Infliximab inhibits progression of radiographic damage in patients with active psoriatic arthritis through one year of treatment: Results from the induction and maintenance psoriatic arthritis clinical trial 2.

OBJECTIVE: To evaluate the effect of infliximab on progression of structural damage over 1 year in patients with active psoriatic arthritis (PsA) enrolled in the Induction and Maintenance Psoriatic Arthritis Clinical Trial 2. METHODS: In this double-blind, placebo-controlled study, 200 patients with active PsA were randomly assigned (1:1 ratio) to receive infusions of infliximab (5 mg/kg) or placebo at weeks 0, 2, and 6, and every 8 weeks thereafter through week 54. At week 24, patients initially assigned to receive placebo crossed over to receive infliximab (5 mg/kg). Based on predefined criteria, patients randomized to receive placebo could enter early escape by receiving infliximab (5 mg/kg) starting at week 16, and patients randomized to receive infliximab could have the dose increased to 10 mg/kg starting at week 38. Patients were analyzed according to the treatment they were randomized to receive. Radiographs of hands and feet were obtained at baseline and at weeks 24 and 54. Two readers blinded to treatment assignment and radiograph sequence independently evaluated erosions and joint space narrowing using the Sharp/van der Heijde scoring method modified for PsA. RESULTS: At week 24, patients randomized to receive infliximab 5 mg/kg had significantly less radiographic progression compared with patients randomized to receive placebo, with mean +/- SD changes from baseline in the total Sharp/van der Heijde score of -0.70 +/- 2.53 and 0.82 +/- 2.62, respectively (P < 0.001). At week 54, mean +/- SD changes from baseline in the total Sharp/van der Heijde score were -0.94 +/- 3.40 in patients randomized to receive infliximab and 0.53 +/- 2.60 in those receiving placebo/infliximab (P = 0.001). CONCLUSION: Infliximab significantly inhibits radiographic progression in patients with PsA as early as 6 months after starting treatment, and the beneficial effect continues through 1 year of infliximab therapy.

Infliximab maintains a high degree of clinical response in patients with active psoriatic arthritis through 1 year of treatment: results from the IMPACT 2 trial.

OBJECTIVE: To evaluate the efficacy and safety of infliximab through 1 year in patients with psoriatic arthritis (PsA) enrolled in the IMPACT 2 trial. METHODS: In this double blind, placebo controlled, phase III study, 200 patients with active PsA were randomised to receive infusions of infliximab 5 mg/kg or placebo at weeks 0, 2, 6, and every 8 weeks thereafter through 1 year. Patients with persistent disease activity could enter early escape at week 16, and all remaining placebo patients crossed over to infliximab at week 24. Patients randomised to infliximab who had no response or who lost response could escalate their dose to 10 mg/kg starting at week 38. Clinical efficacy was assessed based on the proportion of patients achieving ACR 20 and PASI 75 responses. Major clinical response (that is, maintenance of ACR 70 response for 24 continuous weeks) was assessed for the first time in PsA. RESULTS: Through 1 year of treatment, 58.9% and 61.4% of patients in the randomised infliximab and placebo/infliximab groups, respectively, achieved ACR 20; corresponding figures for PASI 75 were 50.0% and 60.3%. At week 54, major clinical response was achieved by 12.1% of patients in the infliximab group. The safety profile of infliximab through week 54 was consistent with that seen through week 24. Two malignancies occurred: basal cell skin cancer (placebo) and stage I Hodgkin's lymphoma (infliximab). CONCLUSION: Infliximab maintains a high degree of clinical efficacy and continues to be well tolerated in patients with PsA through 1 year of treatment.

The homeobox gene repo is required for the differentiation and maintenance of glia function in the embryonic nervous system of Drosophila melanogaster.

We describe the cloning, expression and phenotypic characterisation of repo, a gene from Drosophila melanogaster that is essential for the differentiation and maintenance of glia function. It is not, however, required for the initial determination of glial cells. In the embryo, the gene, which encodes a homeodomain protein, is expressed exclusively in all developing glia and closely related cells in both the central and peripheral nervous systems. The only observed exceptions in the CNS are the midline glia derived from the mesectoderm and two of three segmental nerve root glial cells. Using a polyclonal antibody we traced the spatial and temporal pattern of the protein expression in detail. Embryos homozygous for null alleles of the protein exhibit late developmental defects in the nervous system, including a reduction in the number of glial cells, disrupted fasciculation of axons, and the inhibition of ventral nerve cord condensation. The expression of an early glial-specific marker is unaffected in such homozygotes. By contrast, the expression of late glial-specific markers is either substantially reduced or absent. The specificity of expression is also observed in the locust Schistocerca gregaria and is thus evolutionarily conserved.

Transcription through the yeast origin of replication ARS1 ends at the ABFI binding site and affects extrachromosomal maintenance of minichromosomes.

