Leflunomide and Polyomavirus-Associated Nephropathy in Renal Transplant

Polyomavirus nephropathy is a major complication in renal transplantation, associated with renal allograft loss in 14 to 80% of cases. There is no established treatment, although improvement has been reported with a variety of approaches. The authors report two cases of polyomavirus infection in renal allograft recipients. In the first case, a stable patient presented with deterioration of renal function, worsening hypertension and weight gain following removal of ureteral stent placed routinely at the time of surgery. Ultrasound examination and radiology studies revealed hydronephrosis due to ureteral stenosis. A new ureteral stent was placed, but renal function did not improve. Urinary cytology revealed the presence of decoy cells and polyomavirus was detected in blood and urine by qualitative polymerase chain reaction. Renal biopsy findings were consistent with polyomavirus -associated nephropathy. In the second case, leucopaenia was detected in an asymptomatic patient 6 months after transplantation. Mycophenolate mophetil dosage was reduced but renal allograft function deteriorated, and a kidney biopsy revealed polyomavirus -associated nephropathy, also with SV40 positive cells. In both patients immunosuppression with tacrolimus was reduced, mycophenolate mophetil stopped and intravenous immune globulin plus ciprofloxacin started. As renal function continued to deteriorate, therapy with leflunomide (40 mg/day) was associated and maintained during 5 and 3 months respectively. In the first patient, renal function stabilised within one month of starting leflunomide and polymerase chain reaction was negative for polyomavirus after 5 months. A repeated allograft biopsy 6 months later showed no evidence of polyomavirus nephropathy. In the second patient, polyomavirus was undetectable in blood and urine by polymerase chain reaction after 3 months of leflunomide treatment, with no evidence of polyomavirus infection in a repeated biopsy 6 months after beginning treatment.

Formation of multiple pulmonary nodules during treatment with leflunomide

O comprometimento pulmonar é uma das manifestações extra-articulares da artrite reumatóide e pode ser devido à própria doença ou secundário às medicações utilizadas para seu tratamento. Este trabalho relata um caso de uma paciente de 60 anos de idade com diagnóstico de artrite reumatoide que evoluiu com múltiplos nódulos pulmonares durante o tratamento com leflunomida.

Rapid determination of the active leflunomide metabolite A77 1726 in human plasma by high-performance liquid chromatography

A simple method for the measurement of the active leflunomide metabolite A77 1726 in human plasma by HPLC is presented. The sample workup was simple, using acetonitrile for protein precipitation. Chromatographic separation of A77 1726 and the internal standard, alpha-phenylcinnamic acid, was achieved using a C-18 column with UV detection at 305 nm. The assay displayed reproducible linearity for A77 1726 with determination coefficients (r(2)) > 0.997 over the concentration range 0.5-60.0 mug/ml. The reproducibility (%CV) for intra- and inter-day assays of spiked controls was

Population pharmacokinetics and association between A77 1726 plasma concentrations and disease activity measures following administration of leflunomide to people with rheumatoid arthritis

Aims To investigate the concentration-effect relationship and pharmacokinetics of leflunomide in patients with rheumatoid arthritis (RA). Methods Data were collected from 23 RA patients on leflunomide therapy (as sole disease modifying antirheumatic drug (DMARD)) for at least 3 months. Main measures were A77 1726 (active metabolite of leflunomide) plasma concentrations and disease activity measures including pain, duration/intensity of morning stiffness, and SF-36 survey. A population estimate was sought for apparent clearance (CL/F ) and volume of distribution was fixed (0.155 l kg(-1)). Factors screened for influence on CL/F were weight, age, gender and estimated creatinine clearance. Results Significantly higher A77 1726 concentrations were seen in patients with less swollen joints and with higher SF-36 mental summary scores than in those with measures indicating more active disease (P < 0.05); concentration-effect trends were seen with five other disease activity measures. Statistical analysis of all disease activity measures showed that mean A77 1726 concentrations in groups with greater control of disease activity were significantly higher than those in whom the measures indicated less desirable control (P < 0.05). There was large between subject variability in the dose-concentration relationship. A steady-state infusion model best described the pharmacokinetic data. Inclusion of age as a covariate decreased interindividual variability (P < 0.01), but this would not be clinically important in terms of dosage changes. Final parameter estimate (% CV interindividual variability) for CL/F was 0.0184 l h(-1) (50%) (95% CI 0.0146, 0.0222). Residual (unexplained) variability (% CV) was 8.5%. Conclusions This study of leflunomide in patients using the drug clinically indicated a concentration-effect relationship. From our data, a plasma A77 1726 concentration of 50 mg l(-1) is more likely to indicate someone with less active disease than is a concentration around 30 mg l(-1). The marked variability in pharmacokinetics suggests a place for individualized dosing of leflunomide in RA therapy.

