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At least 415 records · Page 23Linked to original sources
PubMed2005

DNA adduct formation of benzo[a]pyrene in white blood cells of workers exposed to polycyclic aromatic hydrocarbons.

The major DNA adducts of anti-benzo[a]pyrene diolepoxide (BPDE) were determined by high performance liquid chromatography with fluorescence detection (HPLC-FLD) in white blood cells (WBC) of workers exposed to benzo[a]pyrene (B[a]P). In addition, ambient concentrations of B[a]P at the workplace were determined by personal air sampling. Workers in a refractory setting were examined before (n=26) and 3 months after (n = 33) changing the production material (binding pitch). Furthermore, 9 coke oven workers were examined. The change in the production process in the refractory setting led to a decrease in the median of ambient B[a]P concentrations (0.14 to <0.07 microg/m3). The median of BPDE-DNA adduct levels in WBC also decreased from 0.9 adducts/10(8) nucleotides before changing the production material to <0.5 adducts/10(8) nucleotides 3 months afterwards. The B[a]P concentrations at the workplace for the coke oven workers were found to be significantly higher than in the refractory setting. However, BPDE-DNA adduct concentrations in coke oven workers and refractory setting workers showed no significant difference, which was probably due to the low number of studied subjects in the coke-oven setting. No significant differences could be observed for BPDE-DNA adduct levels between current smokers (n=21) and non-smokers (n=14; p = 0.93) from both plants. In addition, no correlation between B[a]P concentrations in the air and DNA adduct levels in refractory workers and in coke oven workers could be found (r = -0.03, p = 0.87). Because of the missing correlation between personal air sampling and BPDE-DNA adduct levels in WBC, the results may indicate that their formation is either influenced by other routes of exposure to B[a]P (e.g., skin absorption, dietary habits) or interindividual differences in their formation and repair.

7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide↗
PubMed2004

Transdermal iontophoresis of insulin: IV. Influence of chemical enhancers.

Transdermal iontophoresis per se may not be able to achieve significant permeation of large peptides like insulin, thereby necessitating the use of combination strategies involving chemical enhancers and iontophoresis. The study investigated effect of pre-treatment with commonly used vehicles such as ethanol (EtOH), propylene glycol (PG), water and their binary combinations, dimethyl acetamide (DMA), 10% dimethyl acetamide in water, ethyl acetate (EtAc) and isopropyl myristate (IPM) on insulin iontophoresis. Solvents, which acted on the lipid bilayer, were able to produce a synergistic enhancement with iontophoresis. The binary solvent systems produced either additive or no effect, when combined with iontophoresis. FT-IR studies showed that EtOH, DMA, EtAc caused lipid extraction and the former two also caused changes in skin proteins, whereas IPM caused increase in lipid fluidity. TGA studies showed that EtOH and PG caused dehydration of skin. Skin barrier property was severely compromised with DMA, followed by EtOH and EtAc, while IPM and PG had relatively minimum skin barrier altering potential. Thus, this study demonstrates the possibility of achieving higher permeation of large peptides like insulin by combining iontophoresis with chemical enhancers that act on the intercellular lipids.

Adjuvants, Pharmaceutic↗
PubMed2005

Transdermal delivery of naloxone: skin permeation, pharmacokinetic, irritancy and stability studies.

