Co-administration of pentoxifylline and thiopental causes death by acute pulmonary oedema in rats

BACKGROUND AND PURPOSE: Pentoxifylline exhibits rheological properties that improve microvascular flow and it is widely used in vascular perfusion disorders. It also exhibits marked anti-inflammatory properties by inhibiting tumour necrosis factor alpha production. Thiopental is one of the most widely used drugs for rapid induction of anaesthesia. During experimental studies on the treatment of acute pancreatitis, we observed that when pentoxifylline was administered after anaesthesia with thiopental, most of the rats exhibited dyspnea, signs of pulmonary oedema and died. The aim of the work described here was to investigate the cause of the unexpected toxic effect of the combined treatment with thiopental and pentoxifylline. EXPERIMENTAL APPROACH: Pulmonary vascular permeability and arterial blood gases were measured, and a histological analysis was performed. The possible role of haemodynamic changes in the formation of pulmonary oedema was also assessed. KEY RESULTS: Co-administration of pentoxifylline and thiopental increased pulmonary vascular permeability and markedly decreased arterial pO2, with one third of rats suffering from hypoxemia. This combined treatment caused death by acute pulmonary oedema in 27% of normal rats and aggravated the respiratory insufficiency associated with acute pancreatitis in which the mortality rate increased to 60%. This pulmonary oedema was not mediated by cardiac failure or by pulmonary hypertension. CONCLUSIONS AND IMPLICATIONS: Co-administration of pharmacological doses of pentoxifylline and thiopental caused pulmonary oedema and death in rats. Consequently, pentoxifylline should not be administered when anaesthesia is induced with thiopental to avoid any possible risk of acute pulmonary oedema and death in humans.     

Serological status: a predictor of response to intensive therapy in rheumatoid arthritis

BackgroundRheumatoid arthritis is the most common chronic inflammatory disease in the UK. Serological status such as rheumatoid factor (RF) and anti-citrullinated peptide antibody (ACPA) positivity predict poor outcomes. Early intensive treatment regimens targeting remission reduce disease activity, structural damage, and long-term disability. However, we do not know whether all patients with active disease should have such intensive treatment regimens. Can serological status be used to predict the need for intensive therapy?MethodsWe analysed samples from a published randomised controlled trial which compared four treatment regimens in patients with early active rheumatoid arthritis (disease duration <2 years): methotrexate monotherapy, double therapy (methotrexate plus either ciclosporin or prednisolone), and triple therapy (methotrexate plus ciclosporin plus prednisolone). The trial randomised 467 patients (68% female, median age 54 years [IQR 46–63]). Disease activity was assessed with the disease activity score of 28 joints (DAS28). Remission was defined as DAS28 less than 2·6 at 24 months. RF isotypes (IgM and IgA) and ACPA levels were measured with commercial ELISA kits. Statistical analysis used Pearson's chi-squared test.Findings402 (86%) patients were positive for IgM RF, 346 (74%) for IgA RF, and 346 (74%) for ACPA. 98 (21%) patients achieved remission at 24 months. In RF IgM negative cases (n=65) the proportion of patients achieving remission at 24 months was similar in all treatment groups (25%, 22%, and 30% for monotherapy, double therapy, and triple therapy, respectively). In RF IgM positive cases, significantly fewer patients achieved remission with monotherapy (13/65, 17%) and double therapy (24/157, 15%) than with triple therapy (27/80, 34%) (p=0·001). There were similar, consistent findings with IgA RF and ACPA, with significantly more seropositive patients achieving remission with triple therapy than with monotherapy.InterpretationContemporary treatment of rheumatoid arthritis emphasises the use of intensive therapy to achieve remission. However, we have shown that not all patients require such an aggressive approach to therapy. Given the heterogeneity of the diease, treatment should be personalised to the individual, which would minimise costs of treatment as well as potentially toxic side-effects. Our study shows that only seropositive patients with rheumatoid arthritis should be given more intensive therapies.FundingNational Institute for Health Research.     

Germline <Emphasis Type="Italic">MUTYH</Emphasis> gene mutations are not frequently found in unselected patients with papillary breast carcinoma

MUTYH- associated polyposis (MAP) is an autosomal recessive disease, which predisposes to polyposis and colorectal cancer. There is a trend towards an increased risk of breast cancer in MAP patients, with a remarkable proportion of papillary breast cancers. To determine whether MUTYH mutations are associated with this specific and rare type of breast cancer, 53 unselected patients with papillary breast cancer were analyzed for founder mutations in the MUTYH gene. No germline mutations were identified, indicating that biallelic MUTYH mutations are not a frequent underlying cause for the development of papillary carcinomas of the breast.