Skin benefits from continuous topical administration of a zinc oxide/petrolatum formulation by a novel disposable diaper.

BACKGROUND: Diaper dermatitis is a common childhood affliction. Aiming to help reduce the prevalence of this problem, we have advanced in our development of a novel diaper that delivers dermatological formulations to help protect the skin from over-hydration and irritation. OBJECTIVE: To determine the clinical benefits of a novel disposable diaper designed to deliver a zinc oxide and petrolatum-based formulation continuously to the skin during use. METHODS: All studies were independent, blinded, randomized clinical trials. Study A was conducted to confirm transfer of the zinc oxide/petrolatum (ZnO/Pet) formulation from the diaper to the child's skin during use. Children wore a single diaper for 3 h or multiple diapers for 24 h. After the use period, stratum corneum samples were taken from each child and analysed for ZnO/Pet. Study B evaluated the prevention of skin irritation and barrier damage from a standard skin irritant (SLS) in an adult arm model. Study C evaluated skin erythema and diaper rash in 268 infants over a 4-week usage period. One half of the infants used the ZnO/Pet diaper, while the other half used a control diaper that was identical except for the absence of the ZnO/Pet formulation. RESULTS: The ointment formulation and ZnO transferred effectively from the diaper to the child's skin during product use. Transfer of ZnO increased from 4.2 microg/cm2 at 3 h to > 8 microg/cm2 at 24 h. Exposure to the formulations directly on adult skin prior to an irritant challenge was associated with up to a 3.5 reduction in skin barrier damage and skin erythema. Greatest reductions were seen for the ZnO containing formulations. Wearing of the formulation treated diaper was also associated with a significant reduction in skin erythema and diaper rash compared to the control product. CONCLUSIONS: The results demonstrated the clinical benefits associated with continuous topical administration of a zinc oxide/petrolatum-based formulation by this novel diaper.

Continuous topical administration of a petrolatum formulation by a novel disposable diaper. 2. Effect on skin condition.

BACKGROUND: Diaper dermatitis is a common childhood affliction. Aiming to help reduce the prevalence of this problem, we have developed a novel diaper to deliver to the skin dermatological formulations intended to help protect the skin from overhydration and irritation. OBJECTIVE: To determine the clinical benefits of a novel disposable diaper designed to deliver a petrolatum-based formulation continuously to the skin during use. METHODS: Two independent, blinded, randomized clinical trials were conducted, involving an aggregate total of 391 children, 8-24 months of age. All comparisons were done versus a control diaper, identical to the test product except for the absence of the petrolatum formulation. The studies determined the effects of the novel diaper on skin erythema and diaper rash. RESULTS: Use of the formulation-treated diaper was associated with significant reductions in severity of erythema and diaper rash compared to the control product. CONCLUSIONS: The results demonstrated the clinical benefits associated with continuous topical administration of a petrolatum-based formulation by this novel diaper. We anticipate that this advance in diaper design will contribute significantly to further reduce the prevalence and severity of irritant contact dermatitis in the diaper area.

Continuous topical administration of a petrolatum formulation by a novel disposable diaper. 1. Effect on skin surface microtopography.

BACKGROUND: Cutaneous problems are commonly associated with the use of diapers. Aiming to help reduce them, we have explored the use of the inner layer of diapers as a means to deliver to the skin dermatological formulations intended to help protect it from overhydration and irritation. OBJECTIVE: To determine the feasibility of using the inner layer of the diaper as a vehicle for topical delivery of a petrolatum-based formulation and to determine its impact on skin surface microtopography. METHODS: Two independent, blinded, randomized clinical trials were conducted, on children 16-24 months of age. All comparisons were done versus a control diaper, identical to the test product except for the absence of the petrolatum formulation. The studies determined the effects of the novel diaper on transfer of formulation to the skin and skin surface microtopography. RESULTS: During normal diaper use, formulation transfer from the diaper to the skin occurred in a cumulative, time-dependent manner and use of the formulation-treated diaper was associated with significant reductions in skin surface roughness compared to the control diaper. CONCLUSIONS: The results demonstrated the feasibility and skin surface benefits associated with continuous topical administration of a petrolatum-based formulation by this novel diaper. This unprecedented dosimetric approach offers new avenues to reduce further the dermatological problems commonly associated with diaper use.

