conditions Uva-ursi folium is a safe therapeutic option for treating lower urinary tract infections.

The co-drug of conjugated hydroquinone and azelaic acid to enhance topical skin targeting and decrease penetration through the skin.

A co-drug of hydroquinone (HQ) and azelaic acid (AA), bis(4-hydroxyphenyl)nonanedioate (BHN), was synthesized and investigated as a topical prodrug with the aim of improving the dermal delivery of the parent drugs. Physicochemical parameters were ascertained, and the enzymatic hydrolysis was examined. Skin permeation of HQ, AA, and BHN was studied by determining the skin deposition and flux across nude mouse skin under equivalent doses with the same thermodynamic activity. The partition coefficient (log P) of the co-drug increased by up to 5.0 with HQ and AA conjugation, which had respective log P values of 0.5 and 1.4. In the skin absorption experiment, BHN in ethanol/pH 7 buffer resulted in a 2-fold enhancement of skin deposition compared to both HQ and AA. With permeation using polyethylene glycol 400/pH 7 buffer as the vehicle, the co-drug, respectively, exhibited 8.1- and 1.4-fold enhancements of skin uptake compared to HQ and AA alone. The transdermal flux from BHN was negligible compared to those with HQ and AA treatments. The results of a preliminary safety evaluation showed no signs of stratum corneum disruption or erythema by BHN application within 24h. The co-drug approach provides a viable option for the treatment of skin hyperpigmentation of HQ and AA.

Hydroquinone PBPK model refinement and application to dermal exposure.

A physiologically based pharmacokinetic (PBPK) model for hydroquinone (HQ) was refined to include an expanded description of HQ-glucuronide metabolites and a description of dermal exposures to support route-to-route and cross-species extrapolation. Total urinary excretion of metabolites from in vivo rat dermal exposures was used to estimate a percutaneous permeability coefficient (K(p); 3.6×10(-5) cm/h). The human in vivo K(p) was estimated to be 1.62×10(-4) cm/h, based on in vitro skin permeability data in rats and humans and rat in vivo values. The projected total multi-substituted glutathione (which was used as an internal dose surrogate for the toxic glutathione metabolites) was modeled following an exposure scenario based on submersion of both hands in a 5% aqueous solution of HQ (similar to black and white photographic developing solution) for 2 h, a worst-case exposure scenario. Total multi-substituted glutathione following this human dermal exposure scenario was several orders of magnitude lower than the internal total glutathione conjugates in rats following an oral exposure to the rat NOEL of 20 mg/kg. Thus, under more realistic human dermal exposure conditions, it is unlikely that toxic glutathione conjugates (primarily the di- and, to a lesser degree, the tri-glutathione conjugate) will reach significant levels in target tissues.

Effect of emulsifiers and their liquid crystalline structures in emulsions on dermal and transdermal delivery of hydroquinone, salicylic acid and octadecenedioic acid.

This study investigated the effect of emulsifiers and their liquid crystalline structures on the dermal and transdermal delivery of hydroquinone (HQ), salicylic acid (SA) and octadecenedioic acid (DIOIC). Emulsions containing liquid crystalline phases were compared with an emulsion without liquid crystals. Skin permeation experiments were performed using Franz-type diffusion cells and human abdominal skin dermatomed to a thickness of 400 mum. The results indicate that emulsifiers arranging in liquid crystalline structures in the water phase of the emulsion enhanced the skin penetration of the active ingredients with the exception of SA. SA showed a different pattern of percutaneous absorption, and no difference in dermal and transdermal delivery was observed between the emulsions with and without liquid crystalline phases. The increase in skin penetration of HQ and DIOIC could be attributed to an increased partitioning of the actives into the skin. It was hypothesized that the interaction between the different emulsifiers and active ingredients in the formulations varied and, therefore, the solubilization capacities of the various emulsifiers and their association structures.

Effect of penetration modifiers on the dermal and transdermal delivery of drugs and cosmetic active ingredients.

