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Proflavine lotion is a commonly used topical antiseptic in the tropics, but its sensitizing potential was never emphasized and many who developed allergic contact dermatitis were never aware of it. In a study of 45 patients, most presented with acute or subacute dermatitis which started on the arms and legs. Concomitant cutaneous sensitivity to other medicaments and lanolin occurred in 66% of the patients.
The incidence of contact allergy to 63 substances, including active principles and excipients used in a variety of topical preparations, has been studied by patch testing in 306 patients being treated conservatively for stasis dermatitis with or without ulceration. Positive reactions to one or more test compounds were recorded in 177 patients. The main offenders among drugs were neomycin, sulphonamide and promethazine; among the excipients, they were parabens, lanolins and benzoyl peroxide. Frequent reactions were observed to certain substances of the 'para' group, benzocaine, diaminodiphenylmethane, aniline and paraphenylendiamine, with the first three acting mainly as indicators of cross-sensitization. The extension and spread of allergic dermatitis can also be produced by drugs administered systematically. Recognition of the allergens responsible for allergic contact dermatitis arising at the lower leg site is a necessary condition if chronicity and spread of the dermatitis are to be prevented. For the same reason it is important to restrict topical applications to non-allergic substances.
Common ingredients of vehicles such as perfumes, antibacterial agents, emulsifiers and other surface active agents, propylene glycol, lanolin and wool alcohols were tested in eczema patients over a three-year period. Perfume allergy was detected in 3.6% of the cases, sensitivity to thiomersal in 2%, to sorbic acid in 0.8%, to parabens in only 0.3%, and to wool alcohols in 1.2%. Reactions to emulsifiers were seen over 1% of those tested.
Common emulsifiers were tested in over 1,200 patients with eczema. Triethanolamine stearate tested at 5% in petrolatum caused irritant reactions in 9.5% of the patients. On the other hand, non-ionic emulsifying agents tested at 10-20% produced irritation in only a few cases. Allergic reactions were found in 2.1% of those tested. Lanette, sorbitan sesquioleate, the Spans, polyoxyethylene oxypropylene stearate, polyoxyethylene sorbitol lanolin derivative, and triethanolamine stearate each elicited allergic reactions in 0.3-0.7% of the cases. The Tweens caused an allergy in only two cases, but glycerol monostearate caused no reaction at all. Five out of six patients sensitive to sorbitan sesquioleate reacted positively to the Spans as well. The patients allergic to one or more emulsifiers were also sensitive to several other substances included in our routine test series with the exception of four patients who reacted only to the emulsifying agents.
Patch tests and photopatch tests with various cosmetics, coal tar dyes, perfumes, lanolin preparations and parabens-mix were performed in 53 patients with pigmented cosmetic dermatitis similar in clinical appearance to Riehl's melanosis. The results showed that coal tar dyes, particularly brilliant lake red R, were closely related to the cause of the disease. In patch testing and photopatch testing with coal tar dyes, the incidence of positive responses to the brilliant lake red R was found to be significantly higher than that to the other coal tar colors (22/38 = 57.9%). The relevance of ultraviolet light to the disease was found to be much less than the ratio expected (14/47 = 29.8%). A high incidence of positive responses to fragrances was also found, but it is considered to play a secondary role in the etiology of the disease.
A study of 1016 patients over a period of 2 years has been performed by using the DALUK computer system in order to find correlations between eczema sites and particular allergens. The study includes a control material of patients with other contact allergies or with negative patch tests. The investigation confirms some well-known correlations, e.g., between lanolin allergy and dermatitis of the lower leg, and between nickel allergy and dermatitis of the palm. Several new correlations are also described, e.g., chromium allergy and dermatitis of the back of the trunk, allergy to balsam of Peru and dermatitis of the forehead and cheek.
In the past 4 years, a high incidence (118/362) of positive patch test reactions to E45 cream were noted in 2 patch testing clinics. 18/54 of those patch tested to all the ingredients demonstrated allergies to ingredients. The most frequent was triethanolamine; lanolin allergy occurring in only 1 patient. The remaining reactions may be explained as irritant reactions resulting from triethanolamine stearate (TES) formation within the cream. The irritancy of triethanolamine stearate was demonstrated in patients and controls. Conductivity studies showed that TES arises from the combination of the ingredients triethanolamine and stearic acid. The formulation of E45 cream was being changed at the time of writing, with the removal of triethanolamine from the product.
