Inhaled corticosteroid use in HIV‐positive individuals taking protease inhibitors: a review of pharmacokinetics,case reports and clinical management

As a consequence of inhibition of the hepatic cytochrome P450 3A4 isozyme, treatment with HIV protease inhibitors can result in significant drug?drug interactions. One noteworthy interaction is between protease inhibitors and inhaled or intranasal corticosteroids. This interaction can result in adrenal insufficiency and iatrogenic Cushing's syndrome (with symptoms such as rapid weight gain, obesity, facial hirsutism and swelling), as well as hypertension, osteoporosis and decreased CD4 cell count. In this paper, we review and unite pharmacokinetic data, case reports and current research regarding this drug?drug interaction in order to suggest options for the clinical management of HIV‐positive patients requiring treatment with protease inhibitors and inhaled or intranasal corticosteroids.     

Detecting diminutive colorectal lesions at colonoscopy: a randomised controlled trial of pan-colonic versus targeted chromoscopy

BACKGROUND: Diminutive and flat colorectal lesions can be difficult to detect using conventional colonoscopic techniques. Previous data have suggested that pan-chromoscopy may improve detection rates. No randomised control trial has been performed examining detection rates of such lesions while controlling for extubation time and lavage effect. AIM: We conducted a randomised controlled trial of pan-colonic chromoscopic colonoscopy for the detection of diminutive and flat colorectal lesions while controlling for extubation time and lavage effect. METHODS: Consecutive patients attending for routine colonoscopy were randomised to either pan-chromoscopy using 0.5% indigo carmine (IC) or targeted chromoscopy (control group). A minimum diagnostic extubation time was set at eight minutes with controls undergoing a matched volume of saline wash. RESULTS: A total of 260 patients were randomised; 132 controls and 128 to pan-colonic chromoscopy. Extubation times did not differ significantly between the control (median 15 minutes (range 8-41)) and chromoscopy (median 17 minutes (range 8-39)) groups. The volume of IC used in the pan-chromoscopy group (median 68 ml (range 65-90)) and normal saline used in the control group (69 ml (range 60-93)) did not differ significantly. There was a statistically significant difference between the groups regarding the total number of adenomas detected (p<0.05) with significantly more diminutive (<4 mm) adenomas detected in the pan-chromoscopy group (p = 0.03). Pan-chromoscopy diagnosed more diminutive and flat lesions in the right colon compared with controls (p<0.05), with more patients with multiple adenomas (>3) detected using pan-chromoscopy (p<0.01). Hyperplastic lesions were more commonly detected in the pan-chromoscopy group compared with controls (p<0.001). More hyperplastic polyps were detected in the left colon (86% rectosigmoid) using chromoscopy compared with controls. CONCLUSION: Chromoscopy improves the total number of adenomas detected and enhances the detection of diminutive and flat lesions. Importantly, eight diminutive lesions had foci of high grade dysplasia. Chromoscopy may benefit patients, assuming a high risk of colorectal cancer, and help in risk stratification and planning follow up colonoscopy intervals.     

The occurrence of terminal ileal histological abnormalities in patients with coeliac disease

INTRODUCTION: Coeliac disease causes histological changes throughout the small bowel, but is often a proximal lesion. We wanted to assess whether terminal ileal histological abnormalities occurred more commonly in patients with coeliac disease and if specific assessment of intraepithelial lymphocytes increases the recognition of undiagnosed coeliac disease. METHODS: Terminal ileal biopsies were prospectively examined over a 3-year period (April 2001-May 2004). Patients were included if they were found to have a synchronous duodenal biopsy that gave a new diagnosis of coeliac disease (n=20). Terminal ileal biopsies taken at colonoscopy during the same period were also examined from four groups of patients: coeliac disease established on a gluten-free diet but with persisting symptoms (n=25), inflammatory bowel disease (n=47), chronic diarrhoea (n=44) and polyp surveillance (n=47). All biopsies were graded according to the Marsh criteria and an intraepithelial lymphocytes count per 100 enterocytes was obtained. RESULTS: There was only one patient from all five groups who had villous atrophy of the terminal ileal. This patient had a new diagnosis of coeliac disease. The mean intraepithelial lymphocytes count in the coeliac disease group was 23.7 intraepithelial lymphocytes/100 enterocytes. This was significantly higher than the control groups: coeliac disease on a gluten-free diet=17.5 (p<0.012), inflammatory bowel disease=12.3 (p<0.0001), diarrhoea=12.6 (p<0.0001) and polyp=13.7 (p<0.0002). Validating terminal ileal villous intraepithelial lymphocytes counts as a test for coeliac disease using an intraepithelial lymphocytes/100 enterocytes of >25 gives a sensitivity of 45% and a specificity of 97.8%. CONCLUSION: Routinely quantifying terminal ileal intraepithelial lymphocytes may be of limited clinical value. However, subjective recognition of raised intraepithelial lymphocytes on a terminal ileal biopsy should alert the clinician to the possibility of coeliac disease.     