Percutaneous absorption of salicylic acid after repeated (14-day) in vivo administration to normal, acnegenic or aged human skin.

The objective of the present work was to determine the relative bioavailability of salicylic acid (SA) after repeated (14-day) topical application to subjects who presented normal, acnegenic, or photodamaged facial skin. To emulate exposure characteristics likely to be encountered by subjects in these two subpopulations, individuals presenting facial acne were treated with 2% SA in a hydroalcoholic vehicle, and volunteers with aged or photodamaged skin received a comparable topical dose of SA in a cream (moisturizer-like) vehicle. Plasma concentration-time profiles and cumulative urinary excretion of SA were measured after the last dose in subjects who had received 15 consecutive daily topical applications of 27 mg of SA or oral doses of 81 mg of acetylsalicylic acid (ASA). The rate and extent of percutaneous absorption of SA were not affected by facial skin condition. Faster rates of absorption (Cmax) were obtained with a hydroalcoholic compared with a cream vehicle. Systemic SA exposures were at least five-fold higher with oral ASA than topical SA. Based on systemic salicylate concentrations resulting from ingestion of 81 mg of ASA, these results support that patients without gross skin disorders are at minimal risk of adverse systemic effects from routine use of topical products containing 2% SA.

Maternal reproductive effects of oral salicylic acid in Sprague-Dawley rats.

Clinical and experimental evidence indicates that exposure to relative ly large doses of acetylsalicylic acid (ASA) prolongs parturition. However, little is known about the dose-response relationship for salicylate-related effects on labor and gestation. As well, the relative potency of salicylic acid (SA) as compared with ASA for these reproductive effects has not been well investigated. This study was designed to define a dose-response relationship for salicylic acid (SA) effects on labor and gestation times in Sprague-Dawley rats. Pregnant females received oral doses of 20,80, or 200 mg/kg/day sodium salicylate, or 260 mg/kg/day acetylsalicylic acid (ASA), as a positive control, on days 15 through 21 of gestation (sperm positive = day 0). Onset of labor was followed in each animal beginning on day 21 of gestation. The data failed to demonstrate a substantial potency difference between ASA and SA but some differences in toxicity were observed. Relative to controls, gestation times were unaffected by SA. SA treatment resulted in a dose-related trend towards increased duration of labor which was statistically significant at 200 mg/kg/day of SA. ASA treatment of pregnant females resulted in both prolonged labor and gestation times. Both the highest administered dose of SA and ASA treatment contributed to increased maternal peripartum death. Overall, the study confirms a dose-response relationship for SA-induced maternal reproductive effects and supports a no observable effect level (NOEL) for this compound of 80 mg/kg/day for adverse effects on parturition.

Comparative efficacy of sunscreen reapplication regimens in children exposed to ambient sunlight.

Undercompliance with sunscreen reapplication recommendations is a probable factor in suboptimal childhood ultraviolet radiation (UVR) protection. However, improving on the ability of sunscreens to absorb UVR without requiring frequent reapplication is difficult because the models most frequently used to develop and evaluate photoprotectants have only a limited ability to incorporate behavioral and environmental variables that are primarily responsible for loss of sunscreen efficacy. Hence, the objective of the present work was to develop a method to evaluate the efficacy of various regimens of sunscreen reapplication in children, under conditions of unrestricted behavior and exposure to ambient sunlight. Ninety-eight children, ages 7-12, Fitzpatrick skin types I-III, were divided between two study groups. The majority were types I-II, and all types were approximately equally represented between the groups. The children received single or multiple applications of a sun protection factor 25 sunscreen to preassigned lateral halves of the body and engaged in unrestricted activities throughout a 6- (group I) or 8-h (group II) period of sun exposure at a seaside location. The end measurement for these studies was incidence and severity of erythema 18 to 22 h after peak UV exposure. The results obtained showed that 1 or 4 sunscreen applications yielded comparable erythema protection after a 6-hour sun exposure, totaling 13 minimal erythema doses (MED). However, after an 8-h, 21 MED exposure, incidence and severity of erythema was greater at body sites treated with 1 compared with 5 sunscreen applications.(ABSTRACT TRUNCATED AT 250 WORDS)

Evaluation of subchronic (13 week), reproductive, and in vitro genetic toxicity potential of 2-ethylhexyl-2-cyano-3,3-diphenyl acrylate (Octocrylene).

