Topical gel containing Polysiloxanes and hyaluronic acid for skin scar: Formulation design, characterization, and In vivo activity.

BACKGROUND: Scar formation is undesirable both cosmetically and functionally. It shows that silicone gel is effective in preventing and improving scars formed due to a wound formation after injury. OBJECTIVES: This study investigates whether a silicone gel composition based on a novel concept of infusing a biologically active material such as hyaluronic acid and/or salts with various polysiloxane derivatives in a specific proportion to achieve desired viscosity range and their action has a synergistic beneficial effect on skin scar after injury. METHODS: We have developed a topical gel utilizing a combination of emulsifiers, sodium hyaluronate, polysiloxane, and its derivatives. The method of preparation comprises mixing of aqueous phase dispersion and polysiloxanes blend under stirring at room temperature. RESULTS: It results in the formation of a homogenous smooth gel formulation. The developed topical gel formulation was characterized for physicochemical properties, rheology, stability, and anti-scar activity in Wistar rats. It was found that the developed formulation system consists of desirable attributes for skin applications. In vivo investigation of developed polysiloxane gel formulation for anti-scar activity shown promising outcomes compared to marketed product (Kelo-cote scar gel). Furthermore, a histopathology study of healed skin tissues observed the formation of microscopic skin structures compared to the Kelo-cote scar gel. CONCLUSIONS: It indicates that the combination of polysiloxanes and sodium hyaluronate resulting an improvement in anti-scar activity compared to the marketed product containing polysiloxanes alone.

Prenatal Octamethylcyclotetrasiloxane Exposure Impaired Proliferation of Neuronal Progenitor, Leading to Motor, Cognition, Social and Behavioral Functions.

Cyclic siloxane octamethylcyclotetrasiloxane (D4) has raised concerns as an endocrine-disrupting chemical (EDC). D4 is widely used in detergent products, cosmetics, and personal care products. Recently, robust toxicological data for D4 has been reported, but the adverse effects of D4 on brain development are unknown. Here, pregnant mice on gestational day 9.5 were treated daily with D4 to postnatal day 28, and the offspring mice were studied. The prenatal D4-treated mice exhibited cognitive dysfunction, limited memory, and motor learning defect. Moreover, prenatal D4 exposure reduced the proliferation of neuronal progenitors in the offspring mouse brain. Next, the mechanisms through which D4 regulated the cell cycle were investigated. Aberrant gene expression, such as cyclin-dependent kinases CDK6 and cyclin-dependent kinase inhibitor p27, were found in the prenatal D4-treated mice. Furthermore, the estrogen receptors ERa and ERb were increased in the brain of prenatal D4-treated mice. Overall, these findings suggest that D4 exerts estrogen activity that affects the cell cycle progression of neuronal progenitor cells during neurodevelopment, which may be associated with cognitive deficits in offspring.

Inhalation toxicity of cyclic semi-volatile methylsiloxanes: Disentangling the conundrum of phase-specific adaptations from adverse outcomes.

This paper compares the phase-specific inhalation toxicity of the cyclic semi-volatile methylsiloxanes (cVMSs) D4, D5 and D6. The objectives of this paper are to re-analyze information from acute to chronic inhalation studies on rats with these cVMSs to identify the unifying principles of phase-specific toxicity at the portal-of-entry and if they depend on acute, acute-on-chronic or chronic mechanisms. This re-analysis supports the hypothesis that concentrations must be high enough to exceed the vapor saturation at any given temperature for stabilizing the aerosol phase and evoking phase-specific effects at sites of the respiratory tract susceptible to the cVMSs-specific physicochemical properties amphiphilicity and surface tension. In summary, the portal-of-entry effects and related findings appear to be acute in nature and specific to liquid aerosol. The repeated inhalation exposure studies with D4 and D5 up to two years in duration did not reveal chronic aggravations of portal of entry outcomes. Findings at a pulmonary location where amphiphilic surfactant molecules are present appear to be caused by the acute adaptation to deposited dose. Such outcome should better be described as a high-dose liquid aerosol phenomenon imparted by the physicochemical properties "liquid" and "hydrophobic". This calls for a phase-specific human risk characterization of cVMSs.

Preliminary evaluation of application of a 3-dimensional network structure of siloxanes Dergall preparation on chick embryo development and microbiological status of eggshells.

