Controlled trial of methotrexate in patients with severe chronic asthma.

The aim of this study was to investigate the efficacy and adverse effects of methotrexate (MTX) in the treatment of severe chronic asthma in 12 patients with severe asthma requiring continuous treatment with oral steroids at the Outpatient Department of Helsinki University Central Hospital. The study was a randomised, double-blind placebo-controlled trial of methotrexate treatment 15 mg weekly on a crossover basis over 24 weeks. During the 2 weeks baseline phase the mean dose of oral steroids administered was 10.9 (3.2-28) mg.day-1, and the mean dose of inhaled steroids administered was 2.3 (1.6-3.2) mg budesonide or beclomethasone. The average dose of oral steroids administered was 12.8 mg.day-1 during the last 2 placebo weeks but only 7.9 mg.day-1 during the last 2 weeks with MTX treatment. The reduction in daily dose of oral steroids was 38%, while daily bronchodilator use was reduced by 22%. During MTX treatment the patients experienced significantly less wheezing, dyspnoea and coughing. Nine out of 12 patients reported better asthma control during MTX treatment. The peak expiratory flow rate (PEF) 1-s forced expiratory volume (FEV1) values did not differ between MTX and placebo treatments. There was no statistical correlation between serum MTX concentration and clinical improvement. No serious adverse effects of MTX were found during the study. It was concluded that low-dose MTX may be beneficial for severe chronic asthma and that this therapy is well tolerated by patients.

Simultaneous quantitation of methotrexate and its two main metabolites in biological fluids by a novel solid-phase extraction procedure using high-performance liquid chromatography.

We have developed an assay for the simultaneous determination of methotrexate (MTX) and its main metabolites, 7-hydroxymethotrexate (7-OHMTX) and 2,4-diamino-N10-methylpteroic acid (DAMPA) in plasma, urine and saliva meeting the requirement of rapidity for routine use in high-dose MTX therapy and the requirement of sensitivity for its potential use in therapeutic drug monitoring in low-dose MTX therapy. Sample preparation is based on solid-phase extraction using C8 Isolute cartridges. Chromatographic separation was achieved with a reversed-phase column (C18), and quantitation by subsequent exposure to UV light of 254 nm, which converted MTX and its two metabolites by photolytic oxidation to fluorescent products. The recoveries of MTX, 7-OHMTX and DAMPA from plasma at 100 nmol/l were 85.8, 91.1 and 102.3%, respectively. The limits of detection for MTX, 7-OHMTX and DAMPA in plasma and saliva were 0.1 nmol/l. In urine the limit of detection was 10 nmol/l for all compounds. The limits of quantitation in plasma and saliva were 0.5 nmol/l for all compounds.

Methotrexate in juvenile rheumatoid arthritis. Evidence of age dependent pharmacokinetics.

Children with juvenile rheumatoid arthritis (JRA) have been reported to require higher doses (per kg body weight) of methotrexate (MTX) than adults with rheumatoid arthritis to control their disease. The purpose of the present study was to characterise the plasma pharmacokinetics of MTX and its major metabolite, 7-hydroxymethotrexate (7-OHMTX) in children, and to compare the results with those previously obtained in adults. Thirteen patients (age 5-16 y) with JRA (median disease duration 5.5 y) were studied after once weekly oral administration of MTX (median 0.21 mg.kg-1). The analytical method was sufficiently sensitive to permit determination of plasma and urinary concentrations of MTX and 7-OHMTX during the entire dose interval in most of the patients. The dose normalized area under the plasma concentration versus time-curve (AUC) of MTX increased with the age of the children and was lower than previously found in adults. The dose normalized AUC of 7-OHMTX was not dependent on age. No correlation was found between the AUCs of MTX and 7-OHMTX. The results suggest that the age-dependence of the pharmacokinetics of MTX might explain the observation that at least some children require higher doses of MTX than adults to obtain a sufficient therapeutic effect.

Methotrexate in rheumatoid arthritis--a limited sampling strategy for estimation of the area under the plasma concentration versus time curve.

