[Local salicylate transcutaneous absorption: an unrecognized risk of severe intoxication: a case report]. / Application cutanée localisée d'acide salicylique : un risque méconnu d'intoxication : à propos d'un cas.

INTRODUCTION: Although rare, salicylate intoxication through the skin should not be ignored as it can be severely life-threatening. We describe an original case of accidental poisoning with salicylates topically applied to the scalp of a 6-week-old infant. CLINICAL REPORT: A 6-week-old infant, with no prior history, was admitted to the pediatric intensive care unit for treatment of severe disorders of consciousness associated with significant tachypnea. Laboratory results revealed metabolic acidosis with elevated anion gap, ketonuria, and normal glycemia. Initial assessment ruled out the hypothesis of accidental ingestion of salicylates. However, the presence of salicylic acid derivatives in organic acid chromatography, confirmed by plasma salicylate levels at 580 mg/L, ultimately re-established the diagnosis. Further inquiry retrospectively highlighted the prolonged topical application in occlusion (3 days) of an extemporaneous preparation containing 23% salicylic acid on the scalp. The course after urine alkalinization was rapidly favorable without sequelae. COMMENT AND CONCLUSIONS: Salicylate intoxication is potentially lethal, particularly in infants under 12 months of age. The vast majority of these intoxications result from accidental ingestion. The present observation underscores the original and undescribed risk of intoxication due to a localized application to the scalp. In the presence of warning symptoms, salicylate poisoning should be investigated, including topical application of salicylic acid, even if localized. Careful attention should be paid to following the indications of use of this product in terms of concentration, characteristics of the infant, and exposed skin. The use of extended topical application of salicylic acid in concentrations greater than 3% should be avoided.

Pregnancy outcome of women transfused during pregnancy with blood products inadvertently obtained from donors treated with acitretin.

We assessed the pregnancy outcome of nine women inadvertently transfused with acitretin-contaminated blood products in South Korea. A total of 18 women matched to cases by age, gravidity, and singleton- or twin-pregnancy, and who were transfused with blood products not contaminated with acitretin, was also recruited. There were nine babies born in the case group. No differences (p > 0.05) were observed between cases and controls in the gestational age at delivery (38.3 +/- 1.6 weeks vs 37.8 +/- 2.2 weeks), birth weight (3,146 +/- 874 g vs 3,106 +/- 568 g), rate of pre-term deliveries (22.2% vs 11.1%) and rate of low birth weight (<2,500 g) (33.3% vs 16.7%). There was no case of malformation or neurological abnormalities born in either group. In conclusion, inadvertent exposure to acitretin-contaminated blood products was not associated with adverse pregnancy outcomes, probably because of the removal of acitretin and etretinate during the manufacturing process of blood products.

A fully validated HPLC method for the simultaneous determination of acitretin and etretinate in plasma and its application to a pharmacokinetic study in healthy Korean subjects.

OBJECTIVE: Acitretin is used for the treatment of psoriasis. The purpose of this study was to validate an HPLC method for the determination of acitretin and etretinate and to investigate the pharmacokinetic characteristics of acitretin in healthy Korean subjects. MATERIALS AND METHODS: Plasma samples or calibrators were mixed with acetonitrile and retinyl acetate (internal standard). Butanol: acetonitrile (1:1 v/v) and K2HPO4 were added later. After vortexing, 30 microl of the supernatant was injected directly into the analytical column of an HPLC system. The samples were separated by C18 reversed phase HPLC and UV detection was performed at 350 nm. Various assay performances were evaluated. RESULTS: The linearity of acitretin and etretinate was adequate up to 500 ng/ml (R2 = 0.9937 for acitretin and R2 = 0.9923 for etretinate). The accuracy was 89.5 - 113.5% and the precision was satisfactory (within-run CV, 4.4 - 15.8%; between-run CV, 3.3 - 17.4%). The LLOQ was 2 ng/ml and the stability and specificity were satisfactory. However, after storage at room temperature for 24 h under light exposure, the concentrations of acitretin and etretinate decreased by 26.0 - 66.5%. Extraction recovery was 75.1 - 91.5%. Nine healthy Korean subjects were evaluated to study the pharmacokinetics of acitretin. A single oral dose of 30 mg acitretin (Neotigason, Roche Pharmaceuticals) was given to all volunteers. The mean +/- SD pharmacokinetics of acitretin in Koreans were as follows: Cmax 148.7 +/- 93.0 ng/ml, tmax 3.2 +/- 1.3 h, t1/2 81.2 +/- 26.5 h, and AUClast 2641.9 +/- 1274.8 ng h/ml. CONCLUSION: A simple HPLC method for the simultaneous determination of acitretin and etretinate was validated, and the pharmacokinetic characteristics of acitretin in the Korean population were investigated.