We report the results of patch testing 85 patients with either long-standing venous ulceration or eczema complicating their leg ulcers. As previously reported, lanolin and its derivatives and topical antibiotics were the most frequent sensitizers. However, unlike previously published data, we found bacitracin to be the most potent sensitizer of all topical antibiotics tested. There were no positive reactions in a control group of patients, although we were unable to repeat the patch tests in patients with a positive reaction to bacitracin. In the past 10 years, our department has used a proprietary mixture of polymyxin and bacitracin in treating infected leg ulcers and other dermatoses. It is therefore possible that chronic usage of topical bacitracin on leg ulcers carries a significant risk of contact sensitization.
Emulsifiers are common constituents of most topical preparations. To study the sensitization rate in a population with frequent use of these agents, we selected 47 patients with chronic or recurrent (> 1 year) inflammatory skin disease (leg ulcers, contact dermatitis, atopic dermatitis, psoriasis) for patch testing with the following emulsifiers: Tween 40 (polyoxyethylene sorbitan monopalmitate). Tween 80 (polyoxyethylene sorbitan monooleate), Span 60 (sorbitan monostearate), Span 80 (sorbitan monooelate), Arlacel 83 (sorbitan sesquioleate), Atlas G 2162 (polyoxyethylene oxypropylene stearate), Atlas G 1441 (polyoxyethylene sorbitol lanolin derivative), triethanolamine, Lanette O (cetylstearyl alcohol), Lanette N. 12 patients had at least 1 positive reaction (25.5%) at 3 or 4 days. Among them, 10 had leg ulcers (43.4% of the leg ulcer group), and 2 had contact dermatitis (13.3% of the contact dermatitis group). No positive reaction was observed in the other patients. When the patients were tested with their own topical preparations or wound dressings, 6 of them, all with leg ulcers, had positive reactions. These results show a surprisingly high prevalence of sensitization to emulsifiers in patients with chronic leg ulcers, in contrast to patients with other inflammatory skin diseases.
Chelating agents and other substances can be used to bind nickel or reduce its penetration through the skin, and hence to reduce the symptoms in subjects with nickel sensitivity. Topical usage is mostly described but, in some studies, chelating agents have been given systemically. The most effective ligand for nickel so far described is 5-chloro-7-iodoquinolin-8-ol. Although normally regarded as safe, its usage in some situations may be limited by concerns about its toxicity. Other ligands with demonstrable effect include ethylenediaminetetraacetic acid in various forms, diphenylglyoxime and dimethylglyoxime. Cation exchange resins can effectively bind nickel and work both in vitro and in vivo. Propylene glycol, petrolatum and lanolin reduce the absorption of nickel through the skin. Corticosteroids and cyclosporin work in nickel dermatitis by suppressing the immunological reaction rather than through an effect on nickel. Studies of the oral administration of ligands such as tetraethylthiuram disulphide have given conflicting results but the use of these agents is limited by hepatoxicity in any case. Some compounds offer potential for use in the prophylaxis of nickel dermatitis. Further work is required to develop the existing agents and to look at the use of novel combinations, such as that of a cation exchanger with a ligand.
This review summarizes published and unpublished data of our 15-year experience with sunscreen allergy and photoallergy. From 1981-1996, 402 patients with suspected clinical photosensitivity were patch and photopatch tested with the commercial sunscreens and facial cosmetics that they had used and with chemical UV absorbers, fragrance materials, preservatives, and emollients. 80 patients (20%) (28 men, 52 women) demonstrated allergic and/or photoallergic contact dermatitis to 1 or more UV absorber(s). In 47 patients with photodermatoses or photo-aggravated dermatoses and in 33 subjects with normal photosensitivity, 91 allergic and 84 photoallergic reactions to UV filters were observed. Over the years sunscreens were added to the test series, which since 1989 comprised the following 10 UV absorbers and which induced allergic (a) and photoallergic (pa) reactions (number, type of reaction): 4 UVA absorbers--isopropyldibenzoylmethane (30a/32pa); butyl methoxydibenzoyl-methane (15a/13pa); benzophenone-3 (3a/9pa); benzophenone-4 (0a/0pa); and 6 UVB absorbers--PABA (2a/2pa); octyl dimethyl PABA (1a/2pa); methylbenzylidene camphor (32a/5pa); octyl methoxycinnamate (3a/4pa); isoamyl p-methoxycinnamate (4a/10pa); and phenylbenzimidazole sulfonic acid (1a/7pa). The frequent (photo)sensitization to isopropyldibenzoylmethane was the reason that its production was discontinued in 1993. 47 patients reacted to fragrance materials, 11 to preservatives and 2 to lanolin alcohol. These constituents were contained in the commercial sunscreens and cosmetics that they had used. Continuous revision of the UV absorber photopatch test series was necessary to be closer to the real frequency of exposure and of reported (photo)allergy to newer sunscreens. Clinicians should consider contact and photocontact allergy, especially in patients with photodermatoses and photo-aggravated dermatoses, and they should perform photopatch testing. Once the culprit has been identified, its INCI (International Nomenclature Cosmetic Ingredients) designation should be given to the patient, who must be warned to avoid products containing the (photo)allergen.