In this study the effect of 2 penetration modifiers, dimethyl isosorbide (DMI) and diethylene glycol monoethyl ether (DGME) on the skin delivery of hydroquinone (HQ), salicylic acid (SA) and octadecenedioic acid (DIOIC) was investigated. Ten percent DMI and DGME were separately formulated into oil-in-water emulsions containing 1.8% HQ, SA and DIOIC, respectively. Skin delivery and the flux across split-thickness human skin of the active ingredients were determined using Franz diffusion cells. An emulsion with 10% water incorporated instead of the water-soluble penetration modifiers served as a control. The study showed that neither 10% DMI nor 10% DGME significantly enhanced the skin permeation of the various lipophilic active ingredients or the uptake into the skin. It was hypothesized that the addition of the penetration modifiers to the emulsions not only enhanced the solubility of the various active ingredients in the skin but also in the formulation, resulting in a reduced thermodynamic activity and hence a weaker driving force for penetration. Therefore, the effect of DMI and DGME on the solubility of the active ingredients in the skin was counteracted by a simultaneous reduction in the thermodynamic activity in the formulation.

Recovery and long-term renal excretion of propofol, its glucuronide, and two di-isopropylquinol glucuronides after propofol infusion during surgery.

BACKGROUND: The metabolism of the short-acting anaesthetic agent propofol has been described over the first 24 h. However, the long-term disposition of propofol and its metabolites is unclear. We describe the pharmacokinetics (renal excretion rates and renal clearance) of propofol and its metabolites over 60 h. METHODS: Ten patients undergoing lung surgery were included in the study. They received anaesthesia with continuous i.v. propofol at an average rate of 10 mg min(-1). During surgery and 60 h thereafter, we sampled blood and urine. Propofol and its metabolites were measured using gradient high performance liquid chromatography (HPLC). RESULTS: In nine patients, propofol and its glucuronides were found in the plasma over the first 15 h. In the urine, however, even after 60 h, propofol and its quinol glucuronides were still detectable. One patient had a markedly different pharmacokinetic profile, showing a limited renal excretion or absorption of 12% of the dose. CONCLUSIONS: After an infusion of propofol, patients excrete propofol and its metabolites in the urine over a period in excess of 60 h. We hypothesize that (re)absorption of propofol and its metabolites by the kidney is a major process in elimination and that the reabsorbed compounds are gradually conjugated in the kidney and excreted in the urine. One patient showed a different pharmacokinetic profile for which we currently have no explanation.

Hydroquinone: an evaluation of the human risks from its carcinogenic and mutagenic properties.

The toxicology of hydroquinone has been reviewed on a number of previous occasions. This review targets its potential for carcinogenicity and possible modes of carcinogenic action. The evaluation made by IARC (1999) of its carcinogenic risk to humans was that hydroquinone is not classifiable as to its carcinogenicity to humans (Group 3). This evaluation was based on inadequate evidence in humans and limited evidence in experimental animals. The epidemiological information comes from four cohort studies involving occupational exposures. A cohort of lithographers, some of whom had worked with hydroquinone, had an excess of malignant melanoma based on five cases, but only two of the cases had reported exposure to hydroquinone. In a study of photographic processors the number of exposed individuals was uncertain and the numbers of cases of individual cancer sites were small. In view of the statistical power limitations of these studies for individual diagnostic categories of cancers, they are not considered to be informative with regard to the carcinogenicity of hydroquinone. A cohort of workers with definite and lengthy exposure to hydroquinone, during either its manufacture or its use, had low cancer rates compared with two comparison populations; the reason for the lower than expected rates is unclear. In a motion picture film processing cohort there were significant excess malignancies of the respiratory system among workers engaged in developing, where there was exposure to hydroquinone as well as other chemicals. There was no information on tobacco smoking habits and no dose-response relationship. Hydroquinone has been shown reproducibly to induce benign neoplasms in the kidneys of male F344 rats dosed orally either by gavage (25 and 50 mg/kg body weight) or diet (0.8%). The gavage study has been evaluated in considerable detail. This evaluation showed that all renal tubule adenomas and all cases of renal tubule atypical hyperplasia occurred in areas of severe or end-stage chronic progressive nephropathy and that the neoplasms were not otherwise confined to any particular part of the kidney. It is likely that the mode of carcinogenic action of hydroquinone is exacerbation of this natural disease process. Hydroquinone is mutagenic in vitro and in vivo, having caused genotoxicity or chromosomal aberrations in rodent bone-marrow cells. At least a portion, if not all, of the chromosomal effects are caused by interference by hydroquinone or its metabolites with chromosomal segregation, probably due to interaction with mitotic spindle proteins. However, the dose routes used to demonstrate these effects in almost all of the studies in vivo were intraperitoneal or subcutaneous injection, which were considered inappropriate. There were five studies by the oral route. These included a mouse bone-marrow cell micronucleus test in which a weak, marginally positive response was obtained following a single oral dose of 80 mg/kg body weight. The remaining oral route studies all showed no significant effect. They included a mouse bone-marrow cell micronucleus test in which there was no genotoxic activity after exposure to a diet containing 0.8% hydroquinone for 6 days; two (32)P-post-labeling assays, one with targets of Zymbal gland, liver, and spleen in Sprague-Dawley rats, the other with the kidney as target in F344 rats; and the last oral assay was for 8-hydroxydeoxyguanosine adducts in F344 rat kidney DNA. Thus, the evidence (and the database) for any genotoxic effect in vivo is sparse and none has been observed in kidney. While glutathione conjugates could be responsible for the tumor induction, careful histology seems to show that the most actively toxic of several glutathione compounds tested, 2,3,5-triglutathion-S-yl hydroquinone, targets a very specific region of the kidney, the outer stripe of the outer medulla (OSOM), whereas hydroquinone-associated adenomas are more randomly distributed and occur in the cortex as well as the medulla. A nongenotoxic mode of action that involves exacerbation of a spontaneously occurring rodent renal disease, chronic progressive nephropathy (CPN), is proposed and evaluated. This disease is particularly prominent in male rats and the evidence is consistent with an absence of any human counterpart; therefore, the increased incidence of renal tubule adenomas in hydroquinone-dosed male rats is without human consequence.