Feasibility of retinoids for the treatment of emphysema study.

BACKGROUND: Retinoids promote alveolar septation in the developing lung and stimulate alveolar repair in some animal models of emphysema. METHODS: One hundred forty-eight subjects with moderate-to-severe COPD and a primary component of emphysema, defined by diffusing capacity of the lung for carbon monoxide (Dlco) [37.1 +/- 12.0% of predicted] and CT density mask (38.5 +/- 12.8% of voxels <- 910 Hounsfield units) [mean +/- SD] were enrolled into a randomized, double-blind, feasibility study at five university hospitals. Participants received all-trans retinoic acid (ATRA) at either a low dose (LD) [1 mg/kg/d] or high dose (HD) [2 mg/kg/d], 13-cis retinoic acid (13-cRA) [1 mg/kg/d], or placebo for 6 months followed by a 3-month crossover period. RESULTS: No treatment was associated with an overall improvement in pulmonary function, CT density mask score, or health-related quality of life (QOL) at the end of 6 months. However, time-dependent changes in Dlco (initial decrease with delayed recovery) and St. George Respiratory Questionnaire (delayed improvement) were observed in the HD-ATRA cohort and correlated with plasma drug levels. In addition, 5 of 25 participants in the HD-ATRA group had delayed improvements in their CT scores that also related to ATRA levels. Retinoid-related side effects were common but generally mild. CONCLUSIONS: No definitive clinical benefits related to the administration of retinoids were observed in this feasibility study. However, time- and dose-dependent changes in Dlco, CT density mask score, and health-related QOL were observed in subjects treated with ATRA, suggesting the possibility of exposure-related biological activity that warrants further investigation.

Temporal variation and identification of factors associated with endogenous retinoic acid isomers in serum from Brazilian women.

OBJECTIVE: Retinoids (natural and synthetic derivatives of vitamin A) have cancer chemotherapeutic and chemopreventive activities. Retinoic acid (RA) treatment has been associated with significant regression of preneoplastic lesions. However, serious toxicity associated with some therapies has made long-term chemoprevention in healthy populations unfeasible. Recently, serum RA has been shown to increase in response to oral retinol (vitamin A) supplementation. Here, we assess the variability of circulating RA levels and the lifestyle, demographic, and nutritional factors that explain such variability. METHOD: Total RA concentration and the concentrations of RA isomers (all-trans-RA, 13-cis-RA, and 9-cis-RA) were measured by high-pressure liquid chromatography in serum samples obtained 4 months apart from 502 women participating in the Ludwig-McGill Cohort (Sao Paulo, Brazil). RESULTS: The relative abundance of the three RA isomers was similar for each visit (baseline and month 4), with 13-cis-RA having the highest concentrations followed by 9-cis-RA and all-trans-RA. The within-person variability of total RA and individual isomers was low. Using multivariate logistic regression models (upper tertile versus low/middle tertile of serum RA), we found that age, race, oral contraceptive use, total number of pregnancies, and season of initial blood draw were significantly associated with at least one endogenous RA isomer level. All endogenous RA isomers were positively associated with serum retinol, beta-carotene, and beta-cryptoxanthin levels. CONCLUSION: These results have implications for the design of future epidemiologic studies focused on assessing RA-disease association and intervention studies aimed at modulating RA levels.

Ethylene glycol developmental toxicity: unraveling the roles of glycolic acid and metabolic acidosis.

