Lumiracoxib does not affect the ex vivo antiplatelet aggregation activity of low-dose aspirin in healthy subjects.

This randomized, double-blind, placebo-controlled study evaluated the pharmacodynamic effects of concomitant low-dose aspirin and lumiracoxib in healthy subjects. Participants received lumiracoxib 400 mg once daily (n = 14) or placebo (n = 14) for 11 days, with concomitant low-dose aspirin (75 mg once daily) from days 5 to 11. Ex vivo pharmacodynamic assessments included assays of platelet aggregation and urinary thromboxane and prostacyclin metabolite profile. Arachidonic acid-stimulated platelet aggregation was reduced from 76.3% on day 4 to 4.8% on day 11 in the placebo group and from 75.8% on day 4 to 5.1% on day 11 in the lumiracoxib group. Collagen-induced platelet aggregation was reduced from 77.5% on day 4 to 52.8% on day 11 in the placebo group and from 79.5% on day 4 to 55.9% on day 11 in the lumiracoxib group. Urinary thromboxane and prostacyclin were unaffected by lumiracoxib. In conclusion, concomitant lumiracoxib did not interfere with the cyclooxygenase-1-mediated antiplatelet effects of low-dose aspirin.

Acute disseminated encephalomyelitis or multiple sclerosis: can the initial presentation help in establishing a correct diagnosis?

The differential diagnosis of CNS white matter disease is broad, and can be divided into vascular, metabolic, infective, or inflammatory aetiologies. Isolated inflammatory disorders of the CNS are often associated with demyelination, and the two terms (inflammatory and demyelinating) are often used in conjunction. When the disease is monophasic, the term acute disseminated encephalomyelitis (ADEM) is used. ADEM typically occurs as a post-infectious phenomenon, and by definition, must be an isolated (monophasic) episode. If a relapse occurs shortly after the ADEM presentation in association with a further infection or steroid withdrawal, the term MDEM (multiphasic disseminated encephalomyelitis) is used. When there are relapses or progressive disease, the term multiple sclerosis (MS) is used (for full recommended diagnostic criteria for multiple sclerosis refer to McDonald and colleagues).

Gastroduodenal tolerability of lumiracoxib vs placebo and naproxen: a pilot endoscopic study in healthy male subjects.

BACKGROUND: Lumiracoxib (Prexige) is a cyclooxygenase-2 (COX-2) selective inhibitor. AIM: To compare the gastroduodenal tolerability of lumiracoxib with placebo and naproxen in a randomized, parallel-group, double-blind study. METHODS: : Sixty-five healthy male subjects were randomized to receive 8 days' dosing with lumiracoxib 200 mg twice daily (b.d.) (n = 21), placebo (n = 22) or naproxen 500 mg b.d. (n = 22). Endoscopic evaluations of gastric and duodenal mucosae were conducted at baseline and after 8 days' dosing. Serum was assayed for ex-vivo concentrations of thromboxane B2 (TxB2) to determine cyclooxygenase-1 (COX-1) inhibitory activity. RESULTS: Sixty subjects (20 per group) completed the study. No gastroduodenal erosions were observed in subjects receiving lumiracoxib. Thirteen subjects receiving naproxen developed duodenal erosions. At the gastric site, one subject in each of the naproxen and placebo groups had erosions; one subject receiving naproxen also developed a small asymptomatic gastric ulcer. Gastrointestinal adverse events accounted for 42.3% of all adverse events, occurring in 3/21, 4/22 and 6/22 of the lumiracoxib, placebo and naproxen groups, respectively. TxB2 levels were similar for patients receiving placebo or lumiracoxib, but were reduced by > 95% in patients receiving naproxen, compared with placebo. CONCLUSIONS: Multiple doses of lumiracoxib resulted in gastroduodenal tolerability similar to placebo and superior to naproxen.

Animal pain and distress in vaccine testing in the United States.

National statistics on animal use in research can provide guidance in setting priorities for research into alternative methods, i.e., those methods that can replace, reduce, or refine animal-based procedures. All else being equal, fields of research causing the most suffering to the largest numbers of animals should be considered prime candidates for alternative research. We examined national statistics on animal use in research in the United States to determine the extent to which vaccine testing accounts for those animals that experience unrelieved pain and distress. During 1998, 96,536 regulated animals were reported to have experienced unrelieved pain and distress in research (laboratory-bred mice and rats, as well as all non-mammals, are excluded from the U.S. reporting system). Vaccine-related testing alone accounted for 61% of this total. Of the 58,820 animals used in such vaccine testing, nearly all were hamsters (68%) and guinea pigs (28%), at least 74% were used in potency tests, and at least 55% were used in testing of Leptospira vaccine. This analysis and an earlier one both underscore the need to develop and implement alternative methods in vaccine testing.