Use of 2-ethylhexyl-2-cyano-3,3-diphenyl acrylate (Octocrylene) in commercial sunscreen products has increased considerably in recent years. To support larger scale human exposure to this compound, additional toxicological information was needed in several key areas. The present studies evaluated subchronic toxicity, developmental toxicity, and in vitro genotoxic potential of Octocrylene. In the subchronic study, male and female New Zealand white (NZW) rabbits treated topically with concentrations of octocrylene up to 534 mg/kg/day for 13 weeks showed slight to moderate dose-dependent skin irritation that correlated positively with a mild depression in body weight gain. Lack of associated histopathologic or clinical hematology abnormalities suggested that the body weight effect probably reflected a nonspecific response to topical irritation. In percutaneous developmental toxicity studies, NZW does were treated topically with Octocrylene at levels up to 267 mg/kg/day on Days 6 through 18 of gestation. Body weight gain, food consumption, and all maternal, reproductive, and offspring parameters evaluated were comparable between Octocrylene-treated and control animals. In the oral developmental toxicity assay, female CD-1 mice received oral doses of Octocrylene up to 1000 mg/kg/day on Days 8-12 of gestation. No evidence of maternal or developmental toxicity was seen at any dose tested. Genotoxicity was evaluated in vitro using the Chinese hamster ovary cell assay to assess clastogenicity and the mouse lymphoma cell assay to assess forward gene mutations. Octocrylene did not induce any significant increase in genotoxicity. This evaluation of toxicological potential supports the use of Octocrylene as a human photoprotectant.

Assessment of the in vivo genotoxicity of 2-hydroxy 4-methoxybenzophenone.

The genotoxic potential of 2-hydroxy 4-methoxy-benzophenone (benzophenone-3, Bz-3), a commonly used sunscreen, has been evaluated previously with in vitro systems. Data from Salmonella studies (with and without activation) have been predominantly negative, but two reports have shown weakly positive results in a single bacterial strain under conditions of metabolic activation. In addition, Bz-3 has been reported to induce chromosome aberrations and equivocal results for sister chromatid exchange in Chinese hamster ovary (CHO) cells. We used the Drosophila somatic mutation and recombination test (SMART) and in vivo cytogenetics in rat bone marrow to define the potential for in vivo expression of this in vitro activity. For the SMART assay, larva from a mating of "multiple wing hair" (mwh) females with heterozygous "flare" (flr) males were exposed to 0, 3000, or 3500 ppm Bz-3 or 25 ppm dimethylnitrosamine (DMN, positive control) for 72 hr. A recombination between the mwh and flr genes produces twin wing spots, while events such as deletions produce single spots. None of the Bz-3-treated larva produced flies with significantly more single or multiple wing spots than controls. In contrast, DMN-treated larva produced flies with significantly more single or multiple wing spots than controls. The in vivo cytogenetic assay in rat bone marrow cells was conducted to evaluate the clastogenicity of Bz-3. Sprague-Dawley rats were treated by oral gavage with a single administration of 0.0, 0.5, 1.67, or 5 gm/kg Bz-3 or a single dose of 5 gm/kg/day Bz-3 for 5 consecutive days. Cyclophosphamide (CP) was the positive control and was administered at 20 mg/kg with both treatment regimens. Colchicine growth-arrested bone marrow cells were collected 8 and 12 hr after the single treatment and 12hr after the last daily treatment. Under either treatment protocol none of the Bz-3 concentrations caused any significant increase in chromosomal aberrations. Results from these two studies strongly support the conclusion that Bz-3 is not genotoxic in vivo.

Effects of chronic stress on in vivo pituitary-adrenocortical responses to corticotropin releasing hormone.

