Gastrointestinal toxicity,antiinflammatory activity,and superoxide dismutase activity of copper and zinc complexes of the antiinflammatory drug indomethacin

Gastrointestinal (GI) toxicity is one of the major problems associated with antiinflammatory drugs. The complexation of the powerful antiinflammatory drug (IndoH) by metal ions, as a means of reducing GI toxicity, has been studied. The in vitro superoxide dismutase (SOD) activity, in vivo antiinflammatory activity, and gastrointestinal ulcerogenic properties of IndoH, [Cu2(Indo)4(DMF)2], and [Zn2(Indo)4(DMA)2] are reported. No SOD activity was observed for IndoH or [Zn2(Indo)4(DMA)2], but [Cu2(Indo)4(DMF)2] inhibited the reduction of nitroblue tetrazolium (NBT) at an IC50 value of 0.23 microM. All three compounds exhibited antiinflammatory activity in male Sprague-Dawley rats at an equivalent Indo dose of 10 mg/kg following oral administration of the drugs in 2% CMC solution. The severity of the toxicity (macroscopic ulcerations) in the stomach following oral dosing with [Zn2(Indo)4(DMF)2] was not significantly lower than that induced by IndoH (P = 0.78). Gastric ulcerations induced by [Cu2(Indo)4(DMF)2] were significantly lower than those induced by IndoH or [Zn2(Indo)4(DMA)2] (P = 0.0012 and P = 0.0175, respectively) but significantly greater than the control (P = 0.0013). The intestinal ulcerations induced by [Cu2(Indo)4(DMF)2] or [Zn2(Indo)4(DMA)2] were approximately 15 times lower than those of IndoH. A further indicator of gastrointestinal toxicity, caecal haemoglobin, increased in the following order: control < [Cu2(Indo)4(DMF)2] < [Zn2(Indo)4(DMA)2] < IndoH.[Cu2(Indo)4(DMF)2] exhibited the most promising results of the Indo complexes assayed, in that it exhibited SOD activity and the lowest gastrointestinal damage while also exhibiting antiinflammatory activity that was comparable to that for IndoH. Low-temperature EPR analyses also showed that the formulation used for [Cu2(Indo)4(DMF)2] administration was crucial to the integrity of the complex.     

Sensitivity of bald eagle (Haliaeetus leucocephalus) hepatocyte cultures to induction of cytochrome P4501A by 2,3,7,8-tetrachlorodibenzo-p-dioxin

Graded doses of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) were added to primary hepatocyte cultures of bald eagle (Haliaeetus leucocephalus) embryos to determine their sensitivity to induction of cytochrome P4501A (CYP1A) and porphyrin accumulation. No porphyrin accumulation was observed, but both CYP1A catalytic activity (using the ethoxyresorufin-O-deethylase (EROD) assay) and immunodetectable CYP1A were induced by relatively high concentrations of TCDD. Bald eagle hepatocytes were less sensitive to CYP1A induction than hepatocytes from any other avian species that we have studied to date. These in vitro results are in general agreement with recent assessments of field data, which indicate that bald eagles are relatively insensitive to some of the effects of TCDD and related compounds. Preparation of bald eagle hepatocytes was challenging because existing methods did not yield monolayers of cells. Here we describe details of a new method that was successful for bald eagle hepatocytes. This new method is used routinely in our laboratory to prepare hepatocyte cultures from birds for examination of various biochemical responses to environmental contaminants.     

