Topically applied heparins for the treatment of vascular disorders : a comprehensive review

Effective treatment of peripheral vascular disorders is important not only for resolution of local symptoms but also for preventing the development of systemic conditions such as deep vein thrombosis. Topical heparins are widely used in Europe for the prevention and treatment of local symptoms associated with peripheral vascular disorders. This comprehensive review of the literature evaluated the efficacy and safety of topically applied heparins for the treatment of vascular disorders. A total of 1055 patients participated in a total of 20 studies that compared topical heparin formulations with placebo, no treatment, subcutaneous heparin or with each other in the treatment of superficial thrombophlebitis or venous insufficiency. Heparin gel 1000 IU/g (Lioton((R)) 1000 gel, Menaven((R)) 1000 gel) was more effective than placebo in reducing the signs and symptoms of superficial thrombophlebitis. Liposomal heparin gel 2400 IU/g (LipoHep Forte((R))) was as effective as subcutaneous low-molecular-weight heparin at relieving local symptoms of superficial venous thrombosis. In head-to-head studies comparing different topical heparin formulations, all preparations appeared effective but heparin gel 1000 IU/g was superior to a heparinoid mucopolysaccharide cream (Hirudoid((R))) in patients with vascular disorders in terms of resolving spontaneous pain, induced pain, oedema and heaviness in the limb. Another study demonstrated the superiority of heparin gel 1000 IU/g compared with a gel formulation containing heparin 100 IU/g, aescinate and essential phospholipids (Essaven((R))), for symptom resolution. All treatments were generally well tolerated, with a relatively low incidence of local skin events. In summary, topical heparin preparations may be useful for relieving the signs and symptoms of vascular disorders while improving microcirculation. There is some evidence to suggest that heparin gel 1000 IU/g may be more effective than other topical preparations in treating these conditions, possibly because of the relatively high heparin levels in this formulation. This remains to be tested in well controlled, adequately powered clinical trials.     

PENETRATION OF CHLOROFORM,TRICHLOROETHYLENE, AND TETRACHLOROETHYLENE THROUGH HUMAN SKIN

In vitro dermal absorption was measured for three volatile organic compounds in dilute aqueous solution through freshly prepared and previously frozen human skin. The permeability coefficients at 26 C for chloroform (0.14 cm/h) and trichloroethylene (0.12 cm/h) were similar but much larger than that for tetrachloroethylene (0.018 cm/h). Storage of the skin at-20 C did not significantly affect the penetration of these chemicals. The dermal absorption of chloroform through freshly prepared human skin was not changed significantly by pretreatment of the skin with commonly used consumer products (moisturizer, baby oil, insect repellent, sunscreen); however, the permeability coefficient was found to increase from 0.071 cm/h at 11 C to 0.19 cm/h at 50 C. These data suggest that exposure estimates for chloroform and other contaminants in water should consider the appropriate exposure scenario to properly assess the dermal dose.     

Penetration of chloroform, trichloroethylene, and tetrachloroethylene through human skin.

In vitro dermal absorption was measured for three volatile organic compounds in dilute aqueous solution through freshly prepared and previously frozen human skin. The permeability coefficients at 26 degrees C for chloroform (0.14 cm/h) and trichloroethylene (0.12 cm/h) were similar but much larger than that for tetrachloroethylene (0.018 cm/h). Storage of the skin at -20 degrees C did not significantly affect the penetration of these chemicals. The dermal absorption of chloroform through freshly prepared human skin was not changed significantly by pretreatment of the skin with commonly used consumer products (moisturizer, baby oil, insect repellent, sunscreen); however, the permeability coefficient was found to increase from 0.071 cm/h at 11 degrees C to 0.19 cm/h at 50 degrees C. These data suggest that exposure estimates for chloroform and other contaminants in water should consider the appropriate exposure scenario to properly assess the dermal dose.     