A limited sampling strategy for determination of the area under the plasma concentration versus time curve (AUC) of methotrexate (MTX) in patients with rheumatoid arthritis (RA), treated with weekly oral doses, has been validated. Stepwise linear regression analysis was used for optimal inclusion of data points in mathematical models to estimate AUC. A new plot for evaluation of the accuracy and precision of the estimated AUC values was introduced in the present study. By plotting the ratio of determined/estimated AUC values versus estimated AUC values, the influence of number of sampling points on the precision and accuracy of estimated AUC values was easily validated. Our results show that AUC values of MTX in RA patients can be estimated from a single plasma sample at 3 h or preferably, due to increased precision, by additional samplings at 5 and 1 h. A further increase of the number of sampling points increased the precision of the AUC estimates only to a minor extent. The accuracy of the estimated AUC values was independent of the number of sampling points. A limited sampling procedure can now be used for further studies on the relationship between MTX levels and its effects.

Reduced sulphoxidation capacity in D-penicillamine induced myasthenia gravis.

Myasthenia gravis may be observed due to treatment with penicillamine (D-PA). The sulphoxidation capacity was measured in nine Swedish patients with rheumatoid arthritis (RA) who had developed myasthenia gravis toward D-PA. The results show that in eight of nine patients tested, this parameter was markedly reduced. A patient with poor sulphoxidation capacity has a twelve-fold greater risk of developing this rare side effect. The significance of this is discussed.

The stereoselective disposition of the enantiomers of ibuprofen in blood, blister and synovial fluid.

1. A sensitive, stereospecific assay using gas chromatography-mass spectrometry (GC/MS) was established to measure the concentrations of the enantiomers of ibuprofen in small volumes (50 microliters) of blister fluid. 2. The concentrations of the enantiomers in blister fluid, assessed in eight patients, were similar to those in synovial fluid, both fluids behaving as peripheral compartments with respect to plasma. 3. The mean rate constants of transfer of R-ibuprofen into (0.14 +/- 0.06 h-1) and out of (0.20 +/- 0.04 h-1) blister fluid were not significantly different from those for synovial fluid (0.19 +/- 0.12 h-1, 0.34 +/- 0.11 h-1, respectively). Similarly, the mean rate constants of transfer of S-ibuprofen into (0.22 +/- 0.07 h-1) and out of (0.27 +/- 0.08 h-1) blister fluid were not significantly different from those for synovial fluid (0.29 +/- 0.10, 0.36 +/- 0.11 h-1). However, the correlations were poor between the transfer constants for each of the enantiomers between plasma, and both blister and synovial fluid (P > 0.2). 4. The complex rate constant of transfer of S-ibuprofen into blister fluid (0.22 +/- 0.07 h-1) was greater than that of R-ibuprofen (0.14 +/- 0.07 h-1), which may be explained by the lesser protein binding of the S-enantiomer.(ABSTRACT TRUNCATED AT 250 WORDS)

Chloroquine reduces the bioavailability of methotrexate in patients with rheumatoid arthritis. A possible mechanism of reduced hepatotoxicity.

OBJECTIVE: To evaluate the effects of a single dose of chloroquine (CQ) on the pharmacokinetics of methotrexate (MTX) in patients with rheumatoid arthritis. METHODS: Eleven patients (ages 41-75 years) who were taking oral doses of MTX (15 mg/week) were studied after a dose of MTX alone and after a dose of MTX plus CQ (250 mg). Plasma and urine samples were collected for 24 hours after dose intake, and the concentrations of MTX and its major metabolite 7-hydroxymethotrexate were determined by high-performance liquid chromatography. RESULTS: Administration of CQ together with MTX caused a reduction in the area under the plasma MTX concentration versus time curve (AUC). The median value of individual AUC ratios (MTX/MTX + CQ) was 1.6 (95% confidence interval 1.2-3.6). CONCLUSION: The most likely mechanism for the interaction is that CQ reduces the bioavailability of MTX. This gives a possible explanation for a suggested reduction in MTX-associated liver toxicity by coadministration of CQ. The significance of the interaction for the therapeutic effect remains to be elucidated.

Additive effect of combined naproxen and paracetamol in rheumatoid arthritis.