How is leflunomide prescribed and used in Australia? analysis of prescribing and adverse effect reporting

Purpose To evaluate the use of leflunomide in the Australian community since introduction in 2000. Trends in adverse drug reaction (ADR) reporting were also studied. Methods Annual Australian prescription and dispensing statistics were analysed. Drug utilisation was estimated as defined daily doses (DDD)/1000 inhabitants/day. ADR data from the Therapeutic Goods Administration's Adverse Drug Reactions Advisory Committee (ADRAC) national monitoring system were compared with the World Health Organisation (WHO) Vigibase records. Results Leflunomide use in Australia (dispensing data) increased from 0.2 in 2000 to 0.4 DDD/1000 inhabitants/day in 2002. The same overall pattern was observed in the 'authority to prescribe' data. From 2000-2002, prescribing of the starter pack (3 x 100 mg loading dose plus 30 x 20 mg tablets) declined (down 74%); likewise for the 20mg (30 tablets) pack. Gradual increases were noted for the 10 mg (30 tablets) pack (up 40%). Approximately 135 reports, detailing about 370 individual ADR, were generated annually. Gastro-intestinal disorders predominated, accounting for 24% of reactions reported to ADRAC. Skin and appendages disorders constituted 14% of reported reactions. Deaths in leflunomide users were attributed to a combination of haematological and gastro-intestinal complications, but it was not possible to ascertain other medication usage or contributing factors. Trends observed with the ADRAC reports were consistent with the WHO database. Conclusions Leflunomide was the first registered DMARD in Australia in over a decade and its use has increased within the community. The ADR reports might have contributed to Australian rheumatologists gradually abandoning loading patients with high doses of leflunomide in favour of starting therapy at lower doses. Copyright (c) 2006 John Wiley & Sons, Ltd.

Leflunomide improves psoriasis in patients with psoriatic arthritis: An in-depth analysis of data from the TOPAS study

Background: Leflunomide has shown promise in the treatment of psoriasis. Objective: To provide an in-depth analysis of the effect of leflunomide on psoriasis in patients with psoriatic arthritis (PsA). Methods: 190 patients with plaque psoriasis (at least 3% skin involvement) and active PsA were randomized to double-blind treatment with leflunomide (100 mg/day loading dose for 3 days followed by 20 mg/day orally) or placebo for 24 weeks. Results: As previously reported, leflunomide resulted in a significantly higher Psoriatic Arthritis Response Criteria response rate than placebo (58.9 vs. 29.7%; p < 0.0001). Significant differences in favor of leflunomide were also observed in the Psoriasis Area and Severity Index (PASI 50 in 30.4% of patients vs. 18.9% for placebo; p = 0.05), target lesion response (46.4 vs. 25.3%; p = 0.0048), combined skin and joint response (27.2 vs. 8.9%; p < 0.0001), Dermatology Life Quality Index (improvement of 1.9 points vs. 0.2; p = 0.0173) and certain SF-36 subdomains. Dermatological responses were observed at the earliest examination (4 weeks) and increased throughout the 24-week study. Conclusion: Once-daily oral leflunomide is an effective and convenient treatment for PsA and plaque psoriasis. Copyright (c) 2006 S. Karger AG, Basel.

