Epidemiology of intoxications in Italy.
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Animals↗
Biomedical subjects
G Mengozzi
Publications and source records attributed to G Mengozzi.
Inhibition of cytochrome p450 enzymes by enrofloxacin in the sea bass (Dicentrarchus labrax).
Currently, there are no reports on the effects of enrofloxacin (EF), a fluoroquinolone antibiotic, on the cytochrome p450 enzymes in fish, although its use as antimicrobial agent in aquaculture has been put forward. Therefore, the in vivo and in vitro effects of EF on hepatic p450 enzymes of sea bass, a widespread food-producing fish, have been evaluated. Sea bass pretreated with a single dose of EF (3 mg/kg i.p.) or with three daily doses of EF (1 mg/kg i.p.) markedly depressed the microsomal N-demethylation of aminopyrine, erythromycin, the O-deethylation of 7-ethoxycoumarin, ethoxyresorufin and the 6beta-testosterone hydroxylase. In vitro experiments showed that EF at 10 microM inhibited the above-mentioned activities and, in particular, the erythromycin N-demethylase (ERND) and 6beta-testosterone-hydroxylase, likely dependant on a p450 3A isoform. When the nature of ERND inhibition by EF was specifically studied with sea bass liver microsomes, it was found that EF is a potent mechanism-based inhibitor, with K(i) of 3.7 microM and a K(inact) of 0.045 min(-1). An immunoblot analysis with anti p450 3A27 of trout showed that the p450 3A isoform, constitutively expressed in sea bass, is particularly susceptible to inactivation by EF. In vitro experiments with sea bass microsomes have also demonstrated that EF is oxidative deethylated by the p450 system to ciprofloxacin (CF) and that this compound maintains the ability to inactivate the p450 enzymes. The mechanism by which EF or CF inactivate the p450 enzymes has not been studied but an attack of p450 on the cyclopropan ring, present, both in EF and CF structure, with the formation of electrophilic intermediates (i.e. radicals) has been postulated. In conclusion, the EF seems to be a powerful inhibitor of p450s in the sea bass. Therefore, the clinical use of this antibiotic in aquaculture has to be considered with caution.
Animals↗
Effects of liquid and freeze-dried grapefruit juice on the pharmacokinetics of praziquantel and its metabolite 4'-hydroxy praziquantel in beagle dogs.
Grapefruit juice changes the pharmacokinetic parameters of a variety of drugs metabolized primarily by cytochrome P450 3A. In a three-phase crossover study, six male beagle dogs were administered 100 ml of water (control), 100 ml of commercial liquid grapefruit juice, or 10 g of freeze-dried grapefruit juice (equivalent to 100 ml of liquid grapefruit juice) with 100 ml of water, followed after 2 h by single oral dose of praziquantel (30 mg kg(-1)). After treatment, the dogs were sampled at different times. Determination of praziquantel and its metabolite 4'-hydroxy praziquantel (identified by GC/MS) was performed by HPLC. Liquid and freeze-dried grapefruit juice preadministration increased the C(max) of praziquantel about three-fold and the AUC 2.5- and 2.3-fold, respectively. The T(max) (0.75 h) was unaffected by liquid or freeze-dried grapefruit juice, while T(1/2) was 2.3- and 1.7-fold higher compared with controls. The amount of 4'-hydroxy praziquantel was also affected by both liquid and freeze-dried grapefruit juice administration: the AUC and C(max) increased four- and three-fold, respectively and the T(max) was significantly enhanced. These findings demonstrate that both freeze-dried grapefruit juice and commercial liquid grapefruit juice significantly increase plasma concentrations and T(1/2) of praziquantel in dogs.
Animals↗
A comparative kinetic study of thiamphenicol in pre-ruminant lambs and calves.