The current investigation aims to evaluate ex vivo, in vivo performance, stability and irritancy potential of a transdermal formulation of naloxone (NLX) developed at our laboratory at different concentrations (10, 20 and 30mg/g of gel) in a transdermal reservoir patch. Ex vivo permeation studies were performed by employing porcine and rat skins. In vivo performance was assessed in Sprague-Dawley rats by single and multiple application of the patch. Further stability of the formulation was established for 3 months at accelerated stability conditions as per ICH guidelines. Amongst the barriers used the rat skin was found to be more permeable than the porcine epidermis and the flux across each barrier increased with increasing thermodynamic activity of drug in the gel. Based on ex vivo data, the surface area (SA) of the patch was predicted to be 39.6 cm(2) in order to achieve therapeutic blood levels. Upon single dose administration, the steady-state levels were maintained from 4-48 h, which proves the clear advantage of transdermal delivery system over the current mode of administration, i.e., intravenous (i.v.) bolus which is effective upto a maximum of 1.5h. Upon multiple dose administration, the sustained steady state for 12h, even after patch removal proves the formation of drug depot in the skin. The formulations were found to be stable with respect to NLX assay and penetration enhancer efficacy upto 3 months under accelerated stability conditions. The alteration of penetration barrier function, as evidenced by increased trans epidermal water loss (TEWL) was not accompanied by any significant amount of skin irritation measured using laser doppler velocimetry (LDV). The developed transdermal delivery system of NLX is efficacious, stable and safe upon single and multiple dose applications each lasting for 48 h.

Administration, Cutaneous↗
PubMed2006

Facilitated skin penetration of lidocaine: combination of a short-term iontophoresis and microemulsion formulation.

The objective of this study was to demonstrate the potential of the application of a short-term iontophoresis on the topical delivery of lidocaine hydrochloride from a microemulsion-based system. Five- and 10-min durations of anodal iontophoresis applied onto porcine skin were examined in combination with a microemulsion containing 2.5% lidocaine hydrochloride. A similar combination (10-min iontophoresis with microemulsion in the anodal electrode) was also examined in vivo in a rat model. It was shown in vitro that by combining microemulsion application with a 10-min iontophoresis of 1.13 mA/cm2 electric current density, a significantly increased flux was obtained compared with a combination of aqueous drug solution with the same iontophoresis protocol. In vivo studies revealed that 57.71 +/- 18.65 and 18.43 +/- 9.17 microg cm(-2) were reached in the epidermis and dermis, respectively, at t = 30 min of microemulsion application, when iontophoresis was applied for 10 min. In contrast, the application of aqueous solution-iontophoresis resulted in a relatively lower drug accumulation (21.44 +/- 10.42 and 5.30 +/- 2.25 microg cm(-2) in the epidermis and dermis, respectively, at t = 30) with more rapid clearance of the drug from the skin. Ten-minute application of a low-current electric field on a new topical microemulsion appears to make significant changes in skin permeability. The potential advantages of this procedure include significantly increased flux, accumulation of a large skin drug depot, short lag times, reduced irritation (compared to long-term iontophoresis), simplicity and ease of compliance.

Anesthetics, Local↗
PubMed2006

Effects of pretreatment of needle puncture and sandpaper abrasion on the in vitro skin permeation of fluorescein isothiocyanate (FITC)-dextran.

Microneedle systems have gained attention as having many advantages over transdermal patches and hypodermic needles. The procedure provides adequate skin permeation rates without pain or severe infection. To obtain information for designing a microneedle system, macroneedles were used instead of microneedles to investigate the effects of pretreatment of needle puncture in the skin barrier stratum corneum on in vitro skin permeation of fluorescein isothiocyanate (FITC)-dextrans (4.3, 9.6 and 42.0 kDa) (FD-4, FD-10 and FD-40). The effect of sandpaper abrasion was also investigated for comparison. Both pretreatments on the skin barrier significantly increased the skin permeation of FDs. Lactate dehydrogenase (LDH) leaching was measured after pretreatment of macroneedle and sandpaper abrasion on the skin to evaluate the skin damage by these pretreatment methods. Lower leaching of LDH was observed after macroneedle puncture than after sandpaper abrasion. Next, a parallel permeation-resistance model of the skin barrier was established. Skin permeation of FD-10 was predicted by the model as a function of the number of pores in the skin barrier. Our results suggest that needle puncture may provide a safe, efficient and controllable alternative for increasing transdermal drug delivery.

Administration, Cutaneous↗
PubMed2005

Cultured skin loaded with tetracycline HCl and chloramphenicol as dermal delivery system: mathematical evaluation of the cultured skin containing antibiotics.

