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PubMed2005

Use of menopausal hormones in the United States, 1992 through June, 2003.

PURPOSE: The Women's Health Initiative (WHI) study that documented an unfavorable benefit to risk ratio of Prempro and subsequently an increased risk of stroke with menopausal estrogen prompted us to investigate the use during 1992 through June 2003 of menopausal hormones in the United States. METHODS: Two pharmaceutical research databases from IMS Health, the National Prescription Audit Plus and the National Disease and Therapeutic Index, were accessed and analyzed. RESULTS: The number of dispensed outpatient prescriptions for oral menopausal estrogens and oral combination estrogen-progestins increased 2.5-fold (153%) from 34.5 million dispensed in 1992 to a high of 87.3 million in 2000. For July 2002 through June 2003, the year following the publication of the results of the WHI trial, prescriptions for these products declined to 59.6 million, a 32% decrease from their peak in 2000. Prescriptions for transdermal estrogen and transdermal combination estrogen-progestin products increased from 5.2 million dispensed in 1992 to their peak of 8.3 million in 2000, and declined 10% to 7.5 million during July 2002 through June 2003. By contrast, prescriptions for oral menopausal progestins rose to 17.5 million in 1995 and then steadily declined. In the year after the WHI, prescriptions for oral progestins decreased 49% to 8.9 million from their peak in 1995. The earlier decline in oral progestin prescriptions was primarily due to the marketing in 1995 of the popular oral combination estrogen-progestin drugs. CONCLUSIONS: Prescriptions dispensed for menopausal hormones increased substantially between 1992 and peaked in 2000. By June 2003, prescriptions for oral menopausal estrogens and oral combination estrogen-progestins had declined by about one-third from their peak year.

Administration, Cutaneous↗
PubMed1994

Extending a Bayesian analysis of the two-period crossover to allow for baseline measurements.

In the context of a two-period crossover study with baseline measurements a graphical method is developed for displaying the dependence of posterior inferences concerning the treatment effect on unavoidable prior beliefs about the 'correct' model. The method is a generalization of the approach developed by Grieve for the corresponding case without baselines.

Administration, Cutaneous↗
PubMed1998

Comparisons of acute toxicity of selected chemicals to rainbow trout and rats.

Median lethal concentration (LC50) and dose (LD50) for 217 chemicals were compared over several exposure routes in rainbow trout and rats. Data were compiled primarily from on-line databases and included octanol-water partition coefficient (Kow), trout LC50, and trout and rat LD50 for oral, dermal, and intraperitoneal (i.p.) routes. Kow and molar lethality data were log-transformed for correlation and regression analyses. Median ratios (rat oral LD50/trout LC50 = 156, rat/trout oral LD50 = 0.80, rat/trout dermal LD50 = 0.43, rat/trout i.p. LD50 = 0.55) demonstrated the effect of similar versus dissimilar exposure routes on lethality, reflecting toxicokinetic differences. Simple linear regressions revealed significant correlations (Bonferroni P < 0.05) for trout LC50 versus rat oral LD50 and for trout LD50 versus rat LD50 when matched on exposure route. When Kow was included with multiple regression to consider the effect of hydrophilic/lipophilic partitioning on uptake and toxicity, correlations improved only for trout LC50 versus rat oral LD50 and for trout i.p. LD50 versus rat i.p. LD50. Stratification of data into pesticides and nonpesticides failed to refine prediction of trout LC50 from rat oral LD50. Simple regressions reported here and in the literature relating fish LC50 and rat oral LD50 exhibited varying degrees of correlation (r = 0.26-0.99), reflecting differences in interspecies sensitivity, chemical group evaluated, and experimental methodologies.

Administration, Cutaneous↗
PubMed2000

A simple and rapid evaluation of methemoglobin toxicity of 8-aminoquinolines and related compounds.

Methemoglobin, a toxic ferric form of hemoglobin, is continuously formed in normal erythrocytes, but during abnormal situations in situ, the level is enhanced. 8-Amino-quinolines and related compounds are causative agents for methemoglobin formation. Employing oxyhemoglobin, methemoglobin toxicity was about six times higher with primaquine compared to CDRI Compound 80/53 at 10(-9) M concentration. Methemoglobin reductase activity was also completely inhibited by primaquine, whereas 24% inhibition was noted in the case of 80/53 at the same concentrations. Mastomys, a rodent animal model, was found to be equally good for comparative evaluation of methemoglobin toxicity. Further, with the use of primaquine transdermal tape on the Mastomys model, a rise in methemoglobin occurred with increase in time. In conclusion, the study presents simple, economical, less time-consuming methods for the evaluation of methemoglobin toxicity, in vitro and in vivo, without employing the conventional Beagle dog model.