A Case Series of Chemical Dermal Injury Requiring Operative Intervention after Prolonged Dermal Methylene Chloride Exposure

IntroductionMethylene chloride, also known as dichloromethane, is a volatile hydrocarbon used in paint strippers and removers. Toxicity from methylene chloride may include narcosis and elevated carbon monoxide (CO) levels. Significant injury to the skin can occur after prolonged exposure to methylene chloride and other hydrocarbon-based solvents causing a chemical dermal injury.Case ReportThis case series describes three male patients with prolonged exposure to a methylene chloride–containing paint remover to the bilateral hands with two of the three patients requiring transfer to a tertiary burn center and operative intervention. The clinical significance and impressive resolution of dermal injury from prolonged methylene chloride exposure are highlighted with detailed images and a literature review.DiscussionChemical dermal injury secondary to methylene chloride exposure likely results from destruction of lipids within the epidermis and dermis and direct chemical injury. Prolonged exposure to skin can result in clinically important injury that requires management by a burn specialist and may necessitate operative intervention. The severity of the dermal injury can range from severe to mild and should be considered by a clinician after skin exposure to hydrocarbons.     

Topical treatments for hydrofluoric acid burns: a blind controlled experimental study

BACKGROUND: Calcium gluconate gel, applied after initial rinsing with water, has a documented effect as first aid treatment for hydrofluoric acid burns. Hexafluorine is a novel liquid compound developed especially for emergency decontamination of hydrofluoric acid eye and skin exposures. However, scientific documentation of the effect of Hexafluorine is insufficient. This study was undertaken to compare Hexafluorine with water rinsing plus topical calcium and with water rinsing alone. METHODS: Thirty-five Sprague-Dawley rats were anesthetized and their backs shaved. Four filter papers 10 mm in diameter were soaked in 50% hydrofluoric acid and applied on the shaved area of each rat for 3 minutes. Thirty seconds later, the acid-exposed skin areas were rinsed with 500 mL Hexafluorine for 3 minutes (group H, n = 10), 500 mL water for 3 minutes (group W, n = 10) or 500 mL water for 3 minutes followed by a single application of 2.5% calcium gluconate gel (group Ca, n = 10), or received no treatment (controls, n = 5). The animals were closely observed for 5 days. Daily at 4 P.M. each of the four burns on every rat was rated on a modified Draize scale graded from 0 to 5 (0 = no visible injury, 1 = diffuse erythema, 2 = distinct erythema, 3 = distinct erythema plus wounds or discolored spots, 4 = distinct erythema plus wounds or discolored areas covering >50% of the burn, 5 = a necrotic wound covering the whole burn). The mean of the four scores was then calculated for each animal and day. The rating procedure was performed by one laboratory assistant who was unaware of the treatment given. Kruskal-Wallis analysis was used to evaluate possible differences between treatment groups on each of the 5 days. If the p-value obtained was <0.05, correction for multiple comparisons was made. RESULTS: The mean severity score in group H was significantly higher than that in group Ca on days 2 and 3. Moreover, Hexafluorine showed a consistent trend towards a worse outcome, both in comparison to water plus topical calcium and to water rinsing alone. CONCLUSION: Based on these observations it is concluded that water rinsing followed by topical calcium should remain the standard first aid treatment for skin exposure to hydrofluoric acid.     

Different clinical features of amitraz poisoning in children

OBJECTIVE: To evaluate clinical experience of amitraz poisoning in children. METHODS: In this study, the clinical and laboratory features of amitraz poisoning in 14 children are presented and compared with previous studies. RESULTS: This study revealed that clinical manifestations of poisoning by oral and dermal routes appeared within 30-150 min, and that central nervous system (CNS) depression, which is the most important sign, improved within 6-24 hours and other signs within 24-72 hours. Unlike the findings in other studies, three severe cases in our study had reversible mydriasis and one of them required resuscitation because of cardiopulmonary arrest occurring as a result of serious respiratory depression. In addition, hepatic function test levels had increased in these three cases, and aspiration pneumonitis existed because of emesis in two of them. CONCLUSION: There is little information in the literature about dermal poisoning. The signs and symptoms of dermal poisoning were relatively mild compared with oral poisoning, and there were no topical signs. The classical signs of alpha2-adrenergic stimulation such as marked sinusal bradycardia and mydriasis as reported in many poisoning cases of animals have not been reported before our three severe cases among children.     