The aim of our study was the evaluation of contact sensitization in pediatric patients with atopic dermatitis (AD). It seems that the frequency of contact allergies in the course of AD, and also the frequency of contact allergies in children, is underestimated in general. Our study has been performed by investigating 137 children with AD. The childrens' history was taken according standardized consultation guidelines and followed by a physical examination. Patch testing was performed systematically, including the European standard series, together with tixocortol pivalate, budesonide and the applied emollient. If necessary, optional patch tests were performed according to the child's history. The results demonstrate contact sensitization in 43% of all children tested. The most frequent contact allergens are: metals (19.3%), fragrance (4.4%), balsam of Peru (2.6%), lanolin (4.4%), neomycin (2.6%) and emollients (2.6%). No contact sensitization to corticosteroids nor any induction of active sensitization were seen. Statistical analysis demonstrates that the risk of developing a contact allergy is significantly elevated in children after the age of 5 years. Female sex is a risk factor only for nickel. Age of onset of AD or its severity is not associated with the development of contact allergy. In conclusion, the results indicate the necessity of performing systematic patch testing in the investigation of allergies in children with AD. Preventive measures from an early age are suggested to avoid exposure to the most frequent contact allergens.
Patch testing was carried out in 424 schoolchildren (223M, 201F), aged 7-12 years, in northern Norway. In 99 (23.3%) of these children, one or more allergic patch test reactions were demonstrated; 30 children reacted to two and 6 to three or more substances; 53 irritant reactions were recorded in 33 (7.8%) of those tested. From a total of 144 positive tests, the most common allergen was nickel (14.9%), followed by cobalt (5.7%), kathon CG (5.2%), lanolin (1.7%) and neomycin (1.4%). Both allergic and irritant reactions were found twice as frequently in girls as in boys. Positive patch tests were significantly more frequent in atopic (28.8%) than in non-atopic (17.9%) children, being most pronounced in atopic girls (37.4%). Hand eczema was reported to have occurred or to be present in 6.5% of cases. Twenty-nine of 36 children reporting hand eczema participated in the clinical examination. Altogether 15 (3.5%) children had hand eczema at the time of the clinical examination but 12 of these children had no previous history of hand eczema. In 14 of these 15 subjects, the eczema was localized to the back of the hands, with 13 having atopic dermatitis. In 4 of these 15 children, an allergic patch test reaction was found; however, in only 2 of these 4 was the test considered to be clinically relevant for the diagnosis allergic hand eczema. In conclusion, irritant hand eczema may occur in early childhood and is most prevalent in children with atopic dermatitis.
Twenty cows and 20 uncalved 20 month old heifers with severely burnt teats were studied. Ten of each group received topical treatment with a mixture of lanoline, cetrimide and dimethyl sulphoxide or vitamin A and petroleum jelly, respectively. Prognosis for survival and future normal milking ability was poor in heifers (8 subsequently normal of 20 assessed) but moderate in cows (9 cows with normal and 5 cows with partial machine milking ability of 18 cows fully assessed). Treatment did not significantly increase the rate of epithelialisation of wounds. Topical treatment had no effect on the prognosis of heifers. However treated cows were more likely than control cows to survive and to show adequate teat function following subsequent calving. Severe clinical mastitis prior to calving, teat distortion and teat canal constriction were common sequelae. Recommendations on the management of heifers and cows with severely burnt teats are made.
Polysorbate 80, which has been widely used in studies of the effects of surfactants on drug absorption, increases the rate of absorption of some drugs at concentrations near its critical micelle concentration (cmc). To determine whether all non-ionic surfactants were capable of inducing this effect, the effects of six commercial non-ionic surfactants on thioridazine absorption in goldfish have been compared with the effect of polysorbate 80. The reciprocal death time (T-1) determined when the fish were immersed in the solution under study was the index of absoprtion rate used. Not all surfactants tested increased T-1. Cremophor EL (polyoxyethylated castor oil), Atlas G1295 (a polyoxyethylene fatty glyceride), Atlas G1300 (a polyoxyethylene glyceride ester) had no effect below their cmc's. Those surfactants that did increase T-1 [polysorbate 80 (a polyoxyethylene lanolin derivative), G2162 (a polyoxyethylene oxypropylene monosterate) and Renex 650 (a polyoxyethylene alkyl aryl ether)] display the concentration-dependent behaviour reported previously - a decrease in absorption rate when the surfactant concentration is increased above its cmc. The factor determining whether or not the surfactant will increas absorption rate appears to be the configuration of the surfactant molecule rather than its hydrophile-lipophile balance or its surface activity.
