At the coalface: medical ethics in practice. A double dose of double effect.
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This paper presents a clinically orientated illustration of the doctrine of double effect. The case of an elderly gentleman with advanced cancer is discussed, with particular emphasis on two dilemmas encountered during the terminal phase of his illness. The author describes how the doctrine of double effect was applied to help the team make some complex management decisions. (+info)
A long-term fish diet modifies the toxic properties of human partially oxidized LDL on vascular preparations in vitro.
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Both LDL oxidation and LDL fatty acid composition affect vascular relaxation and contraction. The aim of this study was to investigate whether long-lasting dietary habits (vegetarian, fish and high saturated fat as a control group) can change those properties of partially oxidized LDL (ox-LDL) which are reflected in altered vascular responses measured with a bioassay. The effects of ox-LDL were investigated on rat mesenteric arteries. In endothelium intact arterial rings the contractile responses to noradrenaline (NA) tended to be diminished in the presence of ox-LDL derived from the fish diet group compared with the other groups. In the endothelium denuded arterial rings the contractile responses to NA and KCl were significantly enhanced by ox-LDL from the fish diet group compared with the control group. The ox-LDL from the fish diet group increased the diclofenac, L-NAME resistant relaxations to ACh compared to the control diet group suggesting the role of endothelium derived hyperpolarizing factor (EDHF). In conclusion, partially oxidized LDL from subjects living on a fish diet is biologically more vasoactive in bioassay systems than partially oxidized LDL from those living on vegetarian or saturated fatty acid containing diets. The impaired responses in vasoconstriction and improved vasodilation seem to be endothelium dependent. (+info)
Determining minimally important changes in generic and disease-specific health-related quality of life questionnaires in clinical trials of rheumatoid arthritis.
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OBJECTIVE: To define clinically meaningful changes in 2 widely used health-related quality of life (HQL) instruments in studies of patients with rheumatoid arthritis (RA). METHODS: Patients with RA (n = 693) who were enrolled in 2 double-blind, placebo-controlled clinical trials completed the Short Form 36 (SF-36) modified health survey and the Health Assessment Questionnaire (HAQ) disability index at baseline and 6-week followup assessments. Data on 5 RA severity measures were also collected at baseline and at 6 weeks (patient and physician global assessments, joint swelling and tenderness counts, and global pain assessment). Comparison of changes in the SF-36 scales and HAQ scores was made between groups of patients known to differ in the level of change on each RA severity measure. RESULTS: With few exceptions, changes in the SF-36 and HAQ scores were different between patients who differed in the level of change on each RA severity measure. Changes in the SF-36 and HAQ scores were more strongly related to changes in the patient and physician global assessments and patient pain assessment than to changes in the joint swelling and tenderness counts. CONCLUSION: Based on these results, minimally important changes in the SF-36 scales and HAQ disability scores were determined, which will be useful in interpreting HQL results in clinical trials. (+info)
Cytoplasmic binding and disposition kinetics of diclofenac in the isolated perfused rat liver.
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1. The binding kinetics of diclofenac to hepatocellular structures were evaluated in the perfused rat liver using the multiple indicator dilution technique and a stochastic model of organ transit time density. 2. The single-pass, in situ rat liver preparation was perfused with buffer solution (containing 2% albumin) at 30 ml min(-1). Diclofenac and [(14)C]-sucrose (extracellular reference) were injected simultaneously as a bolus dose into the portal vein (six experiments in three rats). An analogous series of experiments was performed with [(14)C]-diclofenac and [(3)H]-sucrose. 3. The diclofenac outflow data were analysed using three models of intracellular distribution kinetics, assuming (1) instantaneous distribution and binding (well-mixed model), (2) 'slow' binding at specific intracellular sites after instantaneous distribution throughout the cytosol (slow binding model), and (3) 'slowing' of cytoplasmic diffusion due to instantaneous binding (slow diffusion model). 4. The slow binding model provided the best description of the data. The rate constants for cellular influx and sequestration were 0.126+/-0. 026 and 0.013+/-0.009 s(-1), respectively. The estimated ratio of cellular initial distribution volume to extracellular volume of 2.82 indicates an almost instantaneous distribution in the cellular water space, while the corresponding ratio of 5.54 estimated for the apparent tissue distribution volume suggests a relatively high hepatocellular binding. The non-instantaneous intracellular equilibration process was characterized by time constants of the binding and unbinding process of 53.8 and 49.5 s, respectively. The single-pass availability of diclofenac was 86%. The results obtained with [(14)C]-diclofenac and [(3)H]-sucrose were not statistically different. (+info)
Anomalous acute inflammatory response in rabbit corneal stroma.
