Diacerhein treatment reduces the severity of osteoarthritis in the canine cruciate-deficiency model of osteoarthritis.
(25/7426)
OBJECTIVE: To determine if diacerhein protects against the early stages of joint damage in a canine model of osteoarthritis (OA). METHODS: OA was induced in 20 adult mongrel dogs by transection of the anterior cruciate ligament of the left knee. Beginning the day after surgery, dogs in the active treatment group were dosed twice a day with capsules of diacerhein, providing a total daily dose of 40 mg/kg, for 32 weeks. Dogs in the control group received placebo capsules on the same schedule. Pathology in the unstable knee was assessed arthroscopically 16 weeks after surgery and by direct observation when the dogs were killed 32 weeks after surgery. The severity of gross joint pathology was recorded, and samples of the medial femoral condyle cartilage and the synovial tissue adjacent to the central portion of the medial meniscus were collected for histologic evaluation. Water content and uronic acid concentration of the articular cartilage from the femoral condyle were determined, and collagenolytic activity in extracts of cartilage pooled from the medial and lateral tibial plateaus was assayed against 14C-labeled collagen fibers. RESULTS: Diacerhein treatment slowed the progression of OA, as measured by grading of gross changes in the unstable knee at arthroscopy 16 weeks after cruciate ligament transection (P = 0.04) and at the time the animals were killed, 32 weeks after surgery (P = 0.05). However, 32 weeks after ACL transection, the mean proteoglycan concentration and water content of the OA cartilage and the level of collagenolytic activity in extracts of the cartilage were not significantly different in the diacerhein treatment group than in the placebo treatment group. CONCLUSION: Diacerhein treatment significantly reduced the severity of morphologic changes of OA compared with placebo. These findings support the view that diacerhein may be a disease-modifying drug for OA. (+info)
Sodium salicylate activates caspases and induces apoptosis of myeloid leukemia cell lines.
(26/7426)
Nonsteroidal antiinflammatory agents (NSAIA) have been shown to exert potent chemopreventive activity against colon, lung, and breast cancers. In this study, we show that at pharmacological concentrations (1 to 3 mmol/L) sodium salicylate (Na-Sal) can potently induce programmed cell death in several human myeloid leukemia cell lines, including TF-1, U937, CMK-1, HL-60, and Mo7e. TF-1 cells undergo rapid apoptosis on treatment with Na-Sal, as indicated by increased annexin V binding capacity, cpp-32 (caspase-3) activation, and cleavage of poly (ADP-ribose) polymerase (PARP) and gelsolin. In addition, the expression of MCL-1, an antiapoptotic member of the BCL-2 family, is downregulated during Na-Sal-induced cell death, whereas the expression of BCL-2, BAX, and BCL-XL is unchanged. Z-VAD, a potent caspase inhibitor, prevents the cleavage of PARP and gelsolin and rescues cells from Na-Sal-induced apoptosis. In addition, we show that Na-Sal accelerates growth factor withdrawal-induced apoptosis and synergizes with daunorubicin to induce apoptosis in TF-1 cells. Thus, our data provide a potential mechanism for the chemopreventive activity of NSAIA and suggest that salicylates may have therapeutic potential for the treatment of human leukemia. (+info)
Contribution of modern cardiovascular treatment and risk factor changes to the decline in coronary heart disease mortality in Scotland between 1975 and 1994.
