tretinoin and tocoretinate

Data from a variety of experimental studies suggesting benefits of the antioxidant supplementation were confronted with those from clinical trials and large metaanalyses which have failed to prove those benefits. Major directions of the biological effects of reactive oxygen species (ROS) and antioxidants were specified. In particular, plausible mechanisms through antioxidants may disturb physiological functions were discussed. The regulatory aspects of ROS potency, and the ways antioxidants may disturb homeostasis were taken particularly into account. Directions of prospective research towards practical use of antioxidants were suggested.

Topics: Antioxidants; Cardiovascular System; Clinical Trials as Topic; Dietary Supplements; Drug Combinations; Homeostasis; Humans; Meta-Analysis as Topic; Myocardium; Oxidative Stress; Reactive Oxygen Species; Treatment Failure; Tretinoin; Vitamin E

Tretinoin tocoferil is an alpha-tocopherol ester of all-trans retinoic acid (ATRA) and safely used to treat skin ulcers. Tretinoin tocoferil stimulates the formation of granulation tissue in the ulcer, and enhances the migration of guinea pig macrophages and stimulates the proliferation of human skin fibroblasts. These effects are different from those of either ATRA or alpha-tocopherol. Tretinoin tocoferil induces the granulocytic differentiation of human promyelocytic leukemia HL-60 cells, and more than additively enhances cellular differentiation induced by sub-optimal concentrations of ATRA. Tretinoin tocoferil and ATRA synergistically inhibit the proliferation of HL-60 cells, suggesting that tretinoin tocoferil acts differently than ATRA on leukemia cells. Tretinoin tocoferil also enhances the differentiation of HL-60 cells induced by dimethyl sulfoxide, phorbol ester and 1alpha,25-dihydroxyvitamin D3(VD3). Tretinoin tocoferil and VD3 synergistically inhibit the proliferation and induce the differentiation of other myelomonocytic leukemia cells. Toxicity tests in animal models have shown that tretinoin tocoferil is at least 150 times less toxic than ATRA and does not induce teratogenesis. Therefore, the combination of tretinoin tocoferil and VD3 may be useful for treating myelomonocytic leukemia.

Topics: Antineoplastic Agents; Cell Differentiation; Drug Combinations; Humans; Leukemia, Myelomonocytic, Acute; Tretinoin; Vitamin E

Maintenance of proper moisture and regulation of infection are simultaneously required to promote healing of pressure ulcers. Continuous use of water-rich ointment may often lead to excess moisture and induce edematous granulation tissue. Use of water soluble ointment may excessively absorb exudates and induce dry granulation tissue. Selection of appropriate topical ointment is desired to avoid worse clinical outcomes. For adjustment of wound moisture a novel blended ointment (tretinoin tocoferil-povidone-iodine (TR-PI)) was developed consisting of emulsion base, tretinoin tocoferil oil-in-water (o/w) emulsion (TR-cream), and sugar base, povidone-iodine and sugar (PI-sugar). For the characterization of TR-PI water absorption was tested using Franz diffusion cell with cellulose membrane. For rheological characteristics spreadability was tested using spread meter and yield value was calculated. Iodine permeation was tested using a permeation cell with silicon membrane. Water absorption rate constant of TR-PI with combination ratio of PI-sugar at 75% (TR-PI75, 18.5 mg cm(-2) min(-0.5)) was equivalent to that of TR-cream alone (16.4 mg cm(-2) min(-0.5)). The yield value of TR-PI75 (26.1 Pa) exhibited intermediate values as compared to those of TR-PI with combination ratio of PI-sugar at 50% (11.3 Pa) and TR-cream alone (46.8 Pa). The amount of released free-iodine from TR-PI75 was similar to that released from PI-sugar alone. TR-PI75 may have superior performance in keeping the moist environment in wounds and in preventing infection. TR-PI75 can be used to promote formation of favorable granulation tissue in pressure ulcers with moderate exudates.

