Pharmacokinetic and local tissue disposition of [14C]sodium diclofenac following iontophoresis and systemic administration in rabbits.

The systemic pharmacokinetics and local drug distribution of sodium diclofenac in skin and underlying tissues was studied. Iontophoresis facilitated local and systemic delivery of diclofenac sodium compared with passive diffusion. The maximum plasma concentration of sodium diclofenac was achieved within 1 h of iontophoresis, and the delivery was proportional to applied current density (371 +/- 141 and 132 +/- 62 microg/L at 0.5 and 0.2 mA/cm(2), respectively). The in vivo delivery efficiency for diclofenac in rabbit was 0.15 mg/mA.h. The concentrations of sodium diclofenac in the skin, subcutaneous tissue, and muscle beneath the drug application site (cathode) were significantly greater than plasma concentrations and concentrations of drug in similar tissues at the untreated sites. The results thus suggest that the cutaneous microvasculature is not always a perfect "sink" and that transdermal iontophoresis facilitated the direct penetration of diclofenac sodium to deeper tissues. No skin irritation was observed up to 0.5 mA/cm(2) current density and 7 mg/mL sodium diclofenac concentration.

In vivo bioavailability and metabolism of topical diclofenac lotion in human volunteers.

PURPOSE: The primary objective of this study was to determine the rate and extent of transdermal absorption for systemic delivery of diclofenac from Pennsaid (Dimethaid Research, Inc.) topical lotion into the systemic circulation after the lotion was applied to human volunteers, in an open treatment, non-blinded, non-vehicle controlled study. In addition, the in vivo metabolism of this topical diclofenac lotion has also been studied. METHODS: Human volunteers were dosed with topical [14C]-diclofenac sodium 1.5% lotion on the knee for 24 h. Sequential time blood and urine samples were taken to determine pharmacokinetics, bioavailability and metabolism. RESULTS: Topical absorption was 6.6% of applied dose. Peak plasma 14C occurred at 30 h after dosing, and peak urinary 14C excretion was at 24-48 h. The urinary 14C excretion pattern exhibits more elimination towards 24 h and beyond, as opposed to early urinary 14C excretion. This suggests a continuous delivery of [14C]-diclofenac sodium from the lotion into and through skin which only ceased when the dosing site was washed. Skin surface residue at 24 h was 26 +/- 9.5% dose (remainder assumed lost to clothing and bedding). Extraction of metabolites from urine amounted to 7.4-22.7% in untreated urine, suggesting substantial diclofenac metabolism to more water soluble metabolites, probably conjugates, which could not be extracted by the method employed. Two Dimensional TLC analysis of untreated urine showed minimal or no diclofenac, again emphasizing the extensive in vivo metabolism of this drug. Treatment of the same urine samples with the enzymes sulfatase and beta-glucuronidase showed a substantial increase in the extractable material. Three spots were consistently present in each sample run, namely diclofenac, 3'hydroxy diclofenac and an intermediate polar metabolite (probably a hydroxylated metabolite). Therefore, there was significant sulfation and glucuronidation of both diclofenac and numerous hydroxy metabolites of diclofenac, but many of the metabolites/conjugates remain unidentified. CONCLUSIONS; There was a continuous delivery of diclofenac sodium from the lotion into and through the skin, which ceased after the dosing site was washed. The majority of the material excreted in the urine were conjugates of hydroxylated metabolites, and not the parent chemical, although further identification is required.

In vitro cutaneous disposition of a topical diclofenac lotion in human skin: effect of a multi-dose regimen.

PURPOSE: This study determines comparative bioavailability of diclofenac sodium lotion compared to an aqueous solution after topical application to viable human skin in vitro. In addition, the difference between a single dose and multiple doses (8 times) was also determined. METHODS: An in vitro flow-through diffusion cell system was employed, using radiolabelled diclofenac sodium. RESULTS: Multiple doses of lotion (2 microl/cm2 and 5 microl/cm2) delivered a total of 40.1 +/- 17.6 microg and 85.6 micro 41.4 microg diclofenac, respectively, at 48 h, compared to only 9.4 +/- 2.9 microg and 35.7 +/- 19.0 microg absorbed after topical application of diclofenac as an aqueous solution (P < 0.05). A single dose study showed no statistical difference between diclofenac delivered in lotion or an aqueous solution. Over 48 h the total absorption from lotion was 10.2 +/- 6.7 microg and 26.2 +/- 17.6 microg (2 microl/cm2 and 5 microl/cm2, respectively), compared to 8.3 +/- 1.5 microg and 12.5 +/- 5.7 microg from an aqueous solution. Both single doses of lotion and aqueous diclofenac showed decreased diclofenac absorption into the receptor fluid between 12 and 24 h. However, when applied multiple times, absorption from lotion was continually increasing up to 48 h. The total dose accountability ranged from 76.8 +/- 8.2% to 110.6 +/- 15. 1% of the applied dose. CONCLUSIONS: Diclofenac lotion exhibited enhanced diclofenac percutaneous absorption rate through human skin (mass, flux and partition coefficient) when applied a multiple number of times and this enhanced absorption was maintained over 48 h. This suggests that a constituent of the lotion (DMSO) will enhance human skin absorption of diclofenac when used in a multi-dose regimen, but not after a single dose.