An improved method for emergent decontamination of ocular and dermal hydrofluoric acid splashes

Accidental hydrofluoric acid (HF) splashes often occur in industrial settings. HF easily penetrates into tissues by initial acid action allowing fluoride ions to penetrate deeply, chelating calcium and magnesium. Resultant hypocalcemia and hypomagnesemia can be fatal. This report describes the utilization of Hexafluorine--a hypertonic, amphoteric, chelating decontamination solution--in workplaces where water decontamination followed by calcium gluconate inunction failed to prevent HF burns and systemic toxicity. Between 1998 and 1999, 16 cases of ocular and dermal HF splashes with either 70% HF or 6% HF/15% nitric acid (HNO3) were decontaminated with Hexafluorine at the worksite. HF burns did not develop and medical treatment other than initial decontamination was not reQuired in 12/16 (75%). In 7/16 (44%) cases, lost work time corresponded to duration of hospital observation (mean < 1 d).     

Comparative dermal pharmacology and toxicology of 4,4'-dihydroxybenzophenone-2,4-dinitrophenylhydrazone (A-007) in rodents and primates

4,4'-Dihydroxybenzophenone-2,4-ditrophenylhydrazone (A-007) has demonstrated anticancer activities, when administered topically to patients with metastatic cancer to the skin. Acute, subacute and subchronic dermal studies with A-007 in adult rabbits, rats, guinea pigs and monkeys failed to demonstrate local or systemic toxicity when applied topically as a 0.25% gel. A-007 did not penetrate the dermal lymphatics and did not produce detectable levels of A-007 in the plasma when applied as a 0.25% gel topically to skin. In the above studies, topically administered A-007 stimulated local sub-epithelial and dermal lymphocyte modulation, with increased CD8+ cytotoxic lymphocytes (CTL) noted, in guinea pig skin. Generally topical A-007 is well tolerated and may have useful immune modulation properties.     

Hexafluorine vs. standard decontamination to reduce systemic toxicity after dermal exposure to hydrofluoric acid

INTRODUCTION: Dermal exposure to hydrofluoric acid (HF) may cause severe burns and systemic toxicity. Hexafluorine (Prevor, France) is a product marketed as an emergency decontamination fluid for HF skin and eye exposures. Documentation concerning Hexafluorine is scanty, and a recent study indicates that its ability to reduce HF burns is at most equal to that of water. OBJECTIVE: The present study was conducted to evaluate Hexafluorine's capacity to reduce HF-induced systemic toxicity. METHODS: Sprague Dawley rats were anesthetized, catheterized in the left femoral artery, and shaved on their back. A filter paper (3.5 x 6 cm) was soaked in 50% HF and applied on the back of each rat for 3 min. Thirty seconds after removal of the paper, a 3-min rinsing with either 500 mL Hexafluorine (group H), 500 mL water (group W), or 500 mL water followed by a single application of 2.5% calcium gluconate gel (group Ca) was carried out. Blood samples were analyzed for ionized calcium and potassium (before injury and 1, 2, 3, and 4 h after) and also for ionized fluoride (1, 2, and 4 h after injury). RESULTS: The animals developed hypocalcemia, hyperkalemia, and hyperfluoridemia after the HF exposure. The only significant difference observed among the groups was in serum potassium at 1 h between group Ca and group W. However, there was a constant trend toward milder hypocalcemia and less pronounced hyperkalemia in group Ca compared to the other groups. There were no differences in the electrolyte disturbances between the Hexafluorine-treated animals and those treated with water only. Five of 39 animals died before completion of the experiment as a result of the HF exposure, one from group Ca and two from each of the other two groups. CONCLUSION: In this experimental study, decontamination with Hexafluorine was not more effective than water rinsing in reducing electrolyte disturbances caused by dermal exposure to hydrofluoric acid.     

