Fragments of Nle3‐angiotensin(1–7) accelerate healing in dermal models

Abstract: The renin angiotensin system (RAS) has been shown to be present in dermal tissue and exogenous peptides from the RAS accelerates healing and reduces scarring. An analogue of Angiotensin(1–7) [A(1–7)], Norleucine³‐A(1–7) [Nle³‐A(1–7)], is the lead compound under development for treatment of dermal injuries. As proteases are prevalent in wounded tissue and at very high levels in chronic wounds, the ability of fragments of Nle³‐A(1–7) to accelerate healing and the effect of proteases on the peptide were determined. Daily application of fragments of Nle³‐A(1–7) of five or six amino acids accelerated healing in two models of dermal injury. In addition, the peptide was found to be stable (not substantially degraded) after incubation for 4 h in the presence of Cathepsin G, collagenases blend (from clostridium), matrix metalloprotease [MMP] 2, MMP 3, MMP 9, elastase (human leukocytic or porcine pancreatic) or plasmin. Only kallikrein, an enzyme known to cleave peptides of the RAS, cleaved the peptide into two major fragments one of which was identified as NorLeu³‐A(1–4). These data support the activity of Nle³‐A(1–7) on dermal wounds.     

Dermal, oral, and inhalation pharmacokinetics of methyl tertiary butyl ether (MTBE) in human volunteers.

Methyl tertiary butyl ether (MTBE), a gasoline additive used to increase octane and reduce carbon monoxide emissions and ozone precursors, has contaminated drinking water and can lead to exposure by oral, inhalation, and dermal routes. To determine its dermal, oral, and inhalation kinetics, 14 volunteers were exposed to 51.3 microg/ml MTBE dermally in tap water for 1 h, drank 2.8 mg MTBE in 250 ml Gatorade(R), and inhaled 3.1 ppm. MTBE for 1 h. Blood and exhaled breath samples were then obtained. Blood MTBE peaked between 15 and 30 min following oral exposure, at the end of inhalation exposure, and ~5 min after dermal exposure. Elimination by each route was described well by a three-compartment model (Rsq >0.9). The Akaike Information Criterion for the three-compartment model was smaller than the two-compartment model, supporting it over the two-compartment model. One metabolite, tertiary butyl alcohol (TBA), measured in blood slowly increased and plateaued, but it did not return to the pre-exposure baseline at the 24-h follow-up. TBA is very water-soluble and has a blood:air partition ratio of 462, reducing elimination by exhalation. Oral exposure resulted in a significantly greater MTBE metabolism into TBA than by other routes based on a greater blood TBA:MTBE AUC ratio, implying significant first-pass metabolism. The slower TBA elimination may make it a better biomarker of MTBE exposure, though one must consider the exposure route when estimating MTBE exposure from TBA because of first-pass metabolism. Most subjects had a baseline blood TBA of 1-3 ppb. Because TBA is found in consumer products and can be used as a fuel additive, it is not a definitive marker of MTBE exposure. These data provide the risk assessment process of pharmacokinetic information relevant to the media through which most exposures occur-air and drinking water.     

In vivo percutaneous absorption of arsenic from water and CCA-treated wood residue.

This study was conducted to evaluate the dermal absorption of arsenic from residues present on the surface of wood preserved with chromated copper arsenate (CCA). The research reported herein used methods parallel to those of earlier research on the dermal absorption of radiolabeled arsenic (R. C. Wester et al., 1993, Fund. Appl. Toxicol. 20, 336-340), with modifications to allow use of environmental matrices that are not radiolabeled. These modifications include the surface area of application and dietary intake of arsenic, thus maximizing the potential for detection of dermally absorbed arsenic in exposed animals above diet-associated background levels of exposure. Two forms of arsenic were administered in this work. The first, arsenic in solution, was applied to the skin of monkeys to calibrate the model against prior absorption research and to serve as the basis of comparison for absorption of arsenic from CCA-treated wood residues. The second substrate was residue that resides on the surface of CCA-treated wood. Results from this research indicate that this study methodology can be used to evaluate dermally absorbed arsenic without the use of a radiolabel. Urinary excretion of arsenic above background levels can be measured following application of soluble arsenic, and absorption rates (0.6-4.4% absorption) are consistent with prior research using the more sensitive, radiolabeled technique. Additionally, the results show that arsenic is poorly absorbed from CCA-treated wood residues (i.e., does not result in urinary arsenic excretion above background levels).     