Stripped skin model to predict irritation potential of topical agents in vivo in humans.

BACKGROUND AND OBJECTIVE: The prediction of the irritation effects of products of low irritation potential remains problematic. An in vivo human model was utilized to define the irritation potential of a topical agent after partial removal of the stratum corneum by cellophane tape stripping. METHODS: The tape was applied to and removed approximately 50 times (mean, 50.0 +/- 16.7) from each test site on the volar aspect of the forearm. One site served as the stripping control, receiving tape stripping only. The other test sites received the topical agent and placebo control. Transepidermal water loss (TEWL) was measured before and daily for 5 days. The TEWL values at baseline after stripping represented the point of maximal stripping barrier disruption. The barrier disruption and irritation potential were assessed with TEWL measurements. RESULTS: The results showed that the model topical agent had no adverse effect on barrier repair, i.e. did not interfere with TEWL normalization. CONCLUSIONS: This model provides a method for the prediction, with exaggerated sensitivity, of chemical irritation and proclivity to enhance or retard water barrier repair. We believe that the model may predict the response of low irritation materials and may be more sensitive than patch testing on normal skin, particularly for products to be used on certain areas, e.g. the face, anus, etc., or even mucous membranes. The model must receive extensive use with chemicals of varying properties in order to define its chemical relevance.

Human cadaver skin viability for in vitro percutaneous absorption: storage and detrimental effects of heat-separation and freezing.

PURPOSE: For decades, human cadaver skin has been banked and utilized by hospitals for burn wounds and to study percutaneous absorption and transdermal delivery. Skin storage maintenance and confirmation of skin viability is important for both uses, especially for the absorption process where the in vivo situation is simulated. METHODS: Our system uses dermatomed human cadaver skin immediately placed in Eagles MEM-BSS, and refrigerated after donor death, then transferred to the laboratory and placed in Eagles MEM-BSS with 50 micrograms/ml gentamicin at 4 degrees C for storage. RESULTS: Skin viability, determined by anaerobic metabolism where glucose is converted to lactose, was highest (p < 0.000) during the 18 hours of the first day after donor death, decreased some 3-fold by day 2 (p < 0.000), but then maintained steady-state viability through day 8. Viability then decreased by approximately one-half by day 13. Thus, using the above criteria, human skin will sustain viability for 8 days following donor death in this system. Heat-treated (60 degrees C water for one minute) and heat-separated epidermis and dermis lose viability. CONCLUSIONS: Human skin viability can be maintained for absorption studies. It is recommended that this system be used, and that heat-separation and skin freezing not be used, in absorption studies where skin viability and metabolism might be contributing factors to the study.

Sodium lauiyl sulphate damaged skin in vivo in man: a water barrier repair model.

BACKGROUND/AIMS: Few studies describe enhancing the repair of surfactant-induced damaged skin. In vivo human studies were conducted to evaluate the efficacy of a topical agent after sodium lauryl sulphate (SLS) induced water barrier disruption. METHODS: Occlusive chambers with 1 % SLS were applied to the upper-backs of volunteers for 24 h, removed and topical agents applied on the SLS-treated skin sites daily for 5 days. Water barrier restoration was monitored by measuring transepidermal water loss (TEWL). RESULTS: The data were expressed as the percentage of recovery representing normalization of water barrier function. Results showed that a topical agent produced more rapid improvement in barrier function than its placebo vehicle, markedly accelerating repair at 48 h (P<0.01), and persisting throughout the experiment (P<0.05), in comparison with SLS-control sites. CONCLUSIONS: This study suggests that topical agents may accelerate the repair rates of water barrier function in SLS-treated human skin. This model appears facile and robust for evaluating such repair.

[The maternal-neonatal characteristics of intrauterine growth retardation in a term pregnancy based on a national curve of intrauterine growth]. / Características materno-neonatales del retardo de crecimiento intrauterino en la gestación de término según curva nacional de crecimiento intrauterino.

Using a national curve of fetal growth development, clinical and laboratory characteristics of 100 term neonates small for dates and 130 term adequate for gestational age newborns are studied. A 91% of the small for dates were classified by the ponderal index as having symmetrical growth retardation. At the same time in the 230 mothers we look for clinical features that have been mentioned to produce intrauterine growth retardation. Results showed marked differences (with statistic significance) between both groups of women in relation to: nutritional factors, maternal height, labor activity and presence of oligoamnios. The newborns of both groups didn't show differences, with exception of congenital malformation. The incidence of the classical morbidity of small for dates (asphyxia, hypoglycemia, polycythemia) was no different in both groups. We believe the explanation is that the national curve is more exigent and neonates with higher weight fall under the 10th percentile. We think that in the study group a high percentage of small for dates, are constitutional small and not really growth retarded. We suggest the possibility to use the 5th percentile for better sensibility.