An analysis of glyphosate data from the California Environmental Protection Agency Pesticide Illness Surveillance Program

Glyphosate is among the pesticides most frequently reported to the California EPA Pesticide Illness Surveillance Program. We analyzed glyphosate-related calls to the Pesticide Illness Surveillance Program in order to assess the number of reports involving systemic symptoms and to better understand the nature and severity of reported cases. Data on glyphosate and other pesticides are available for the years 1982-1997 including: type of exposure (agricultural/other); target organ(s) affected (skin/eye/respiratory/systemic); exposure(s); an assessment of causal relationship (possible, probable, or definite); and limited medical text. Of 815 total glyphosate calls, most involved topical irritation of the eye (n = 399), skin (n = 250), upper airway (n = 7), or combinations of these sites (n = 32) without systemic symptoms. Of the 187 systemic cases, only 22 had symptoms recorded as probably or definitely related to glyphosate exposure alone. The reported symptoms were not severe, expected to be limited in duration, and frequently inconsistent with the route of exposure and/or previous experience with glyphosate. We conclude that call volume is not a reliable indicator of the actual incidence or severity of glyphosate-related incidents in California.     

Dermal sensitization quantitative risk assessment (QRA) for fragrance ingredients

Based on chemical, cellular, and molecular understanding of dermal sensitization, an exposure-based quantitative risk assessment (QRA) can be conducted to determine safe use levels of fragrance ingredients in different consumer product types. The key steps are: (1) determination of benchmarks (no expected sensitization induction level (NESIL)); (2) application of sensitization assessment factors (SAF); and (3) consumer exposure (CEL) calculation through product use. Using these parameters, an acceptable exposure level (AEL) can be calculated and compared with the CEL. The ratio of AEL to CEL must be favorable to support safe use of the potential skin sensitizer. This ratio must be calculated for the fragrance ingredient in each product type. Based on the Research Institute for Fragrance Materials, Inc. (RIFM) Expert Panel's recommendation, RIFM and the International Fragrance Association (IFRA) have adopted the dermal sensitization QRA approach described in this review for fragrance ingredients identified as potential dermal sensitizers. This now forms the fragrance industry's core strategy for primary prevention of dermal sensitization to these materials in consumer products. This methodology is used to determine global fragrance industry product management practices (IFRA Standards) for fragrance ingredients that are potential dermal sensitizers. This paper describes the principles of the recommended approach, provides detailed review of all the information used in the dermal sensitization QRA approach for fragrance ingredients and presents key conclusions for its use now and refinement in the future.     

Polymeric microparticles-based formulation for the eradication of cutaneous candidiasis: development and characterization

Abstract

Cutaneous candidiasis is a common topical fungal infection which may be more prominent in patients associated with AIDS. It is usually treated by conventional formulations such as cream, gel, which show various adverse effects on skin along with systemic absorption. To overcome these drawbacks, various novel drug delivery systems have been explored. Poly(lactic-co-glycolic acid) (PLGA)-based microparticulate systems have shown good dermal penetration after topical application. Therefore, in the present study clotrimazole-loaded PLGA microspheres were prepared for targeted dermal delivery. Microspheres were prepared by using a single emulsification (oil-in-water, O/W) evaporation technique and characterized for different parameters. Prepared microparticulate systems were dispersed in Carbopol 934® gel and antifungal activity was carried out on experimentally induced cutaneous candidiasis in immunosuppressed guinea pigs. Particle size of optimized formulation was 2.9?µm along with 74.85% entrapment of drug. Skin retention studies revealed that drug accumulation in the skin was higher with microspheres gel as compared to marketed gel. Confocal microscopy of skin further confirmed penetration of microspheres up to 50?µm into the dermal region. In-vivo antifungal activity studies demonstrated that microsphere gel showed better therapeutic activity, lowest number of cfu/ml was recorded, as compared to marketed gel after 96?h of application. Based on the results of the study, it can be concluded that PLGA microparticles may be promising carriers to deliver clotrimazole intradermally for the treatment of invasive fungal infections.     

