Metotrexát (MTX) je konvenční imunosupresivum první volby k perorální farmakoterapii středně těžké a těžké ložiskové psoriázy. Léčba je komfortní a cenově výhodná. Zlepšuje stav kůže hodnocený pomocí skóre PASI o 50 % nebo více až u 75 % nemocných. Vysoká interindividuální variabilita farmakokinetiky je jednou z hlavních příčin nedostatečného účinku nebo předčasného ukončení terapie z důvodu nežádoucích účinků MTX. Přehledová práce kriticky posuzuje výhody terapeutického monitorování MTX (TDM) jako prostředku personalizace farmakoterapie psoriázy. Prospektivní klinické studie odhalily vztah mezi farmakokinetikou a účinkem MTX. Byl navržen a ověřen postup TDM, který zlepšil výsledky iniciální fáze léčby (indukce remise). Kromě dávkování MTX byla individualizována i suplementace kyselinou listovou, ke které bylo přistupováno pouze u nemocných s prokázaným deficitem folátů při léčbě MTX.

Methotrexate (MTX) is a conventional immunosuppressive drug of first choice in oral therapy of moderate‑to‑severe plaque psoriasis. Its use is comfortable and cost effective. The therapy improves the skin status according to the PASI score (psoriasis area and severity index) by 50% or more in up to 75% of patients. However, a high inter‑individual variability in pharmacokinetics is one of the major factors responsible for either insufficient efficacy of the therapy or its premature discontinuation due to adverse effects of MTX. The review article critically evaluates the possible benefits of therapeutic drug monitoring (TDM) of MTX as a tool for personalized pharmacotherapy of psoriasis. Prospective clinical studies unraveled a relationship between the pharmacokinetics and the therapeutic effect of MTX. Recommendations on how to perform TDM were worked out and verified, which helped to improve the outcomes of the initial treatment phase (remission induction). Besides the individualization of MTX dosing, supplementation with folic acid was individually tailored only to patients with a proven folate deficit.

• MeSH
• aplikace orální MeSH
• dermatologické látky aplikace a dávkování   farmakokinetika   krev   MeSH
• imunosupresiva aplikace a dávkování   farmakokinetika   krev   MeSH
• individualizovaná medicína MeSH
• kyselina listová krev   škodlivé účinky   terapeutické užití   MeSH
• kyselina polyglutamová krev   MeSH
• lidé MeSH
• methotrexát * aplikace a dávkování   farmakokinetika   krev   MeSH
• monitorování léčiv * metody   MeSH
• plocha pod křivkou MeSH
• psoriáza * farmakoterapie   krev   MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• práce podpořená grantem MeSH
• přehledy MeSH

BACKGROUND: Clinical studies of low-dose oral methotrexate (MTX) in the treatment of psoriasis and rheumatoid arthritis document a large interpatient variability in the pharmacokinetics of MTX, including its polyglutamates (MTXPGs) in erythrocytes (RBC). This can be a factor contributing to the variability of therapeutic and toxic effects. AIM: This pilot trial aimed to investigate the MTXPG concentrations in RBC as well as their relation to therapeutic and adverse effects during the initial 4 months of pharmacokinetically guided therapy with a divided-dose schedule (three doses of MTX separated by 12-h intervals once a week). SUBJECTS AND METHODS: Sixteen psoriatic patients (4 men and 12 women; mean age, 53 years; range, 28-69 years) with moderate-to-severe chronic plaque psoriasis [mean Psoriasis Area and Severity Index (PASI) = 24; range, 9-42] were enrolled in the study. Concentrations of plasma MTX and that of MTXPGs in RBC were assayed using liquid chromatography methods. The area under the concentration-time curve of plasma MTX in the interval 0-8 h post-dose (AUC(0-8 h)) was measured after a test bolus dose of 10 mg, and the starting weekly dose was individualized in order to achieve the target AUC(0-8 h) of 1800 nmol.h/L. The PASI, biochemistry, and haematology tests and MTXPGs levels in RBC were evaluated at baseline and at 4-week intervals. RESULTS: The AUC(0-8 h )achieved 1360 +/- 425 nmol.h/L (mean +/- SD: range, 778-2400 nmol.h/L). The mean (range) of individualized doses was 14.5 mg/week (7.5-22.5 mg). The mean (SD) steady-state concentration of total MTXPGs observed between days 85 to 110 reached 113 (34.6) nmol/L (range, 66.1-174 nmol/L). The PASI decreased from 24.0 +/- 8.0 (mean +/- SD) at baseline to 8.0 +/- 6.1 at day 110 (P < 0.001). Thirteen patients (87%) achieved a greater than 50% improvement in baseline PASI, and seven (47%) experienced a greater than 75% improvement. There was no relationship between the percent improvement from baseline PASI and the steady-state concentration of MTXPGs in RBC. All patients tolerated MTX well. Throughout the study period, there was a continuous increasing trend in the geometric mean values of the mean corpuscular volume from 92.6 to 96.4 fL (P < 0.001) and of plasma homocysteine from 9.5 to 12.3 micromol/L (P < 0.005). The geometric mean serum alanine aminotransferase (ALT) activity slightly increased from 0.49 to 0.80 microkat/L (P < 0.05). However, only two patients had the ALT activity transiently elevated above twice the upper limit of normal. CONCLUSION: Results of this pilot trial show that the steady-state levels of MTXPGs in RBC vary less than threefold between patients and did not correlate with the change in PASI observed after 4 months of therapy with an individualised weekly dose of MTX. Whether pharmacokinetically guided dosing can improve the results of psoriasis therapy with MTX should be prospectively tested in large controlled studies.