Dermal patches consisting of cultured human skin with antibiotics, which have a protective effect on wound skin as well as a preventative effect on second infection of the skin, were prepared and mathematically analyzed as a new drug delivery system (DDS) that can be applied to serious skin defects such as severe burns. In the present study, a three-dimensional cultured human skin model (living skin equivalent-high, LSE-high) was used as a cultured skin membrane and tetracycline HCl (TC-HCl) and chloramphenicol (CP) were used as antibiotics. At first, antibiotics were entrapped in the LSE-high from the dermal side through culture medium in order to obtain a drug-loaded LSE-high. The antibiotic release from the drug-loaded LSE-high was then examined and the resulting release data were used to calculate the effective diffusion coefficient of the antibiotics (D(LSE)) and initial loading concentration of the antibiotics (C0) in the LSE-high. The release profile of TC-HCl was represented by general diffusion-limited kinetics, whereas an initial burst effect was found in the release profile of CP. Therefore, the burst effect was taken into account for analyzing the release profile of CP. Stripped skin excised from hairless rats was used as a wound model, and the antibiotic permeation through the skin from aqueous solution was examined and evaluated using differential equations for Fick's second law of diffusion to obtain the effective diffusion coefficient of the antibiotics in the wound skin (D(skin)). Furthermore, the antibiotic permeation profile through the excised stripped skin from the drug-loaded LSE-high was measured and theoretically evaluated by Fick's second law of diffusion with previously obtained parameters (C0, D(LSE), D(skin)) using a newly constructed two- or three-layered diffusion model. The calculated concentrations of TC-HCl and CP in the upper epidermis of the model wound skin were over their minimum inhibitory concentration (MIC) for several hours against various bacteria, suggesting that this dosage system is useful for the treatment of severe burns. In addition, the present analytical method and diffusion model, with the drug-loaded LSE-high and stripped rat skin, are useful tools for evaluating this new DDS.

Administration, Cutaneous↗
PubMed2003

Sunless skin tanning with dihydroxyacetone delays broad-spectrum ultraviolet photocarcinogenesis in hairless mice.

Sunless tanning with dihydroxyacetone (DHA) is not considered to be a sunscreen although it does absorb parts of the ultraviolet (UV) spectrum. We investigated the protection with topical application of DHA against solar UV-induced skin carcinogenesis in lightly pigmented hairless hr/hr C3H/Tif mice. Broad-spectrum UV radiation, simulating the UV part of the solar spectrum was obtained from one Philips TL12 and five Bellarium-S SA-1-12 tubes. Three groups of mice were UV-exposed four times a week to a dose-equivalent of four times the standard erythema dose (SED), without or with application of 5 or 20% DHA only twice a week. Similarly, three groups of mice were treated with DHA and irradiated with a high UV dose (8 SED), simulating a skin burn. Two groups (controls) were not irradiated, but either left untreated or treated with 20% DHA alone. The UV-induced skin pigmentation by melanogenesis could easily be distinguished from DHA-induced browning and was measured by a non-invasive, semi-quantitative method. Application of 20% DHA reduced by 63% the pigmentation produced by 4 SED, however, only by 28% the pigmentation produced by 8 SED. Furthermore, topical application of 20% DHA significantly delayed the time to appearance of the first tumor >or=1mm (P=0.0012) and the time to appearance of the third tumor (P=2 x 10(-6)) in mice irradiated with 4 SED. However, 20% DHA did not delay tumor development in mice irradiated with 8 SED. Application of 5% DHA did not influence pigmentation or photocarcinogenesis. In conclusion, this is the first study to show that the superficial skin coloring generated by frequent topical application of DHA in high concentrations may delay skin cancer development in hairless mice irradiated with moderate UV doses.

Animals↗
PubMed2004

Phthalate treatment does not influence levels of IgE or Th2 cytokines in B6C3F1 mice.