Dermal penetration potential of perfluorooctanoic acid (PFOA) in human and mouse skin

Recent data, using a murine model, have indicated that dermal exposure to perfluorooctanoic acid (PFOA) induces immune modulation, suggesting that this may be an important route of PFOA exposure. To investigate the dermal penetration potential of PFOA, serum concentrations were analyzed in mice following topical application. Statistically significant and dose-responsive increases in serum PFOA concentrations were identified. In vitro dermal penetration studies also demonstrated that PFOA permeates both mouse and human skin. Investigation into the mechanisms mediating PFOA penetration demonstrated that dermal absorption was strongly dependent upon the ionization status of PFOA. In addition, PFOA solid, but not 1% PFOA/acetone solution, was identified as corrosive using a cultured epidermis in vitro model. Despite its corrosive potential, expression of inflammatory cytokines in the skin of topically exposed mice was not altered. These data suggest that PFOA is dermally absorbed and that under certain conditions the skin may be a significant route of exposure.     

Unintentional poisoning by phosphine released from aluminum phosphide

Aluminum phosphide as a releaser of phosphine gas is used as a grain preservative. In this case report, we describe an accidental severe poisoning in a 35-year-old woman, her 18-year-old daughter, and 6-year-old son caused by inhalation of phosphine gas released from 20 tablets of aluminum phosphide stored in 15 rice bags. The boy died 2 days after exposure before admission to hospital and any special treatment, but the others were admitted 48 h after exposure. They had signs and symptoms of severe toxicity, and their clinical course included metabolic acidosis, electrocardiographic changes, and hypotension. They were treated by intravenous administration of sodium bicarbonate, magnesium sulfate, and calcium gluconate. The patients were discharged after 3 days and followed up for 1 week after discharge. Rapid absorption of phosphine by inhalation, induction of hyperglycemia, and surviving of patients are interesting issues of this case report.     

Assessing the risk of type 1 allergy to enzymes present in laundry and cleaning products: Evidence from the clinical data

Microbial enzymes have been used in laundry detergent products for several decades. These enzymes have also long been known to have the potential to give rise to occupational type 1 allergic responses. A few cases of allergy among consumers using dusty enzyme detergents were reported in the early 1970s. Encapsulation of the enzymes along with other formula changes were made to ensure that consumer exposure levels were sufficiently low that the likelihood of either the induction of IgE antibody (sensitization) or the elicitation of clinical symptoms be highly improbable. Understanding the consumer exposure to enzymes which are used in laundry and cleaning products is a key step to the risk management process. Validation of the risk assessment conclusions and the risk management process only comes with practical experience and evidence from the marketplace. In the present work, clinical data from a range of sources collected over the past 40 years have been analysed. These include data from peer reviewed literature and enzyme specific IgE antibody test results in detergent manufacturers’ employees and from clinical study subjects. In total, enzyme specific IgE antibody data were available on 15,765 individuals. There were 37 individuals with IgE antibody. The majority of these cases were from the 1970s where 23 of 4687 subjects (0.49%) were IgE positive and 15 of the 23 were reported to have symptoms of allergy. The remaining 14 cases were identified post-1977 for a prevalence of 0.126% (14/11,078). No symptoms were reported and no relationship to exposure to laundry and cleaning products was found. There was a significant difference between the pre- and post-1977 cohorts in that the higher rates of sensitization with symptoms were associated with higher exposure to enzyme. The clinical testing revealed that the prevalence of enzyme specific IgE in the population is very rare (0.126% since 1977). This demonstrates that exposure to these strong respiratory allergens via use of laundry and cleaning products does not lead to the development of sensitization and disease. These data confirm that the risk to consumers has been properly assessed and managed and support the concept that thresholds of exposure exist for respiratory allergy. Expansion of enzyme use into new consumer product categories should follow completion of robust risk assessments in order to continue ensuring the safe use of enzymes among consumers.     

Acute neuropathy and erythromelalgia following topical exposure to isopropanol

Adverse effects resulting from topical exposure to isopropanol appears exceptional in adults with intact skin. We describe the case of a young woman who developed an acute sensori-motor axonal polyneuropathy after walking bare-feet for several hours on carpets soaked by a disinfectant containing isopropanolol. The persistence and severity of symptoms raised the possibility of her neuropathy being partly related to immunizations she received 1 mo earlier. The occurrence shortly after contact, however, strongly suggested responsibility of the dermal isopropanol exposure. This case being, to our knowledge, the second reported, peripheral nerve toxicity appears possible in adults on prolonged topical exposure, probably in susceptible individuals.     

