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PubMed1991

[Skin sutures in pediatric surgery. Use of a fast-resorption synthetic thread].

Vicryl Rapide is a new, fast absorption skin suture material. Its spontaneous elimination avoids the conventional stitch removal. The tolerability of this material and the cosmetic results obtained were tested in a paediatric surgery department in elective surgery and in emergency surface wound sutures. Provided certain precautions are taken (tense sutures and sutures of the face must be avoided, since the thread passages are visible in 25 percent of the cases), the material is well tolerated; the cosmetic results and child comfort it provides and the absence of stitch removal makes Vicryl Rapide a first-choice material in paediatric surgery.

Child↗
PubMed1996

Effect of calcitonin gene-related peptide on sodium absorption through isolated skin of Rana esculenta.

Calcitonin gene-related peptide (CGRP) added to the internal fluid bathing the isolated skin of Rana esculenta strongly stimulates the active sodium absorption. This action is dose-dependent, the dose eliciting the maximal effect being 2 . 10(-7) M; alpha and beta CGRP exhibit the same potency. The CGRP action on sodium transport is mainly due to its interaction with CGRP1 receptors, since it is inhibited by CGRP8-37, its specific antagonist. The second messengers probably involved in the action of CGRP are cAMP and Ca+2, since this action is reduced by SQ22536 and W7, which are inhibitors of adenyl cyclase and calmodulin respectively. On the contrary, inhibitors of protein kinase C (1-O-hexadecyl-2-O-methyl-sn-glycerol) and nitric oxide synthase (L-NAME) do not modify the action on sodium transport. ETYA, an inhibitor of all the metabolic pathways of arachidonic acid, decreases the CGRP action by 38%. In order to search for the arachidonic acid metabolites involved in the CGRP action, the effect of the following inhibitors was tested: aspirin and naproxen (for cyclooxygenases), NDGA (for cyclooxygenases), NDGA (for lipoxygenases) clotrimazole (for epoxygenases). None of these substances is able to inhibit the CGRP action on sodium transport. Moreover, adding arachidonic acid inhibits the CGRP action, but this effect was also obtained by another unsaturated fatty acid, oleic acid. Since unsaturated fatty acids are able to inhibit the protein kinase A, these results indirectly support the role of cAMP as a second messenger of the CGRP action on sodium transport.

Animals↗
PubMed1998

Factors determining drug residence in skin during transdermal absorption: studies on beta-blocking agents.

The factors determining drug residence in skin during penetration across rat abdominal skin were investigated using five beta-blocking agents with different lipophilicities as model drugs in vivo and in vitro. The amount of beta-blocking agent in the skin at steady state correlated well with lipophilicity. The distribution of beta-blocking agents to the stratum corneum and the contribution of intercellular lipids in the stratum corneum to their skin distribution were also correlated with their lipophilicity, suggesting that the stratum corneum, especially intercellular lipids in the stratum corneum, would be responsible for the residence of beta-blocking agents in the skin. Furthermore, cholesterol-3-sulfate, palmitic acid, stearic acid and oleic acid were found to interact with the beta-blocking agents, which are cationized under the physiological condition, and were assumed to play an important role in the skin accumulation. On the other hand, the binding to keratinocyte was so small that keratinocyte might have little effect on the skin accumulation of the beta-blocking agents. Drug transport from the stratum corneum to viable skin was suggested to be regulated by the lipophilicity of these agents. To investigate the residence of these drugs in viable skin, in vitro transport studies using stripped skin were performed. The transport rate constant across viable skin to receptor cells (k23) was inversely correlated with the lipophilicity of the drugs. The elimination rate constants from viable skin (k(vs)) obtained in the in vivo study were much smaller than the values of k23 obtained in the in vitro study, and they were inversely correlated with the binding to cytosol components of viable skin but not the lipophilicity. The viable skin-to-muscle concentration ratio of these drugs, obtained at the beta-phase of the plasma concentration-time curve after intravenous administration, was also inversely correlated with the binding to the cytosol components of viable skin. These results suggest that k(vs) reflects the transport from viable skin to muscle rather than to blood circulation and that the binding of drugs to cytosol components in viable skin would be one of the important factors determining the residence in viable skin.