Recent developments in the psychobiology and pharmacotherapy of depression: optimising existing treatments and novel approaches for the future

Effective antidepressants include monoamine oxidase inhibitors and tricyclic antidepressants, selective serotonin re-uptake inhibitors and novel agents, including serotonin and noradrenaline re-uptake inhibitors. Although effective, current treatments most often produce partial symptomatic improvement (response) rather than symptom resolution and optimal functioning (remission). While current pharmacotherapies target monoaminergic systems, different symptoms of major depressive disorder (MDD) may have distinct neurobiological underpinnings and other neurobiological systems are likely involved in the pathogenesis of MDD. In this article a review of current pharmacotherapeutic options for MDD, current understanding of the neurobiology and pathogenesis of MDD and a review of new and promising directions in pharmacological research will be provided. It is generally accepted that no single neurotransmitter or system is responsible for the dysregulation found in MDD. While agents that affect monoaminergic systems will likely continue to be first-line treatments for MDD for the foreseeable future, a number of new and novel agents, including corticotropin-releasing factor antagonists, substance P antagonists and antiglucocorticoids show considerable promise for refining treatment options. In order to better understand the neurobiology and treatment response of MDD, it is probable that more sophisticated theory-driven typologies of MDD will have to be developed.     

Indexing powder patterns in physical form screening: instrumentation and data quality

Two multisample laboratory powder diffractometers have been evaluated for the purpose of pattern indexing in the context of physical form screening. Both diffractometers utilise foil transmission geometry, primary monochromated radiation, and a position-sensitive detector. Data collected from six compounds (sotalol hydrochloride, hydroflumethiazide, verapamil hydrochloride, captopril, clomipramine hydrochloride, and famotidine) showed good angular resolution (FWHM as small as ca. 0.06 degrees ) and lattice parameters were easily obtained using the indexing program DICVOL-91. The extent of preferred orientation in each pattern was estimated using the DASH implementation of the March-Dollase function and is most evident with clomipramine hydrochloride and famotidine. Otherwise, the data compare favorably with reference capillary data sets. In conclusion, where there is a requirement to analyze 20-30 samples per day, with an emphasis on obtaining the high-quality data that are important in pattern recognition and imperative in indexing, the combination of foil transmission geometry, primary monochromated radiation, plus a position-sensitive detector is highly effective. The data also afford opportunities for crystal structure determination.     

Two new paracetamol/dioxane solvates--a system exhibiting a reversible solid-state phase transformation

This work reports on the crystal structures of two dioxane solvates of paracetamol that are true polymorphs. The high temperature phase is an orthorhombic form, space group Pbca, Z = 8, a = 12.6078(3) A, b = 12.1129(2) A, c = 13.4138(3) A, V = 2048.52(7) A(3), (at 295 K) and the low temperature form is monoclinic, space group P21/c, Z = 4, a = 12.325(6) A, b = 11.965(4) A, c = 13.384(6) A, beta = 92.01 degrees, V = 1972.6(14)A(3) (at 123 K). The structures of these polymorphs are described as is the interrelationship between the two structures. In addition to the structural interrelationship, it is shown that the two forms undergo a reversible phase transformation. Desolvation of either form generates the stable monoclinic phase of paracetamol.     

Does clinical trial subject selection restrict the ability to generalize use and cost of health services to "real life" subjects?

OBJECTIVES: To explore one aspect of the external validity of the randomized controlled trial (RCT), specifically how being selected for inclusion in a trial and having participated has influenced the use and cost of asthma-related health services. METHODS: Services used by asthmatic users of inhaled corticosteroids (iCSTs) having previously participated in an RCT (TS, n = 46) were compared with individuals who had never participated (NS, n = 51). RESULTS: TS were more likely to use higher (> or = 400 microg) daily doses of iCSTs than NS (OR, 3.3; 95% Cl, 1.1-8.3) but less likely to visit emergency departments (OR, 0.3; 95% Cl, 0.1-0.7). Total asthma-related costs did not differ significantly. CONCLUSIONS: Subject differences may impede generalizing from RCTs to real life.     

Exposure assessment in epidemiology: Does gender matter?