The spatial network structure of Dergall is based on substances nontoxic to humans and the environment which, when applied on solid surfaces, creates a coating that reduces bacterial cell adhesion. The bacteriostatic properties of siloxanes are based on a purely physical action mechanism which excludes development of drug-resistant microorganisms. The aims of the present study were to 1) evaluate a Dergall layer formed on the eggshell surface regarding the potential harmful effects on the chick embryo; 2) evaluate antimicrobial activity and estimate the prolongation time of Dergall's potential antimicrobial activity. Dergall at a concentration of 0.6% formed a layer on the eggshell surface. In vitro testing of the potential harmful effects of Dergall by means of a hen embryo test of the chorioallantoic membrane showed no irritation reaction at a concentration of 3% and lower. The hatchability of the groups sprayed with a Dergall water solution with a concentration of 0 to 5% was 89.1 to 93.8% for fertilized eggs (P > 0.05) but decreased to 63.7% (P < 0.05) in the group sprayed with a 6% concentration of the solution. This phenomenon was caused by embryo mortality in the first week of incubation. At the concentration of 0.6%, Dergall exhibited strong antibacterial properties against bacteria such as Staphylococcus aureus, Escherichia coli, Shigella dysenteriae, Shigella flexneri, and Salmonella typhimurium. For Streptococcus pyogenes, the highest antibacterial activity of Dergall was reported in the concentrations of 100 and 50%. For Pseudomonas aeruginosa, no antibacterial activity of Dergall was generally observed, but in vivo testing showed a strong decrease of all gram-negative bacteria growth. Moreover, a prolonged antimicrobial effect lasting until 3 D after disinfection was observed, which makes Dergall a safe and efficient disinfectant.

Efficacy and tolerability of an investigational nitric oxide-releasing topical gel in patients with molluscum contagiosum: A randomized clinical trial.

BACKGROUND: Although a variety of ablative, topical, and systemic therapies are used for molluscum contagiosum (MC), none has been well studied or approved by the US Food and Drug Administration. OBJECTIVES: To compare the efficacy and tolerability of topical SB206 (berdazimer sodium gel coadministered with hydrogel) with vehicle. METHODS: A 12-week, phase 2, multicenter, randomized, double-blind, vehicle-controlled clinical trial of topical SB206. RESULTS: A total of 256 patients (mean age, approximately 7 years) participated. Of patients who completed 12 weeks of treatment (n = 217), all MC lesions cleared in 20.0% of patients who received vehicle compared with 13.2%, 41.0%, and 35.1% of patients treated with twice daily SB206 4%, 8%, and 12%, respectively, and 41.9% of patients treated with once daily SB206 12%. Application-site erythema occurred in 10.6% of patients treated with SB206. Application-site reactions were the most common adverse events leading to treatment discontinuation, affecting 2 patients (approximately 4%) in each of the SB206 4%, 8%, and 12% twice daily groups and 0 patients in the vehicle or SB206 12% once daily groups. LIMITATIONS: A larger study is needed to confirm the efficacy of SB206 12% once daily and provide additional safety assessments. CONCLUSION: Of the doses studied, SB206 12% applied once daily provided the best balance between MC lesion clearance and tolerability for evaluation in a larger study.

A Phase 2, Controlled, Dose-Ranging Study of SB208, an Investigational Topical Nitric Oxide-Releasing Drug, for the Treatment of Tinea Pedis.

BACKGROUND: Tinea pedis, or athlete's foot, is a superficial, skin infection caused by dermatophytes. It is usually topically treated. Nitric oxide is endogenously produced in humans and has a variety of physiologic and antimicrobial properties. SB208 is a novel topical treatment comprising berdazimer sodium (a nitric oxide-storing macromolecule) and a hydrogel. Admixing these two components releases nitric oxide to the application site. METHODS: A phase 2, double-blind, randomized trial evaluated the safety and efficacy of 3 doses of SB208 (2%, 4%, and 16%) vs matching vehicle, administered once daily for 14 days, in subjects with culture-confirmed interdigital tinea pedis. The primary efficacy outcome was the proportion of subjects with negative fungal cultures at end of treatment (day 14). Secondary outcomes at days 14 and 42 were the proportion of subjects with mycological cure (negative potassium hydroxide wet mount skin test and culture), clinical cure (reduced signs and symptoms from baseline graded on a 4-point scale). Safety was monitored through physical examinations, adverse events, and hemoglobin and methemoglobin levels. Efficacy outcomes were analyzed using a two-sided Cochran-Mantel-Haenszel test for general association, stratified by site. RESULTS: At day 14, a higher proportion of patients had negative fungal cultures in the pooled SB208-treated group (62%; P=0.04) than the vehicle-treated group (43%). Of SB208 groups, the 4% group had higher incidence of negative fungal cultures vs the vehicle group (67.6% vs 42.9%; P=0.03). At day 42, pooled SB208-treated groups had significantly more mycological cure vs vehicle group (47% vs 31%, respectively; P=0.08), and clinical cure was maintained in 23% of pooled SB208-treated patients vs 14% of vehicle-treated patients. No safety concerns were reported. Adverse events were mild, not serious, and considered unrelated to study medications. CONCLUSIONS: Topical SB208 was effective and well tolerated in the treatment of tinea pedis. J Drugs Dermatol. 2018;17(8):888-893.