Platelet glycoproteins IIb and IIIa as a calcium channel in liposomes

Human platelet membrane glycoproteins IIb and IIIa (GPIIb and IIIa) were incorporated into phospholipid vesicles by the reverse-phase technique to assess the ability of GPIIb and IIIa to function as a Ca2+ channel. Movement of Ca2+ across the lipid bilayer was quantitated by injection of proteoliposomes with encapsulated Fura-2 into Ca2+ buffers and measurement of Fura-2 fluorescence as an indicator of Ca2+ influx. Reciprocally, to assess the function of proteins in an inside-out orientation, Ca2+-loaded vesicles were injected into Ca2+-free buffer and Ca2+ efflux monitored by a calcium electrode. Incorporation of the IIb-IIIa complex produced significant facilitation of Ca2+ movement across the lipid bilayer. No net transmembrane Ca2+ movement was seen with dissociated IIb and IIIa. Movement of Ca2+ was proportional to the transmembrane Ca2+ gradient. Ca2+ movement into the vesicles was inversely proportional to extravesicular NaCl from 25 to 150 mmol/L, analogous to several studies in the intact platelet. Adenosine triphosphate had no effect on Ca2+ movement into or out of the vesicles. Specific inhibition of a Ca2+ shift into the vesicles was seen with M148, a monoclonal antibody to IIb/IIIa, while no inhibition was observed with a panel of other anti-IIb/IIIa monoclonal antibodies. This suggests that a specific site on the complex or orientation of the complex is essential for calcium channel function. These data demonstrate that the GPIIb/IIIa complex can serve as a passive Ca2+ channel across a phospholipid bilayer and has the potential to play a role in Ca2+ flux across the platelet plasma membrane.     

Genetic markers may predict disease behavior in patients with ulcerative colitis

BACKGROUND & AIMS: Recent studies have suggested that HLA DRB1*0103 and allele 2 of the interleukin 1 receptor antagonist (IL-1RA) gene predict severe and extensive ulcerative colitis, respectively. The aim of this study was to test these hypotheses in patients undergoing surgery for their colitis. METHODS: HLA DRB1 and DQB1 genotyping was performed in 99 patients and 472 controls. Genotyping for polymorphisms of genes encoding tumor necrosis factor alpha and IL-1RA was performed in 107 patients and 89 controls. Measurement of antineutrophil cytoplasmic antibody (ANCA) was performed in 72 patients and 58 healthy subjects by fixed neutrophil enzyme-linked immunosorbent assay and indirect immunofluorescence. RESULTS: The DRB1*0103 allele was increased in patients (14.1% vs. 3.2% in controls; P < 1 x 10[-5]). This association was greatest in patients with extensive disease (15.8%; P < 0.0001) or extraintestinal manifestations (22.8%; P < 0.0001): mouth ulcers (25.8%; P < 0.0001), arthritis (27.2%; P < 0.0001), and uveitis (35.7%; P < 0.0001). The DRB1*04 alleles were reduced in patients (P = 0.005). Differences were noted between extensive and distal disease in the frequency of allele 2 of IL-1RA (10.9% in distal vs. 28.6% in extensive; P = 0.01) and allele 2 homozygosity. ANCA was detected in 76.4% of patients. Carriage of IL-1RA allele 2 and tumor necrosis factor 2 allele was increased in ANCA-positive patients. CONCLUSIONS: Genetic markers may predict disease behavior in ulcerative colitis. (Gastroenterology 1997 Jun;112(6):1845-53)     

A novel treatment for chronic pancreatitis

Background Hereditary pancreatitis is an important cause of chronic pancreatitis, which may result in endocrine and exocrine failure. This may necessitate simultaneous pancreas and kidney transplant (SPK). Bladder drainage of the exocrine secretions may cause problems. Aim To report one such case and its surgical correction. Methods A 20-year-old male with insulin-dependent diabetes mellitus secondary to idiopathic chronic pancreatitis had a SPK with bladder drainage. Urological and metabolic complications secondary to the drainage of pancreatic secretions, rich in proteolytic enzymes required convertion from bladder to enteric drainage. Results He was able to discontinue his pancreatic enzyme supplements, ceased to have steatorrhoea and gained weight. He was referred to the €pean Registry of Hereditary Pancreatitis and Familial Pancreatic Cancer (€PAC), hereditary pancreatitis was confirmed by genetic analysis. Conclusion Enteric-drained pancreas transplantation is a successful treatment for exocrine as well as endocrine pancreatic failure and should be considered as a treatment option in patients with chronic pancreatitis.