Renova Retin-A
Percutaneous absorption of [3H]tretinoin and systemic exposure to mequinol after dermal application of 2% mequinol/0.01% [3H]tretinoin (Solage) solution in healthy volunteers.

Everett DW, Franz TJ, Chando TJ, Gale PJ, Lehman PA, Schwarzel EH, Parab PV, D'Arienzo CJ, Kripalani KJ.

Department of Metabolism and Pharmacokinetics, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, NJ 08543-4000, USA. everettd bms.com

Solage is a combination product composed of 2% mequinol (4-hydroxyanisole) and 0.01% tretinoin (all-trans-retinoic acid) in an ethanolic solution, which is being studied for its safety and efficacy as a topical treatment for disorders of skin hyperpigmentation. The purpose of this study was to evaluate the extent of percutaneous absorption of [3H]tretinoin and to estimate the systemic exposure to mequinol from this combination product when topically applied to the backs of healthy subjects. Eight subjects received bid topical applications of nonradiolabelled 2% mequinol/0.01% tretinoin solution on a 400 cm2 area of the back for 14 days. The subjects then received a single topical application of 2% mequinol/0.01% [3H]tretinoin solution. After 12 h, the radiolabelled dose was removed and bid treatment with nonradiolabelled 2% mequinol/0.01% tretinoin solution was continued for 7 days. Plasma, urine and faecal samples were analysed for total radioactivity and plasma was analysed for both mequinol and tretinoin by GC/MS procedure. Mean percutaneous absorption of [3H]tretinoin based on the cumulative recoveries of radioactivity in the urine and faeces was about 4.5% (median 2.18%). Tretinoin concentrations in plasma did not increase above endogenous levels. This was consistent with the concentrations of radioactivity in plasma, which showed an average Cmax of 91 pg-eq/mL (median 26 ng/mL). Average Cmax and AUC(0-12 h) values for mequinol were 10 ng/mL and 33 ng h/mL, respectively. Based on the results of this study, systemic toxicity from topical application of tretinoin in this formulation is unlikely, because percutaneous absorption of tretinoin is minimal and because endogenous levels of tretinoin are not increased following bid dosing with this combination formulation. The safety of mequinol in this combination formulation is supported by the low systemic exposures of the subjects in this study compared with the systemic exposures at the highest doses in the dermal toxicity studies in mice (16.6-fold) and rats (34.6-fold).

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10701701&dopt=Abstract tretinoin Retin-A Renova



Renova Retin-A
Investigation of the chemical stability of an erythromycin-tretinoin lotion by the use of an optimization system.

Brisaert M, Gabriels M, Plaizier-Vercammen J.

Laboratory of Pharmaceutical Technology and Physical Pharmacy, Pharmaceutical Institute, Free University of Brussels, Laarbeeklaan 103, B-1090, Brussels, Belgium. apobrimy yahoo.com

A combination of 2% erythromycin and 0.05% tretinoin in an alcohol-isopropanol lotion was prepared. Two parameters were investigated for their influence on the stability of erythromycin and/or tretinoin, namely pH and the concentration of butylhydroxytoluene (BHT) as antioxidant. To investigate these two parameters, an optimization technique was used with two factors (pH and concentration of BHT) at two levels. Accelerated stability analysis was performed at 45 degrees C in the dark to exclude isomerization of tretinoin. To analyse erythromycin and tretinoin in the combination preparation, a TLC method, previously developed in the laboratory, was used. The degradation of erythromycin seemed to be much faster than the tretinoin degradation. Optimal stability is shown in the pH range of 8.2-8.6 for erythromycin and 7.2-8.2 for tretinoin while the concentration of BHT had no significant influence.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10704802&dopt=Abstract tretinoin Retin-A Renova



Renova Retin-A
Investigation on the photostability of a tretinoin lotion and stabilization with additives.

Brisaert M, Plaizier-Vercammen J.

Laboratory of Pharmaceutical Technology and Physical Pharmacy, Pharmaceutical Institute, Free University of Brussels, Laarbeeklaan 103, 1090, Brussels, Belgium. apobrimy yahoo.com

Tretinoin, a drug that is used in topical preparations for the treatment of acne vulgaris, is known to be very susceptible to degradation under daylight. The objective of this work was to investigate the degradation of a tretinoin lotion placed in front of a xenon lamp. Analysis was performed with HPLC. The tretinoin lotion was degraded to about 20% of its initial concentration within 30 min. Incorporation of tretinoin in beta-cyclodextrin or in some surfactants (Brij(R)s) did not have any effect on the photodegradation of tretinoin. Neither could a UV-B sunscreen retard the photodegradation of tretinoin while a UV-A sunscreen had very little effect. Irradiation with selected wavelengths revealed that 420 nm seemed to be the most harmful wavelength for the degradation of tretinoin and not the wavelength of maximum absorption (350 nm) as expected. Then the addition of the yellow colourants chrysoin and fast yellow, absorbing in the region of 420 nm, was tested. These colourants did indeed retard the photo-degradation of tretinoin more or less depending on the concentration of the dye. Finally we only had to select a concentration that was still effective but that did not colour the skin.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10794926&dopt=Abstract tretinoin Retin-A Renova



Renova Retin-A
Tretinoin prevents age-related renal changes and stimulates antioxidant defenses in cultured renal mesangial cells.

Manzano VM, Puyol MR, Puyol DR, Cazana FJ.

Department of Physiology, University of Alcala, Alcala de Henares, Madrid, Spain.

Age-related progressive glomerular sclerosis in the rat is associated with increased expression of tumor necrosis factor-beta1 and increased protein content in the renal cortex, enhanced production of H2O2, in both renal glomeruli and mesangial cells (MCs) cultured from them, as well as augmented glomerular oxidative damage. We have previously shown that tretinoin-treated old male Fischer 344 rats have 30% lower protein content in the renal cortex than control old rats. Here, we report that this effect may depend on the inhibition of the expression of tumor necrosis factor-beta1, a matrigenic cytokine, and osteopontin, a protein with cell adhesive and chemotactic properties. In addition, we show that tretinoin prevents the cytotoxicity of H2O2 in cultured human MCs by increasing both the catalase activity and the reduced glutathione content, which are dose- and time-dependent changes. These increases were not dependent on each other: when these effects were previously inhibited with 3-amino-1,2,4-atriazole or L-buthionine-(S, R)-sulfoximine, respectively, tretinoin still induced the increase of the other noninhibited antioxidant defense. An enhanced gene transcription is the most likely mechanism involved in the tretinoin-induced stimulation of MC antioxidant defense systems because 1) preincubation of MCs with actinomycin D or cycloheximide fully abolished it; 2) tretinoin-incubated MCs showed increased levels of catalase mRNA and gamma-glutamyl-cysteine synthetase (catalytic subunit) mRNA, the latter being the rate-limiting step in de novo reduced glutathione synthesis; and 3) the stability of both mRNA was unchanged by tretinoin. These results show one strategy of protecting renal cells from H2O2-mediated injury based on increasing their antioxidant defenses.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10086995&dopt=Abstract tretinoin Retin-A Renova