Effects of chronic exposure to octamethylcyclotetrasiloxane and decamethylcyclopentasiloxane in the aging female Fischer 344 rat.

Octamethylcyclotetrasiloxane (D4) and decamethylcyclopentasiloxane (D5) are used as intermediates or monomers in the synthesis of silicon-based polymers for industrial or consumer applications. D4 and D5 may remain as residual monomer in these polymers at less than 1000ppm and may therefore be present as a minor impurity in consumer products. For D5, in addition to the manufacture of polymers, its uses include intentional addition to consumer products, personal care products and some dry- cleaning solvents. Two-year rodent chronic bioassays were conducted with both substances and borderline increases in the incidence of uterine tumors were observed, specifically, benign uterine adenoma with D4 and adenocarcinoma with D5. The effects profile and induction of uterine tumors share some similarity with that seen with chronic exposure to dopamine agonists. The current study investigated the potential for D4 and D5 to elicit dopamine agonist-like effects on estrous cyclicity. Separate groups of reproductively senescent female Fischer 344 rats (F344) were exposed via vapor inhalation to D4 (700ppm, 9.3mg/L) or D5 (160ppm, 2.1mg/L) or to a diet containing 0.0045, 0.045, or 4.5ppm pergolide mesylate (PM), a potent dopamine agonist used here as a reference substance, from 11 through 24 months of age. The primary focus was to characterize the effects of D4 and D5 exposure on estrous cyclicity relative to that observed with PM. As a monitoring effort, circulating endogenous estradiol, progesterone, prolactin and corticosterone levels were evaluated monthly. A blood sample from each rat was obtained via tail vein in the afternoon after the daily inhalation exposure period once every 4 weeks. Histomorphologic examination of the major organs including the reproductive tract was conducted on all animals at study termination. This study has shown that chronic exposure to D4 and D5 can affect cyclicity in the reproductively senescent F344 rat. For each substance the effect on cyclicity involved reduction in the incidence of pseudopregnancy with a shift toward cycles more typical of younger animals. D4 and D5 induced an increase in estrous cycle repetition whereas D4 also increased the incidence of extended estrus. These shifts resulted in animals entering proestrus/estrus significantly more times over the duration of the study than seen in the control group. Similar effects were observed with the reference substance, PM. However, distinct differences in the timing and magnitude of the effects on the estrous cycle and impact on prolactin, progesterone, estradiol, and corticosterone suggest that D4 and D5 are not classical dopamine agonists even though a similar increased incidence of proestrus/estrus was also observed with PM. These results may prove important with respect to understanding D4- and D5-induced uterine tumor response in the F344 rat, given the relationship between increased incidence of uterine endometrium stimulation by endogenous estrogen as a consequence of extended or more frequent proestrus/estrus, uterine tumor risk, and questions of relevance to humans. Recent publications have summarized the existing data on D4 and D5, with emphasis on exploring the biological relevance of the uterine tumors (Klaunig et al., 2016a,b; Franzen et al., 2017; Dekant and Klaunig, 2016; Dekant et al., 2017). The authors concluded that although the mode of action has not yet been fully established, the data, including the findings from this study, indicate that the D4- and D5-induced uterine tumors observed in the rodent chronic bioassays have no relevance for human risk characterization based not only on the distinct species differences in regulation of the reproductive systems, but also the high exposure levels and duration required for expression in rats.

Chronic toxicity and oncogenicity of octamethylcyclotetrasiloxane (D4) in the Fischer 344 rat.