The safety of hydroquinone: a dermatologist's response to the 2006 Federal Register.

Recently, the US Food and Drug Administration proposed a ban on over-the-counter hydroquinone mainly on the basis of high absorption, reports of exogenous ochronosis in humans, and murine hepatic adenomas, renal adenomas, and leukemia with large doses over extended time periods. Systemic exposure to hydroquinone from routine topical application is no greater than that from quantities present in common foods. While murine hepatic adenomas increased, murine hepatocellular carcinomas decreased, suggesting a protective effect. Renal tumors are sex, species, and age specific and therefore do not appear relevant to humans after decades of widespread use. Murine leukemia has not been reproducible and would not be expected from small topical doses. Finally, a literature review of exogenous ochronosis and clinical studies employing hydroquinone (involving over 10,000 exposures under careful clinical supervision) reveal an incidence of exogenous ochronosis in the United States of 22 cases in more than 50 years. Therefore, the proposed ban appears to be unnecessarily extreme.

Chemoprotective and carcinogenic effects of tert-butylhydroquinone and its metabolites.

Tert-butylhydroquinone (tBHQ) has been commonly used as a synthetic food antioxidant to prevent oils and fats from oxidative deterioration and rancidity due to its potent anti-lipid peroxidation activity. In North America, the maximum level of tBHQ allowed in fat products is 0.02% with an acceptable daily intake of 0-0.7 mg/kg body weight. Extensive studies have demonstrated that tBHQ exhibit anti-carcinogenic effect. The ability of tBHQ to induce phase II xenobiotic metabolizing enzymes through an Nrf2-dependent pathway is thought to be responsible for the observed protective effect of tBHQ. It has been proposed that tBHQ enhances Nrf2-mediated transcription by promoting reactive oxygen species-mediated dissociation of Nrf2-Keap1, Nrf2 stabilization, phosphatidylinositol 3-kinase (PI3K)/Akt activity, and MAPK pathway activation. In contrast to the beneficial effects of tBHQ, a number of studies have shown that chronic exposure to tBHQ may induce carcinogenicity. However, the precise mechanisms of tBHQ carcinogenicity are not well understood. The toxicity or carcinogenicity of tBHQ has been attributed to the formation of reactive GSH-conjugates, generation of reactive species, CYP1A1 induction, caspase activation and reduced GSH/ATP levels. This review provides an account of recent mechanisms proposed for both chemoprotective and carcinogenic effect of tBHQ.