Systemic exposure to benzoic acid and hippuric acid following topical application of clindamycin 1%/benzoyl peroxide 3% fixed-dose combination gel in Japanese patients with acne vulgaris.

Clindamycin 1%/benzoyl peroxide 3% fixed-dose combination gel (CLDM/BPO3%) is a topical product for the treatment of acne vulgaris. In this study, plasma and urine concentrations of benzoic acid (BA) and hippuric acid (HA) were analyzed to estimate the pharmacokinetics (PK) of BPO after application of CLDM/BPO3% twice-daily for 7 days in Japanese patients with acne vulgaris. Seven-day repeated application of CLDM/BPO3% appears to be safe in this patient population. Concentrations of plasma and urine BA were below the limit of quantification before and after repeated application in most of the 12 adult male patients. Mean difference in Cmax and AUC0-last for plasma HA indicated increased exposures after repeated application, but with wide 90% confidence intervals. Mean Ae0-12 for urine HA was similar before and after repeated application. Repeated application of CLDM/BPO3% is thus unlikely to result in accumulation of BA and HA. The study suggests negligible systemic exposure to BPO metabolites from CLDM/BPO3% after 7-day repeated application in male patients with acne vulgaris.

Topical dose justification: benzoyl peroxide concentrations.

BACKGROUND: Benzoyl peroxide (BPO) is widely utilized in acne treatment as an alternative to antibiotics against which Propionibacterium acnes becomes more resistant. OBJECTIVE: This overview examines BPO dose justification. METHODS: PubMed, Embase® and Science Citation Index searches were conducted using the keywords "benzoyl peroxide" and "acne vulgaris". RESULTS: Limited experimental data are available. However, there appears no significant difference in the efficacy of concentrations from 2.5% to 10%. DISCUSSION: The extent of free fatty acids and the percutaneous penetration of BPO may not play a critical role in acne vulgaris.

The topical delivery of benzoyl peroxide using elegant dynamic hydrofluoroalkane foams.

Formulating benzoyl peroxide (BPO) in an effective topical product is challenging due to its poor water solubility and chemical instability, but delivering BPO using elegant foams is an attractive solution to this problem. The aim of this work was to investigate how nanoparticle properties influence BPO release and permeation when administrated using dynamic hydrofluoroalkane foams. Lipid (LN, approximately 50 nm) and polymeric (PN, approximately 350 nm) nanoparticles were produced and loaded into topical foams. Drug release and permeation was measured using ultrafiltration and Franz cells studies, respectively. No BPO release was detected when the nanoparticles were stored in the aqueous solvent, but upon administration to silicone membrane the pluronic surfactant-induced LN swelling and BPO delivery (35.7 +/- 3.8 microg cm(-2) h(-1)). In the same situation the PN aggregated with a delivery rate of 2.5 +/- 0.2 microg cm(-2) h(-1). Surprisingly the aqueous nanosuspensions delivered BPO at an equivalent rate to the foams despite the poor drug solubility in the dispersing medium presumably due to ultra-rapid BPO solubilization kinetics of the drug in water. The delivery of BPO from the foams (0.1% BPO) was superior compared to the commercial products (5% BPO), but further testing in human skin is required prior to clinical use.

The stability of tretinoin in tretinoin gel microsphere 0.1%.

Topical tretinoin is highly effective and widely used in the treatment of acne vulgaris. In studies to determine the degree of tretinoin photo degradation (isomerization), 2 tretinoin formulations, tretinoin gel microsphere 0.1% and tretinoin gel 0.025%, alone or in combination with erythromycin-benzoyl peroxide topical gel, were exposed to fluorescent light, incandescent light, or darkness for up to 24 hours. Results of the investigations revealed that after 24 hours of exposure to fluorescent light, 98% of the initial tretinoin in the tretinoin gel microsphere 0.1% formulation remained unchanged. When tretinoin gel microsphere 0.1% was combined with erythromycin-benzoyl peroxide topical gel and exposed to fluorescent light, 99% and 87% of the tretinoin was recovered after 4 and 24 hours, respectively, indicating only a limited amount of degradation. In contrast, exposure of tretinoin gel 0.025% to 24 hours of fluorescent light resulted in up to 69% tretinoin degradation and up to 89% degradation when the gel was combined with the erythromycin-benzoyl peroxide topical gel. The data suggest that the tretinoin gel microsphere 0.1% formulation offers marked protection against tretinoin photo degradation, even in the presence of a strong oxidizing agent such as benzoyl peroxide.

Enzyme-catalyzed decomposition of dibenzoyl peroxide in organic solvents.

Catalytic activity of catalase (CAT, EC 1.11.1.6), immobilized on carbon black NORIT and soot PM-100, with respect to decomposition of dibenzoyl peroxide (BPO) in non-aqueous media (acetonitrile and tetrachloromethane), was investigated with a quantitative UV-spectrophotometrical approach. Progress of the above reaction was controlled by selected kinetic parameters: the apparent Michaelis constant (Km(app)), the specific rate constant (k(sp)), the activation energy (Ea), the maximum reaction rate (Vmax), and the Arrhenius' pre-exponential factor (Z0). Conclusions on the tentative mechanism of the catalytic process observed were drawn from the calculated values of the Gibbs energy of activation (deltaG*), the enthalpy of activation (deltaH*), and entropy of activation (deltaS*).