Topics: Drug Combinations; Drug Stability; Emulsions; Ointments; Povidone-Iodine; Rheology; Tretinoin; Vitamin E; Water

Topics: Administration, Topical; Animals; Cell Proliferation; Drug Combinations; Guinea Pigs; Humans; Indicators and Reagents; Keratinocytes; Male; Skin Pigmentation; Tretinoin; Vitamin E; Vitiligo

Lichen amyloidosis and macular amyloidosis are commonly therapy-resistant. Tocoretinate is a hybrid compound of retinoic acid and tocopherol that is commonly used for the treatment of skin ulcers. Although beneficial effect of oral retinoic acid on lichen amyloidosis is reported, tocoretinate has not been reported to be useful for the treatment of lichen amyloidosis or macular amyloidosis. We evaluated the effects of topical tocoretinate on lichen amyloidosis and macular amyloidosis lesions. Tocoretinate was topically applied daily to the lesions and clinical improvement and histological changes were evaluated. The outcome was very good for four, good for two, moderate for two and poor for two of 10 treated patients. Epidermal hypertrophy was reduced and expression of involucrin, keratin 1 and keratin 10 was decreased by tocoretinate treatment, suggesting the normalization of epidermal differentiation. Amyloid deposits remained histologically detectable, even in clinically responsive patients. Together, topical application of tocoretinate reduced the clinical symptoms of lichen amyloidosis and macular amyloidosis, and normalized disturbed epidermal differentiation.

Topics: Administration, Topical; Adult; Aged; Amyloidosis; Dermatologic Agents; Drug Combinations; Female; Humans; Male; Middle Aged; Treatment Outcome; Tretinoin; Vitamin E; Young Adult

Discoid lupus erythematosus (DLE), the most common lupus erythematosus (LE)-specific chronic manifestation of the skin, is often resistant to therapy. Atrophy, scarring, and pigmentation are often observed. In this study, we report two cases of DLE that were successfully treated with tocoretinate, a compound containing a mixture of retinoic acid and tocopherol. Atrophy and pigmentation improved in both cases. The mechanism of action of tocoretinate is discussed.

Topics: Adult; Anti-Inflammatory Agents, Non-Steroidal; Antiphospholipid Syndrome; Aspirin; Dermatologic Agents; Drug Combinations; Female; Humans; Lupus Erythematosus, Discoid; Male; Patient Satisfaction; Treatment Outcome; Tretinoin; Vitamin E

Pressure ulcers can form with excess pressure and shearing stress on skin tissue. Because pressure ulcer is often accompanies by exudates, selection of appropriate topical emulsion ointment is difficult. Blended ointments consisting of emulsion base and water-soluble base are clinically used for adjustment of wound moist environment. Because regulating the amount of wound exudates can enhance treatment efficacy, two new blended ointments were developed. LY-SL blended ointment consisted of lysozyme hydrochloride water-in-oil (w/o) emulsion (LY-cream) and sulfadiazine macrogol (polyethylene glycol) ointment (SL-pasta). TR-SL blended ointment consisted of tretinoin tocoferil oil-in-water (o/w) emulsion (TR-cream) and SL-pasta (TR-SL). LY-SL and TR-SL were applied to Franz diffusion cell with cellulose membranes for the evaluation of water absorption characteristics at 32 °C. Water absorption rate constants (mg/cm(2)/min(0.5)) were 12.5, 16.3 and 34.6 for LY-cream, TR-cream and SL-pasta, respectively. Water absorption rate constants for LY-SL and TR-SL (SL-pasta 70%) exhibited intermediate values of 21.2 and 27.2, as compared to each ointment alone, respectively. Because amount of water absorbed was linearly related to square root of time, it was suggested that water-absorbable macrogol was surrounded by oily ingredients forming matrix structure. This diffusion-limited structure may regulate water absorption capacity. This is the first report of physicochemical properties of macrogol ointment and emulsion ointment blend developed for regulation of water absorption. The blended ointment can properly regulate amount of exudates in wounds and may be useful for treatment of pressure ulcers.

Topics: Cellulose; Diffusion Chambers, Culture; Drug Carriers; Drug Combinations; Emulsions; Exudates and Transudates; Membranes, Artificial; Muramidase; Ointments; Polyethylene Glycols; Pressure Ulcer; Solubility; Sulfadiazine; Time Factors; Tretinoin; Vitamin E; Water

A 51-year-old male who had intractable leg ulcers during treatment for chronic myelogenous leukaemia with hydroxyurea (HU) is reported. His leg ulcers were treated by application of tretinoin tocoferil (TT) ointment after surgical debridement; good results were obtained. Although stopping HU administration is vitally important, surgical debridement and TT application are effective for treating leg ulcers due to HU.