BACKGROUND: There is a strong influence of lower leg dermatitis on the spectrum of allergic contact sensitivity in elderly patients. OBJECTIVE: To quantitatively assess the impact of this factor which confounds the age-related pattern of allergic contact sensitivity. METHODS: Stratified analysis of allergic contact sensitivity data collected between 1996 and 1999 in the 32 centres of the Information Network of Departments of Dermatology (three age groups: < or =60, 61-75, > or =76 years), both as crude and as directly standardised (for sex and leg dermatitis) proportions. RESULTS: Among the 36,070 patients tested with the German standard series, allergic contact sensitivity to neomycin, lanolin, cetostearylic alcohols, colophony, fragrance mix and balsam of Peru, among others, was (much) more common in the elderly, with proportions more or less affected by standardisation. CONCLUSION: The comparison of crude and standardised proportions provides evidence that allergic contact sensitivity to several allergens strongly depends not only on age itself, but on age-related and thus confounding co-morbidity.
Excipients are essential components of drug products. They are also potential toxicants. Examples of known excipient-induced toxicities include renal failure and death from diethylene glycol, osmotic diarrhea caused by ingested mannitol, hypersensitivity reactions from lanolin, and cardiotoxicity induced by propylene glycol. Proposals to test or market new drug products in the United States should adequately address the safety of the proposed exposure to the excipients in those products. The specific safety data that may be needed will vary depending upon the clinical situation, including such factors as the duration, level, and route of exposure, but may include acute, repeat-dose, reproductive, and genetic toxicity data, carcinogenicity data, and specialized toxicology information, such as sensitization or local irritation data. Many guidances exist to aid in the development of pharmaceuticals, including the International Conference on Harmonization (ICH) documents and various Food and Drug Administration/Center for Drug Evaluation and Research (FDA/CDER) pharmacology and toxicology guidances. The FDA/CDER has recently adopted a new guidance for industry, "Nonclinical Studies for Development of Pharmaceutical Excipients," which focuses on issues associated with development of safety databases that will support clinical use of excipients in drug products. The new guidance document is introduced and discussed in this article.
The effects of the non-ionic surfactants polysorbate 20, polysorbate 60, polysorbate 85, cholesteryl poly (24) oxyethylene ether (Solulan C24) and the lanolin-based poly (16) oxyethylene ether (Solulan 16) on the epithelial integrity of monolayers of human intestinal epithelial (Caco-2) cells has been studied using metformin as a model drug. The aim was to identify the surfactants and their optimal concentrations capable of enhancing drug transport while causing no, or only minor, cellular damage. Effects on cell permeability were assessed by measurements of the transport of metformin, a hydrophilic drug, by monitoring transepithelial electrical resistance. Cell viability was determined by the diphenyltetrazolium bromide test (the MTT test). All the surfactants studied demonstrated concentration-dependent effects on cell permeability and cell viability. The effects on transepithelial electrical resistance correlated with cell viability, i.e. increased transepithelial electrical resistance and increased cell-monolayer permeability for metformin corresponded to decreased cell viability. The results indicate that the Solulan and polysorbate surfactants were active as absorption enhancers, Solulan C24 and 16 being more effective than polysorbates 20, 60 or 85, causing an increase in metformin transport at lower concentrations than the polysorbates. Polysorbate 20 exerted its greatest effect at a concentration of 5%-increasing the flux of metformin after 3 h by a factor of around 20 over the control. Large increases in the transport of metformin, especially at surfactant levels of 0.05%, 0.1% and 0.5%, were related to the effect of Solulan C24 and Solulan 16 on the cell permeability. The Caco-2 cell monolayer experiments confirmed the ability, especially of polysorbate 20, Solulan C24 and Solulan 16, to increase the absorption of metformin. The polysorbates increased permeability as a result of solubilisation of membrane components, while Solulans did so by penetrating and solubilising the membrane. Correlation between increase in membrane permeability and the toxicity of the surfactants towards the cell membrane has been established.