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PURPOSE: To investigate the nature and cause of an acute, anomalous stromal edema after epithelial debridement in the rabbit cornea. METHODS: Series I: Adult New Zealand White rabbit corneas were mounted in perfusion chambers. The endothelium was bathed with Ringer's fluid, and the outer surface was covered with silicone oil. The epithelium of one eye was debrided with a scalpel before mounting, and the cornea of the fellow eye was debrided with a rotating brush after stabilization in the perfusion chamber. Using specular microscope tracking software, it was possible to measure total swelling and local swelling within the cornea. Series II: Diclofenac sodium ophthalmic solution 0.1% or a placebo was applied topically, 1 drop per 45 minutes for 3 hours before animals were euthanatized. RESULTS: Series I: Corneas with their epithelium scraped with a scalpel before mounting were 37.5 +/- 17.5 microm (n = 6; P < 0.001) thicker in vitro than the stromas of perfused, intact fellow corneas. Epithelial debridement with a rotating brush after mounting resulted in an immediate (within 8 minutes) stromal swelling that plateaued in 1 hour at 31.0 +/- 5.3 microm (n = 6; P < 0.001). Curiously, in six of six corneas, the anterior stroma swelled more than the posterior stroma. In four of six corneas, the posterior stroma thinned. Analysis showed this pattern to be consistent with a sudden increase in anterior swelling pressure or osmotic pressure and to be inconsistent with a change in endothelial transport properties. Series II: Placebo-treated corneas swelled 30.6 +/- 7.7 microm (n = 5) 1 hour after debridement, whereas corneas pretreated with diclofenac sodium swelled only 19.2 +/- 3.1 microm (n = 6; P < 0.008). CONCLUSIONS: The anterior stromal swelling occurs rapidly and near the site of epithelial injury suggesting messenger and/or enzymatic involvement with an effect parallel to apoptosis. Reduction of the swelling response with nonsteroidal anti-inflammatory drugs (NSAIDs) implicates the cyclooxygenase pathway. The swelling is similar to the unexplained acute edema that occurs during inflammation in the rat paw edema model, and may represent a general mechanism for mobilization of inflammatory cells. (+info)
An endothelium-derived hyperpolarizing factor distinct from NO and prostacyclin is a major endothelium-dependent vasodilator in resistance vessels of wild-type and endothelial NO synthase knockout mice.