This study sought to determine the relative roles of glycolic acid (GA), a toxicologically important metabolite of ethylene glycol (EG), and metabolic acidosis in causing developmental toxicity in Sprague-Dawley rats. To tease apart these two interrelated factors, we developed an experimental approach in which high blood glycolate levels could be achieved, in either the presence or absence of metabolic acidosis. Initially, rats previously implanted with a carotid artery cannula were given, on gestation day (gd) 10, 40.3 mmol/kg (2500 mg/kg) of EG via gavage, 8.5 mmol/kg (650 mg/kg) of GA via gavage, 8.5 mmol/kg (833 mg/kg) of sodium glycolate (NaG; pH 7.4) via subcutaneous (sc) injection, or distilled water via gavage (control). Peak serum glycolate was nearly identical (8.4-8.8 mM) in the EG, GA, and NaG groups and, as expected, EG and GA caused a metabolic acidosis, but acid base balance was normal with NaG. Subsequently, these treatments were given on gd 6-15 to groups of 25 time-mated rats, followed by fetal evaluation on gd 21. EG and GA decreased fetal body weights and caused a similar spectrum of developmental effects, including numerous axial skeleton malformations. NaG treatment also caused slight decreases in fetal body weight, increases in skeletal variations, and totally malformed fetuses. These results indicate that glycolate, in the absence of metabolic acidosis, can cause the most sensitive of EG's developmental effects, whereas metabolic acidosis appears to interact with glycolate at very high doses to markedly enhance teratogenesis. These results support previous studies, which indicated that glycolate is the proximate developmental toxicant for EG, and that GA toxicokinetic parameters can be used to define a quantitative, physiologically based threshold for EG-induced developmental effects.

Fomepizole for the treatment of ethylene glycol poisoning. Methylpyrazole for Toxic Alcohols Study Group.

BACKGROUND: Ethylene glycol poisoning causes metabolic acidosis and renal failure and may cause death. The standard treatment is inhibition of alcohol dehydrogenase with ethanol, given in intoxicating doses, and adjunctive hemodialysis. We studied the efficacy of fomepizole, a new inhibitor of alcohol dehydrogenase, in the treatment of ethylene glycol poisoning. METHODS: We administered intravenous fomepizole to 19 patients with ethylene glycol poisoning (plasma ethylene glycol concentration, > or =20 mg per deciliter [3.2 mmol per liter]). Patients who met specific criteria also underwent hemodialysis. Treatment was continued until plasma ethylene glycol concentrations were less than 20 mg per deciliter. Acid-base status, renal function, the kinetics of fomepizole, and ethylene glycol metabolism were assessed at predetermined intervals. RESULTS: Fifteen of the patients initially had acidosis (mean serum bicarbonate concentration, 12.9 mmol per liter). Acid-base status tended to normalize within hours after the initiation of treatment with fomepizole. One patient with extreme acidosis died. In nine patients, renal function decreased during therapy; at enrollment, all nine had high serum creatinine concentrations and markedly elevated plasma glycolate concentrations (> or =97.7 mg per deciliter [12.9 mmol per liter]). None of the 10 patients with normal serum creatinine concentrations at enrollment had renal injury during treatment; all 10 had plasma glycolate concentrations at or below 76.8 mg per deciliter (10.1 mmol per liter). Renal injury was independent of the initial plasma ethylene glycol concentration. The plasma concentration of glycolate and the urinary excretion of oxalate, the major metabolites of ethylene glycol, uniformly fell after the initiation of fomepizole therapy. Few adverse effects were attributable to fomepizole. CONCLUSIONS: In patients with ethylene glycol poisoning, fomepizole administered early in the course of intoxication prevents renal injury by inhibiting the formation of toxic metabolites.

Percutaneous absorption of salicylic acid in man after topical administration of three different formulations.

OBJECTIVE: To determine the amount of drug which is absorbed during 1 day following topical application of three different preparations containing salicylic acid. METHODS: Ten grams of the formulations, either (a) Kerasaltrade mark 5% ointment, (b) salicylic acid 5% or (c) 10% in petrolatum, were administered consecutively to a 600-cm2 area on alternating sides of the back of healthy volunteers (n = 9). Thirty minutes after application, a skin area of 2.54 cm2 was stripped with D-Squametrade mark adhesive disks to determine the amount of salicylic acid in the stratum corneum. The entire application site was then covered by a thin gauze bandage and was not washed for the next 24 h. Urine was collected for 26 h following administration, hydrolyzed and assayed by HPLC analysis. RESULTS: The absolute amounts absorbed and excreted were 52.6 +/- 29.4 mg (mean +/- SD), 127.1 +/- 43.9 mg and 208.0 +/- 81.7 mg, and the doses absorbed in relation to the doses applied (500 mg salicylic acid in case of formulations a and b and 1,000 mg for formulation c) were 9.3 +/- 3.8, 25.1 +/- 8.5 and 20.2 +/- 7.7%, respectively. The amounts of salicylic acid in the skin 30 min after application were 36.3 +/- 16.5, 18.2 +/- 11.9 and 31.3 +/- 15.4 microg/ cm2 as determined by the tape stripping procedure. CONCLUSIONS: Significant differences in the doses absorbed were detected between the two formulations a and b (same concentration) with different vehicles (p value < 0.001) as well as between b and c (same vehicle) with different concentrations (p value = 0.018) using Student's paired t test. These results demonstrate that salicylic acid is well absorbed by healthy skin.