Octamethylcyclotetrasiloxane (D4) is a cyclic volatile methylsiloxane primarily used in the synthesis of silicon-based materials used in a variety of consumer products. This paper details the chronic toxicity and oncogenicity evaluation of D4 in the Fischer 344 rat. Animals were exposed to 0, 10, 30, 150, or 700ppm D4 vapor for 6h/day, 5days/week for up to 104 weeks in whole-body inhalation chambers. Effects of two year chronic exposure included increased liver, kidney, testes, and uterine weight with correlating microscopic findings of hepatocellular hypertrophy (males only), chronic nephropathy (both sexes), interstitial cell hyperplasia, and cystic endometrial hyperplasia and endometrial adenoma, respectively. Upper respiratory tract irritation and lymphocytic leukocytosis were evident in both sexes. Increased neoplasia was demonstrated only in the uterus. Uterine endometrial adenomas were present in four of sixty animals exposed to 700ppm D4 for 24 months. None were present in the other treatment groups. In contrast, in 700ppm D4 group males the incidence of pituitary and pancreatic neoplasia was reduced as was thyroid c-cell adenoma/carcinoma in 700ppm females. This study has identified that D4 is a mild respiratory irritant and increases liver and kidney weight without inducing neoplasia in these tissues. The increased incidence of uterine adenoma was the only treatment-related neoplastic finding associated with chronic exposure to D4.

Toxicology of octamethylcyclotetrasiloxane (D4).

Octamethylcyclotetrasiloxane (D4) is a volatile cyclic siloxane used primarily as a monomer or intermediate in the production of some silicon-based polymers widely used in industrial and consumer applications and may be present as a residual impurity in a variety of consumer products. A robust toxicological data set exists for D4. Treatment-related results from a chronic inhalation study conducted in rats are limited to mild effects on the respiratory tract, increases in liver weight, increases in the incidence of uterine endometrial epithelial hyperplasia, and a dose-related trend in the incidence of endometrial adenomas. The observed increases in liver weight appear to be related to the induction of hepatic metabolizing enzymes, similar to those that are induced in the presence of phenobarbital. D4 is not mutagenic or genotoxic in standard in vitro and in vivo tests; therefore, the benign uterine tumors observed likely occur by a non-genotoxic mechanism. Results from mechanistic studies suggest that D4 has very weak estrogenic and antiestrogenic activity, as well as dopamine agonist-like activity. In rats, D4 exposure delays ovulation and hypothesized to prolong exposure of the uterine endometrium to endogenous estrogen. Though this mode of action may play a role in the development of benign uterine tumors in the rat, it is considered unlikely to occur in the human due to the marked differences in cycle regulatory mechanisms. Reproductive effects were observed following D4 exposure in female rats. These effects appear to be related to a delay of the luteinizing hormone (LH) surge, which fails to induce complete ovulation in the rat. However, based on differences in ovulatory control in rats and humans, it appears these effects may be species-specific with no risk or relevance to human health. Results from pharmacokinetic studies indicate that dermal absorption of D4 is limited, due to its high volatility and, if absorbed via dermal, oral or inhalation exposure, the majority of D4 is rapidly cleared from the body, indicating bioaccumulation is unlikely.

A global human health risk assessment for octamethylcyclotetrasiloxane (D4).

Octamethylcyclotetrasiloxane (D4) is a low-molecular-weight volatile cyclic siloxane, primarily used as an intermediate in the production of some widely-used industrial and consumer silicone based polymers and may be present as a component in a variety of consumer products. A global "harmonized" risk assessment was conducted to meet requirements for substance-specific risk assessments conducted by regulatory agencies such as USEPA's Integrated Risk Information System (IRIS), Health Canada's Chemical Management Program (CMP) and various independent scientific committees of the European Commission (e.g. the Scientific Committee on Consumer Safety (SCCS), the Scientific Committee on Health and Environmental Risks (SCHER)), as well as to provide guidance for chemical safety assessments under REACH in Europe. This risk assessment incorporates global exposure information combined with a Monte Carlo analysis to determine the most significant routes of exposure. Utilization of a multi-species, multi-route physiologically based pharmacokinetic (PBPK) model was included to estimate internal dose metrics, benchmark modeling was used to determine a point of departure (POD), and a margin of safety (MOS) evaluation was used to compare the estimates of intake with the POD. Because of the specific pharmacokinetic behaviors of D4 including high lipophilicity, high volatility with low blood-to-air partition coefficients and an extensive metabolic clearance that regulates tissue dose after exposure, the use of a PBPK model was essential to provide a comparison of a dose metric that reflects these processes. The characterization of the potential for adverse effects after exposure to D4 using a MOS approach based on an internal dose metric removes the subjective application of varying uncertainty factors from various regulatory agencies and allows examination of the differences between internal dose metrics associated with exposure and those associated with adverse effects.