A dynamic system for delivering controlled bromine and chlorine vapor exposures to weanling swine skin

Context: Assessing the hazards of accidental exposure to toxic industrial chemical (TIC) vapors and evaluating therapeutic compounds or treatment regimens require the development of appropriate animal models.

Objective: The objective of this project was to develop an exposure system for delivering controlled vapor concentrations of TICs to the skin of anesthetized weanling pigs. Injury levels targeted for study were superficial dermal (SD) and deep dermal (DD) skin lesions as defined histopathologically.

Materials and methods: The exposure system was capable of simultaneously delivering chlorine or bromine vapor to four, 3-cm diameter exposure cups placed over skin between the axillary and inguinal areas of the ventral abdomen. Vapor concentrations were generated by mixing saturated bromine or chlorine vapor with either dried dilution air or nitrogen.

Results: Bromine exposure concentrations ranged from 6.5?×?10^?4 to 1.03?g/L, and exposure durations ranged from 1 to 45?min. A 7-min skin exposure to bromine vapors at 0.59?g/L was sufficient to produce SD injuries, while a 17-min exposure produced a DD injury. Chlorine exposure concentrations ranged from 1.0 to 2.9?g/L (saturated vapor concentration) for exposures ranging from 3 to 90?min. Saturated chlorine vapor challenges for up to 30?min did not induce significant dermal injuries, whereas saturated chlorine vapor with wetted material on the skin surface for 30–60?min induced SD injuries. DD chlorine injuries could not be induced with this system.

Conclusion: The vapor exposure system described in this study provides a means for safely regulating, quantifying and delivering TIC vapors to the skin of weanling swine as a model to evaluate therapeutic treatments.     

A non‐fatal case of invasive zygomycete (Lichtheimia corymbifera) infection in an allogeneic haematopoietic cell transplant recipient

Post‐transplant infections in allogeneic haematopoietic cell transplant (allo‐HCT) recipients often have severe consequences. This is especially the case when dealing with zygomycete infections where the result is often fatal. A major problem when dealing with zygomycete infections is the need for an accurate and fast diagnosis as the phylum is highly resistant towards the conventional antifungals. We herein describe a non‐fatal case of Lichtheimia corymbifera infection in an allo‐HCT recipient.     

Prevention of pertussis across the age spectrum through the use of the combination vaccines PENTACEL™ and ADACEL™

Acellular pertussis-containing combination vaccines are widely used in the developed world for the control of pertussis and have been successful in controlling disease in preschool-aged children. Combination vaccines formulated for use in adolescents and adults have been developed more recently and are increasingly being implemented for the control of pertussis in these age groups. One such family of products is PENTACEL? (Haemophilus influenzae type b conjugate vaccine reconstituted with component pertussis vaccine and diphtheria and tetanus toxoids adsorbed combined with inactivated poliomyelitis vaccine, DTaP-IPV-Hib), for use in young children, and ADACEL? (tetanus and diphtheria toxoids adsorbed combined with component pertussis vaccine, dTap) for use in adolescents and adults. These products have been demonstrated to be safe, immunogenic and effective for the control of pertussis and the other included diseases.     

Dermal absorption and hydrolysis of methylparaben in different vehicles through intact and damaged skin: Using a pig-ear model in vitro

Currently, there is a trend to reduce of parabens use due to concern about the safety of their unmetabolised forms. This paper focused on dermal absorption rate and effectiveness of first-pass biotransformation of methylparaben (MP) under in-use conditions of skincare products. 24-h exposure of previously frozen intact and tapestripped (20 strips) pig-ear skin to nine vehicles containing 0.1% MP (AD, applied dose of 10 μg/cm²), resulted in 2.0–5.8%AD and 2.9–7.6%AD of unmetabolised MP, and 37.0–73.0%AD and 56.0–95.0%AD of p-hydroxybenzoic acid, respectively, in the receptor fluid. The absorption rate of MP was higher from emulsions than from hydrogels, from enhancer-containing vehicles than from enhancer-free vehicles, and when skin was damaged. Experiments confirmed that the freezing of pig-ear skin slightly reduces hydrolysis of MP.After 4-h exposure of intact freshly excised and intact frozen stored skin, amount of <LOQ-2.3%AD and 2.3–3.3%AD unmetabolised MP, respectively, were found in the receptor fluid. Taking into account the number of useful properties of MP, but also the potential of systemic availability of unmetabolised MP, we consider that MP is more suitable for preserving rinse-off topical products than for leave-on products. Risk of systemic absorption of parabens should also be explored via the skin with damaged barrier.