Administration, Cutaneous↗
PubMed1993

Physiologically based modeling of 2-butoxyethanol disposition in rats following different routes of exposure.

2-Butoxyethanol (BE) is widely used as a solvent in coatings and other consumer products and has shown hematotoxicity in laboratory animals. To provide a physiological basis for extrapolating toxicokinetic data observed in rats to humans, a blood flow rate-limited, physiologically based pharmacokinetic model was developed to describe the distribution and metabolism of BE in rats following drinking water, dermal, and inhalation exposures. The major urinary metabolite, butoxyacetic acid, represented 45 to 60% of the absorbed dose in all three routes of exposure. Other identified urinary metabolites in our studies included ethylene glycol and BE-glucuronide. A model formulation of the possible metabolic pathways based on the experimental data was proposed. The amounts of individual urinary metabolites were used to develop the model. Metabolic constants were estimated by fitting the data within the constraints of in vitro measurements. The model explained the change of profiles of urinary metabolites in different exposure routes by taking into account the differences in absorption rate and by incorporating a minor pathway for metabolism by skin. Sensitivity analysis showed that metabolic constants and blood flow rate to liver had a relatively larger influence on the production of urinary metabolites than the organ volume or the partition coefficient for BE.

Administration, Cutaneous↗
PubMed1997

The effects of betamethasone derivatives on endotoxin-induced uveitis in rats.

The anti-inflammatory effects of betamethasone and its derivatives (betamethasone 21-phosphate, betamethasone 21-acetate, betamethasone 17-valerate, clobetasol 17-propionate and betamethasone dipropionate) on endotoxin-induced uveitis (EIU) in rats was investigated. Among the compounds examined, betamethasone, betamethasone 21-phosphate, betamethasone 21-acetate and clobetasol 17-propionate strongly inhibited cell infiltration into the aqueous humor in the EIU by instillation into the eye in a dose-dependent manner (0.01-1.0%) and by systemic administration (1 mg kg-1). On the other hand, betamethasone 17-valerate and betamethasone dipropionate showed only weak inhibitory effects or enhancement of cell infiltration by instillation into the eye (0.01-1.0%) and by systemic administration (1 mg kg-1). Combined systemic administration of betamethasone dipropionate and betamethasone reduced the inhibitory effect of betamethasone on cell infiltration and gene expression of IL-1 beta. In an in vitro interleukin-8 (IL-8) release assay, betamethasone showed stronger inhibition of the IL-8 release from rat peritoneal exudate cells (PEC) than betamethasone dipropionate, and simultaneous addition of betamethasone dipropionate with betamethasone reduced the inhibitory effect of the latter. These results suggest that the betamethasone derivative betamethasone dipropionate might behave as an anti-glucocorticoid in rats.

Administration, Cutaneous↗
PubMed1993

Effects of dose and routes of exposure on the disposition of 2,3,7,8-[3H]tetrabromodibenzo-p-dioxin (TBDD) in the rat.

Polybrominated dibenzo-p-dioxins and dibenzofurans are of major concern because of potential occupational and environmental exposures and their structural similarity to the highly toxic chlorinated analogues. 2,3,7,8-Tetrabromodibenzo-p-dioxin (TBDD) is a closely related analogue in both structure and activity to the most toxic isomer 2,3,7,8-tetrachlorodibenzo-p-dioxin. The objectives of this study were to characterize the effects of dose and routes on absorption, excretion, and terminal tissue distribution of [3H]TBDD in the rat 72 hr after dosing. Rats were treated orally by gavage with 1, 10, 100, or 500 nmol/kg, intratracheally with 1 nmol/kg, or dermally with 1 nmol/kg (200 pmol/1.8 cm2). TBDD exhibited nonlinear oral absorption kinetics with maximum absorption (approximately 80%) occurring at dose < or = 10 nmol/kg, similar to the transpulmonary absorption. In contrast, dermal absorption of TBDD was low (approximately 12%). The major tissue depots of radioactivity were liver, adipose tissue, and skin. Tissue distribution of the oral dose was dose-dependent, with disproportionally greater hepatic concentrations occurring at absorbed doses of > 8 nmol/kg. Liver:adipose tissue (L:F) concentration ratios were 2.9 to 6.6 (lowest to highest oral dose, respectively). The lower L:F ratios observed for the dermal and intratracheal doses at 1 nmol/kg (1.5 and 2, respectively) were likely due to differences in absorbed dose and dose-related tissue distribution. Elimination of radioactivity in feces, the major route of excretion for all dose groups and routes, and urine was also nonlinear with respect to the oral dose. The results of the present study provide important considerations for high- to low-dose and route-to-route extrapolations with TBDD and other dioxins and furans in human risk assessments.

