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- Hedner, Thomas, 1949, et al.
(författare)
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Nabumetone: therapeutic use and safety profile in the management of osteoarthritis and rheumatoid arthritis.
- 2004
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Ingår i: Drugs. - : Springer Science and Business Media LLC. - 0012-6667. ; 64:20
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Forskningsöversikt (refereegranskat)abstract
- Nabumetone is a nonsteroidal anti-inflammatory prodrug, which exerts its pharmacological effects via the metabolite 6-methoxy-2-naphthylacetic acid (6-MNA). Nabumetone itself is non-acidic and, following absorption, it undergoes extensive first-pass metabolism to form the main circulating active metabolite (6-MNA) which is a much more potent inhibitor of preferentially cyclo-oxygenase (COX)-2. The three major metabolic pathways of nabumetone are O-demethylation, reduction of the ketone to an alcohol, and an oxidative cleavage of the side-chain occurs to yield acetic acid derivatives. Essentially no unchanged nabumetone and < 1% of the major 6-MNA metabolite are excreted unchanged in the urine from which 80% of the dose can be recovered and another 10% in faeces. Nabumetone is clinically used mainly for the management of patients with osteoarthritis (OA) or rheumatoid arthritis (RA) to reduce pain and inflammation. The clinical efficacy of nabumetone has also been evaluated in patients with ankylosing spondylitis, soft tissue injuries and juvenile RA. The optimum oral dosage of nabumetone for OA patients is 1 g once daily, which is well tolerated. The therapeutic response is superior to placebo and similar to nonselective COX inhibitors. In RA patients, nabumetone 1 g at bedtime is optimal, but an additional 0.5-1 g can be administered in the morning for patients with persistent symptoms. In RA, nabumetone has shown a comparable clinical efficacy to aspirin (acetylsalicylic acid), diclofenac, piroxicam, ibuprofen and naproxen. Clinical trials and a decade of worldwide safety data and long-term postmarketing surveillance studies show that nabumetone is generally well tolerated. The most frequent adverse effects are those commonly seen with COX inhibitors, which include diarrhoea, dyspepsia, headache, abdominal pain and nausea. In common with other COX inhibitors, nabumetone may increase the risk of GI perforations, ulcerations and bleedings (PUBs). However, several studies show a low incidence of PUBs, and on a par with the numbers reported from studies with COX-2 selective inhibitors and considerably lower than for nonselective COX inhibitors. This has been attributed mainly to the non-acidic chemical properties of nabumetone but also to its COX-1/COX-2 inhibitor profile. Through its metabolite 6-MNA, nabumetone has a dose-related effect on platelet aggregation, but no effect on bleeding time in clinical studies. Furthermore, several short-term studies have shown little to no effect on renal function. Compared with COX-2 selective inhibitors, nabumetone exhibits similar anti-inflammatory and analgesic properties in patients with arthritis and there is no evidence of excess GI or other forms of complications to date.
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| 3. |
- Ung, Kjell-Arne, 1951, et al.
(författare)
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In vitro determination of active bile acid absorption in small biopsy specimens obtained endoscopically or surgically from the human intestine.
- 2002
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Ingår i: European journal of clinical investigation. - 0014-2972. ; 32:2, s. 115-21
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: In the construction of a Kock reservoir for continent urinary diversion, 70 cm of the distal ileum are used. Impaired absorption of bile acids in these patients might cause diarrhoea. Data on the absorption of bile acids in different parts of the human intestine are limited. METHODS: Biopsies were taken during endoscopy from the duodenum, the terminal ileum or the right colon, and during surgery 10, 50, 100 and 150 cm proximally to the ileo-caecal valve using standard endoscopy biopsy forceps. The biopsy specimens were incubated in vitro with radio-labelled taurocholic acid at 37 degrees C for 22 or 45 min The radioactivity was determined using the liquid scintillation technique. RESULTS: A linear increase in the uptake was observed, with increased concentrations of taurocholic acid between 100 and 500 microm in all specimens tested, that represented passive uptake or unspecific binding. The active uptake could be calculated from the intercept of the line representing passive uptake with the ordinate. The active uptake in the terminal ileum was 3-4 times greater than 100 cm proximal to the valve. CONCLUSIONS: The active absorption of bile acids in humans can be determined in small biopsy specimens taken using standard biopsy forceps during endoscopy or surgery. This method is suitable for clinical studies of bile acid absorption. Active uptake of bile acids not only takes place in the very distal part of the ileum but also to a considerable degree 100 cm proximally to the ileo-colonic valve. This should be taken into account when selecting the ileal segment for continent urinary diversion.
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| 4. |
- Ung, Kjell-Arne, 1951
(författare)
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On the role of bile acids in chronic diarrhoea
- 2001
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Bile acids which promote lipid absorption are actively reabsorbed in the distal ileum. Bile acid malabsorption (BAM) and microscopic colitis (lymphocytic and collagenous) are both associated with chronic watery diarrhoea. The aims were to study: 1) the role of bile acids in collagenous and lymphocytic colitis, 2) the correlation between BAM and steatorrhoea in patients with chronic diarrhoea 3) bile acid absorption after a standardized resection of 55-70cm of the ileum leaving the distal 40cm intact. Patients with chronic diarrhoea underwent the 75SeHCAT test and a clinical work-up including colonoscopy. All patients recorded their symptoms. Faecal fat excretion was measured in 94 patients. Patients with microscopic colitis were treated with a bile acid binder. Collagenous colitis patients were reinvestigated after a median time of 4.2 years. Correlations between 75SeHCAT values, histopathology and symptoms were calculated. Patients operated on with a continent urinary diversion underwent the 75SeHCAT test. Twenty-nine healthy controls underwent the 75SeHCAT test.BAM was present in 44% of collagenous colitis patients and persisted in 32% at follow-up. BAM was uncommon in lymphocytic colitis but the median retention was significantly lower than in the control group. Bile acid binders were effective in >70% with collagenous colitis and in >40% with lymphocytic colitis. Histopathology improved in the long-term course of collagenous colitis in those who had stopped bile acid binder treatment and was unchanged in those with maintained treatment although symptoms were comparable. Ileum was normal irrespective of BAM. 75SeHCAT retention decreased from 32% to 17% after the ileal resection. No correlation between 75SeHCAT retention and faecal fat excretion was found. Patients with BAM had more frequent bowel movements and looser stool consistency compared with those without bile acid malabsorptionConclusions: BAM is a permanent finding in one third of patients with collagenous colitis. Absorption of bile acids is disturbed in both collagenous and lymphocytic colítis. Bile acid binders are effective in many patients with microscopic colitis. BAM and collagenous colitis are associated but presumably independant diseases. The 75SeHCAT value can not predict occurrence of steatorrhoea. BAM worsen the symptoms in chronic diarrhoea. The distal 40cm of the ileum is not enough to preserve normal absorption of bile acids
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