The clinical effect and plasma naproxen levels were studied in 20 patients with RA receiving three doses of naproxen and two naproxen doses combined with paracetamol (acetaminophen) in a randomized, double-blind, comparison in five 2-wk treatment periods. A significant dose-concentration effect relationship was found for the three naproxen doses (500, 1000 and 1500 mg daily). The following variables were measured: global clinical effect, joint index, morning stiffness, activity of daily living (ADL), pain during movement and at rest. The naproxen dose-concentration effect relationship curve was moved to the left by the addition of 4 g paracetamol daily. No major side effects were observed, but complaints concerning the gastrointestinal tract were fewer on lower naproxen doses and these were not increased by concomitant paracetamol treatment. The results show that the clinical effect of naproxen in RA may be significantly increased by concomitant paracetamol administration.

Renal effects of aspirin and low dose methotrexate in rheumatoid arthritis.

OBJECTIVES: The aim of this investigation was to study the glomerular and tubular effects of low doses (15 mg) of methotrexate in patients with rheumatoid arthritis with and without combined treatment with aspirin (2 g single dose). METHODS: Renal function was measured by the plasma clearance of EDTA labelled with chromium-51 (51Cr-EDTA) and mercaptoacetyltriglycine labelled with technetium-99m (99mTc-MAG-3). RESULTS: Clearance of 51Cr-EDTA was reduced from 98 (6) to 87 (5) ml/min (mean (SEM)) for patients receiving methotrexate only and further reduced to 76 (5) ml/min for patients receiving methotrexate and aspirin. This effect was reversible as 51Cr-EDTA increased to 85 (6) ml/min during continued treatment with methotrexate alone. Clearance of 99mTc-MAG-3 also decreased from 366 (18) to 315 (17) ml/min in patients receiving methotrexate alone and further to 295 (17) ml/min during treatment with aspirin and methotrexate. Continued treatment with methotrexate alone resulted in a further decrease in the 99mTc-MAG-3 clearance to 253 (17) ml/min. CONCLUSIONS: The study shows that treatment with low doses of methotrexate particularly when combined with aspirin affects glomerular and tubular function. These effects may be of clinical importance and renal function should therefore be monitored with more sensitive methods than serum creatinine as this may not reflect these changes.

Methotrexate--the relationship between dose and clinical effect.

Methotrexate (MTX) is an effective anti-rheumatic drug. Despite its frequent use, the relationship between different MTX doses and clinical effects remain unclear. In a randomized double-blind study in patients with RA, the effects of four MTX doses (5 to 20 mg) was studied. MTX (5 mg) induced a significant effect on the Ritchie joint index, morning stiffness, pain, ESR and C-reactive protein. The effect of MTX on those variables was related to the dose in the range from 5 to 20 mg MTX weekly. Interindividual differences in dose-response curves were observed. The study shows that MTX doses should be adjusted individually for each patient in order to improve efficacy and decrease dose-dependent side effects.

Pharmacokinetics of ibuprofen enantiomers in plasma and suction blister fluid in healthy volunteers.

After a single oral dose of (R,S)-ibuprofen (1200 mg) to five healthy volunteers, paired plasma and blister fluid concentrations of drug were determined by a stereospecific HPLC assay. A pharmacokinetic model that incorporated blister fluid as a separate peripheral compartment adequately characterized the data. The plasma concentrations were consistently higher for (S)-ibuprofen than (R)-ibuprofen in both plasma and blister fluid. No significant difference in the elimination half-life of the enantiomers was observed. Similar to synovial fluid, there were relatively small fluctuations in blister fluid concentrations of both enantiomers. Blister fluid, similar to synovial fluid, therefore behaves pharmacokinetically as a peripheral compartment for drug distribution. This use of skin blisters, which can be sampled repetitively, may therefore prove to be a valuable experimental technique in pharmacokinetic and pharmacodynamic studies of drugs, especially in patients in whom synovial fluid is not available for sampling.

Renal effects of low dose methotrexate in rheumatoid arthritis.

OBJECTIVE: Methotrexate (MTX) treatment at high doses may cause renal failure. The effects of treatment with low MTX doses on kidney function are, however, unknown. The objective of our study was to investigate the effect of low MTX doses on kidney function. METHODS: The glomerular filtration rate was measured as the plasma clearance of 51Cr-EDTA and the clearance of 99mTc-dimercaptoacetyl-triglycine (correction of triglycerine) (99mTc-MAG3), a new renal tubular function agent, was used to measure tubular effects of MTX. RESULTS: Significant decrease of both 51Cr-EDTA clearance from 92 +/- 7 to 83 +/- 5 ml/min x 1.73 m2 (mean +/- SEM) and of the 99mTc-MAG3 clearance from 360 +/- 18 to 309 +/- 15 ml/min x 1.73 m2 (p < 0.05) was observed. CONCLUSION: Our results indicate that low dose MTX treatment (15 mg weekly) may significantly impair kidney function which has to be considered particularly in situations with combined treatment with other potentially nephrotoxic substances.