BACKGROUND: The pathway from potential hazards in the work environment to the measurement or estimation of personal exposure for epidemiologic studies comprises many steps, each of which can be influenced by factors that may or may not differ by gender. This article explores this pathway to address the question, "Should the potential for gender differences be taken into account in the activity of exposure assessment for epidemiologic studies?" METHODS: Evidence from previously published studies and data from the investigators' own research were examined to explore whether or not several theoretical sources of gender 'bias' in exposure assessment have been found in actual studies. Sources of bias examined included: differences in job tasks despite same job titles; differences in delivered exposure due to differences in protective equipment, body size, or other relationships to exposure sources; and differences in estimated exposure arising from study methods or design. RESULTS AND CONCLUSIONS: Evidence was found for gender differences (and thus potential bias) from all these sources, at least in some studies. We conclude that the answer to the question posed, "Does gender matter, in exposure assessment for epidemiology?" is a qualified 'yes,' but that the magnitude and direction of the potential bias cannot be predicted, a priori. Am. J. Ind. Med. 44:576-583, 2003.     

Role of underlying pulmonary obstruction in short-term airway response to metal working fluid exposure: a reanalysis

BACKGROUND: Among epidemiologic studies that found evidence for associations between exposures to metal working fluids (MWF) and pulmonary function impairments, one found effects restricted to workers with fixed obstruction at baseline. We reanalyzed a previously published study on MWF exposure and cross-shift pulmonary function to further evaluate this finding. METHODS: Pulmonary function was measured cross-shift on Monday and Friday in 131 male automotive workers. Quantitative personal MWF exposure data were available. Those with an FEV(1)/FVC ratio of 相似文献   

Metabolic effects of an enteral nutrition formula for diabetes: comparison with standard formulas in patients with type 1 diabetes

AIM: To evaluate the metabolic response (glucose, cholesterol, triglycerides and beta-hydroxy-butyrate) in patients with type 1 diabetes after a trial breakfast with an enteral nutrition formula designed for patients with diabetes and compare it with standard formulas (with and without fibre). MATERIAL AND METHODS: Each of 11 patients with type 1 diabetes consumed three types of liquid breakfast with a 1 week interval between each. (1). A standard diet (SD) with 49% carbohydrates, 35% lipids, 16% proteins-casein-and without fibre; (2). A fibre-enriched diet (FD): with 49% carbohydrates, 35% lipids, 16% casein and 15 g/1000 ml fibre; (3). A diet designed for patients with diabetes (DD) with 45% carbohydrates, 38% lipids, 16% soy protein and 15 g/1000 ml fibre. Each subject consumed 250 ml of each preparation at 9.00 AM after having administered their usual insulin dose, which was the same for each diet. Blood samples were taken at baseline and each 30 min, up to 150 min. RESULTS: The increase in postprandial glycaemia was lower with DD than with the standard preparations, reaching statistical significance at 60 min. There were no significant variations in the levels of cholesterol, triglycerides or beta-hydroxy-butyrate between the three preparations. CONCLUSIONS: After a trial breakfast, a diet designed for patients with diabetes provoked lower increases in postprandial glycaemia (with no changes in lipid or beta-hydroxy-butyrate levels) compared to the standard diets evaluated (with and without fibre).     

A comparison of travel related ID admissions in Glasgow: (1985; 1998/99)

A comparative study was made of patients admitted over 12 months to the principal infectious diseases unit for Glasgow in 1985 and in 1998/99. During this interval UK travel statistics show a 135% growth in visits abroad and a 5% rise to 17% in destinations with a risk of malaria. Travel associated admissions rose by 96% to a total of 108. Patients of Asian/Oriental ethnicity declined from 55% to 18%, whilst Caucasians increased from 38% to 81%. Travellers aged 20-39 years formed the modal age groups (51% and 50%). Gastro-intestinal problems accounted for the largest single diagnostic category in both study periods, 38% and 40% respectively. In-patients diagnosed with malaria fell by 20%; these figures are cause for encouragement to those involved in the teaching and dissemination of advice on malaria prophylaxis. The findings re-enforce the need for the continuation and expansion of travel health education for both healthcare professionals and the public.