Topics: Antineoplastic Agents; Debridement; Drug Combinations; Humans; Hydroxyurea; Leg Ulcer; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Male; Middle Aged; Ointments; Tretinoin; Vitamin E

The photostability of tretinoin tocoferil was investigated under irradiation with three kinds of lamps, i.e., a cool white fluorescent lamp, a UV-A fluorescent lamp and a D65 fluorescent lamp. A combination of the cool white fluorescent lamp and the UV-A fluorescent lamp, and the D65 lamp having relative spectral power distribution similar to that of direct daylight, correspond to options 2 and 1 in ICH Guidelines, respectively. The photodegradation apparently followed second-order kinetics under these light sources and the degradation rate constant under exposure by the D65 lamp was larger than that by the cool white fluorescent lamp. The drug was susceptible to degradation by visible and UV light below 480 nm and was degraded most remarkably at around 420 nm, showing a wavelength-dependency. The semi-logarithmic plots of apparent degradation rate constant against the reciprocal of illuminance showed a good linear relationship in the Arrhenius-type fashion, and the photostability under ordinary illumination conditions could be predicted from the data obtained under the accelerated illumination conditions. The rate of oxidative degradation was slightly accelerated with the rise of temperature. Thermodynamic parameter was calculated from the Arrhenius plot. The degradation rate constant rapidly increased in proportion to partial pressure of oxygen below 20 kPa.

Topics: Chemical Phenomena; Chemistry, Physical; Chromatography, High Pressure Liquid; Drug Combinations; Light; Oxidation-Reduction; Oxygen; Spectrophotometry, Ultraviolet; Temperature; Tretinoin; Ultraviolet Rays; Vitamin E

Four patients with systemic scleroderma (SSc), 4 patients with morphea, and 4 patients with hypertrophic scar were treated with topical tocoretinate for 6 months to 3 years and studied clinically and histopathologically. Clinically, all of the lesions responded to this therapy. The stiffness of the skin lesions, glossy appearance of the lesions, and telangiectasia improved. Histopathologically, the proliferated collagen fibers decreased in thickness, and the inter-fiber spaces increased. Immunoreactive tenascin-C expressed in the proliferated deep dermal fibers of the SSc and hypertrophic scar lesions was markedly decreased compared with the level before the topical tocoretinate therapy. Topical tocoretinate has been used for the treatment of ulcers; it is also a potent treatment for sclerotic skin diseases.

Topics: Administration, Topical; Adolescent; Adult; Aged; Child; Child, Preschool; Cicatrix, Hypertrophic; Drug Combinations; Female; Humans; Middle Aged; Scleroderma, Localized; Scleroderma, Systemic; Skin; Tretinoin; Vitamin E

Retinoids are strong tissue modifiers and have been used to treat severe acne, keloids and photo-aged skin. Tocoretinate (TR), ester bound retinoic acid and tocopherol, has been topically applied for skin ulcers and, more recently, for sclerotic skin diseases. To clarify the mechanism of tissue softening by retinoids and TR, we investigated their effects on the contraction of hydrated type-1 collagen gel matrices by human dermal fibroblasts and on tenascin-C expression. TR, 13-cis-retinoic acid/isotretinoin and all trans-retinoic acid significantly inhibited collagen gel matrices contraction at concentrations from 10(-4) to 10(-8) M without significant changes of the fibroblast growth. TR and the other two retinoids dose-dependently induced tenascin-C expression in the fibroblasts. Since tenascin-C is involved in cellular detachment and tissue remodeling, these results suggest that TR and other retinoids down-regulated the tensile tension of fibroblasts in collagen gel matrices by the induction of tenascin-C.

Topics: Cells, Cultured; Collagen; Drug Combinations; Extracellular Matrix; Fibroblasts; Humans; Skin; Tenascin; Tretinoin; Vitamin E

Acute promyelocytic leukemia (APL) has a specific genetic rearrangement between the retinoic acid receptor (RAR)-alpha gene and the pml nuclear protein gene. All-trans retinoic acid (ATRA) induces granulocytic differentiation of APL-derived cells and is used to treat APL patients. However, ATRA interacts with normal cells with RAR throughout the entire body, and when used at high doses or over a long duration, it induces several adverse effects. The development of drugs that selectively act on APL cells may contribute to increasing the therapeutic efficacy of APL treatment as well as elucidating the mechanisms of response to ATRA. In this study, 9-cis retinoic acid alpha-tocopherol ester (9CTT) inhibited the proliferation of APL-derived NB4 and HT93 cells and induced differentiation markers, such as granulocytic maturation, nitroblue tetrazolium reduction, and CD11b expression, in these cells. The effects of 9CTT on non-APL cells, including HL-60 and U937 cells, were much weaker than those on APL cells, and tretinoin tocoferil (TT), which is an alpha-tocopherol ester of ATRA, did not induce the differentiation of APL cells as effectively as 9CTT. The differentiation-inducing effects of 9CTT were inhibited by RAR antagonists. 9CTT and TT similarly induced the transactivating activity of RARs, but were not effective on RXRs. 9CTT downregulated the expression of PML/RAR-alpha protein more effectively than TT, which suggests that it may be involved in the selectivity of 9CTT against APL cells. Interestingly, 9CTT enhanced the differentiation of APL cells induced by ATRA, 9-cis retinoic acid, and synthetic retinobenzoic acids. Combined with 1alpha,25-dihydroxyvitamin D3 (VD3), 9CTT also more than additively induced the differentiation of APL cells. Thus, 9CTT, alone or in combination with other retinoids or VD3, may be useful for the treatment of APL.