• MeSH
• aplikace orální MeSH
• dermatologické látky aplikace a dávkování   farmakokinetika   krev   MeSH
• dospělí MeSH
• erytrocyty metabolismus   MeSH
• financování organizované MeSH
• lidé středního věku MeSH
• lidé MeSH
• methotrexát aplikace a dávkování   farmakokinetika   krev   MeSH
• nežádoucí účinky léčiv MeSH
• pilotní projekty MeSH
• psoriáza farmakoterapie   krev   MeSH
• rozvrh dávkování léků MeSH
• senioři MeSH
• stupeň závažnosti nemoci MeSH
• výsledek terapie MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• klinické zkoušky MeSH

OBJECTIVE: We assessed the effect of folic acid (FA) on the pharmacokinetics and pharmacodynamics of low-dose oral methotrexate (MTX) during the remission-induction phase of psoriasis treatment. METHODS: In a 32-week, open-label, two-way cross-over study, patients (n=20, seven men, aged 35-70 years) with moderate-to-severe plaque psoriasis were randomly assigned to receive MTX plus FA (20 mg/week) for 16 weeks followed by MTX monotherapy (three doses of MTX separated by 12-h intervals once a week) for an additional 16 weeks (treatment arm A, n=10) or to receive the opposite sequence of treatments (arm B, n=10). Dosing of MTX was individualised with the help of pre-study evaluation of plasma MTX pharmacokinetics. The Psoriasis Area and Severity Index (PASI), biochemistry and haematology tests and erythrocyte concentration of MTX polyglutamates (MTXPG) were evaluated throughout the study. RESULTS: In arms A and B, the mean (range) concentrations of MTXPG (nmol/L) were comparable [week 16: 96.2 (32.0-157) vs. 111 (73.7-175), P=0.32; week 32: 103 (55.8-173) vs. 83.6 (27.4-129), P=0.24]. After 16 weeks, the mean+/-SEM PASI decreased from 20.1+/-2.1 to 8.8+/-1.3 in arm A, while a greater reduction from 27.2+/-2.1 to 5.1+/-1.0 occurred in arm B (P<0.001). Positive correlations were found between the percent improvement in PASI at week 16 and the ratios of the concentration of MTXPG to plasma folate (rho=0.59, P=0.008) or RBC folate concentration (rho=0.56, P=0.013). Due to an accelerated decline in PASI in arm A and a trend to its worsening in arm B after crossing over of treatments, the mean absolute PASI scores in both arms were comparable at week 32. CONCLUSION: 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.

• MeSH
• adherence pacienta MeSH
• antagonisté kyseliny listové farmakokinetika   škodlivé účinky   terapeutické užití   MeSH
• aplikace orální MeSH
• dermatologické látky farmakokinetika   škodlivé účinky   terapeutické užití   MeSH
• erytrocyty metabolismus   MeSH
• financování organizované MeSH
• klinické křížové studie MeSH
• kyselina listová krev   škodlivé účinky   terapeutické užití   MeSH
• kyselina polyglutamová MeSH
• lidé středního věku MeSH
• lidé MeSH
• methotrexát farmakokinetika   škodlivé účinky   terapeutické užití   MeSH
• potravní doplňky MeSH
• psoriáza farmakoterapie   MeSH
• senioři MeSH
• vitaminy krev   škodlivé účinky   terapeutické užití   MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• randomizované kontrolované studie MeSH

Lítium sa používá v psychiatrii najma na liečbu bipolárnych afektívnych poruch. V literatuře bolo opísaných množstvo dermatologických nežiaducich účinkov celkovej liečby lítiom. Najčastejšie sa vyskytuje akné a psoriáza, menej často je opisovaná seboroická dermatitída, morbus Darier, folikulitída, xeróza koze, strata vlasov a mnohé iné dermatózy. Paradoxné je, že lítium aplikované lokálně má terapeutický efekt na seboroickú dermatitídu a rekurentné infekcie herpes simplex. Zaujímavý je aj poznatok, že 30 % pacientov s pustulóznou psoriázou Barberovho typu, ktorí nikdy neboli liečení celkovo lítiom, majú výrazné zvýšenu hladinu lítia v sére. Ďalšie studie mechanizmov interného a externého posobenia lítia na kožu v budúcnosti zrejme pomožu pochopit' aj patogenézu spomínaných kožných ochorení.