(27/7426)
OBJECTIVE: To estimate the fall in coronary heart disease (CHD) mortality in Scotland attributable to medical and surgical treatments, and risk factor changes, between 1975 and 1994. DESIGN: A cohort model combining effectiveness data from meta-analyses with information on treatment uptake in all patient categories in Scotland. SETTING AND PATIENTS: The whole Scottish population of 5.1 million, including all patients with recognised CHD. INTERVENTIONS: All cardiological, medical, and surgical treatments, and all risk factor changes between 1975 and 1994. Data were obtained from epidemiological surveys, routine National Health Service sources, and local audits. MAIN OUTCOME MEASURES: Deaths from CHD in 1975 and 1994. RESULTS: There were 15 234 deaths from CHD in 1994, 6205 fewer deaths than expected if there had been no decline from 1975 mortality rates. In 1994, the total number of deaths prevented or postponed by all treatments and risk factor reductions was estimated at 6747 (minimum 4790, maximum 10 695). Forty per cent of this benefit was attributed to treatments (initial treatments for acute myocardial infarction 10%, treatments for hypertension 9%, for secondary prevention 8%, for heart failure 8%, aspirin for angina 2%, coronary artery bypass grafting surgery 2%, and angioplasty 0.1%). Fifty one per cent of the reduction in deaths was attributed to measurable risk factor reductions (smoking 36%, cholesterol 6%, secular fall in blood pressure 6%, and changes in deprivation 3%). Other, unquantified factors apparently accounted for the remaining 9%. These proportions remained relatively consistent across a wide range of assumptions and estimates in a sensitivity analysis. CONCLUSIONS: Medical treatments and risk factor changes apparently prevented or postponed about 6750 coronary deaths in Scotland in 1994. Modest gains from individual treatments produced a large cumulative survival benefit. Reductions in major risk factors explained about half the fall in coronary mortality, emphasising the importance and future potential of prevention strategies. (+info)
Arterial thromboembolism in patients with sick sinus syndrome: prediction from pacing mode, atrial fibrillation, and echocardiographic findings.
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OBJECTIVE: To evaluate whether thromboembolism in sick sinus syndrome can be predicted by pacing mode, atrial fibrillation, or echocardiographic findings. METHODS: Patients were randomised to single chamber atrial (n = 110) or ventricular (n = 115) pacing. They were divided into subgroups with and without brady-tachy syndrome at time of randomisation. The occurrence of atrial fibrillation and thromboembolism during follow up were investigated and compared with echocardiographic findings. RESULTS: The annual risk of thromboembolism was 5.8% in patients with brady-tachy syndrome randomised to ventricular pacing, 3.2% in patients without brady-tachy syndrome randomised to ventricular pacing, 3% in patients with brady-tachy syndrome randomised to atrial pacing, and 1.5% in patients without brady-tachy syndrome randomised to atrial pacing. In atrial paced patients without brady-tachy syndrome at randomisation and without atrial fibrillation during follow up, the annual risk of thromboembolism was 1.4%. Left atrial size measured by M mode echocardiography was of no value in predicting thromboembolism. CONCLUSIONS: Arterial thromboembolism in patients with sick sinus syndrome is very common and is associated primarily with brady-tachy syndrome at randomisation and with ventricular pacing. The risk of thromboembolism is small in atrial paced patients in whom atrial fibrillation has never been documented. (+info)
Prevention of alphaII(b)beta3 activation by non-steroidal antiinflammatory drugs.
(29/7426)
We have studied the effect of non-steroidal antiinflammatory drugs (NSAIDs) on alphaII(b)beta3 integrin activation and platelet aggregation. NSAIDs such as meloxicam, piroxicam, indomethacin and aspirin, but not aceclofenac or diclofenac interfered with the activation state of alphaII(b)beta3. NSAIDs that inhibited alphaII(b)beta3 activation were also able both to partially inhibit platelet primary aggregation and to accelerate platelet deaggregation. These effects of NSAIDs were not dependent on cyclooxygenase inhibition. The results obtained indicate that some NSAIDs exert a specific action on alphaII(b)beta3 activation, and provide an additional mechanism that accounts for their beneficial effects in diseases in which platelet activation is involved. (+info)
Inhibition of cyclooxygenase-2 expression by 4-trifluoromethyl derivatives of salicylate, triflusal, and its deacetylated metabolite, 2-hydroxy-4-trifluoromethylbenzoic acid.