Administration, Cutaneous↗
PubMed1983

1976 Hanford americium exposure incident: organ burden and radiation dose estimates.

A Hanford worker received an intake of 241Am by skin absorption and inhalation which was later evaluated to be in excess of 1 mCi. The skin was the main pathway for introduction of 241Am into the body; however inhalation was also a significant pathway. Intensive DTPA therapy prevented 99% of 241Am which entered the blood stream from being deposited in the internal organs. Retention and distribution of 241Am in various internal organs and tissues was determined from sequential measurements in vivo using several arrangements of externally located scintillation detectors. The organ and tissue retention and distribution have been followed for longer than 5 yr. Excretion patterns and estimates of radiation dose to the lung, liver, bone and skin are described.

Accidents, Occupational↗
PubMed1994

Percutaneous absorption of benzyl acetate through rat skin in vitro. 3. A comparison with human skin.

The comparative absorption of the fragrance and industrial compound, benzyl acetate, has been studied in rat and human skin, using shaved, full-thickness dorsal skin of male Fischer 344 rats and full-thickness human skin obtained from patients undergoing surgical resection. Penetration of the compound through rat and human skin was evaluated in vitro in flow-through diffusion cells following topical application of neat [methylene-14C] benzyl acetate (33.1 mg/cm2) to the epidermal surface and occlusion with a teflon cap, 2.9 cm above the skin surface. The absorption of benzyl acetate across rat skin was rapid and extensive, reaching 34.3 +/- 3.9% of the applied dose (11.3 +/- 1.3 mg/cm2) (mean +/- SD, n = 12) at 24 hr and 55.8 +/- 5.0% of the applied dose (18.5 +/- 1.7 mg/cm2) at 72 hr. The penetration of benzyl acetate was significantly (P < 0.05) less rapid and extensive through human skin, reaching 5.5 +/- 0.1% of the applied dose (1.8 +/- 0.0 mg/cm2) (mean +/- SD, n = 12) at 24 hr and 17.8 +/- 3.3% of the applied dose (5.9 +/- 1.1 mg/cm2) at 72 hr. The rate of penetration of benzyl acetate was greater through rat skin than through human tissue at all time points studied up to 72 hr. The maximum rate of skin penetration was 0.6 +/- 0.1 mg/cm2/hr and 0.1 +/- 0.0 mg/cm2/hr through rat and human skin, respectively. These data indicate that systemic exposure to benzyl acetate may occur after skin contact in humans. They also support the evidence from the literature that human skin is generally less permeable to xenobiotics than rat skin.

Animals↗
PubMed1982

2-14C-1-Allyl-3,5-diethyl-6-chlorouracil I: Synthesis, absorption in human skin, excretion, distribution, and metabolism in rats and rabbits.

With 14C-potassium cyanate as the starting material, 2-14C-1-allyl-3,5-diethyl-6-chlorouracil was synthesized for in vitro and in vivo absorption studies in human skin and for metabolic studies in rats and rabbits. The radioactivity in the horny layer, epidermis, and dermis of the human skin was determined after different intervals of time, and the radioactivity excreted in the urine was measured by collecting samples for 5 days from a patient and also under occlusion conditions. Almost 90% of the radioactivity remained on the surface and approximately 6.28% penetrated and was systemically absorbed. Over a 5-day period, a total of 3.25% was excreted. Almost 3% was systemically absorbed and cumulated in the system. After intraperitoneal application in male and female rats, most of the radioactivity was excreted in the feces and urine, with female rats excreting more in the urine than male rats. The radioactivity rose in the organs in the first 3 hr and then decreased. At the end of 144 hr, no appreciable radioactivity could be found in the organs and tissues, except in the carcass where the cumulation was maximum (1%). After intravenous injection in rabbits, most of the radioactivity (80%) was excreted in the urine and only 4% in the feces. At the end of 96 hr, approximately 3% was cumulated in the body. The drug was quantitatively metabolized in both rats and rabbits: Metabolite 1 (70-85%), Metabolite 2 (10-15%), Metabolite 3 (5-10%), and Metabolite 4 (0.3%).

Administration, Topical↗
PubMed1988

Preventing percutaneous absorption of industrial chemicals: the "skin" denotation.

Percutaneous absorption has received comparatively little attention in occupational health, although this route of entry has repeatedly caused occupation-related intoxications. In practice, the evaluation of skin penetration rates is far from simple. Much evidence has been obtained from studies of chemicals used for cosmetics and topical therapeutics, but the information available on compounds encountered in occupational health is limited. The data obtained from experimental studies have confirmed that the concentration, type of vehicle, skin area, skin condition, and extent of occlusion are important factors in determining the degree of percutaneous absorption, but no general model has been developed. Also, too little is known about the basic chemical properties governing the rate of penetration. Thus, prediction is difficult and bound to be rather inaccurate. Current preventive practice follows the procedure used by ACGIH and is mainly based on a "skin" denotation in official listings of chemicals to which exposure limits have been allocated. The number of substances and groups of chemicals which have received skin denotation in 17 selected countries varies between 24 and 179 and a total of 275 are listed as a skin hazard in one or more countries; ACGIH lists 143. Thus, the denotation practice varies. As an unfortunate result of these discrepancies and the dichotomy of skin denotation, the absence of skin denotation may erroneously indicate that efforts to protect the skin are unnecessary. Thus, an evaluation of skin penetration potentials should be incorporated in occupational health practice as a supplement to the official denotations.