Lithium represents an effective therapy for bipolar affective disorders. Many cutaneous adverse effects related to lithium treatment were published. The most prevalent dermatoses related to lithium therapy are acne and psoriasis, but seborrhoeic dermatitis, Darier's disease, folliculitis, xerosis cutis, hair loss and many others were reported. On the other side, therapeutic effects of topically applied lithium were noted in seborrhoeic dermatitis and recurrent herpes infections. Finding that 30% of patients with Barber's psoriasis pustulosa who were never treated with oral lithium have markedly higher serum levels of lithium is also very interesting. Further study of internal and external influence of lithium on the skin may help to understand the pathogenesis of above mentioned skin diseases.

• MeSH
• acne vulgaris etiologie   komplikace   MeSH
• antiinfekční látky lokální farmakokinetika   farmakologie   terapeutické užití   MeSH
• dermatologické látky farmakokinetika   farmakologie   terapeutické užití   MeSH
• lidé MeSH
• lithium farmakologie   škodlivé účinky   terapeutické užití   MeSH
• psoriáza etiologie   komplikace   MeSH
• Check Tag
• lidé MeSH

• MeSH
• aplikace kožní MeSH
• dermatologické látky aplikace a dávkování   farmakokinetika   terapeutické užití   MeSH
• dítě MeSH
• kojenec MeSH
• mladiství MeSH
• novorozenec MeSH
• péče o kůži MeSH
• Check Tag
• dítě MeSH
• kojenec MeSH
• mladiství MeSH
• novorozenec MeSH
• Publikační typ
• brožury MeSH
• populární práce MeSH
• příručky MeSH

• Konspekt
• Pediatrie
• NLK Obory
• pediatrie
• dermatovenerologie

• MeSH
• dermatologické látky farmakokinetika   moč   terapeutické užití   MeSH
• dospělí MeSH
• lidé MeSH
• methotrexát analogy a deriváty   aplikace a dávkování   MeSH
• psoriáza farmakoterapie   metabolismus   MeSH
• senioři MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• senioři MeSH

• MeSH
• dermatologické látky farmakokinetika   farmakologie   terapeutické užití   MeSH
• kožní nemoci farmakoterapie   MeSH
• Publikační typ
• přednášky MeSH

• Konspekt
• Patologie. Klinická medicína
• NLK Obory
• dermatovenerologie

OBJECTIVE: The aim of the present study was to investigate the pharmacokinetics and pharmacodynamics of low-dose methotrexate (MTX) in the early phase (3 months) after the start of antipsoriatic therapy. METHODS: Ten male and female psoriatic patients who failed to respond to previous conventional therapy were treated with 15 mg oral MTX once per week. The pharmacokinetics in plasma and the urinary excretion of MTX and 7-hydroxymethotrexate (7-OH MTX) were investigated after doses 1, 5 and 13 (corresponding to phases I, II and III, respectively). On the same occasions, MTX accumulation in erythrocytes obtained before MTX administration was investigated. Pharmacodynamics of MTX were evaluated using the psoriasis area and severity index (PASI) score. RESULTS: There were marked intersubject differences (range of coefficients of variation 34.9-76.3%) in the area under the curve (AUC), peak concentration (Cmax) and clearance (CL) of MTX. Total CL was proportional to renal clearance (CLR) (r2 = 0.735, P < 0.0001) which accounted for 73 (19)% of the former. There was a strong linear relationship (r2 = 0.819, P < 0.0001) between CL of MTX and creatinine clearance. Within 48 h of drug administration, the urinary excretion of MTX was 46-99% of the dose, while that of 7-OH MTX was 1.5-8.6%. In 8 of 10 patients, more than 70% of the MTX dose was recovered. No intraindividual variations of MTX kinetic parameters during treatment were observed. MTX concentrations in erythrocytes reached the steady-state concentration in the range 40.7-170 nmol.l(-1) after 2 months of therapy. Pharmacodynamic measurement versus pharmacokinetics revealed a significant inverse relationship between PASI score and MTX AUC (rs = -0.912, P < 0.002) and between PASI score and erythrocytic MTX (rs = -0.988, P < 0.002). CONCLUSION: The relationship between MTX pharmacokinetics (AUC or erythrocytic MTX) and pharmacodynamics (PASI score) may exist. It is likely that the efficacy of psoriasis therapy with MTX could be improved by adjusting the dose according to plasma concentrations obtained after the first MTX administration.

• MeSH
• časové faktory MeSH
• dermatologické látky aplikace a dávkování   farmakokinetika   krev   moč   MeSH
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• methotrexát aplikace a dávkování   farmakokinetika   krev   moč   MeSH
• psoriáza * farmakoterapie   krev   moč   MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• klinické zkoušky MeSH
• práce podpořená grantem MeSH