Experimental evidence indicates that animals exposed to chronic stress demonstrate increased adrenocorticotropin (ACTH) and corticosterone (CORT) responses to novel stimuli (facilitation) but attenuated ACTH and CORT responses to the chronic stressor (adaptation). The mechanisms responsible for facilitation and adaptation of ACTH and CORT responses are not known. In the present experiments, we chronically exposed male Fischer-344 rats to sessions of a two-way shock-escape stress procedure following a schedule which we had previously shown to elicit adaptation of ACTH and CORT responses. To determine if pituitary-adrenocortical adaptation to stress was mediated by alterations in pituitary responsiveness to corticotropin-releasing hormone (CRH), control and chronically stressed rats received intra-arterial injections of a low and a high dose of CRH and blood samples from each animal were assayed for ACTH and CORT levels. The results showed that ACTH responses to the low (but not the high) dose of CRH were attenuated by chronic stress. In addition we confirmed previous reports which showed that chronic stress increased adrenocortical sensitivity to ACTH. Thus, we concluded that adaptation of ACTH responses to chronic stress may be in part mediated by a reduction of the CRH-induced ACTH secretory response.

Glucoregulatory responses of adult and aged rats after exposure to chronic stress.

Stress has been implicated as an environmental factor that may accelerate the process of biological aging. However, this proposal has remained largely anecdotal due to relatively few studies that directly tested this hypothesis. In the present experiments groups of 6-month-old and 20-month-old male F-344 rats were chronically stressed for a six-month period. After the last stress session, when the animals were 12 months of age (adult) and 26 months of age (old), control and chronically stressed rats were tested for their ability to: (a) elicit glucose and insulin responses to an acute, novel stressor; (b) remove a circulatory glucose load elicited either by acute stress exposure or by injection of d-glucose; and (c) raise insulin levels after a glucose challenge. In control rats, we observed a deficit in each of these parameters in old compared to adult rats. Exposure to chronic stress did not exacerbate deterioration of these response mechanisms in either adult or old rats. In fact, the data showed a modest improvement in glucose tolerance in chronically stressed compared to age-matched control rats. We conclude that chronic stress did not exacerbate age-dependent decline of glucoregulatory capacity. From these results and from our earlier work, we speculate that the decline during aging of the functional integrity of systems involved in the response to stress may be sustained by periodic challenges from the organism's external environment.

Effects of age on metabolic responses to acute and chronic stress.

The effect of age on the capacity of an organism to mobilize glucose and free fatty acids during stress and to adapt these responses from an acute to a chronic stress situation is not known. The purpose of this study was to determine whether aging impaired the capacity to 1) raise glucose and free fatty acid levels and suppress insulin release in acute stress situations and 2) develop adaptation of these responses to exposure to chronic stress. Our results indicate that 6-mo-old rats (young) trained to escape electric shock (short-term modulation) showed greater acute stress-induced hyperglycemic, hypoinsulinemic, and lipolytic responses than untrained young rats. By contrast, in 22-mo-old rats (old), responses of trained and untrained animals were not different. In the chronic stress (long-term adaptation) experiments, it was found that 1) adaptation of stress-induced hyperglycemia occurred at a faster rate in young than in old animals; 2) in young but not in aged rats, a strong positive correlation was observed between adaptation of stress-induced hyperglycemia and hypoinsulinemia; and 3) in young rats, stress-induced lipolytic responses declined proportionately to the duration of chronic stress exposure, whereas by contrast in chronically stressed aged rats steady-state levels of free fatty acids were not raised during exposure to stress. Thus we conclude that 1) glucose intolerance may play a key role in the altered stress-induced metabolic responses of aged rats; 2) with age, there is a loss of plasticity in physiological adaptive response mechanisms associated with metabolic responses to stress.

Comparative biochemical responses of rats to different stressful stimuli.

Adult male rats were exposed to single applications of one of three stressful stimuli (low environmental temperature, immobilization, random footshock) for periods up to 4 hours and plasma levels of corticosterone (PCS), fatty acids (PFA), and glucose (PGL) were determined at various points during the stress exposure and 1 and 2 hours post-exposure. The levels of PCS were increased by all 3 stressful stimuli in a similar temporal pattern, with the greatest magnitude of effect seen for immobilization and the least for cold exposure. The time courses of increased PFA levels were similar for immobilization and cold exposure; the response to foot shock was delayed in onset by 2 hours. The PGL response was minimal for cold exposure and foot shock, but showed a marked elevation during the first 2 hours of immobilization. The results suggest that the response pattern obtained is characteristic of the stressful stimulus employed, with PCS showing the least degree of specificity.