Humans↗
PubMed1988

Respiratory failure from severe organophosphate toxicity due to absorption through the skin.

Organophosphates are the most common group of chemicals involved in poisoning in Sri Lanka. Usually, poisoning is by ingestion for suicidal purposes, although accidental poisoning is not uncommon. Poisoning due to absorption through intact or damaged skin is rare. A 32-year-old man was admitted to a peripheral hospital following assault with a 100-ml bottle of insecticide called Monocrotophos, an organophosphate. He had a 2-in. long laceration just above his left eyebrow and there was spilling of the liquid contained in the bottle over his head and face. The liquid was wiped off but the head or face was not washed. After about 3 h the patient developed symptoms and signs of early organophosphate poisoning which were treated with atropine and pralidoxime. On the 3rd day, while on therapy, the patient developed severe weakness of limbs and respiratory distress needing intubation and assisted ventilation. The patient was transferred to the neurology intensive care unit of the General Hospital, Colombo, on the eighth day. His serum potassium levels were low and an ECG showed prominent U waves in all leads. The plasma cholinesterase levels were within 37.5-50% of normal even on the 20th day indicating severe exposure.

Adult↗
PubMed2003

Pharmacokinetics and metabolism of transdermal oxybutynin: in vitro and in vivo performance of a novel delivery system.

PURPOSE: The purpose of this work was to characterize in vitro/in vivo delivery and pharmacokinetics of oxybutynin (OXY) and its active metabolite. N-desethyloxybutynin (DEO), by a novel matrix transdermal system (TDS). METHODS: Two in vivo, randomized, three-way crossover trials examined single/multiple OXY TDS doses. Abdomen, buttock, and hip application sites were compared and dose proportionality was evaluated. Model independent pharmacokinetics, elimination rate constants, and metabolite/drug ratios were derived from both plasma OXY and DEO concentrations. RESULTS: Single/multiple applications of the OXY TDS to the abdomen yielded mean Cmax OXY concentrations of 3.4 +/- 1.1/6.6 +/- 2.4 ng/mL and median tmax of 36/10 h, with steady state achieved during the second application. Plasma OXY and DEO concentrations decreased gradually after Cmax until system removal. Buttock and hip applications resulted in bioequivalent OXY absorption. AUC ratios of DEO/OXY were 1.5 +/- 0.4 (single dose) and 1.3 +/- 0.3 (multiple dose). Mean in vitro OXY skin absorption (186 microg/h) was comparable to the estimated in vivo delivery (163 microg/h) over 96 h. CONCLUSIONS: Sustained delivery over 4 days and multiple sites allow a convenient, well-tolerated, twice-weekly OXY TDS dosing. A low incidence of anticholinergic side effects is expected during clinical use because of the avoidance of presystemic metabolism and low DEO plasma concentrations. The consistent delivery, absorption, and pharmacokinetics should result in an effective treatment of patients with overactive bladder.

Administration, Cutaneous↗
PubMed2002

Topiglan MacroChem.

MacroChem is developing Topiglan, a topical gel containing prostaglandin E1 (PGE1 or alprostadil) and its patented through-the-skin absorption enhancer excipient (SEPA), for the potential treatment of erectile dysfunction. By September 2000, it was in phase III clinical trials [382682]. By October 2000, MacroChem expected to file an NDA for Topiglan in late 2002 [387433]. In January 2002, at the JP Morgan Hambrecht & Quist 20th Annual Healthcare Conference in San Francisco, CA, MacroChem stated that further phase III studies were planned, including a reformulation that could reduce initation and increase dosage, as well as providing new packaging that improves dose consistency These studies should be underway by the third quarter of 2002, with a potential launch in late 2003 or early 2004 [436390]. The company's patented SEPA technology used in Topiglan is an absorption enhancer for transdermal delivery that has the potential to effectively increase the passage of therapeutic agents through the skin. The application of SEPA alone to the skin of carcinogenic-sensitive rats did not cause the development of tumors attributable to the SEPA [357621]. The company received a US notice of allowance of all patent claims covering Topiglan in February 1999. The patent (US-05942545) was issued in August 1999 [316028], [337720]. Further patent applications are pending in Canada, Europe and Japan [337720]. In February 2000, MacroChem filed further patent applications in 13 countries in Europe, Asia and Latin America and with the EPO [355947].