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In addition to nitric oxide (NO) and prostacyclin (PGI(2)), the endothelium generates the endothelium-derived hyperpolarizing factor (EDHF). We set out to determine whether an EDHF-like response can be detected in wild-type (WT) and endothelial NO synthase knockout mice (eNOS -/-) mice. Vasodilator responses to endothelium-dependent agonists were determined in vivo and in vitro. In vivo, bradykinin induced a pronounced, dose-dependent decrease in mean arterial pressure (MAP) which did not differ between WT and eNOS -/- mice and was unaffected by treatment with N(omega)-nitro-l-arginine methyl ester and diclofenac. In the saline-perfused hindlimb of WT and eNOS -/- mice, marked N(omega)-nitro-l-arginine (l-NA, 300 micromol/liter)- and diclofenac-insensitive vasodilations in response to both bradykinin and acetylcholine (ACh) were observed, which were more pronounced than the agonist-induced vasodilation in the hindlimb of WT in the absence of l-NA. This endothelium-dependent, NO/PGI(2)-independent vasodilatation was sensitive to KCl (40 mM) and to the combination of apamin and charybdotoxin. Gap junction inhibitors (18alpha-glycyrrhetinic acid, octanol, heptanol) and CB-1 cannabinoid-receptor agonists (Delta(9)-tetrahydrocannabinol, HU210) impaired EDHF-mediated vasodilation, whereas inhibition of cytochrome P450 enzymes, soluble guanylyl cyclase, or adenosine receptors had no effect on EDHF-mediated responses. These results demonstrate that in murine resistance vessels the predominant agonist-induced endothelium-dependent vasodilation in vivo and in vitro is not mediated by NO, PGI(2), or a cytochrome P450 metabolite, but by an EDHF-like principle that requires functional gap junctions. (+info)
Cytochrome P450 3A4-mediated interaction of diclofenac and quinidine.
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The metabolism of diclofenac to its 5-hydroxylated derivative in humans is catalyzed by cytochrome P450 (CYP)3A4. We report herein that in vitro this biotransformation pathway is stimulated by quinidine. When diclofenac was incubated with human liver microsomes in the presence of quinidine, the formation of 5-hydroxydiclofenac increased approximately 6-fold relative to controls. Similar phenomena were observed with diastereoisomers of quinidine, including quinine and the threo epimers, which produced an enhancement in the formation of 5-hydroxydiclofenac in the order of 6- to 9-fold. This stimulation of diclofenac metabolism was diminished when human liver microsomes were pretreated with a monoclonal inhibitory antibody against CYP3A4. In contrast, neither cytochrome b(5) nor CYP oxidoreductase appeared to mediate the stimulation of diclofenac metabolism by quinidine, suggesting that the effect of quinidine is mediated through CYP3A4 protein. Further kinetic analyses indicated that V(max) values for the conversion of diclofenac to its 5-hydroxy derivative increased 4.5-fold from 13.2 to 57.6 nmol/min/nmol of CYP with little change in K(m) (71-56 microM) over a quinidine concentration range of 0 to 30 microM. Conversely, the metabolism of quinidine was not affected by the presence of diclofenac; the K(m) value estimated for the formation of 3-hydroxyquinidine was approximately 1.5 microM, similar to the quinidine concentration required to produce 50% of the maximum stimulatory effect on diclofenac metabolism. It appears that the enhancement of diclofenac metabolism does not interfere with quinidine's access to the ferriheme-oxygen complex, implicating the presence of both compounds in the active site of CYP3A4 at the same time. Finally, a approximately 4-fold increase in 5-hydroxydiclofenac formation was observed in human hepatocyte suspensions containing diclofenac and quinidine, demonstrating that this type of drug-drug interaction occurs in intact cells. (+info)
Non-steroidal anti-inflammatory drugs as a possible cause for reversible infertility.
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OBJECTIVE: To highlight the possible association between infertility and treatment with long-term non-steroidal anti-inflammatory drug (NSAIDs). NSAIDs act mainly through the inhibition of cyclooxygenase, the enzyme that catalyses the synthesis of prostaglandins, which are essential mediators of ovulation, implantation and placentation of the conceptus. METHODS: Case reports of four women suffering from severe arthritis, on long-term NSAIDs and undergoing extensive investigation and treatment for infertility. RESULTS: During the last 2 yr, four out of five women with severe arthritis and difficulty conceiving were counselled to stop NSAIDs, and they successfully conceived shortly after the withdrawal of NSAIDs. CONCLUSION: NSAIDs, used largely for the treatment of rheumatological conditions, may be responsible for some cases of infertility. (+info)