Prevalence of dislocation after total hip arthroplasty through a posterolateral approach with partial capsulotomy and capsulorrhaphy.

The senior author altered his surgical technique during total hip arthroplasty from capsulectomy and capsulotomy with closure of the external rotator muscles to capsulotomy and capsulorrhaphy. One thousand patients (500 treated with each procedure) were studied retrospectively in order to determine the prevalences of dislocation after surgery with the two different techniques. The prevalence of dislocation was 2.8% after the capsulectomy and capsulotomy, whereas it was 0.6% after the new technique; this was a significant decrease in the rate of dislocation (p < 0.005, [symbol: see text] = 0.10).

Safety of a clinical surveillance protocol with 3- and 6-week warfarin prophylaxis after total joint arthroplasty.

The charts of 1869 patients were reviewed for the occurrence of deep venous thrombosis (DVT) and pulmonary embolism after total hip or knee arthroplasty. Prophylaxis consisted of 3 (group 1; n=1235) or 6 (group 2; n=634) weeks low-dose warfarin, pneumatic compression boots worn by patients in the hospital, mobilization on the first postoperative day, and a clinical surveillance protocol. Venous ultrasound or ventilation/perfusion lung scintigraphy (V/Q) was performed only if patients became symptomatic. patients. Twenty-three (1.8%) patients were positive for DVT. Ventilation/perfusion lung scintigraphy was performed on 25 patients, and 5 (0.4%) patients were positive for pulmonary embolism. In group 2, 117 patients were evaluated for DVT, and 19 (3%) patients had positive results determined by ultrasound. Twenty-five patients were evaluated with V/Q and only 1 (0.16%) patient was positive for pulmonary embolism. No patient developed a fatal pulmonary embolism or postphlebitic syndrome. This prophylaxis protocol is an efficient and cost-effective method for the prevention of significant events after surgery.

Sequential bilateral total knee arthroplasty.

As the senior citizen population has grown, the incidence of osteoarthritis and joint replacement has increased. Bilateral total knee arthroplasty (BTKA) can be performed sequentially during one anesthetic. Studies have shown the complication rates differ only slightly for total knee arthroplasty procedures performed sequentially during one anesthetic or separately requiring two hospitalizations. With the use of staggered tourniquet deflation times, efficient OR time and motion techniques, and careful postoperative management, patients can achieve successful outcomes after BTKA during one anesthetic.

Effects of Mg(2+) on the pre-steady-state kinetics of the biotin carboxylation reaction of pyruvate carboxylase.

The effects of Mg(2+) concentration on the kinetics of both ATP cleavage and carboxyenzyme formation in the approach to steady state of the biotin carboxylation reaction of pyruvate carboxylase have been studied. It was found that the enzyme underwent dilution inactivation at low Mg(2+) concentrations and that this occurred at higher enzyme concentrations than had been previously observed. At 10 mM Mg(2+), dilution inactivation was prevented and activation of the enzyme also occurred. When the enzyme was mixed with an ATP solution to initiate the carboxylation reaction, dilution inactivation was reversed and further enzyme activation was induced to a final level that was dependent on Mg(2+) concentration. With the exception of the reaction at 10 mM Mg(2+) in the presence of acetyl CoA, the experimental data could be adequately described as first-order exponential approaches to steady state. At 10 mM Mg(2+) in the presence of acetyl CoA, both ATP cleavage and carboxyenzyme formation data were best described as a biexponential process, in which there was little ATP turnover at steady state. Modeling studies have been performed which produced simulated data that were similar to the experimental data, using a reaction scheme modified from one proposed previously [Legge, G. B., et al. (1996) Biochemistry 35, 3849-3856]. These studies indicate that the major foci of action of Mg(2+) are in the decarboxylation of the enzyme-carboxybiotin complex, the return of the biotin to the site of the biotin carboxylation reaction, and the coupling of ATP cleavage to biotin carboxylation.

Effects of acetyl CoA on the pre-steady-state kinetics of the biotin carboxylation reaction of pyruvate carboxylase.