Adjuvants, Pharmaceutic↗
PubMed1985

Absorption of lignocaine through split-skin donor sites.

Seventeen patients undergoing split-skin grafting each received 3 mg/kg of a sterile 1% lignocaine gel applied to an area of the donor site equal to 3 sq cm/kg. Serial venous blood samples were taken for one hour following application and analysed for serum lignocaine concentration by high pressure liquid chromatography. The concentrations in all the patients were well below those associated with systemic toxicity. Clinical assessment included haemodynamic monitoring during the procedure, and postoperative evaluation of possible central nervous effects and of the degree of donor site analgesia obtained. No untoward effects were noted and the degree of analgesia, although difficult to assess, appeared good.

Administration, Topical↗
PubMed1995

Treatment of ectoparasitic infections: review of the English-language literature, 1982-1992.

We reviewed the English-language literature of 1982-1992 for papers concerning scabies, pediculosis, and their treatments; this information was supplemented with opinions of workers in the field of ectoparasitic disease. Six treatment trials for scabies, one study of the treatment of pediculosis pubis, and additional studies on the treatment of pediculosis capitis were included. Both lindane 1% and permethrin 5% are effective treatments for scabies, although resistance to lindane does exist. Lindane 1%, permethrin 1%, and pyrethrins with piperonyl butoxide are all effective treatments for pediculosis. Severe reactions to lindane therapy may occur when increased skin absorption of lindane occurs. Permethrin 5% or lindane 1% is recommended for the treatment of scabies. Lindane should be used with precautions to avoid excess skin penetration and should not be used to treat infants, young children, or pregnant or lactating women. Permethrin 1%, lindane 1%, or pyrethrins with piperonyl butoxide is recommended for the treatment of pediculosis pubis. Pregnant and lactating women should be treated with either permethrin or with pyrethrins containing piperonyl butoxide.

Adult↗
PubMed2006

The effect of water solubility of solutes on their flux through human skin in vitro.

The Flynn database (n=97) for determining the effect of the physicochemical properties of solutes on their skin absorption has been edited to give a database for which the solubilities of the solutes in water, S(AQ), and their maximum fluxes from water through human skin in vitro, J(MAQ), are known or can be calculated (n=76). Data from the six major contributors to the original Flynn database have been included. Data for solutes, which were significantly ionized or for experiments using different thicknesses of skin were not excluded so that the edited database is as diverse as the original. The edited database was fit to five equations where the independent variables were solubility in octanol (S(OCT)) in water (S(AQ)) or molecular weight (MW), and combinations of those three variables; and the dependent variable was J(MAQ). The best fit was obtained from the Roberts-Sloan (RS) equation: logJ(MAQ)=x+ylogS(OCT)+(1-y)logS(AQ)-zMW, x=-3.00, y=0.73, z=0.0048, r(2)=0.934, S.D.=0.37 and F=274. This result is important because J (amount/area time) is the more clinically useful descriptor of permeation compared to P (distance/time); and because the identification of S(AQ) as a significant variable in predicting flux changes the design parameters for optimizing topical delivery of drugs from solubility in lipids (or partition coefficients between OCT and AQ, K(OCT:AQ)) and MW, to solubility in lipids, S(OCT), and in water, S(AQ), as well as MW.

Analgesics↗
PubMed1977

Human exposure to tetrachloroethylene: inhalation and skin contact.

There is considerable potential for worker exposure to tetrachloroethylene, both by skin contact and by inhalation, during its use in dry cleaning and degreasing operations. This paper reviews accounts of both accidental overexposures of workers and controlled exposures of human subjects by these two routes of exposure. Several reported cases of accidental overexposure to anesthetic doses of the chemical reveal that recovery was generally complete but prolonged, and accompanied by many days of measurable levels of the chemical in the patient's alveolar breath. Chronic overexposures of workmen have lessened since the general acceptance by the Western world of the recommended TLV of 100 ppm for 8 hr of daily exposure. Controlled inhalation studies with volunteer subjects at this level of exposure revealed no effects upon health but did indicate a slight decrement in performance on a coordination test. Additional behavioral and neurological tests revealed no interactive effects when alcohol or diazepam, two depressant drugs, were added singly to tetrachloroethylene exposures. Individual susceptibility to the vapor of this chemical, as evidenced by subjective complaints, was noted in approximately one of ten subjects. The authors conclude that the TLV concentration of 100 ppm in the workplace has a negligible margin of safety regarding unimpaired performance during repeated exposures which could be especially hazardous if the worker is physically active or is in a situation where skin absorption presents an added burden.

