Acute anti-inflammatory activity and gastrointestinal tolerability of diclofenac and nitrofenac

Diclofenac and its derivative nitrofenac were compared to test their anti-inflammatory efficacy and gastrointestinal toxicity in rats.A similar good anti-inflammatory activity of the two drugs was observed in carrageenan oedema and a marked gastrointestinal toxicity was induced by diclofenac, while nitrofenac failed to produce gastric damage even with very high doses (50 and 100 mg/kg).The lack of the gastric ulcers in rats treated with nitrofenac could be due to the absorption of the drug as an inactive inhibitor of PG synthesis and/or to the fact that probably nitric oxide is release in the intestine and plays an important protective role in maintaining the tissue integrity.     

Effect of acute exercise on some haematological parameters and neutrophil functions in active and inactive subjects

In this work we studied the possible effects of acute exercise on some haematological parameters and on some functions of neutrophils in seven active and six inactive subjects. Physical exercise (10 min on a cycle ergometer at a heart rate of 150 beats · min^–1) induced a significant increase in total leucocyte, lymphocyte and neutrophil concentrations in active subjects; serum iron and ferritin concentrations were lower in active compared to inactive subjects. Cellular adhesion, bactericidal activity and superoxide anion production did not change after exercise, while we also observed some differences between active and inactive subjects before exercise. In particular, the neutrophils from active subjects showed a significantly higher percentage of adhesion, higher bactericidal activity and lower superoxide anion production. In conclusion, the training induced changes in some neutrophil functions, while acute exercise influenced, overall, leucocyte concentrations.     

Nitric oxide-releasing NSAIDs,a novel class of safe and effective anti-inflammatory agents

In this work, we tested the pharmacotoxicological profile of three new nitro-anti-inflammatory agents, nitrofenac, nitronaproxen and nitroflurbiprofen with the following results:

1. In models of acute (carrageenan oedema) and chronic (adjuvant arthritis) inflammation in the rat, the nitroderivatives, compared with the parent drugs, showed similar anti-inflammatory properties by significantly inhibiting both oedema volume and arthritis development.
2. The nitroso compounds showed markedly less ulcerogenic activity compared with the parent drugs both in acute conditions and at the end of the chronic inflammation test.
3. The lack of gastrointestinal damage observed with these new anti-inflammatory drugs is the consequence of their ability to release NO. This hypothesis is supported by pharmacokinetic studies and a significant increase in nitrite/nitrate plasma levels.

     

An epidemiological study of collagenous colitis in southern Sweden from 2001-2010

AIM: To estimate the incidence of collagenous colitis (CC) in southern Sweden during 2001-2010.METHODS: Cases were identified by searching for CC in the diagnostic registers at the Pathology Departments in the county of Skåne. The catchment area comprised the south-west part of the county (394 307 inhabitants in 2010) and is a mixed urban and rural type with limited migration. CC patients that had undergone colonoscopy during the defined period and were living in this area were included in the study regardless of where in Skåne they had been diagnosed. Medical records were scrutinized and uncertain cases were reassessed to ensure that only newly diagnosed CC cases were included. The diagnosis of CC was based on both clinical and histopathological criteria. The clinical criterion was non-bloody watery diarrhoea. The histopathological criteria were a chronic inflammatory infiltrate in the lamina propria, a thickened subepithelial collagen layer ≥ 10 micrometers (μm) and epithelial damage such as flattening and detachment.RESULTS: During the ten year period from 2001-2010, 198 CC patients in the south-west part of the county of Skåne in southern Sweden were newly diagnosed. Of these, 146 were women and 52 were men, i.e., a female: male ratio of 2.8:1. The median age at diagnosis was 71 years (range 28-95/inter-quartile range 59-81); for women median age was 71 (range 28-95) years and was 73 (range 48-92) years for men. The mean annual incidence was 5.4/10⁵ inhabitants. During the time periods 2001-2005 and 2006-2010, the mean annual incidence rates were 5.4/10⁵ for both periods [95% confidence interval (CI): 4.3-6.5 in 2001-2005 and 4.4-6.4 in 2006-2010, respectively, and 4.7-6.2 for the whole period]. Although the incidence varied over the years (minimum 3.7 to maximum 6.7/10⁵) no increase or decrease in the incidence could be identified. The odds ratio (OR) for CC in women compared to men was estimated to be 2.8 (95% CI: 2.0-3.7). The OR for women 65 years of age or above compared to below 65 years of age was 6.9 (95% CI: 5.0-9.7), and for women 65 years of age or above compared to the whole group the OR was 4.7 (95% CI: 3.6-6.0). The OR for age in general, i.e., above or 65 years of age compared to those younger than 65 was 8.3 (95% CI: 6.2-11.1). During the last decade incidence figures for CC have also been reported from Calgary, Canada during 2002-2004 (4.6/10⁵) and from Terrassa, Spain during 2004-2008 (2.6/10⁵). Our incidence figures from southern Sweden during 2001-2010 (5.4/10⁵) as well as the incidence figures presented in the studies during the 1990s (Terrassa, Spain during 1993-1997 (2.3/10⁵), Olmsted, United States during 1985-2001 (3.1/10⁵), Örebro, Sweden during 1993-1998 (4.9/10⁵), and Iceland during 1995-1999 (5.2/10⁵) are all in line with a north-south gradient, something that has been suggested before both for CC and inflammatory bowel disease.CONCLUSION: The observed incidence of CC is comparable with previous reports from northern Europe and America. The incidence is stable but the female: male ratio seems to be decreasing.     