Transdermal absorption of clindamycin and tretinoin from topically applied anti-acne formulations in man.

The percutaneous absorption of clindamycin was studied in healthy male volunteers, comparing two investigative clindamycin (% w/v)/tretinoin (0.025% w/v) gels, containing clindamycin phosphate ester and clindamycin HCl, respectively, relative to a clindamycin phosphate lotion (1% clindamycin; Dalacin T). Formulations were applied daily for 5 days on the face, according to a balanced complete block design. Redness of the skin was scored visually, and blood and urine were collected. Clindamycin plasma levels did not exceed the limit of quantification (5 ng mL(-1)) with the clindamycin phosphate formulations, but one volunteer who received the clindamycin HCl/tretinoin gel showed plasma levels of up to 13 ng mL(-1). Clindamycin urinary excretion for 12 h after application of the clindamycin phosphate/tretinoin gel was comparable to the values of the reference lotion, whereas the clindamycin HCl/tretinoin gel gave significantly higher values. Erythema appeared to be associated with increased urinary excretion. The formulations were tolerated well. In a separate clinical pilot study in acne patients, the transdermal uptake of tretinoin and clindamycin from the clindamycin phosphate/tretinoin gel was monitored. Plasma samples were collected after 4 and 12 weeks of daily treatment. None of the study plasma samples contained measurable tretinoin levels. Clindamycin levels were not quantifiable in the majority (87%) of samples, the highest plasma level was 11 ng mL(-1). The chemical form of clindamycin proved to modulate skin irritation and percutaneous uptake of clindamycin from a gel formulation in healthy subjects. There was no indications for a notable transdermal uptake of tretinoin during daily application of the gel in patients, nor for an enhancing effect of tretinoin on clindamycin uptake.

Use of the deconvolution principle in the estimation of absorption and pre-systemic intestinal elimination of drugs.

The deconvolution principle was used to evaluate the extent of absorption and first-pass elimination of selected drugs. In the first example, deconvolution of the portal blood profiles of etretinate (ET, a synthetic retinoid) indicated that there was significant gut-wall conversion of ET to acitretin (ETA, the primary metabolite of ET) during a 60-min intestinal perfusion of ET. In the second example, deconvolution was used to confirm that the extent of carbovir disappearing from the gastrointestinal lumen was matched by the extent of carbovir appearance in the portal blood. Thus, deconvolution has several important applications in the study of absorption and intestinal first-pass metabolism.

Simultaneous determination of all-trans-, 13-cis-, 9-cis-retinoic acid and their 4-oxo-metabolites in plasma by high-performance liquid chromatography.

A gradient reversed-phase high-performance liquid chromatographic technique is described for the easy separation and quantification of some retinoids; all-trans-retinoic acid, 13-cis-retinoic acid, 9-cis-retinoic acid and their corresponding 4-oxometabolites, in plasma. The method involved a diethyl ether-ethyl acetate (50:50, v/v) mixture extraction at pH 7 with acitretin and 13-cis-acitretin as internal standards. A Nova-Pak C18 steel cartridge column was used. The mobile phase was methanol-acetonitrile (65:35, v/v) and 5% tetrahydrofuran (solvent A) and 2% aqueous acetic acid (solvent B) at 1 ml/min. The gradient composition was (only the percentages of solvent B are mentioned): I, 25% solvent B at the time of injection; II, 12% solvent B at 11 min until min; III, 25% solvent B and maintenance of 25% solvent B for 10 min until a new injection. Total time between injections was 40 min. Detection was by absorbance at 350 nm. The precision calculated for plasma concentrations ranging from 2 to 250 ng/ml was better than 15% and the accuracy was less than 12%. The linearity of the method was in the range of 2 to 400 ng/ml of plasma. The limit of quantification was 2 ng/ml for each of the compounds. The HPLC method was applied to plasma specimens collected from animals receiving single dose administrations of all-trans-retinoic acid, 13-cis-retinoic acid and 9-cis-retinoic acid.

Oxidative and reductive metabolism of 9-cis-retinoic acid in the rat. Identification of 13,14-dihydro-9-cis-retinoic acid and its taurine conjugate.