Environmental Exposure↗
PubMed1975

Absorption, distribution and excretion of terephthalic acid and dimethyl terephthalate.

Data from a radiotracer study in rabbits and rats to determine the absorption, distribution, and excretion of terephthalic acid (TA) and dimethyl terephthalate (DMT) following oral, intratracheal, dermal and ocular administration indicate the following: (1) a rapid absorption and excretion of 14C-TA and 14C-DMT with no evidence of tissue accumulation in rats following single or repeated oral and intratracheal administration; (2) no evidence of skin irritation in rats after a single or repeated dermal application of 80 mg of 14C-TA or 14C-DMT and no significant skin absorption of 14C-TA; (3) recovery of approximately 11% of a single dose and 13% of five repeated cutaneous doses of 14C-DMT from the urine and feces of rats within 10 days after initial dosing; (4) no significant absorption of 14C-TA when applied to the conjunctival sac of one eye of eight rabbits; (5) excretion of approximately 33% of a single ocular dose (50 mg) of 14C-DMT in the urine and feces of rabbits within 10 days after instillation with no evidence of tissue accumulation or ocular damage. These results suggest that TA and DMT are rapidly absorbed and excreted and that no significant quantities of these compounds accumulate in the tissues following single or repeated oral, intratracheal, dermal, or ocular administration to laboratory animals.

Administration, Oral↗
PubMed1999

The systemic exposure to the polycyclic musks, AHTN and HHCB, under conditions of use as fragrance ingredients: evidence of lack of complete absorption from a skin reservoir.

7-Acetyl-1,1,3,4,4,6-hexamethyl-1,2,3,4-tetrahydronaphthalene (AHTN) and 1,3,4,6,7,8-hexahydro-4,6,6,7,8,8-hexa-methylcyclopenta-gamma-2-be nzopyran (HHCB) are two large volume fragrance ingredients widely used in consumer products. As part of the risk evaluation, the systemic exposures to these materials was determined in rats under occlusion and in humans under simulated conditions of exposure. Ring 14C-labeled AHTN or HHCB were applied dermally in alcoholic solutions to rats at doses of 4.5 mg/kg and occluded for 6 h. Urine, feces and air were collected for up to 120 h and analyzed for radioactivity. Pairs of rats were sacrificed periodically for analysis of tissues and organs. The total amount absorbed was approximately 19% for AHTN and 14% for HHCB. In both cases, significant amounts diffused into the skin, most of which was further absorbed but a significant amount of which was lost to surface dressing by reverse diffusion and/or desquamation. Ring 14C-labeled AHTN or HHCB were applied in alcoholic solutions without occlusion to three male volunteers at concentrations approximating that which might be encountered in a typical cologne type product. After a 6-h period, all material was removed from the surface of the skin. Blood, feces and urine were collected over a 5-day period. For both materials, levels in blood and plasma were below limits of detection at all times. Based on excretion, primarily in the urine, the total absorbed dose was approximately 1 and 0.1% for AHTN and HHCB, respectively. However, over the 5-day period, 14.5% of AHTN and 19.5% of HHCB was recovered from the skin in dressings over the site of application indicating that a 'reservoir' had formed in the skin but the material in the reservoir was lost, by desquamation and/or by reverse absorption, and not available systemically. A mean of 24% (AHTN) and 22% (HHCB) was shown to evaporate under the conditions of exposure.

Animals↗
PubMed1987

Excretion kinetics of the rubber anti-oxidant N-isopropyl-N'-phenyl-p-phenylendiamine (IPPD).

Sixteen rubber vulcanizers using IPPD as anti-oxidant were monitored for the presence of the parent compound in the urine during two consecutive working weeks using HPLC for analysis. At least two components in the excretion kinetics could be demonstrated: a fast one, as end-shift urinary concentrations significantly exceeded before-shift ones, and a less rapid one, as before-shift values at the end of the week significantly differed from those determined at the beginning. A skin absorption experiment was also performed. It demonstrated three components in the excretion kinetics, with apparent half-times of approximately 3, 7 and 24 h. Excretion ceased 7 d after skin exposure.

Adult↗