Effect of benzoyl peroxide on antioxidant status, NF-kappaB activity and interleukin-1alpha gene expression in human keratinocytes.

Benzoyl peroxide (BP) is used as a topical treatment for acne. Besides its anti-bacterial activity, the exact molecular mechanisms underlying its mode of action are not fully understood. In the current study, the effects of BP on cell viability, antioxidant status and, IL-1 and IL-8 gene expression were investigated in HaCaT keratinocytes. Keratinocytes incubated for 24 h with BP exhibited a dose-dependent cytotoxicity at concentrations above 250 microM. Furthermore, in the presence of 300 microM BP about 50% of the cellular vitamin E was depleted within the first 30 min. The intracellular ratio of oxidized to reduced glutathione (GSSG/GSH) was increased significantly starting 6 h after BP treatments indicating that BP reacts rapidly with targets in the cell membrane and more slowly with those in the cytosol. NF-kappaB transactivation was not significantly affected by BP. However, BP treatment of HaCaT keratinocytes resulted in a dose-dependent increase in IL-1alpha gene expression whereas no changes in IL-8 mRNA levels were observed. These results demonstrate that BP induces an inflammatory reaction mediated by oxidative stress by a pathway independent of the redox-sensitive transcription factor NF-kappaB.

Benzoyl peroxide increases UVA-induced plasma membrane damage and lipid oxidation in murine leukemia L1210 cells.

Ultraviolet A radiation induces oxidative stress and cell damage. The purpose of this investigation was to examine whether ultraviolet A-induced cell injury was amplified by the presence of a non-ultraviolet A absorbing molecule capable of generating free radicals. Benzoyl peroxide was used as a lipid soluble potential radical-generating agent. Plasma membrane permeability assessed by trypan blue uptake was used to measure cell damage in murine leukemia L1210 cells. Cells were irradiated with a pulsed Nd/YAG laser at 355 nm using 0-160 J per cm2. The ratio of the fluence-response slope in the presence of 40 microM benzoyl peroxide to that of irradiated controls was 4.3 +/- 2.6. Benzoyl peroxide alone or benzoyl peroxide added after irradiation did not cause increased trypan blue uptake. The ratio of the fluence-response slopes in the presence of 40 microM benzoyl peroxide to that of irradiated controls was 4.7 +/- 1.4 when cells were irradiated (0-43 J per cm2) with a xenon lamp, filtered to remove wavelengths <320 nm. The increased trypan blue uptake in 355 nm-irradiated cells in the presence of benzoyl peroxide was inhibited in a concentration-dependent manner by butylated hydroxytoluene, vitamin E, and trolox, a water-soluble vitamin E derivative. Lipid oxidation, assessed as thiobarbituric acid reactive substances, was significantly increased in samples irradiated with ultraviolet A in the presence of benzoyl peroxide at fluences >34 J per cm2. The increased trypan blue uptake and thiobarbituric acid reactive substances were inhibited by butylated hydroxytoluene. These results suggest that agents not absorbing ultraviolet A radiation may enhance ultraviolet A-initiated oxidative stress in cells.

Bioavailability of components of resin-based materials which are applied to teeth.

Chemical components of many materials used in dental practice can move into the local biophase, where they can have beneficial or adverse effects. The strongest indirect evidence that components of resin-based materials used in dentistry can move into the biophase are the many reports of allergic dermatitis in dental personnel. Direct measurement of component release has shown that triethylene glycol dimethacrylate (TEGDMA), hydroxyethyl methacrylate (HEMA), and, in the case of some orthodontic cements, bis-glycidyl methacrylate and benzoyl peroxide can move into an aqueous medium from a range of resin-based materials which are applied to teeth as part of oral care. In the case of resin composite restorations, HEMA and TEGDMA are available in microgram quantities via the salivary surface in the minutes and hours after clinical placement and via dentin and pulp in the hours and days after placement. Fortunately, moderate thickness of dentin protects pulp tissue against local toxicity. There are no data which suggest that systemic toxicity is a risk with any of these materials. There are some case reports of allergic responses to the monomers in patients, but the incidence of such responses appears at present to be much lower than that in dental personnel.

The isolated perfused bovine udder as an in vitro model of percutaneous drug absorption. Skin viability and percutaneous absorption of dexamethasone, benzoyl peroxide, and etofenamate.