9-cis-Retinoic acid (9-cis-RA), a hormone that binds and activates all known retinoid receptor subtypes, is structurally similar to all-trans-retinoic acid and may share common metabolic fates. Both oral and intravenous doses of 9-cis-RA to rats led to hydroxylation and ketone formation at carbon-4. 9-Cis-RA also isomerized in vivo to 13-cis-retinoic acid, 9-cis, 13-cis-retinoic acid, and all-trans-retinoic acid. After administration of [11-3H]9-cis-RA, the proportion of plasma radioactivity that was volatile increased over time, which suggested that beta-oxidative chain-shortening of 9-cis-RA might occur. An equimolar mixture of [1-13C2H3]9-cis-RA and 9-cis-RA was administered to rats for stable-isotope-labeled metabolite production. A chromatographic peak that had a lambdamax = 290 nm vs. 348 nm for the parent compound, had a retention time similar to the parent, and yielded a 1:1 positive-ion isotope cluster at m/z 303/307 in its mass spectrum. NMR analysis revealed 9-cis and 13,14-dihydro configurations, indicating that 9-cis-RA can be metabolized in rat by reduction to 13,14-dihydro-9-cis-RA. An earlier-eluting HPLC peak that exhibited a lambdamax at 290 nm, and a negative-ion-MS isotope cluster at m/z 408/412 was observed during separations of rat liver extracts. LC/MS/MS analysis revealed product ions for this peak diagnostic for carboxylic acid taurine conjugates. In rats, reduction of 9-cis-RA to 13,14-dihydro-9-cis-RA may represent an initial step leading to beta-oxidation, although available data demonstrate it is conjugated with taurine to form a novel metabolite.

Pharmacokinetic studies of 13-cis-retinoic acid in pediatric patients with neuroblastoma following bone marrow transplantation.

A phase I clinical trial of 13-cis-retinoic acid (cis-RA) was undertaken to determine the maximally tolerated dose (MTD) and pharmacokinetics (PK) of cis-RA following bone marrow transplantation (BMT) in children with high-risk neuroblastoma. Mean peak serum levels of cis-RA in 31 pediatric patients ranged from 4.9 to 8.9 microM following doses of 100-200 mg/m2 per day, divided into two doses every 12 h administered orally. The PK of cis-RA obeyed a single-compartment model following first-order absorption in the majority of patients. A linear increase in the mean peak serum levels and area under the time-concentration curve (AUC) with increasing dose was observed. The average half-lives of absorption and elimination were 1.0 and 5.8 h, respectively. At the MTD of 160 mg/m2 per day, the mean cis-RA peak serum concentration was 7.2 +/- 5.3 microM. AUC values were not altered significantly during a 2-week course of treatment or over a long period of multiple courses. Levels of trans-retinoic acid, a metabolite of cis-RA, remained low but were similar on days 1 and 14, whereas the 4-oxo-13-cis-RA metabolite had increased in 64% of patients by day 14. Peak serum cis-RA concentrations correlated with clinical toxicity as grade 3 to 4 toxicity was seen in 44% of patient-courses (8/18) with peak serum levels > 10 microM, but only 13% (12/96) with peak serum levels < 10 microM. These results show that cis-RA given at 160 mg/m2 to children achieved serum concentrations known to be effective against neuroblastoma in vitro, and the PK for cis-RA differs from that reported for trans-retinoic acid in children.

Podophyllotoxin in serum: absorption subsequent to three-day repeated applications of a 0.5% ethanolic preparation on condylomata acuminata.

High-performance liquid chromatography was used for quantitative determination of podophyllotoxin in serum subsequent to repeated applications of a 0.5% ethanolic preparation on condylomata acuminata. The drug was not detectable in the serum of ten men treated with < or = 50 microliters. In serum of seven patients receiving 100-1,500 microliters on extraordinarily large en-plaque lesions, peak levels of 1-17 ng/ml were measured within 1-2 hr. The drug did not accumulate in serum. Dispersion of 100 microliters gave rise to peak levels of < or = 5.0 ng/ml and to subsequent levels of < or = 3.0 ng/ml for 4 hr. Larger doses gave rise to traceable amounts in serum for < or = 12 hr. Investigations with 52 patients indicated that volumes of > 100 microliters are rarely required for topical treatment of condylomata. It is concluded that application of volumes of < or = 250 microliters twice daily for three days would satisfy the most stringent safety precautions and avoid any danger of systemic toxicity. Potential hazards associated with use of the nonstandardized 20% podophyllin preparations are emphasized.