Topics: Cell Differentiation; Cell Division; Drug Combinations; HL-60 Cells; Humans; Leukemia, Promyelocytic, Acute; Tretinoin; Vitamin E

Tretinoin tocoferil is an alpha-tocopherol ester of all-trans retinoic acid (RA) and safely used in the treatment of skin ulcer. Tretinoin tocoferil inhibited proliferation of human promyelocytic leukemia HL-60 cells and induced granulocytic differentiation of the cells, but less than RA. alpha-Tocopherol did not affect differentiation of HL-60 cells, but at high concentrations enhanced its nitroblue tetrazolium (NBT)-reducing activity and expression of surface antigen CD11b, which are markers of myelomonocytic differentiation induced by RA. Tretinoin tocoferil increased NBT reduction in HL-60 cells treated with RA. It also enhanced the differentiation of HL-60 cells induced by dimethyl sulfoxide, phorbol-12-myristate 13-acetate or 1alpha,25-dihydroxyvitamin D3 (VD3). In combination with a low concentration of VD3, it induced the NBT-reducing activity of human monoblastic U937 cells very effectively. Moreover, it enhanced the differentiation of human myelomonocytic ML-1, THP-1, P39/TSU, and P31/FUJ cells induced by VD3. In combination with VD3, it synergistically inhibited the proliferation of HL-60, U937, ML-1, THP-1, P39/TSU, and P31/FUJ cells and decreased the effective concentration of VD3 to a 10(-10) mol/L level. Because tretinoin tocoferil was reported to induce neither retinoid-related toxicity nor teratogenicity, the therapeutic advantage of the use of it in treatment of myelomonocytic leukemia is suggested.

Topics: Antineoplastic Agents; Calcitriol; Cell Differentiation; Cell Division; Dimethyl Sulfoxide; Drug Combinations; Drug Screening Assays, Antitumor; Drug Synergism; Growth Inhibitors; HL-60 Cells; Humans; Leukemia, Monocytic, Acute; Leukemia, Myelomonocytic, Acute; Lymphoma, Large B-Cell, Diffuse; Neoplastic Stem Cells; Tetradecanoylphorbol Acetate; Tretinoin; Tumor Cells, Cultured; Vitamin E

Tocoretinate (TR) is a hybrid compound composed of alpha-tocopherol esterified with retinoic acid. The present study was conducted to clarify whether or not TR affects DNA synthesis in a human intestinal cell line, FHs 74 Int. In these cells, addition of 10% serum resulted in an approximately 10-fold increase in DNA synthesis as assessed by [3H]thymidine incorporation. Epidermal growth factor (EGF) augmented DNA synthesis three- to fourfold. When EGF was added together with insulin-like growth factor-I (IGF-I), which had only a small effect by itself, a combination of these growth factors reproduced the effect of serum. In quiescent FHs 74 Int cells, TR had no effect on DNA synthesis by itself. However, when quiescent cells were pretreated with TR for 24 hr, DNA synthesis induced by EGF was markedly enhanced. Thus, in TR-pretreated cells, EGF stimulated DNA synthesis to the same extent as 10% serum. The effect of TR was dose-dependent and the maximal effect was obtained by 10(-7) M TR. Pretreatment with TR enhanced the effect of EGF on DNA synthesis but did not change the dose-response relationship for EGF-mediated DNA synthesis. All-trans-retinoic acid had similar stimulatory effect on EGF-induced DNA synthesis. When the medium was changed during the treatment with TR, the effect of TR on DNA synthesis was reduced. In addition, pretreatment with TR resulted in release of immunoreactive IGF-I into medium. Finally, the effect of TR was attenuated by an addition of antibody against IGF-I.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Cell Line; Cells, Cultured; DNA; Drug Combinations; Drug Synergism; Epidermal Growth Factor; Epithelial Cells; Epithelium; Humans; Insulin-Like Growth Factor I; Intestinal Mucosa; Recombinant Proteins; Stimulation, Chemical; Tretinoin; Tritium; Vitamin E