Phytotherapic compounds: the consumer-pharmacist relationship.

Pharmacists play an important role in providing information about natural products and in preventing risks related to these substances, particularly with respect to interactions with conventional drugs. For these reasons, a survey was specifically designed to investigate the quality of self-care counselling by pharmacists on phytotherapy. Twenty-three pharmacy stores took part in the project. Face-to-face interviews, using a pre-structured questionnaire, were undertaken by trained pharmacists to consumers buying a herbal product. The questionnaire included socio-demographic data and 17 items designed to elicit information regarding the reason of consumption, product knowledge, relationship/communication with healthcare providers, level of satisfaction, concurrent drug use and adverse reactions. The collection of interviews started in November 2006 until April 2007. From the analysis of 1420 questionnaires, it is evident that herbal use is increasing in Italy: 12% of our interviewees were buying a herbal product for the first time. The present survey highlights the favourable perception of efficacy of phytotherapic compounds by the pharmacy's consumers, who consider this healthcare modality to be an important and effective way to promote health/wellness and disease management as well as being safer overall than conventional drugs. Moreover, findings from this study demonstrate that pharmacists are more likely to answer correctly about the uses of herbal medicines than about drug interactions, adverse drug effects and cautions about these products.     

Effect of a new non-steroidal anti-inflammatory drug, nitroflurbiprofen, on the expression of inducible nitric oxide synthase in rat neutrophils.

The effects of a non-steroidal anti-inflammatory drug, flurbiprofen, and its nitro-derivative, nitroflurbiprofen, on inducible nitric oxide synthase in rat neutrophils were examined. Nitroflurbiprofen was shown to inhibit nitric oxide synthase induction caused by lipopolysaccharide administration, while flurbiprofen had no effect on nitric oxide synthase induction. This inhibitory action may be ascribed to nitric oxide released from nitroflurbiprofen.     

Urinary nitrite/nitrate concentrations and total antioxidant capacity in patients with chronic hepatitis C in therapy with interferon and ribavirin

In this study we tried to elucidate the role of nitric oxide (NO) in chronic hepatitis C in relation to antioxidant status, since the mechanisms by which hepatitis C virus (HCV) causes cell damage and the factors underlying its resistance to therapy are not well understood. Before and after one and six months of therapy with alpha-interferon and ribavirin, we measured nitrite/nitrate urinary levels, total antioxidant capacity and selenium serum concentrations in 14 patients with chronic hepatitis C and in 9 healthy subjects. Before therapy, mean urinary nitrite/nitrate levels of patients were not different from those of healthy subjects, but after a 6-month treatment with alpha-interferon and ribavirin, these NO metabolites were higher in virologically negative patients (responders). Moreover, while no changes in selenium were observed in all patients, total antioxidant capacity was significantly higher in non-responders and well correlated with hyperuricemia (due to cell damage) observed in these subjects. Instead, uric acid decreased as free molecule in serum in responders, while we found the excretion of high NO levels as nitrite/nitrate. Our data allow us to hypothesize a role for NO as predictive of the success of therapy, since nitrite/nitrate increase in the urine of some patients precedes disappearance of the virus observed at the end of therapy.     

Prediction of the disposition of midazolam in surgical patients by a physiologically based pharmacokinetic model.

The aim of this study was to predict the disposition of midazolam in individual surgical patients by physiologically based pharmacokinetic (PBPK) modeling and explore the causes of interindividual variability. Tissue-plasma partition coefficients (k(p)) were scaled from rat to human values by a physiologically realistic four-compartment model for each tissue, incorporating the measured unbound fraction (f(u)) of midazolam in the plasma of each patient. Body composition (lean body mass versus adipose tissue) was then estimated in each patient, and the volume of distribution at steady state (V(dss)) of midazolam was calculated. Total clearance (CL) was calculated from unbound intrinsic CL, f(u), and estimated hepatic blood flow. Curves of midazolam plasma concentration versus time were finally predicted by means of a perfusion-limited PBPK model and compared with measured data. In a first study on 14 young patients undergoing surgery with modest blood loss, V(dss) was predicted with an only 3.4% mean error (range -24-+39%) and a correlation between predicted and measured values of 0.818 (p < 0.001). Scaling of k(p) values by the four-compartment model gave better predictions of V(dss) than scaling using unbound k(p). In the PBPK modeling, the mean +/- standard deviation (SD) prediction error for all data was 9.7 +/- 33%. In a second study with 10 elderly patients undergoing orthopedic surgery, hemodilution and blood loss led to a higher f(u) of midazolam. The PBPK modeling correctly predicted a marked increase in V(dss), a smaller increase in CL, and a prolonged terminal half-life of midazolam, as compared with findings in the first study. Interindividual variation in the disposition of midazolam could thus in part be related to the physiological characteristics of the patients and the f(u) of the drug in their plasma.     

A mixed endocrine adrenal tumour causing steatorrhoea.

A 60 year old man developed steatorrhoea, weight loss, mild diabetes mellitus, labile hypertension and limb cramps. Raised plasma concentrations of catecholamines, particularly noradrenaline and a computed tomography-scan showing an adrenal tumour strongly suggested a pheochromocytoma. Adrenoreceptor blockade reversed the symptoms, decreased faecal fat, and increased duodenal trypsin to normal concentrations. After adrenalectomy the patient was asymptomatic and there was no steatorrhoea. The blood glucose concentrations became normal. Immunocytochemistry revealed the tumour cells to store large amounts of enkephalin and somatostatin reactive material and moderate amounts of immunoreactive beta-endorphin and dynorphin.