Eight healthy Holstein-Friesian calves and 8 Massese lambs of either sex (10-15-days old) were used to evaluate the pharmacokinetics of thiamphenicol after intravenous (i.v.) and oral (p.o.) administration (30 mg/kg). Plasma concentrations of thiamphenicol were determined by high-performance liquid chromatography on blood samples collected over 24h following treatment. Pharmacokinetic variables of the drug were calculated for both species and after both administration routes. After intravenous administration of thiamphenicol, a rapid distribution phase was followed by a slower elimination phase and, when thiamphenicol was administered p.o., the bioavailability was about 60% in both species. The higher volume of distribution and the longer biological elimination half-lives in pre-ruminant compared with adult animals indicate that thiamphenicol distributes widely into the extravascular compartment of pre-ruminants. Interspecies differences were observed in the kinetic behaviour of thiamphenicol with respect to peak plasma concentration (C(max)), time of peak plasma concentration (T(max)), elimination half-life (T(1/2)) and total clearance (Cl(B)). In conclusion intravenous or oral administration of 30 mg/kg of thiamphenicol provides plasma concentrations higher than minimum effective concentrations inhibiting bacterial growth (MICs) against most pathogens in pre-ruminant lambs and calves.
Administration, Oral↗
Effect of perioperative infusion of antioxidants on neutrophil activation during liver transplantation in humans.
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Adult↗
Coronary microcirculation in essential hypertension: a quantitative myocardial contrast echocardiographic approach.
AIMS: The aims of the present study were: (a) to demonstrate whether quantitative myocardial contrast echocardiography can detect the increase in coronary flow induced by dipyridamole infusion vasodilation through the myocardial opacification due to the transit of microbubbles, both at rest and after dipyridamole induced vasodilation; (b) to explore the coronary microcirculatory function before and after dipyridamole in two different models: asymptomatic and relatively young hypertensive patients with a mild degree of left ventricular hypertrophy, and healthy controls. METHODS AND RESULTS: Two groups of strictly age-matched males were studied (case-control study): 10, relatively young and asymptomatic essential hypertensive patients with a mild degree of left ventricular hypertrophy with a normal left ventricular function, and 10 healthy controls. The main findings were: the microbubbles' appearance area was significantly lower in hypertensive patients than in controls (P<0.05) because of a significantly lower time to peak. The peak intensity at rest was higher in hypertensives than in controls (P<0.05); but the per cent increase after vasodilatory stimulus was significantly higher in controls (+71% in controls vs +31% in hypertensives; P<0.05). The microbubbles' disappearance area was comparable in both groups at rest; the per cent increase of this parameter after dipyridamole was significantly higher in controls (+124%) than in hypertensives (+90%) (P<0.05). The results achieved in this study documented that the coronary microcirculation in hypertensive patients presenting a mild degree of left ventricular hypertrophy, explored with quantitative myocardial contrast echocardiography, showed a different behaviour in comparison with controls, in the vasodilatory response to dipyridamole. CONCLUSION: The coronary microcirculation in hypertensives showed a reduced vasodilation capacity of the resistance arterioles under dipyridamole induced vasodilatation, and a possible impairment of the endothelium dependent vasodilation. This happened despite an increase in the left ventricular mass, where the relation between capillary bed distribution and hypertrophied myocardium (rarefaction phenomenon) is not completely respected.
Adult↗
Systemic nitric oxide production and renal function in nonazotemic human cirrhosis: a reappraisal.