When the function of origins of replication in yeast was compromised by placing ARS sequences downstream of strong promoters, ARS activity might have been affected either by transcription or by an altered chromatin configuration induced by the construct. To distinguish between these possibilities, derivatives of the yeast TRP1ARS1 minichromosome were constructed that contained either the DED1 or the PET56 promoter firing against ARS1 (DEDARS and PETARS constructs). PETARS constructs transformed yeast at high frequencies and were maintained as minichromosomes consistent with efficient ARS1 function, but DEDARS constructs transformed at low frequencies and had to be rescued as minichromosomes by insertion of a second ARS (H4-ARS). Chromatin analysis revealed that the ARS1 regions in PETARS and H4-DEDARS constructs were indistinguishable from the ARS1 region of the host TRP1ARS1 circle showing a nuclease sensitive region flanked by a nucleosome. However, RNA-analysis in the ARS region showed high and low levels of transcripts in H4-DEDARS and PETARS, respectively. Transcription elongated through the A, B1, and B2 elements and ended in B3, the binding site for ABFI. We conclude that transcription through ARS1 and not an altered chromatin structure affected ARS activity in these constructs.

Insufficiency os pubis fractures in rheumatoid arthritis.

There is a paucity of information regarding insufficiency fractures of the os pubis in rheumatoid arthritis. While only 7 such fractures have been recorded thus far in the English literature, we have encountered 5 os pubis fractures in the past 4-year period. We report these cases to heighten awareness of their existence, describe their sometimes misleading clinical presentations, and to discuss possible etiologic factors.

Thoracic outlet syndrome mimicking angina pectoris with elevated creatine phosphokinase values.

Four patients with elevated creatine phosphokinase (CPK) values and recurrent chest pain were found to have thoracic outlet syndrome. This association of abnormal CPK levels and chest pain due to thoracic outlet syndrome has not been previously reported. Symptoms and CPK values improved with anti-inflammatory medications and/or proper posture instruction. It is proposed that CPK values become elevated by ischemic or neurologic compromise of muscles supplied by the subclavian artery or brachial plexus respectively. Accordingly, chest pain in the same dermatomal distribution as that of angina pectoris may be simulated by ischemic skeletal muscle. Thoracic outlet syndrome therefore should be suspected in any patient with chronically abnormal CPK values and chest pain in whom no other etiology can be determined.

Influence of hepatic insufficiency in pharmacokinetics of drugs: example for an anthranilic diuretic.

Hepatic insufficiency is responsible for numerous modifications of drug metabolism and pharmacokinetics, because the liver is the most important organ for the transformation and, with the kidney, elimination of drugs. Pharmacokinetics of furosemide, an anthranilic diuretic, was compared in normal subjects and cirrhotics with hepatic insufficiency, after oral administration. In patients, we observed few modifications of the bioavailability. The total elimination of the drug was normal when the urinary excretion compensated a slight reduction in biliary secretion, but when this reduction was important the total clearance of furosemide decreased. In urine, the elimination time was lengthened, but the percentage of excretion was about the same as for normal subjects. The pharmacological effects were also modified for cirrhotics with decrease of sodium and water excretion, for the same blood concentration of drug as in controls. Also, we observed a shift between the salidiuretic effect and the blood concentration in patients, when there was an exact concordance of these times in control subjects. Two hypotheses have been proposed to explain this phenomenon: (1) modifications in hepatic metabolism or, (2) in drug protein binding.

[Pharmacokinetic study of intravenous furosemide in nephrotic syndrome in children]. / Etude pharmacocinetique du furosemide intraveineux dans les syndromes nephrotiques de l'enfant.

The pharmacokinetics and pharmacological effect of intravenous furosemide (F) (2 mg/kg body weight) were studied in 12 children with the nephrotic syndrome with or without renal failure (R.F.). The concentration of F in blood and urine was determined by a new spectrophotometric method. In the nephrotic syndrome alone, the rate of renal excretion was increased (increased slope of the pharmacokinetic curve, decreased t 1/2), which may be due to a decrease in the fraction bound to plasma albumin. In children with the nephrotic syndrome and renal failure, the decrease in the renal excretion of F was related to the degree of renal failure. In normal children the mean F clearance is 296. In patients with N.S. alone the clearance is greatly increased (X = 377) and in N.S. with R.F. it is reduced (0.17-90). The possible mechanisms and therapeutic implications of the results are discussed.

[Spectrofluorometric determination of furosemide in biological fluids. Application to pharmaco- and biokinetic studies]. / Dosage spectrofluorimétrique du furosémide dans les liquides biologiques. Application aux études de pharmaco- et de biocinétique

The present report describes spectrofluorimetric methods for evaluation of furosemide (a sulfamide diuretic derived from anthranilic acid) in plasma or urine. The availability of these methods is discussed. These methods can be used for pharmacokinetic and pharmacological studies and sometimes resolution of therapeutic problems.