Biological relevance of effects following chronic administration of octamethylcyclotetrasiloxane (D4) in Fischer 344 rats.

Octamethylcyclotetrasiloxane (D4) is a cyclic siloxane primarily used as a monomer or intermediate in the production of silicone polymers resulting in potential exposure of workers, and potential low level inhalation or dermal exposure for consumers and the general public. Following a two-year inhalation toxicity study with D4 in rats, increases in uterine endometrial cystic hyperplasia and adenomas were observed at the highest concentration of D4 administered (700ppm). No other neoplasms were increased with D4 treatment. In addition, chronic inhalation exposure of rats to D4 induced changes in relative liver and kidney weights, and produced a chronic nephropathy. This manuscript examines the biological relevance and possible modes of action for the effects observed in the F344 rat following chronic inhalation exposure to D4. D4 is not genotoxic and appears to exert its effects through a nongenotoxic mode of action. An alteration in the estrous cycle in the aging F344 rat was the most likely mode of action for the observed uterine effects following chronic inhalation exposure. Data support the conclusion that D4 acts indirectly via a dopamine-like mechanism leading to alteration of the pituitary control of the estrous cycle in aging F344 rats with a decrease in progesterone and an increase in the estrogen/progesterone ratio most likely induced by a decrease in prolactin concentration. D4 also inhibited the pre-ovulatory LH surge causing a delay in ovulation, persistent follicles and thus a prolonged exposure to elevated estrogen in the adult Sprague Dawely rat. A lengthening of the estrous cycle in the F344 rat with an increase in endogenous estrogen was also induced by D4 inhalation. Although the mode of action responsible for induction of uterine adenomas in the female F344 rat has not been clearly confirmed, the subtlety of effects on the effects of D4 on cyclicity may prevent further assessment and definition of the mode of action. The occurrence of uterine endometrial adenoma in the rat is not relevant for human risk characterization because (1) there are differences in ovulatory cycle regulation in rats compared to humans, (2) cystic hyperplasia without atypia in women is not a cancer precursor, and (3) there is no endometrial lesion in women that is directly analogous to endometrial adenoma in the rat. The effects of D4 on liver are due to a phenobarbital-like mechanism that results in induction of cytochrome P450 and other enzymes of xenobiotic biotransformation. The liver effects are adaptive and not adverse. Kidney findings included chonic progressive nephropathy, a rat lesion that has no counterpart in the human and that should not be used in human risk assessment.

Standardized Index of Shape (DCE-MRI) and Standardized Uptake Value (PET/CT): Two quantitative approaches to discriminate chemo-radiotherapy locally advanced rectal cancer responders under a functional profile.

PURPOSE: To investigate dynamic contrast enhanced-MRI (DCE-MRI) in the preoperative chemo-radiotherapy (CRT) assessment for locally advanced rectal cancer (LARC) compared to18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT). METHODS: 75 consecutive patients with LARC were enrolled in a prospective study. DCE-MRI analysis was performed measuring SIS: linear combination of percentage change (Δ) of maximum signal difference (MSD) and wash-out slope (WOS). 18F-FDG PET/CT analysis was performed using SUV maximum (SUVmax). Tumor regression grade (TRG) were estimated after surgery. Non-parametric tests, receiver operating characteristic were evaluated. RESULTS: 55 patients (TRG1-2) were classified as responders while 20 subjects as non responders. ΔSIS reached sensitivity of 93%, specificity of 80% and accuracy of 89% (cut-off 6%) to differentiate responders by non responders, sensitivity of 93%, specificity of 69% and accuracy of 79% (cut-off 30%) to identify pathological complete response (pCR). Therapy assessment via ΔSUVmax reached sensitivity of 67%, specificity of 75% and accuracy of 70% (cut-off 60%) to differentiate responders by non responders and sensitivity of 80%, specificity of 31% and accuracy of 51% (cut-off 44%) to identify pCR. CONCLUSIONS: CRT response assessment by DCE-MRI analysis shows a higher predictive ability than 18F-FDG PET/CT in LARC patients allowing to better discriminate significant and pCR.