Naproxen and paracetamol compared with naproxen only in coxarthrosis. Increased effect of the combination in 18 patients.

In a double-blind study of 18 patients with coxarthrosis the effect of 3 naproxen doses (0.5, 1.0, and 1.5 g daily) and 2 naproxen doses combined with paracetamol (0.5 g + 4 g daily and 1.0 g + 4 g daily) was investigated. Plasma levels of naproxen and paracetamol were measured (HPLC), and clinical assessment of pain, joint movement, activity of daily life and side-effects were performed at the end of the 5 treatment periods. A relationship was found between the 3 naproxen doses, naproxen plasma levels, pain at rest, and pain during movement. The combined treatment was more effective than treatment with the same naproxen dose alone. The effect of naproxen (0.5 g daily) combined with paracetamol (4 g daily) did not differ from that obtained during treatment with higher naproxen doses only. Furthermore, the effect of the highest naproxen dose was not better than the effect of the lower naproxen dose (1.0 g daily) combined with paracetamol. The main finding was that treatment with naproxen and paracetamol is more effective than treatment with higher naproxen doses alone.

Better effect of methotrexate on C-reactive protein during daily compared to weekly treatment in rheumatoid arthritis.

Treatment with methotrexate (MTX) is well established in rheumatoid arthritis (RA), but dosing remains arbitrary as studies on the effect of different dosing schedules are lacking. In a randomised crossover design of 20 patients with RA, the effect of low (2.5mg) oral daily doses of MTX (15 mg weekly) was compared to intermittent weekly dosing (15 mg). C-reactive protein (CRP) values were lower and more stable on daily dosing compared to the significant (p < 0.05) changes in CRP observed during treatment with the same weekly dose. It may be postulated that nonresponders or patients with dose-dependent side effects may have clinical advantage from daily MTX dosing if hepatotoxicity and other side effects are not increased.

The pharmacokinetics of methotrexate and its 7-hydroxy metabolite in patients with rheumatoid arthritis.

1. The pharmacokinetics of MTX and its 7-hydroxy metabolite (7-OHMTX) were investigated in nine patients with rheumatoid arthritis (RA). Each patient received 15 mg MTX i.v., i.m. and p.o. after an overnight fast in a randomized cross-over design. The plasma concentrations of MTX and 7-OHMTX were measured over 7 days and their urinary excretion over 24 h. 2. Plasma concentrations of MTX were described by a triexponential function after i.v. administration, a triexponential function with zero or first order absorption after oral administration, and a biexponential function with zero of first order absorption after i.m. injection. Plasma concentrations of 7-OHMTX were described by a biexponential function after all three routes of administration. The median terminal elimination half-lives of MTX and 7-OHMTX were 55 h and 116 h, respectively. The area under the plasma concentration-time curve (AUC (0,170 h)) of MTX did not differ between i.m. and oral administration indicating similar bioavailability after these routes of administration. The AUC (0,170 h) values of 7-OHMTX after i.v., oral and i.m. administration were similar. Over 80% of MTX was excreted in urine as intact drug and about 3% was excreted as 7-OHMTX during 24 h after drug administration. 3. Plasma concentrations of MTX and 7-OHMTX were measurable at the end of the dose interval in most of the patients and may help to identify non-responders or patients with increased risk of side-effects.

Adverse drug interactions with nonsteroidal anti-inflammatory drugs (NSAIDs). Recognition, management and avoidance.