OBJECTIVES: Several studies in human cirrhosis have demonstrated increased nitric oxide (NO) production. In experimental animals, intracerebroventricular administration of NO donors causes a marked depression of the endogenous dopaminergic activity, a function known to be physiologically recruited and exerting a natriuretic function in patients with compensated cirrhosis. The aim of this study is to evaluate the interaction between the systemic plasma levels of NO, the endogenous dopaminergic activity and the main parameters of renal function in patients with liver cirrhosis of differing degrees of severity. METHODS: A total of 21 patients (11 with preascitic and 10 with nonazotemic diuretic-free ascitic cirrhosis) and 10 healthy control subjects underwent the following tests: a) basal plasma renin activity (PRA) and aldosterone levels; b) renal clearances of sodium, potassium, inulin, para-minohippurate and lithium (the latter being a measure of the fluid delivery to the distal nephron); c) NO systemic plasma levels measured through paramagnetic resonance spectroscopy as nitrosylhemoglobin complexes; d) endogenous dopaminergic activity, evaluated by means of the incremental prolactin and aldosterone plasma levels after dopaminergic blockade with i.v. metoclopramide. RESULTS: NO plasma values and endogenous dopaminergic activity, although significantly increased with respect to healthy controls, were not different in the two groups of patients. The plasma NO/PRA ratio was significantly higher in the group of compensated patients with respect to ascitic cirrhotics (respectively, 18.3 +/- 11.8 vs 3.5 +/- 2.6 A.U./ng/ml/h, p < 0.001). Compared with compensated cirrhotics, patients with ascites showed significantly lower values of glomerular filtration rate (GFR) and renal plasma flow (RPF). Interestingly, GFR values were substantially the same in the ascitic patients and the control subjects. Compensated patients displayed a significant positive correlation between metoclopramide-induced incremental aldosterone plasma levels (i.e., endogenous dopaminergic tone) and fractional excretion of sodium (r = 0.58; p < 0.05). In the group of compensated patients, NO levels correlated inversely with creatinine plasma concentrations (r = -0.85; p < 0.001) and directly with inulin clearance (r = 0.65; p < 0.05). CONCLUSIONS: These data show that, at least in compensated cirrhotic patients, the stimulation of systemic NO production and the increased dopaminergic function may be mechanisms preventing renal perfusion, GFR, and fractional excretion of sodium from precocious reductions.
Adult↗
Bladder tumor antigen assay as compared to voided urine cytology in the diagnosis of bladder cancer.
BACKGROUND: The study was aimed at comparing the diagnostic accuracy of the quantitative bladder tumor antigen (BTA) TRAK immunoassay with exfoliative urine cytology in the detection of primary and recurrent bladder cancer. METHODS: The analysis was carried out on 194 high risk patients undergoing a diagnostic cystoscopy, 279 patients with previous history of transitional cell carcinoma awaiting a follow-up cystoscopy, and 45 healthy controls. Urine cytology was performed by a skilled cytopathologist on three consecutive samples. RESULTS: BTA TRAK values resulted significantly higher in tumor positive cases than in absence of bladder tumor for both groups of patients. Non neoplastic urothelial diseases as well as the absence of mucosal abnormalities were associated with a marked increase in BTA TRAK levels with respect to the control group. Overall sensitivity and specificity was 63 and 63% for BTA TRAK (cut-off 34 U/ml), and 68.3 and 73.4% for urine cytology, respectively. The diagnostic advantage of urine cytology was maintained when patients were stratified by tumor grade. CONCLUSIONS: The clinical performance of the BTA TRAK in the detection of primary or recurrent bladder cancer is acceptable and reproducible as shown by similar results with previous reports, although urine cytology performed on three samples showed the highest sensitivity and specificity.
Aged↗
Pharmacokinetics and microsomal oxidation of praziquantel and its effects on the P450 system in three-month-old lambs infested by Fasciola hepatica.
Praziquantel (PZQ) is a broadly effective trematocide and cestocide, widely employed in veterinary and human medicine. In view of several differences in both its pharmacokinetic profile in different animal species and in the cytochrome P450-dependent system between ruminant and nonruminant species, the present study was undertaken to determine the pharmacokinetics of this drug, its effects on the P450 system and the involvement of cytochrome P450 in its metabolism in 3-month-old lambs infested by Fasciola hepatica. Following both oral and i.m. administration, PZQ disposition was best described by a linear one-compartment open model with a rapid absorption and elimination. Although the PZQ dose used by the i.m. route was only half of that used by the oral route, the mean PZQ plasma concentration was higher after i.m. than after oral treatment. Oral treatment with 30 mg/kg/day of PZQ did not modify the mono-oxygenase activities tested, whilst the administration of PZQ at a dose of 60 mg/kg/day for 2 days caused a significant decrease in the P450 3A-dependent erythromycin N-demethylase and 6beta testosterone hydroxylase activities. From the incubation of microsomes from lambs not treated with PZQ, a single metabolite (PZQ 11b-OH or PZQ 1-OH) was identified by GC/MS analysis. By selective inhibition of the 3A subfamily performed with triacetyloleandromycin, the production of this metabolite declined by about 90% suggesting a prominent role of P450 3A isoforms in this oxidation. These features indicate that agents or drugs which are able to modulate P450 3A-dependent catalysis may interfere with the metabolism, bioavailability and therapeutic effects of PZQ.