Administration, Cutaneous↗
PubMed1994

Physiologically based pharmacokinetics of 2-butoxyethanol and its major metabolite, 2-butoxyacetic acid, in rats and humans.

A physiologically based pharmacokinetic model was developed to describe the disposition of 2-butoxyethanol (CAS 111-76-2) and its major metabolite, 2-butoxyacetic acid, in rats and humans. A previous human inhalation model by Johanson (Toxicol. Lett. 34, 23 (1986)) was expanded to include additional routes of exposure, physiological descriptions for rats, competing pathways for metabolism of 2-butoxyethanol, and measured partition coefficients for 2-butoxyethanol and 2-butoxyacetic acid. Simulations were compared to data gathered from rats following either intravenous infusion or oral or inhalation exposure and from humans following either inhalation or dermal exposure to 2-butoxyethanol. It was necessary to add equations for both protein binding of 2-butoxyacetic acid in blood and saturable elimination of 2-butoxyacetic acid by the kidneys to consistently describe the data. While the model predicted that rats metabolize 2-butoxyethanol and eliminate the acid metabolite faster per kilogram body weight than humans, the balance of these two processes in addition to physiological differences between species resulted in higher predicted peak blood concentrations as well as total areas under the blood concentration time curves for 2-butoxyacetic acid for rats versus humans. These species differences in kinetics coupled with the fact that human blood is significantly less susceptible than rat blood to the hemolytic effects of 2-butoxyacetic acid indicate that there is considerably less risk for hemolysis in humans as a result of exposure to 2-butoxyethanol than would have been predicted solely from standard toxicity studies with rats.

Administration, Cutaneous↗
PubMed1996

Comparison of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) disposition following pulmonary, oral, dermal, and parenteral exposures to rats.

In evaluating human health risks posed by dioxins, it is necessary to accurately predict systematic dosimetry or the fate of these chemicals. Pharmacokinetic parameters pertaining to inhalation, ingestion, and dermal absorption may be estimated using animal models. The present study was designed to assess absorption, tissue distribution, and elimination of TCDD following intratracheal instillation (itr.), oral gavage (p.o.), or intravenous administration (i.v.) of 1 nmol [3H]TCDD/kg to male rats; experimental conditions were chosen to permit comparison to a previous dermal disposition study (Banks and Birnbaum, Toxicol. Appl. Pharmacol. 107, 302-310, 1991). After treatment, rats were housed in individual metabolism cages for 3 days with daily excreta collection. Following termination, radioactivity was quantified in tissues and excreta. By 3 days postexposure, fecal excretion accounted for 22 (i.v.), 26 (itr.), and 32% (p.o.) of dose, while urinary excretion was only 2.2 (i.v.), 1.3 (itr), and 1.4% (p.o.). Pulmonary absorption was calculated as 95% of administered dose, while oral absorption was 88%. Dermal absorption of an equivalent administered dose was 40% (Banks and Birnbaum, 1991). For all exposure routes by 3 days, major tissue depots for absorbed dose were liver and fat. Distribution of absorbed dose was 37% (i.v.) and 35% (itr.) to liver and 21% (i.v.) and 16% (itr.) to fat. Oral gavage-treated rats had similar dosimetry (28-30% absorbed dose) in both liver and fat. In contrast following dermal exposure, distribution to liver and fat was 52 and 22%, respectively (Banks and Birnbaum, 1991). Results suggest that inhalation can be an important route for systemic absorption of dioxins. Moreover, all environmentally relevant routes of exposure (oral, dermal, and respiration) must be uniquely considered as important routes of systemic exposure for TCDD and related compounds.

Adipose Tissue↗
PubMed1999

Biotransformation and toxicokinetics of musk xylene in humans.