The effectiveness of leflunomide etanercept and infliximab in the treatment of rheumatoid arthritis:a systematic review

DUE TO COPYRIGHT RESTRICTIONS ONLY AVAILABLE FOR CONSULTATION AT ASTON UNIVERSITY LIBRARY AND INFORMATION SERVICES WITH PRIOR ARRANGEMENT

Defects in vesicle core induced by Escherichia coli dihydroorotate dehydrogenase

Dihydroorotate dehydrogenase (DHODH) catalyzes the oxidation of dihydroorotate to orotate during the fourth step of the de novo pyrimidine synthesis pathway. In rapidly proliferating mammalian cells, pyrimidine salvage pathway is insufficient to overcome deficiencies in that pathway for nucleotide synthesis. Moreover, as certain parasites lack salvage enzymes, relying solely on the de novo pathway, DHODH inhibition has turned out as an efficient way to block pyrimidine biosynthesis. Escherichia coli DHODH (EcDHODH) is a class 2 DHODH, found associated to cytosolic membranes through an N-terminal extension. We used electronic spin resonance (ESR) to study the interaction of EcDHODH with vesicles of 1,2-dioleoyl-sn-glycero-phosphatidylcholine/detergent. Changes in vesicle dynamic structure induced by the enzyme were monitored via spin labels located at different positions of phospholipid derivatives. Two-component ESR spectra are obtained for labels 5- and 1 0-phosphatidylcholine in presence of EcDHODH, whereas other probes show a single-component spectrum. The appearance of an additional spectral component with features related to fast-motion regime of the probe is attributed to the formation of a defect-like structure in the membrane hydrophobic region. This is probably the mechanism used by the protein to capture quinones used as electron acceptors during catalysis. The use of specific spectral simulation routines allows us to characterize the ESR spectra in terms of changes in polarity and mobility around the spin-labeled phospholipids. We believe this is the first report of direct evidences concerning the binding of class 2 DHODH to membrane systems.

Investigation on Brazilian Clinical Practices in Rheumatoid Arthritis The Brazilian Rheumatoid Arthritis Clinical Practices Investigation-BRACTICE

Rheumatoid arthritis (RA) is a systemic inflammatory autoimmune disease causing significant social, medical, and economic impact. Several therapeutic regimens are available within the medical arsenal. The rational and reasoned use of various medications approved for their treatment is imperative. This study aimed to evaluate how Brazilian rheumatologists use the drugs available to combat the disease. For this, 128 Brazilian rheumatologists from public and private health services responded to an 18-item questionnaire, sent over the Internet, about different situations of drug treatment of RA. The answers helped to confirm the trends among Brazilian rheumatologists in the drug treatment of RA. The study results have shown that most Brazilian rheumatologists follow the guidelines and consensus established by the Brazilian Society of Rheumatology for the treatment of RA. A small proportion, however, start the biologic therapy in early stages of the disease, including the very early stage, as the first treatment option. Most experts use corticosteroids in low doses early in the treatment. Conclusions: This study confirms that the majority but not all Brazilian rheumatologists follow, in their daily practice, established guidelines and consensus for the treatment of RA. However, it also shows that some few rheumatologists start with anti-tumor necrosis factor therapy in very early arthritis independently of disease severity or prognostic factors.

Cost analysis of drug therapy in rheumatoid arthritis

With the aim to compare the cost of treatment for rheumatoid arthritis therapy with desease-modifying antirheumatic drugs (DMARDS) for a 48-month period, were studied five different treatment stage based on clinical protocols recommended by the Brazilian Society of Rheumatology, and then five therapy cycles. The analytical model based on the Markov Analysis, considered chaces for the patient continue in some stages or change between them according with a positive effect on outcomes. Only direct costs were comprised in the analyzed data, like drugs, materials and tests used for monitoring these patients. The results of the model show that the stage in with metotrexato drug is used like monotherapy was cost-effective (R$ 113,900,00 for patient during 48 months), followed by refractory patient (R$ 1,554,483,43), those that use therapy triplicate followed by infleximable drug (R$ 1, 701, 286.76), the metotrexato intolearant patient (R$ 2,629,919,14), and final the result from that use metotrexato and infliximable in the beginning (R$ 9,292,879,31). The sensitivity analysis confirm this results, when alternate the efficacy of metotrexato and infliximabe.