Bronchial asthma is mediated, in part, by the immunoregulatory cytokines interleukins 4 and 13 (IL-4 and IL-13). These cytokines stimulate IgE synthesis that in turn is associated with airway hyper-responsiveness. Compounds that stimulate IgE synthesis and elicit bronchial reactivity are generally considered to be respiratory sensitizers. Recently, it has been hypothesized that exposure to phthalates may contribute to childhood asthma. To address this question, di-(2-ethylhexyl) phthalate (DEHP) was tested using a protocol adapted from work by Dearman that involves topical application (and challenge) of test substances to mice followed by measurements of total serum IgE. In addition, auricular lymph nodes were harvested for measurement of IL-4 and IL-13 proteins and their corresponding messenger RNAs. Because skin absorption of high molecular weight phthalates is limited, liver weight increase, a measure of peroxisomal proliferation, was monitored to assure that internal dosing had been achieved. ELISA and RNAse protection assays demonstrated that DEHP treatment did not significantly affect IgE, IL-4, or IL-13 levels. Similarly, IL-4 and IL-13 mRNA levels were not elevated. In contrast, all of these were significantly elevated by trimellitic anhydride (TMA), a respiratory sensitizer used as the positive control in this assay. Liver weights were significantly elevated by DEHP, providing evidence of sufficient percutaneous absorption to induce physiological responses. To extend these observations, three other commercial phthalate ester plasticizers, di-isononyl phthalate (DINP), di-isohexyl phthalate (DIHP), and butyl benzyl phthalate (BBP), were assessed using the same protocol. As above, ELISA and RNAse protection assays showed that IgE, IL-4, and IL-13 proteins, and IL-4 and IL-13 mRNAs in the phthalate-treated animals were all at levels similar to that of control values. The positive control, TMA, produced large, statistically significant increases in all parameters, demonstrating responsiveness of the assay. Another control, dinitrochlorobenzene (DNCB), a contact sensitizer, also responded as expected, producing smaller but statistically significant increases in IgE and in mRNA for IL-4 and IL-13 but not in the levels of these cytokines. In summary, treatment with DEHP, DINP, DIHP, and BBP did not result in significant elevations in total serum IgE, IL-4, or IL-13. As such it is unlikely that these substances would produce antibody-mediated respiratory allergy.

Animals↗
PubMed2005

Bladder cancer screening and monitoring of 4,4'-methylenebis(2-chloroaniline) exposure among workers in Taiwan.

OBJECTIVES: Transitional cell carcinoma of the urinary bladder is associated with occupational exposure to 4,4'-methylenebis(2-chloroaniline) (MBOCA). A program to monitor MBOCA levels in the work environment and to screen for bladder cancer was performed at four MBOCA manufacturing factories. METHODS: The U.S. Occupational Safety and Health Administration analytic method No. 24 was adopted in this study to measure air MBOCA concentrations. A total of 70 MBOCA-exposed workers and another 92 nonexposed workers were recruited for screening. Urine occult blood tests, urine cytology, tests for the urine tumor marker nuclear matrix protein, and abdominal ultrasonography were performed in all patients. Intravenous urography and cystoscopy were used to confirm the presence of bladder cancer. RESULTS: The air concentration of MBOCA was greatest in the purification area (0.23 to 0.41 mg/m3), followed by the washing area (less than 0.02 to 0.08 mg/m3) and neutralization area (less than 0.05 to 0.06 mg/m3). This study identified a current worker with proved bladder cancer. In addition, we also identified 1 worker with suspected malignant cells on urine cytology and 1 worker with atypical cytology combined with gross hematuria. Although the prevalence of atypical urinary cells and the nuclear matrix protein 22 tumor marker was not significantly different between the MBOCA-exposed workers and nonexposed workers as a whole or when grouped by sex, the prevalence of positive occult blood was marginally significantly (P = 0.055) greater in male exposed workers (18%) than in male nonexposed workers (7%). CONCLUSIONS: The findings of this study support the conclusions from other studies that MBOCA is potentially carcinogenic to humans. Control measures are needed to prevent overexposure from inhalation and skin absorption.

Adult↗
PubMed2005

Effects of single and repeated exposure to biocidal active substances on the barrier function of the skin in vitro.