The prevalence and incidence of adverse drug interactions involving nonsteroidal anti-inflammatory drugs (NSAIDs) remains unknown. To identify those proposed drug interactions of greatest clinical significance, it is appropriate to focus on interactions between commonly used and/or commonly coprescribed drugs, interactions for which there are numerous well documented case reports in reputable journals, interactions validated by well designed in vivo human studies and those affecting high-risk drugs and/or high-risk patients. While most interactions between NSAIDs and other drugs are pharmacokinetic, NSAID-related pharmacodynamic interactions may be considerably more important in the clinical context, and prescriber ignorance is likely to be a major determinant of many adverse drug interactions. Prescribing NSAIDs is relatively contraindicated for patients on oral anticoagulants due to the risk of haemorrhage, and for patients taking high-dose methotrexate due to the dangers of bone marrow toxicity, renal failure and hepatic dysfunction. Combination NSAID therapy cannot be justified as toxicity may be increased without any improvement in efficacy. Where lithium or anti-hypertensives are coprescribed with NSAIDs, close monitoring is mandatory for lithium toxicity and hypertension, respectively, and aspirin (acetylsalicylic acid) or sulindac are preferred. Phenytoin or oral hypoglycaemic agents may be administered with NSAIDs other than pyrazoles and salicylates provided that patients are monitored carefully at the initiation and cessation of NSAID treatment. Digoxin, aminoglycosides and probenecid may be coprescribed with NSAIDs, but close monitoring is required, particularly for high-risk patients such as the elderly. Indomethacin and triamterene should be avoided due to the risk of renal failure. High dose aspirin should be replaced by naproxen in patients on valproic acid (sodium valproate) and care is required when corticosteroids are administered to patients taking salicylates long term in high dosage. Interactions between NSAIDs and antacids or cholestyramine are generally avoidable. Adverse drug interactions involving NSAIDs may be limited by rational prescribing and by careful monitoring, particularly for high-risk patients, drugs and therapy periods.

Paracetamol in rheumatoid arthritis.

The need for supplementary analgesic treatment in RA has partially been neglected. Increasing evidence now support that paracetamol supplementation can increase the effect of NSAIDs. A hypothesis may be postulated that prostaglandin (PG) mediated anti-inflammatory effects of NSAIDs are only marginally increased by higher NSAID doses and that non PG mediated analgesic effects obtained at higher NSAID doses may instead be obtained by supplementing NSAIDs with paracetamol. Combined paracetamol treatment may increase the effect and decrease dose-dependent side-effects of NSAIDs.

Sensitivity to UV light during treatment with chloroquine in rheumatoid arthritis.

Chloroquine and hydroxychloroquine have long been suspected of causing light sensitivity in patients with rheumatoid arthritis (RA). To gain insight into the effect of chloroquines and ultraviolet (UV) light in RA we have phototested 25 RA patients with and without chloroquine. The thresholds for UVA and UVB did not change upon treatment with chloroquine or hydroxychloroquine. Provocation with high dose UVA and UVB was similar with and without treatment with chloroquine or hydroxychloroquine. Our results have shown that photosensitivity during medication with chloroquine and hydroxychloroquine is uncommon and that there is no need to stop this treatment due to sun exposure.

NSAIDs, musculoskeletal disorders and gastrointestinal adverse effects.

Paracetamol should be considered as first line treatment for the common painful musculoskeletal disorders, especially osteoarthrosis. NSAIDs, which are beneficial should this fail and inflammation be present, should be prescribed in the lowest dose for the shortest possible time.

Trace analysis of methotrexate and 7-hydroxymethotrexate in human plasma and urine by a novel high-performance liquid chromatographic method.

A new high-performance liquid chromatographic method for the quantitative determination of methotrexate (MTX) and its metabolite 7-hydroxymethotrexate (7-OHMTX) in blood plasma and urine was developed. The method utilized a solid-phase extraction procedure (Certify II cartridges) for the simultaneous isolation of MTX and 7-OHMTX. Chromatographic separation was achieved using a C18 reversed-phase column with isocratic elution. The eluent was irradiated with UV light of 254 nm, which converted MTX and 7-OHMTX by photolytic oxidation to fluorescent products. The limits of detection of MTX and 7-OHMTX in plasma were approximately 0.2 and 1 nmol/L, respectively. The intraday variability in the quantitation of MTX and 7-OHMTX was less than 8% down to 1 nmol/L and 4.6 nmol/L, respectively. Both MTX and 7-OHMTX could be detected in plasma from a patient being treated for rheumatoid arthritis 1 week after the last dose (10 mg orally).