The approach to steady-state for the formation of the enzyme-carboxybiotin complex obeys first-order kinetics, with the proportion of the total enzyme present as the enzyme-carboxybiotin complex in the steady-state being about 60%. The approach to steady-state for ATP cleavage also obeys first-order kinetics. The apparent first-order rate constants for the approach to steady-state, in the presence and absence of acetyl CoA, respectively, are 6.6 and 0.028 s(-1) for ATP cleavage and 6.1 and 0.028 s(-1) for enzyme-carboxybiotin formation. The similarities of the values of the rate constants for the two reactions indicates that there is a common rate-limiting step. The large enhancement of these rate constants in the presence of acetyl CoA suggests that a major effect of acetyl CoA in the reaction is to enhance the rate of the step in which the putative carboxyphosphate complex is formed and in which ATP is cleaved. In addition, in the presence of acetyl CoA, the formation of the enzyme-carboxybiotin complex is much more tightly coupled to ATP cleavage in the presence of acetyl CoA than in its absence. Modeling studies were performed, and reaction schemes are proposed which give simulations similar to the experimental data. In the reaction schemes, the carboxyphosphate intermediate is able to undergo abortive decomposition without carboxylating biotin. The rate of this abortive reaction is greatly reduced in the presence of acetyl CoA.

Kinetics of nucleotide binding to pyruvate carboxylase.

The kinetics of nucleotide binding to pyruvate carboxylase have been studied by measuring the fluorescence changes that occur on the binding and release of FTP and FDP, which are fluorescent formycin analogues of ATP and ADP. The rate constants and equilibrium binding constants for both MgFTP and MgFDP binding to pyruvate carboxylase have been determined. From the kinetics of displacement of MgFTP by MgATP and binding of MgFTP in the presence of MgATP, the rate constants of MgATP binding were estimated. A slow component to the fluorescence changes was seen to occur after the initial rapid, bimolecular binding step, when formycin nucleotides were mixed with the enzyme. HCO3- and pyruvate were shown to quench the fluorescence of enzyme-bound MgFTP, but did not affect the affinity of the enzyme for the nucleotide. Acetyl CoA reduced the affinity of the enzyme for both MgFDP and MgFTP by about 3-fold by decreasing the association rate constants (by 25%) and increasing the dissociation rate constants (by 2-fold). In the absence of Mg2+ a very rapid component to FTP binding was observed that was complete within about 3 ms, but no fast component was observed comparable to that seen in the presence of 4.5 mM MgCl2. Increasing the [Mg2+] gradually abolished this very fast component of the binding, while the amplitude of the fast component increased, although the rate constant for this component did not appear to be strongly dependent on [Mg2+]. The rate constants of the slow component of Mg.formycin nucleotide binding did not appear to be dependent on nucleotide concentration.(ABSTRACT TRUNCATED AT 250 WORDS)

The effects of water soluble contrast agents on the respiratory tract.

The water soluble contrast agents Gastrografin (Sodium diatrizoate and meglumine diatrizoate, Schering, Berlin), Iopamiro 300 (Iopamidol, Schering, Berlin), and Dionosil Aqueous (propyliodone BP, Glaxo, England) were instilled into the tracheobronchial tree of rats in doses of either 0.1 ml and 0.25 ml. Rats being used as controls, underwent sham operations with the instillation of air instead of contrast agent. In all, 85 rats were used. All rats that had not already died from the effects of contrast agent were sacrificed 30 minutes after instillation. The relative effects of the contrast agents were measured by comparing: 1. survival time; 2. radiographic effects of the contrast agents on the lungs and; 3. pathological changes as estimated by post mortem lung section and microscopy. The least toxic agent was the one with the lowest osmotic activity, namely Aqueous Dionosil. It is therefore recommended that Aqueous Dionosil be used in preference to Gastrografin or Iopamidol for studies of the oesophagus whenever there is a danger of aspiration of contrast agent into the tracheobronchial tree.

Chylomicrons and chylomicron remnants in coronary artery disease: a case-control study.