Effects of a topical microemulsion in house dust mite allergic rhinitis

We have previously demonstrated that a topical microemulsion can attenuate symptoms and signs of seasonal allergic rhinitis. This likely reflects that the microemulsion interferes with the interaction between the allergen and the mucosa. Whether or not the finding translates to conditions caused by other inhaled agents such as house dust mite allergen is unknown. Patients with perennial allergic rhinitis caused by house dust mite were subjected to topical microemulsion treatment in a randomized, double-blinded and crossover design with isotonic saline as control. Morning symptoms were monitored, change from baseline was assessed and the treatments were compared. On the first days of the isotonic saline and microemulsion runs, before any treatment was given, total nasal symptoms were scored to 2.8 and 3.1 (range 0-9), respectively. Nasal symptoms were reduced by intervention with the microemulsion: the change from baseline was consistent for the microemulsion and the difference between the microemulsion and isotonic saline reached statistical significance in favour of the former. We conclude that intervention with a microemulsion may reduce symptoms of house dust mite allergic rhinitis at natural allergen exposure. Our findings suggest the possibility that topical microemulsions can be a useful option to reduce nasal mucosal exposure to allergen in perennial allergic rhinitis..     

Solvent-based paint and varnish removers: a focused toxicologic review of existing and alternative constituents

Paint and varnish removers constitute a major potential source of organic solvent exposure to contractors and home improvement enthusiasts. Unfortunately, the leading paint remover formulations have traditionally contained, as major ingredients, chemicals classified as probable human carcinogens (eg, methylene chloride) or reproductive toxicants (eg, N-methylpyrrolidone). In addition, because of its unique toxicology (ie, hepatic conversion to carbon monoxide compounding generic solvent narcosis and arrythmogenesis), high volatility, and rigorous requirements for personal protective equipment, methylene chloride exposures from paint removers have been linked to numerous deaths involving both occupational and consumer usage. The aim of this review is to summarize the known toxicology of solvent-based paint remover constituents (including those found in substitute formulations) in order to provide health risk information to regulators, chemical formulators, and end-users of this class of products, and to highlight any data gaps that may exist.     

全数字化乳腺X线摄影对早期乳癌的诊断价值探讨

目的评价全数字化乳腺X线摄影在早期乳腺癌诊断中的价值。方法对41例经手术病理证实的早期乳腺癌X线征象进行回顾性分析。结果X线征象:有微细钙化14例(34%),其中仅见钙化不伴其他征象者7例,钙化伴致密结节影7例;致密结节影8例(19.5%),局灶致密影10例(24%),局部结构扭曲紊乱7例(17%);因腺体致密无异常征象显示者2例(5.0%)。结论微细钙化是早期乳腺癌的重要征象甚至是唯一征象,数字化乳腺X线摄影发现钙化有明显的优势,对早期乳腺癌诊断有重大价值。     

葡萄糖酸钙、维生素K1联合奥美拉唑与单独给予奥美拉唑治疗消化道出血的疗效及安全性比较

目的探讨葡萄糖酸钙、维生素K1联合奥美拉唑与单独给予奥美拉唑治疗消化道出血的疗效及安全性比较。方法回顾分析我院收治的180例消化道出血患者,随机分为对照组和观察组,每组90例。对照组单独给予奥美拉唑,观察组给予萄糖酸钙、维生素K1联合奥美拉唑,观察两组患者的临床疗效及安全性比较。结果治疗后观察组患者的总有效率为97.78%明显高于对照组的90.00%(χ2=4.74,P<0.05);各临床症状的缓解时间均显著短于对照组(P<0.05);两组均无严重的不良反应发生,观察组患者的不良反应发生率低于对照组,但两组无显著性差异(P>0.05)。结论应用葡萄糖酸钙、维生素K1联合奥美拉唑治疗消化道出血疗效显著,能更好的发挥止血作用,且不良反应少、发生率低,适宜临床广泛应用。