Musk xylene (1-tert-butyl-3,5-dimethyl-2,4,6-trinitrobenzene, MX) is widely used as a fragrance ingredient in detergents and toiletries and is an environmental contaminant. High concentrations of MX have been found in fish, and humans are constantly exposed to MX as a result of its stability in the environment. We investigated the biotransformation and toxicokinetics of MX in humans. A single dose of 0.3 mg/kg body wt of 15N-labeled MX (15N-MX) was given to six volunteers (three male and three female) by the oral route and to another six volunteers (three males and three females) by the dermal route. Urine was collected for 96 h after exposure. Blood samples were taken at intervals for up to 140 days after administration. The metabolite 1-tert-butyl-3,5-dimethyl-15N-4-amino-2,6-dinitrobenzene in urine and 15N-MX in plasma were quantified by gas chromatography/electron-capture mass spectrometry (GC-MS/NCI). Peak plasma concentrations of 15N-MX after oral administration were 36-262 and 1.6-5.5 ng/ml plasma after dermal administration. The toxicokinetics of 15N-MX in plasma can be described by a two-compartment kinetic model with an initial rapid decrease, due to the distribution from the blood into a second compartment (likely fat tissue) and a terminal elimination phase with an average half-life of 70 days for both routes of administration. The amount of 1-tert-butyl-3,5-dimethyl-15N-4-amino-2,6-dinitrobenzene (15N-4-A-MX) in recovered urine represented 0.1-0.5% of the oral applied dose of 15N-MX, respectively, 0.02-0.16% of dermal dose. After a short time of invasion the concentrations of 15N-4-A-MX in urine reached a maximum 18-24 h after administration. The further elimination of the metabolite occurred by first-order kinetics with an average elimination half-life of 11.8 h. After the single oral or dermal dose of 15N-MX, 15N-4-A-MX was not detected in hemoglobin. However, hemoglobin samples contained 1-tert-butyl-3, 5-dimethyl-4-amino-2,6-dinitrobenzene (4-A-MX) (11.4-18.9 fmol/mg Hb), likely derived from chronic environmental exposures.

Administration, Cutaneous↗
PubMed2000

Percutaneous penetration and metabolism of 2-nitro-p-phenylenediamine in human and fuzzy rat skin.

2-Nitro-p-phenylenediamine (2NPPD) is a dye used in semipermanent and permanent (tinting color) hair dye formulations. National Toxicology Program toxicology and carcinogenesis testing of 2NPPD has raised concerns about its safety. Therefore, we initiated in vitro studies to measure absorption and metabolism of 2NPPD in human and fuzzy rat skin and rat jejunal tissue. Intestinal tissue metabolism of 2NPPD was compared to skin metabolism since toxicology data from oral 2NPPD studies will be used for future safety assessment purposes. Absorption was measured over 24 h by using flow-through diffusion cells with a receptor fluid consisting of Hepes-buffered Hank's balanced salt solution. Dosing vehicles were applied to skin and intestine in the diffusion cells for 30 min. 2NPPD metabolites were determined by high-performance liquid chromatography methodology. In human skin, the percentages of total applied dose absorbed (receptor fluid + skin) over 24 h were 9.2 +/- 5.7 (mean +/- SD) and 9.5 +/- 3.2 for the ethanol and semipermanent vehicles, respectively, with approximately 3% remaining in skin. In rat skin, the percentages of total applied dose absorbed over 24 h were 9.3 +/- 1.2 (mean +/- SE), 6.9 +/- 1.2, and 4.2 +/- 0.1 for the ethanol, semipermanent, and permanent formulation vehicles, respectively, with approximately 3% remaining in skin. In rat intestinal tissue, the percentage of total applied dose absorbed over 24 h was 10.9 +/- 1.2, with approximately 5% remaining in the tissue. In human and rat skin, 2NPPD was metabolized to triaminobenzene and N4-acetyl-2NPPD. 2NPPD was also metabolized to a sulfated 2NPPD metabolite in rat skin, but not in human skin. 2NPPD was extensively metabolized in both human and rat skin with ethanol application; metabolism was not as extensive with a semipermanent formulation application. In rat intestinal tissue, 62% of 2NPPD was metabolized upon absorption to triaminobenzene and N4-acetyl-2NPPD. Differences in the metabolic profiles (proportion of each metabolite formed) were found between the skin and intestinal tissue. These results suggest that 2NPPD is rapidly absorbed and extensively metabolized in both skin and intestinal tissue. The extent of metabolism and the metabolic profile were found to be species-, tissue-, and dosing vehicle-dependent. Metabolism information will be useful in predicting the extent of 2NPPD and/or 2NPPD metabolite systemic absorption relative to a dermal exposure, which will improve the health hazard assessment of 2NPPD.