HMDSO-plasma coated electrospun fibers of poly(cyclodextrin)s for antifungal dressings.

Electrospun mats containing cyclodextrin polymers (poly-αCD or poly-ßCD) were developed to act as wound dressings showing tunable release rate of the antifungal agent fluconazole incorporated forming inclusion complexes. Poly-αCD and poly-ßCD were prepared via cross-linking with epichlorohydrin (EPI) as water-soluble large molecular weight polymers. Then, polyCDs forming complexes with fluconazole were mixed with poly-(ε-caprolactone) (PCL) or poly(N-vinylpyrrolidone) (PVP) for electrospinning. Obtained bead-free fibers showed a random distribution, diameters in the 350-850nm range, and a variety of physical stability behaviors in aqueous environment. Mats were coated by hexamethyldisiloxane (HMDSO) plasma polymerization to create a hydrophobic layer that prevented rapid drug diffusion. HMDSO coating was evidenced by the Si content of mat surface (EDX analysis) and by the increase in the water contact angle (up to 130°). In physiological-mimicking medium, non-treated mats showed burst release of fluconazole, whereas HMDSO-coated mats sustained the release and delayed disintegration of PVP-based mats. Antifungal tests evidenced that both coated and non-coated mats efficiently inhibited the growth of Candida albicans.

Formulation and characterization of ORMOSIL particles loaded with budesonide for local colonic delivery.

In this study, hybrid silica xerogel particles were developed as carriers of budesonide (BDS) for efficient local treatment of inflammatory bowel diseases (IBD). Organically modified silica particles (ORMOSILs) were prepared by co-condensation of 3-aminopropyltriethoxysilane (APTES) and tetraethyl orthosilicate (TEOS) by an ambient temperature acid catalysed sol-gel process followed by spray-drying. Formulation for preparation of BDS-loaded particles was optimized and their physicochemical parameters and drug release profiles were evaluated in vitro. Optimal formulation had a small particle size (mean diameter of 1.45±0.02µm) with unimodal narrow size distribution and high encapsulation efficiency (98.0 ± 1.85%). Due to the positive surface charge originated from amino group of APTES, ORMOSILs showed excessive mucoadhesiveness in comparison to native TEOS particles. The drug release decreased with increasing pH from 2.0 to 7.4. In order to avoid undesirable erroneous performance in the upper GI tract, particles were additionally coated with Eudragit(®) FS 30D, as a barrier to the drug release at pH range from 2.0 to 7.0. After Eudragit(®) FS 30D coating, the release of BDS in acidic media was sustained, while no significant differences in drug release were observed at pH 7.4. In conclusion, pH-responsive ORMOSILs showed great potential for efficient BDS delivery to the colon region.

Aggregate dermal exposure to cyclic siloxanes in personal care products: implications for risk assessment.

Consumers who use personal care products (PCPs) are internally exposed to some of the organic components present of which some may be detected in exhaled air when eliminated. The aim of this study was the quantitative determination of octamethylcyclotetrasiloxane (D4) and decamethylcyclopentasiloxane (D5) in end-exhaled air to study dermal absorption of substances in PCPs. We exposed the forearm of fifteen healthy volunteers for 60min to pure D4 or D5 and to commercial products containing D4 and D5. Inhalation uptake was kept to a minimum by keeping the forearm in a flow cabinet during dermal exposure and supplying filtered air to the breathing zone of the volunteer during the post-exposure period. End-exhaled air was collected using a breath sampler (Bio-VOC), transferred to carbograph multi-bed adsorbent tubes and analyzed by thermal desorption gas chromatography mass spectrometry (TD-GC-MS). In the end-exhaled air of non-exposed volunteers background concentrations of D4 (0.8-3.5ng/L) and D5 (0.8-4.0ng/L) were observed. After exposing the volunteers, the level of D4 and D5 in end-exhaled air did not or barely exceed background concentrations. At t=90min, a sharp increase of the D4/D5 concentration in end-exhaled air was observed, which we attributed to the inhalation of the substances during a toilet visit without using inhalation protection devices. When this visit was taken out of the protocol, the sharp increase disappeared. Overall, the results of our study indicate that dermal absorption of D4 and D5 contributes only marginally to internal exposure following dermal applications. As in our study inhalation is the primary route of entry for these compounds, we conclude that its risk assessment should focus on this particular exposure route.