Using udders from slaughtered cows as a new in vitro model of percutaneous drug absorption, the tissue viability and the percutaneous absorption of dexamethasone, benzoyl peroxide, and etofenamate were studied. The organ was perfused with gassed tyrode solution for up to 6 hr. As shown by measurement of glucose consumption, lactate production, lactate dehydrogenase activity, and pH in the perfusate, the tissue was viable over a 6-hr period. This was confirmed by a histological examination. Determination of the udder skin-fold thickness demonstrated that no edema developed within the perfusion period. A maximum skin penetration of dexamethasone was found after administration of dexamethasone dissolved in acetone with dimethyl sulfoxide, followed by ointment with salicylic acid, ointment without salicylic acid, and acetone solution. Experiments with benzoyl peroxide and etofenamate demonstrated that the perfused udder skin was capable of metabolizing drugs in vitro. In conclusion, the isolated perfused bovine udder is a new in vitro model, which maintains bovine udder skin with an isolated vasculature in a viable state. Using this in vitro model, we note it is possible to compare the dermal penetration, metabolism, and absorption of substances after topical administration of different drug formulations.

[The use of the organs of slaughtered animals for the testing of drugs: suitability of the bovine udder for the study of substances active through the skin]. / Die Verwendung von Schlachttierorganen zur Prüfung von Arzneimitteln: Eignung des Rindereuters zur Untersuchung von hautwirksamen Stoffen.

Various in vitro models are used to study the transdermal penetration and absorption of test compounds. The isolated perfused bovine udder is described as a new in vitro model. Using bovine udders from slaughtered healthy cows, the percutaneous absorption of dexamethasone, benzoyl peroxide and isosorbide dinitrate was measured. For further validation of the described model, additional studies are necessary.

Controlled release of benzoyl peroxide from a porous microsphere polymeric system can reduce topical irritancy.

Skin absorption of benzoyl peroxide from a topical lotion containing freely dispersed drug was compared with that from the same lotion in which the drug was entrapped in a controlled-release styrene-divinylbenzene polymer system. In an in vitro diffusion system, statistically significant (p = 0.01) differences were found in the content of benzoyl peroxide in excised human skin and in percutaneous absorption. In vivo, significantly (p = 0.002) less benzoyl peroxide was absorbed through rhesus monkey skin from the polymeric system. This controlled release of benzoyl peroxide to skin can alter the dose relation that exists between efficacy and skin irritation. Corresponding studies showed reduced skin irritation in cumulative irritancy studies in rabbits and human beings, whereas in vivo human antimicrobial efficacy studies showed that application of the formulations containing entrapped benzoyl peroxide significantly reduced counts of Propionibacterium acnes (p less than 0.001) and aerobic bacteria (p less than 0.001) and the free fatty acid/triglyceride ratio in skin lipids. These findings support the hypothesis that, at least for this drug, controlled topical delivery can enhance safety without sacrificing efficacy.

Role of the benzoyloxyl radical in DNA damage mediated by benzoyl peroxide.

Benzoyl peroxide (BzPO) is both a tumor promoter and progressor in mouse skin; however, BzPO is neither an initiator nor a complete carcinogen in this tissue. Although not mutagenic, BzPO has been observed to produce strand breaks in DNA of exposed cells. These actions are presumed to be mediated by free-radical derivatives of BzPO. Previous studies suggested that the metabolism of BzPO in keratinocytes proceeds via the initial cleavage of the peroxide bond, yielding benzoyloxy radicals which, in turn, can either fragment to form phenyl radicals and carbon dioxide or abstract H atoms from biomolecules to yield benzoic acid. Benzoic acid is the major stable metabolite of BzPO produced by keratinocytes. In the present study we have investigated the role of BzPO and its metabolites in the generation of strand scissions in a cell-free system using phi X-174 plasmid DNA. In this system BzPO produced DNA damage that was dose-dependent over a concentration range of 0.1-1 mM and required the presence of copper but not other transition metals. By contrast, benoic acid did not produce DNA damage in this system, either in the presence or in the absence of copper. The inclusion of spin trapping agents, such as N-tert-butyl-alpha-phenylnitrone (PBN), 3,5-dibromo-4-nitrosobenzenesulfonate, and nitrosobenzene, in incubations was found to significantly reduce the extent of DNA damage generated via the copper-mediated activation of BzPO. Electron paramagnetic resonance spectroscopy studies suggested that the primary radical trapped by PBN following copper-mediated decomposition of BzPO was the benzoyloxy radical.(ABSTRACT TRUNCATED AT 250 WORDS)

The role of topical agents in the healing of full-thickness wounds.

Eight topical agents in current use were studied for their effects on wound contraction and rate of reepithelialization of full-thickness excisions using a porcine animal model. The following agents were applied daily for a period of 27 days: scarlet red ointment, benzoyl peroxide lotion, bacitracin ointment, silver sulfadiazine cream, aloe vera gel, tretinoin cream, capsaicin cream, and mupirocin ointment. The rate of reepithelialization was significantly enhanced by treatment with capsaicin, bacitracin, silver sulfadiazine, and scarlet red, and was markedly retarded by treatment with tretinoin. Wound contraction was significantly retarded by mupirocin, bacitracin, and silver sulfadizine. Knowledge of the effects of topical agents on various aspects of healing allows the clinician to choose the most appropriate material to use in a given clinical situation to optimize the healing process and produce the best final result.