Lonapalene (RS4317)

Percutaneous absorption and metabolism of lonapalene in psoriatic skin

The percutaneous absorption and metabolism of lonapalene (6-chloro-2,3-dimethoxynaphthalene-1,4-diol-diacetate; RS-43179), a topically effective 5-lipoxygenase inhibitor, has been measured in six subjects with stable plaque-type psoriasis of the lower extremities. Lonapalene readily penetrates psoriatic skin, is rapidly and completely metabolized, and is almost entirely excreted in the urine. Unexpectedly we observed a trend for thigh (T) plaque skin to be more permeable than lower leg (LL) plaque skin as measured by total absorption (T, 44.8 +/- 13.4%; LL, 24.9 +/- 12.6% applied dose excreted), peak plasma levels (T, 209 +/- 107; LL, 146 +/- 81 ng Eq/ml), and peak rate of urinary excretion (T, 591.7 +/- 112.2; LL, 318.4 +/- 143.9 micrograms Eq/hr). There were also differences in the metabolic profiles between the two sites as measured by the quantity and proportion of dealkylated and conjugated products excreted in the urine.

Release of lonapalene from two-phase emulsion-type ointment systems

The in vitro release of lonapalene, a novel nonsteroidal antipsoriatic agent, was studied from two-phase emulsion-type ointment systems into a perfect sink of propylene carbonate at 32 degrees C. Lonapalene was completely solubilized in the ointments consisting of an internal phase of propylene carbonate (PC)-propylene glycol (PG) mixture dispersed within an external phase of a petrolatum base. The PC:PG ratio was varied to investigate separately the effects of (1) the initial concentration of lonapalene, (2) its saturation level, and (3) the volume fraction of the internal phase. The release profile consisted of an initial release rate which was higher than the ensuing diffusion-controlled release rate. The initial rate was attributed to the release of lonapalene from the surface globules of internal phase directly into the sink. Both rates increased with increasing lonapalene initial concentration in the ointment. For ointment systems in which the saturation level of lonapalene was kept constant, neither release rate was affected by the increasing volume fraction of the internal phase up to 12%. Further increase in this volume fraction to 25% afforded a significantly higher initial rate, while the diffusion-controlled rate was unchanged. However, an increase in the volume fraction of the internal phase with a concomitant decrease in the saturation level of lonapalene in the ointment resulted in a decrease in the initial rates and, to a lesser degree, the diffusion-controlled release rates. The diffusion coefficient in the external phase, calculated from the effective diffusion coefficient, was (2.68 +/- 0.24) X 10(-9) cm2/sec.

Pharmacologic and clinical effects of lonapalene (RS 43179), a 5-lipoxygenase inhibitor, in psoriasis

The pharmacologic and clinical effects of the 5-lipoxygenase inhibitor, lonapalene, have been determined in a double-blind, placebo-controlled, topical study in ten volunteers with psoriasis. A statistically significant clinical improvement was seen in lesions treated with 2% lonapalene ointment as compared with vehicle-treated sites. Although there was a statistically significant reduction in the levels of material similar or identical to the chemoattractant arachidonate 5-lipoxygenase product, leukotriene B4, in skin chamber fluid samples from lonapalene versus vehicle treated lesions, no significant reduction in arachidonic acid or 12-hydroxy-5,8,10,14-eicosatetraenoic acid was seen. The reduction in leukotriene B4 equivalents occurred before significant clinical improvement in lesions was seen. This and the selectivity of the pharmacologic response suggest that the therapeutic effect of topical lonapalene in psoriasis might be related to inhibition of leukotriene B4 synthesis. These results support the view that 5-lipoxygenase inhibitors may be useful in the treatment of psoriasis, and that leukotriene B4 is a relevant mediator of the pathology of this disease.

Effect of lonapalene on metabolism of exogenous arachidonic acid in human platelets

Lonapalene was studied as a topical antipsoriatic agent on the basis of its inhibitory effect on 5-lipoxygenase. We studied the effect of lonapalene on the metabolism of exogenous arachidonic acid in washed platelet suspensions by RP-HPLC. Lonapalene was shown to inhibit platelet cyclooxygenase, with substrate diversion towards 12-HETE production. The pattern of inhibition was similar to that of indometacin, although lonapalene was about 1,000 times weaker. The dual inhibition of lonapalene and concomitant deviation of arachidonic acid metabolism may have potential implications, with regard to therapeutic indications and side effects, which deserve further study.

5-lipoxygenase inhibitors and their anti-inflammatory activities

A wide variety of agents have been reported as 5-LO inhibitors. The majority of the series appear to be lipophilic reducing agents, including phenols, partially saturated aromatics, and compounds containing heteroatom-heteroatom bonds. Many of these are not selective 5-LO inhibitors, but often affect CO and other LOs as well. In vivo systemic activity for many of these has been, in general, disappointing, probably because of poor bioavailability caused by lipophilicity and metabolic instability (oxidation, and conjugation of phenolic compounds). However, topically a number of agents have shown promise for skin inflammation, with Syntex's lonapalene the most advanced of these. Most results published to date appear more disappointing in the allergy/asthma field. More excitingly, a few structural types are selective 5-LO inhibitors which have shown systemic activity in vivo and in the clinic. Abbott's zileuton (136) appears to be one of the leading compounds in this category, along with other hydroxamates such as BW-A4C (129) from Burroughs-Wellcome. Recent selective non-reducing agents such as Wyeth-Ayerst's Wy-50,295 (143) and the similar ICI compounds such as ICI 216800 (145) also hold promise. The enantiospecific effects of (106) and (145) are especially interesting for the design of new inhibitors. If compounds like these validate the hypothesis that inhibition of 5-LO will have a significant anti-inflammatory effect, a redoubling of effort throughout the industry to find second- and third-generation selective agents may be expected. Part of the difficulty in interpreting and comparing the 5-LO literature is the plethora of test methods and activity criteria. As pointed out in the introduction, inhibition of product release from cells, often stimulated with A23187, has commonly been used to demonstrate 5-LO inhibition. However, this type of assay cannot be assumed to be diagnostic for 5-LO inhibition. Only if specificity for 5-LO product generation and (ideally) activity in cell-free enzymes is also shown should mechanistic interpretations be made. Recently, a new class of compounds was found at Merck which inhibited LT biosynthesis without inhibiting 5-LO, but apparently by a novel, specific mechanism. L-655,240 (169) and L-663,536 (MK-886) (170) were both active in human ISN, with IC50 values in the low micromolar range. Both also orally inhibited GPB (< 1 mg/kg). MK-886 was effective in Ascaris-induced asthma in squirrel monkeys, in rat carrageenan pleurisy, in rat Arthus pleurisy, and (topically) in guinea-pig ear oedema induced by A23187.(ABSTRACT TRUNCATED AT 400 WORDS)