Pulmonary toxicity following exposure to a tile coating product containing alkylsiloxanes. A clinical and toxicological evaluation.

CONTEXT: Coating products are widely used for making surfaces water and dirt repellent. However, on several occasions the use of these products has been associated with lung toxicity. OBJECTIVE: In the present study, we evaluated the toxic effects of an aerosolized tile-coating product. METHODS: Thirty-nine persons, who reported respiratory and systemic symptoms following exposure to the tile-coating product, were clinically examined. The product was analysed chemically and furthermore, the exposure scenario was reconstructed using a climate chamber and the toxicological properties of the product were studied using in vivo and by in vitro surfactometry. RESULTS: The symptoms developed within few hours and included coughing, tachypnoea, chest pain, general malaise and fever. The physical examination revealed perihilar lung infiltrates on chest radiograph and reduced blood oxygen saturation. The acute symptoms resolved gradually within 1-3 days and no delayed symptoms were observed. By means of mass spectrometry and X-ray spectroscopy, it was shown that the product contained non-fluorinated alkylsiloxanes. The exposure conditions in the supermarket were reconstructed under controlled conditions in a climate chamber and particle and gas exposure levels were monitored over time allowing estimation of human exposure levels. Mice exposed to the product developed symptoms of acute pulmonary toxicity in a concentration-and time-dependent manner. The symptoms of acute pulmonary toxicity likely resulted from inhibition of the pulmonary surfactant function as demonstrated by in vitro surfactometry. Among these patients only a partial association between the level of exposure and the degree of respiratory symptoms was observed, which could be because of a high inter-individual difference in sensitivity and time-dependent changes in the chemical composition of the aerosol. CONCLUSION: Workers need to cautiously apply surface coating products because the contents can be highly toxic through inhalation, and the aerosols can disperse to locations remote from the worksite and affect bystanders.

Solid MRI contrast agents for long-term, quantitative in vivo oxygen sensing.

Targeted MRI contrast agents have proven useful in research and clinical studies for highlighting specific metabolites and biomarkers [Davies GL, et al. (2013) Chem Commun (Camb) 49(84):9704-9721] but their applicability in serial imaging is limited owing to a changing concentration postinjection. Solid enclosures have previously been used to keep the local concentration of contrast agent constant, but the need to surgically implant these devices limits their use [Daniel K, et al. (2009) Biosens Bioelectron 24(11):3252-3257]. This paper describes a novel class of contrast agent that comprises a responsive material for contrast generation and an injectable polymeric matrix for structural support. Using this principle, we have designed a contrast agent sensitive to oxygen, which is composed of dodecamethylpentasiloxane as the responsive material and polydimethylsiloxane as the matrix material. A rodent inspired-gas model demonstrated that these materials are functionally stable in vivo for at least 1 mo, which represents an order of magnitude improvement over an injection of liquid siloxane [Kodibagkar VD, et al. (2006) Magn Reson Med 55(4):743-748]. We also observed minimal adverse tissue reactions or migration of contrast agents from the initial injection site. This class of contrast agents, thus, represented a new and complementary method to monitor chronic diseases by MRI.

In vivo caprine model for osteomyelitis and evaluation of biofilm-resistant intramedullary nails.

Bone infection remains a formidable challenge to the medical field. The goal of the current study is to evaluate antibacterial coatings in vitro and to develop a large animal model to assess coated bone implants. A novel coating consisting of titanium oxide and siloxane polymer doped with silver was created by metal-organic methods. The coating was tested in vitro using rapid screening techniques to determine compositions which inhibited Staphylococcus aureus growth, while not affecting osteoblast viability. The coating was then applied to intramedullary nails and evaluated in vivo in a caprine model. In this pilot study, a fracture was created in the tibia of the goat, and Staphylococcus aureus was inoculated directly into the bone canal. The fractures were fixed by either coated (treated) or non-coated intramedullary nails (control) for 5 weeks. Clinical observations as well as microbiology, mechanical, radiology, and histology testing were used to compare the animals. The treated goat was able to walk using all four limbs after 5 weeks, while the control was unwilling to bear weight on the fixed leg. These results suggest the antimicrobial potential of the hybrid coating and the feasibility of the goat model for antimicrobial coated intramedullary implant evaluation.