(30/7426)
The therapeutic potential of drugs that block the induction of cyclooxygenase-2 has been emphasized. When two 4-trifluoromethyl salicylate derivatives [2-acetoxy-4-trifluoromethyl-benzoic acid (triflusal) and its deacetylated metabolite 2-hydroxy-4-trifluoromethylbenzoic acid (HTB)] were compared with aspirin and sodium salicylate as cyclooxygenase-2 (COX-2) inhibitors, we observed that in bacterial lipopolysaccharide-activated human blood, triflusal, aspirin, and HTB, but not sodium salicylate, inhibited COX-2-mediated prostaglandin E2 (PGE2) production (IC50 = 0.16, 0.18, 0.39, and >10 mM, respectively). However, only triflusal and aspirin inhibited purified COX-2 enzyme. To test this apparent discrepancy, we realized that HTB and triflusal (but neither aspirin nor salicylate) produced a concentration-dependent inhibition of COX-2 protein expression in peripheral human mononuclear cells. This observation was further confirmed in a rat air pouch model in vivo, in which both aspirin and triflusal inhibited PGE2 production (ID50 = 18.9 and 11.4 mg/kg p.o., respectively) but only triflusal-treated animals showed a decrease in COX-2 expression. This different behavior may be, at least in part, due to the ability of HTB and triflusal to block the activation of the transcription factor nuclear factor-kappaB to a higher extent than aspirin and sodium salicylate. Thus, in addition to inhibiting the COX-2 activity at therapeutic concentrations, triflusal is able to block through its metabolite HTB the expression of new enzyme, and hence the resumption of PGE2 synthesis. Triflusal and HTB may exert beneficial effects in processes in which de novo COX-2 expression is involved and, in a broader sense, in pathological situations in which genes under nuclear factor-kappaB control are up-regulated. (+info)
Intestinal metabolism and transport of 5-aminosalicylate.
(31/7426)
The purpose of this study was to determine the characteristics of intestinal absorption and metabolism of 5-aminosalicylic acid (5ASA). Regional perfusions of 5ASA in the anesthetized rat resulted in the appearance of N-acetyl-5-aminosalicylic acid in the intestinal lumen. Lumenal metabolite appearance was proportional to 5ASA permeability, which was 5-fold higher in the jejunum than in the ileum. Intestinal elimination significantly decreases 5ASA absorption at low lumenal drug concentrations and this process is saturated at high drug concentrations. Metabolite levels in intestinal tissue were higher than plasma levels at low perfusion drug concentrations, whereas the reverse was observed at high concentrations. Transport and metabolism of 5ASA was studied in Caco-2 monolayers. At low drug concentrations, 5ASA was preferentially transported in the basolateral (BL) to apical (AP) direction. With 5ASA incubation in either the AP or BL chamber, the N-acetyl metabolite appeared only in the AP compartment. Transport of N-acetyl-5-aminosalicylic acid was also exclusively observed in the BL to AP direction. Clinical data indicate that anti-inflammatory response to oral 5ASA correlates with the amount of 5ASA delivered to the intestinal tissue. This study shows that at lumenal levels below 200 microg/ml (concentrations that are typically achieved by controlled release dosage forms), intestinal secretion of 5ASA accounts for more than 50% of the total elimination and can significantly affect tissue levels and, therefore, may be an important factor in determining the response to 5ASA therapy. (+info)
Biotransformation of curcumin through reduction and glucuronidation in mice.
(32/7426)
Curcumin, the yellow pigment in turmeric and curry, has antioxidative and anticarcinogenic activities. In this study, we investigated the pharmacokinetic properties of curcumin in mice. After i.p. administration of curcumin (0.1 g/kg) to mice, about 2.25 microg/ml of curcumin appeared in the plasma in the first 15 min. One hour after administration, the levels of curcumin in the intestines, spleen, liver, and kidneys were 177.04, 26.06, 26.90, and 7.51 microg/g, respectively. Only traces (0.41 microg/g) were observed in the brain at 1 h. To clarify the nature of the metabolites of curcumin, the plasma was analyzed by reversed-phase HPLC, and two putative conjugates were observed. Treatment of the plasma with beta-glucuronidase resulted in a decrease in the concentrations of these two putative conjugates and the concomitant appearance of tetrahydrocurcumin (THC) and curcumin, respectively. To investigate the nature of these glucuronide conjugates in vivo, the plasma was analyzed by electrospray. The chemical structures of these metabolites, determined by mass spectrometry/mass spectrometry analysis, suggested that curcumin was first biotransformed to dihydrocurcumin and THC and that these compounds subsequently were converted to monoglucuronide conjugates. Because THC is one of the major metabolites of curcumin, we studied its stability at different pH values. THC was very stable in 0.1 M phosphate buffers of various pH values. Moreover, THC was more stable than curcumin in 0.1 M phosphate buffer, pH 7.2 (37 degrees C). These results, together with previous findings, suggest that curcumin-glucuronoside, dihydrocurcumin-glucuronoside, THC-glucuronoside, and THC are major metabolites of curcumin in vivo. (+info)