Epidemiologic studies of coronary artery disease have largely overlooked the role of triglyceride-rich lipoproteins circulating in the post-prandial state. We have conducted a case-control study in males which examined fasting plasma lipoproteins and lipoproteins circulating 4 h after ingestion of a test meal containing fat and cholesterol. The cases were 82 subjects with coronary artery disease confirmed by angiography, while there were two control groups: one group of 38 'hospital controls' free of significant coronary disease by angiography, and a second group of 61 'workforce controls' free of coronary disease on historical grounds. Mean plasma and LDL cholesterol levels were significantly higher and HDL cholesterol levels were significantly lower in cases than in controls. The apo-B48/apo-B100 ratio in lipoproteins Sf greater than 60 obtained 4 h post-prandially, a relative measure of chylomicron and remnant presence, was significantly higher in cases than in controls. After pooling of all data, the prevalence of coronary artery disease was found to increase progressively with the concentration of plasma cholesterol and triglycerides, total cholesterol/HDL cholesterol ratio and the apo-B48/apo-B100 ratio in Sf greater than 60, the relative risk being highest for total cholesterol/HDL cholesterol ratio. After controlling for the confounding effects of age and other lipid factors via multiple logistic regression, apo-B48/apo-B100 ratio was still a significant predictor of coronary artery disease presence (z = 1.97, P less than 0.05) in a 'dose-response' fashion. The risk of coronary artery disease in the top quartile of apo-B48/apo-B100 distribution was 2.2-fold greater than that for the bottom quartile, after adjustment for the effects of other risk factors.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of glyceryl trinitrate on peripheral arteries alters left ventricular hydraulic load in man.

Effects of sublingual glyceryl trinitrate (GTN) were studied in ten patients without heart failure during diagnostic cardiac catheterisation following angiography. GTN caused substantial reduction in peak left ventricular and aortic pressure (19 mmHg) with lesser reduction in mean aortic pressure (9 mmHg) and no change in diastolic aortic pressure. Reduction in stroke volume (by 15%), associated with fall in left ventricular end diastolic pressure (by 4 mmHg) was insufficient to explain the marked (17 mmHg - 34%) reduction in pulse pressure. Decrease in pulse pressure was associated with loss of the late systolic peak on both the aortic and left ventricular pressure wave. This peak is caused by pulse wave reflection. GTN caused no change in peripheral resistance or in indices of aortic compliance (characteristic impedance, total arterial compliance) but was associated with reduction in fluctuations of both modulus and phase of aortic impedance. All these changes in pressure waves and in impedance spectra are explicable on the basis of decreased peripheral wave reflection. This can be attributed to the known vasodilatory effect of GTN on the peripheral arteries. Simulation of arterial vasodilatation in a multi-branched model of the systemic arterial system confirmed this interpretation. Dilatation of peripheral arteries explains in part the beneficial effects of GTN in adult man.

Contribution of left ventricular contraction to the generation of right ventricular systolic pressure in the human heart.

To determine whether left ventricular (LV) contraction contributes to the generation of right ventricular (RV) systolic pressure in humans, LV and RV pressures and their first derivative (dP/dt) were recorded simultaneously with micromanometer-tipped catheters in 11 conscious subjects. Seven subjects had normal LV and coronary angiograms. Four subjects had moderate LV dysfunction (resting ejection fraction 0.40 to 0.50), and three of these had coronary artery disease. During normal sinus rhythm, LV contraction slightly preceded RV contraction (mean 20 msec), and LV and RV dP/dt recordings showed single positive systolic peaks that were coincident. During endocardial pacing of the RV free wall, RV contraction preceded LV contraction (mean 23 msec) and two systolic RV dP/dt peaks were recorded, the first (peak I) occurring significantly before (mean +/- SD = 67 +/- 23 msec, p less than .01), and the second (peak II) coincident with the single systolic LV dP/dt peak. RV ectopic beats produced a similar RV dP/dt pattern, with peak I occurring 63 +/- 11 msec (p less than .01) before, and peak II coincident with the single LV dP/dt peak. Conversely, during LV ectopic beats, LV contraction preceded RV contraction (mean 63 msec) and two systolic RV dP/dt peaks were recorded, but peak I was coincident with the single LV dP/dt peak, while peak II occurred significantly later (63 +/- 26 msec, p less than .01). In two subjects right bundle branch block produced similar findings. In three subjects left bundle branch block produced little ventricular asynchrony (mean 14 msec), but did delay the development of peak LV dP/dt after LV contraction.(ABSTRACT TRUNCATED AT 250 WORDS)

OCLC for the hospital library: the justification plan for hospital administration.

This paper delineates the necessary steps to provide hospital administrators with the information needed to evaluate an automated system, OCLC, for addition to the medical library. Based on experience at the Norton-Children's Hospitals, included are: (1) cost analyses of present technical processing systems and cost comparisons with OCLC; (2) delineation of start-up costs for installing OCLC; (3) budgetary requirements for 1981; (4) the impact of automation on library systems, personnel, and services; (5) potential as a shared service; and (6) preparation of the proposal for administrative review.