Administration, Cutaneous↗
PubMed1996

Intermittent or continuous transdermal nitroglycerin: still an issue, or is the case closed?

After a decade of controversy and debate, many experts have now concluded that continuous nitroglycerin patch treatment leads to complete tolerance development and therefore cannot be recommended for any angina patient. This conclusion is largely based on the disappointing results of the large Transdermal Nitroglycerin Cooperative Study, in which continuous patch treatment in doses of 15-105 mg daily failed to increase exercise duration more than placebo after 2 and 8 weeks of treatment. However, other well-designed studies recently reported maintained efficacy during continuous treatment, and the differences in results has remained unexplained. The disagreeing data may be better understood if certain facts are considered: (1) The cooperative study tested a patient population with a very low first-dose treatment response--only 34 seconds (or 10-12%) improvement compared with placebo. At the end of the study, 25% of the patients terminated exercise for reasons other than angina, and a reduced nitrate responsiveness had developed, even in the placebo group. (2) Patients who demonstrate a large first-dose nitrate responsiveness tend to be less susceptible to tolerance development. (3) Even during continuous therapy, maintained efficacy is often observed in exercise tests done 2-5 hours after patch renewal, while typically no effect is seen at the end of the application period. Attenuation of the initial effects is seen with all long-acting nitrate treatment regimens, but the degree of tolerance varies with the patient population, the efficacy parameter (exercise test vs. attack counts), the timing of the efficacy test, the patch dose, and whether or not nitrate-free (-low) intervals are used. In general, intermittent patch therapy is superior to continuous therapy in improving exercise duration, but even continuous therapy may retain some effect. Rebound phenomena do occur but are clinically relevant only in a minority of the patients. Rebound phenomena are not a problem during continuous therapy, which therefore may be of value in patients with frequent and/or nocturnal angina attacks. Patients experiencing angina during exercise only and with low first-dose effects are likely to benefit more from intermittent therapy. Doses of 0.6-0.8 mg/hr (15-20 mg/24 hr) are usually optimal, and the efficacy is comparable with that observed after oral nitrates.

Administration, Cutaneous↗
PubMed1990

Transdermal administration of the dopamine agonist N-0437 and seven ester prodrugs: comparison with oral administration in the 6-OHDA turning model.

The potent and selective D2-agonist N-0437 [2-(N-propyl-N-2-thienylethylamino)-5-hydroxytetralin] undergoes considerable first-pass metabolism after oral administration due to glucuronidation of the phenolic group. In an attempt to improve its bioavailability, seven ester prodrugs of N-0437 were synthesized, i.e. the acetyl-, propionyl-, isobutyryl-, pivaloyl-, 2-amino-phenyl-, 2-methoxy-phenyl- and 2,4-dimethylphenyl-analogues. In vivo activities were assessed by measuring contralateral turning after transdermal administration of N-0437 and its prodrugs to rats with unilateral 6-OHDA lesions of the nigrostriatal pathway. From time-effect curves the area under the curve for separate time intervals was taken as a measure of dopaminergic activity during that interval. It was found that slowly hydrolyzing prodrugs, which are known to show an improved duration of action after oral administration, are devoid of activity after transdermal application. The acetyl-, the propionyl- and the isobutyryl analogues, which are prodrugs with a relatively high hydrolysis rate, were found to have interesting and promising profiles following transdermal application.

Administration, Cutaneous↗
PubMed1996

The anti-ulcer drug sucralfate does not affect gastric nicotine levels.

OBJECTIVE: It has been claimed that sucralfate can overcome the negative effects of nicotine in patients with peptic ulcer disease, although the possible mechanism being unknown. This study was performed in order to test whether sucralfate was capable of binding intragastric nicotine, thus making it impossible for the substance to exert effect. METHOD: Nicotine was administered via transdermal patches or as capsules yielding gastric concentrations of 40-2980 ng.ml-1. Gastric juice aspirates (n = 9) were incubated with sucralfate, which was then separated by centrifugation, and the nicotine concentration was compared in incubated and non-incubated samples. RESULTS: A median decrease of 13% (range 0-27%) in nicotine concentration was seen after incubation with sucralfate (P = 0.01). CONCLUSION: The binding of nicotine to the precipitating agent sucralfate is not sufficient effectively to remove nicotine from the gastric juice.

Administration, Cutaneous↗