The antipsoriatic effect of MTX during the remission-induction phase of treatment is influenced by folate status and may be significantly less if combined treatment with FA is used, irrespective of pre-treatment folate levels. The individual tailoring of MTX dosing needs further attention because the mean percent PASI improvement from baseline was 83% and the inter-patient variability in response was low after 16 weeks of monotherapy with MTX.

Aims The aim of this 13 week, randomized, parallel-group study was to evaluate the relationship between the pharmacokinetics (PK) and pharmacodynamics (PD) of low-dose intermittent oral methotrexate (LDMTX) in patients with psoriasis. Methods Twenty-four psoriatic patients (15 male and 9 female, aged 31-73 years) were given weekly doses of MTX doses of either 7.5 mg or 15 mg with each dose divided into three aliquots given at 12 h intervals. The pharmacokinetics of MTX were evaluated at weeks 1 and 13. Skin impairment was assessed using the PASIscoring system (The Psoriasis Area and Severity Index) at baseline and at weeks 5, 9 and 13 of therapy. Haematological and biochemistry tests were also performed at these times. Results The comparison of the areas under the plasma concentration-time curve (AUC MTX ) after the first and third weekly doses showed that the extent of MTX accumulation in plasma was only about 12%. Two-way ANOVA (factors: subject and the week of therapy) on the log-transformed AUC MTX showed no effect of the week of therapy (P>0.8). Moreover, the intraindividual variability in the AUC MTX was at least 4-fold less than the interindividual variability (F-test; P<0.01). The steady-state total plasma clearance of MTX ranged from 5.0 to 18.2 l h x1 and was proportional to the renal clearance (r 2 =0.45, P<0.001) which accounted for 65t20% of the former. The renal clearance of 7-OHMTX was approximately 4-8% of that of the parent compound. PK/PD analysis revealed a highly significant inverse relationship between PASI (expressed as a percent of the initial value) and a steady-state AUC MTX (r s =x0.65, P<0.001). Seventeen subjects (8 from the 7.5 mg group and 9 from the 15 mg group MTX, P=0.67) achieved a greater than 50% decrease in the initial PASI score and were classified as responders. Thirteen of 14 subjects with AUC(24,36 h)i700 nmol l x1 h responded to pharmacotherapy. Conversely, only 4 out of 10 subjects with AUC(24,36 h)<700 nmol l x1 h were responders (P<0.01, Fisher's exact test).Conclusions A strong correlation was observed between the pharmacokinetics (AUC MTX at the steady state) and antipsoriatic effect (PASI-score) of LDMTX. The considerable interindividual variability and low intraindividual variability in MTX pharmacokinetics support a role for therapeutic monitoring and dose individualization at the start of pharmacotherapy. The results of this study suggest that a steady state AUC MTX values of 700 nmol l x1 h and higher are associated with a significantly better success rate of antipsoriatic therapy than lower values.

The initiation of stomata, microscopic valves in the epidermis of higher plants that control of gas exchange, requires a co-ordinated sequence of asymmetric and symmetric divisions, which is under tight environmental and developmental control. Arabidopsis leaves grown under elevated photosynthetic photon flux density have a higher density of stomata. STOMAGEN encodes an epidermal patterning factor produced in the mesophyll, and our observations indicated that elevated photosynthetic irradiation stimulates STOMAGEN expression. Our analysis of gain and loss of function of STOMAGEN further detailed its function as a positive regulator of stomatal formation on both sides of the leaf, not only in terms of stomatal density across the leaf surface but also in terms of their stomatal index. STOMAGEN function was rate limiting for the light response of the stomatal lineage in the adaxial epidermis. Mutants in pathways that regulate stomatal spacing in the epidermis and have elevated stomatal density, such as stomatal density and distribution (sdd1) and too many mouth alleles, displayed elevated STOMAGEN expression, suggesting that STOMAGEN is either under the direct control of these pathways or is indirectly affected by stomatal patterning, suggestive of a feedback mechanism. These observations support a model in which changes in levels of light irradiation are perceived in the mesophyll and control the production of stomata in the epidermis by mesophyll-produced STOMAGEN, and whereby, conversely, stomatal patterning, either directly or indirectly, influences STOMAGEN levels.