For more than 100 years dithranol has been successfully used for the treatment of psoriasis . It is still not fully understood, however, how it exerts its antipsoriatic effect. From the information available to date it is clear that the actual process of decomposition is central to the therapeutic action of dithranol. Since there is an obvious parallel between the mechanism of decomposition in solution and that of decomposition/metabolism in skin stability studies were carried out in aqueous buffer (PH 5.5). The effect of various factors such as the presence of various metal ions and surfactants on the decomposition pattern (individual rates of dimer and danthron formation) of dithranol in solution were quantified. The effect of, in particular, surfactants on the skin permeation and decomposition/metabolism of dithranol were then investigated. Because of dithranol's poor water solubility it was necessary to develop an analytical technique capable of the successful quantification of low levels of dithranol and breakdown products in aqueous systems. A previously reported hplc system, which has adequate sensitivity for dithranol and danthron quantification, was used. Improved sensitivity for dimer (3 fold increase), thus allowing the accurate quantification of low levels of dimer in aqueous solutions, was achieved by a modification of the mobile phase. As it was also necessary to establish the amounts of dithranol and breakdown products on and in skin an appropriate extraction method was needed. A procedure whereby skin was first extracted using a mixture of trichloro acetic acid and methanol followed by hplc analysis of the extract was developed. Surfactant solubilisation of dithranol was used to enhance the water solubility of dithranol. Data from the solubilisation studies shows that in sodium lauryl sulphate and tween 80 (above c. m.c in aqueous buffer pH 5.5) the amount of dithranol in solution is directly proportional to the % of surfactant present. In cetrimide, solubilisatiori was observed only at low pH e.g pH 0.4. At pH 5.5, because of the interaction that takes place between dithranol and cetrimide causing dithranol to ionise, dithranol ionisation is responsible for enhanced solubility. About 3 fold more dithranol goes into such cetrimide solutions compared to equivalent concentrations of sodium lauryl sulphate and tween 80. Surfactant presence, however, had implications on dithranol's decomposition pattern. In the sodium lauryl sulphate and tween 80 solutions little change from that seen in buffer pH 5.5 was observed namely - 94 % dimer and - 4 % danthron were produced following complete decomposition. In the presence of cetrimide (PH 5.5) a marked change was seen with - 84% danthron and -14% dimer being formed on complete decomposition. The effect of the inclusion of metal ions i.e Cu2+, Zn2+ and Fe2+ on the kinetics of the decomposition of dithranol to dimer and danthron were quantified. All had a catalytic effect on the rate of dimer formation, while suppressing that of danthron. The catalytic coefficients were in the order of Cu2+ > Fe2+ > Zn2+. Concentration vs time data generated on placing surfactant solutions of dithranol in contact with animal skin (in vitro) and human skin (in vivo) allowed estimates of the amount of dithranol and breakdown products penetrating into the skin, along with the degree of skin surface decomposition taking place during the permeation process. A pronounced deviation was observed for dithranol decomposition in the formulations on the skin and when not in contact with skin. Skin surface decomposition was found to result in the formation of an ,as yet unknown, breakdown product (P4). Using the 12-0-tetradecanoylphorbol-13-acetate/hairless mouse psonasls model it was visually established that the cetrimide-dithranol formulation negated the anti inflammatory effects of dithranol . The tween 80 and sodium lauryl sulphate dithranol formulations reduced the inflammatory response in the psoriasis model to the same degree as an equivalent amount of dithranol delivered in acetone. A preliminary clinical investigation on the influence of cetrimide on the therapeutic outcome of conventional dithranol therapy was carried out using two patients with psoriasis. Cleansing the skin with a solution of cetrimide before and after treatment with dithranol resulted in both a reduction of side effects and a loss in the therapeutic effectiveness of dithranol. The data gathered allowed the discussion of the effect of dithranol's decomposition pathway on its therapeutic outcome.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:260044 |
| Date | January 1994 |
| Creators | Lubwika, Paul |
| Contributors | Moody, R. R. ; Winfield, A. J. |
| Publisher | Robert Gordon University |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://hdl.handle.net/10059/2348 |
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