The dermal route of exposure is important in worker exposure to biocidal products. Many biocidal active substances which are used on a daily basis may decrease the barrier function of the skin to a larger extent than current risk assessment practice addresses, due to possible skin effects of repeated exposure. The influence of repeated and single exposure to representative biocidal active substances on the skin barrier was investigated in vitro. The biocidal active substances selected were alkyldimethylbenzylammonium chloride (ADBAC), boric acid, deltamethrin, dimethyldidecylammonium chloride (DDAC), formaldehyde, permethrin, piperonyl butoxide, sodium bromide, and tebuconazole. Of these nine compounds, only the quaternary ammonium chlorides ADBAC and DDAC had a clear and consistent influence on skin permeability of the marker compounds tritiated water and [(14)C]propoxur. For these compounds, repeated exposure increased skin permeability more than single exposure. At high concentrations the difference between single and repeated exposure was quantitatively significant: repeated exposure to 300 mg/L ADBAC increased skin permeability two to threefold in comparison to single exposure. Therefore, single and repeated exposure to specific biocidal products may significantly increase skin permeability, especially when used undiluted.

Adult↗
PubMed1996

Influence of nitric oxide on transepithelial transport in toad skin: effects of cholinergic agents and morphine.

The effects induced by L-arginine (L-Arg) on the short-circuit current and potential difference of Pleurodema thaul skin were investigated. L-Arg, but not D-Arg significantly increased the short-circuit current and potential difference when applied to the serosal surface. The effects of L-Arg were antagonized by amiloride, NG-nitro-methyl-L-arginine (L-NAME) and by methylene blue. Carbachol and acetylcholine induced significant increases of both electrical parameters of the toad skin. These effects of the muscarinic cholinergic drugs were potentiated by a low concentration of L-Arg and antagonized by L-NAME or methylene blue. Carbachol and acetylcholine induced significant increases of both electrical parameters of the toad skin. These effects of the muscarinic cholinergic drugs were potentiated by a low concentration of L-Arg and antagonized by L-NAME or methylene blue. Addition of dibutyryl cyclic guanosyl monophosphate (db cGMP) or dibutyryl cyclic adenosine monophosphate (db cAMP) increased short-circuit current and potential difference. The effects of db cGMP, but not those of db cAMP were antagonized by L-NAME. The consecutive application of db cGMP and db cAMP induced additive effects. These results suggest that L-Arg increases transport in toad skin presumably acting through the formation of nitric oxide, which then stimulates cytoplasmic guanylate cyclase and leads to increased Na+ and K+ transport. The effects of L-Arg and carbachol were antagonized by acute application of morphine; however, a rebound response was observed when carbachol or noradrenaline were given after prolonged exposure of the skin to morphine, which suggests an adaptive response of the skin involving both cGMP and cAMP. Responses to both nucleotides were unchanged by morphine.

Acetylcholine↗
PubMed1978

Early laminar excision: improved control of burn wound sepsis by partial dermatome debridement.

The large mass of devitalized tissue that comprises the burn eschar is gradually becoming recognized as the principal source of complications in the burn patient. Clinical observations suggest that the topical agent silver sulfadiazine does not penetrate the eschar sufficiently to prevent bacterial infection from becoming established in the deeper levels of the wound but does penetrate to a depth of approximately 1.5 mm in bactericidal concentrations. A new technique that takes advantage of this fact, early laminar excision, has been developed at the Children's Hospital of Michigan Burn Center. The eschar is excised layer by layer with the electric dermatome under general anesthesia within the first 72 hr post burn, and the thickness of the devitalized tissue is reduced to a remnant of less than 1 mm. This is less than the depth to which silver sulfadiazine is capable of penetrating in bactericidal concentrations, and greatly enhanced control of burn wound sepsis is achieved. Early laminar excision of the eschar, combined with silver sulfadiazine dressings, aggressive resurfacing of the wound, and increased emphasis on nutrition, is an approach to management of the victims of thermal trauma that should significantly improve survival in patients with burn injuries greater than 60% body surface area.

Adolescent↗