Administration, Oral↗
Evidence of an increased nitric oxide production in primary biliary cirrhosis.
OBJECTIVE: Although possible implications of nitric oxide in the pathophysiology of liver cirrhosis have been extensively studied, until now few articles have addressed the assessment of nitric oxide production in primary biliary cirrhosis. This study was directed to evaluate circulating nitrosyl-hemoglobin levels as well as neutrophil elastase and soluble adhesion molecule concentrations in this condition, by assuming these parameters as possible markers of either inflammatory response or neutrophil activation. METHODS: Laboratory investigations were performed in 30 patients with primary biliary cirrhosis, in 13 patients with postviral and/or alcoholic cirrhosis, and in a group of eight subjects with chronic hepatitis. RESULTS: Although no difference was detected with respect to chronic hepatitis subjects, higher levels of nitrosyl-hemoglobin adducts were found in primary biliary cirrhosis patients than in postviral or alcoholic cirrhotics and in normal subjects (3.55+/-1.75 arbitrary units vs 1.95+/-0.57 and 0.84+/-0.34, p = 0.0004 and p < 0.0001, respectively). Similarly, more elevated concentrations of neutrophil elastase (213.7+/-192.0 microg/L vs 51.1+/-34.3 and 38.0+/-11.5, p < 0.0001 and p < 0.0001, respectively) as well as of soluble forms of intercellular adhesion molecule 1 and endothelial-leukocyte adhesion molecule 1 were shown in primary biliary cirrhosis patients than in subjects with cirrhosis of other etiologies and in controls. CONCLUSIONS: Highly enhanced nitric oxide production in primary biliary cirrhosis could be related to the development of strong inflammation and at least partially to neutrophil activation, thus suggesting a putative role of these cellular mediators in the development of liver damage owing to their ability to synthesize and release a wide variety of important factors, including elastase and nitric oxide.
Adult↗
Duration of gluten exposure in adult coeliac disease does not correlate with the risk for autoimmune disorders.
BACKGROUND AND AIMS: Duration of gluten exposure seems to predispose adolescents with coeliac disease to autoimmune diseases. In a retrospective cohort study, we assessed the relationship between autoimmune disorders and actual gluten exposure in patients in whom coeliac disease was diagnosed in adult life (> or = 16 years). METHODS: We screened for the presence of autoimmunity in 605 controls (16-84 years) and 422 patients (16-84 years), all of whom had been on gluten withdrawal for at least one year (median follow up 9.5 years). A logistic regression analysis, setting the prevalence of autoimmunity as the dependent variable, was employed to control for independent covariates as predictors of the risk of autoimmunity. RESULTS: The prevalence of autoimmunity was threefold higher (p < 0.00001) in patients than in controls. Mean duration of gluten exposure was 31.2 and 32.6 years for patients with or without autoimmunity. Logistic regression showed that increased age at diagnosis of coeliac disease was related to the prevalence of autoimmune disease while "actual gluten exposure" which takes into account diet compliance, follow up, and age at diagnosis of autoimmune disorders were not predictive for the risk of developing autoimmune diseases (odds ratio 0.82 per year). CONCLUSION: The prevalence of autoimmune diseases in patients with a late coeliac disease diagnosis does not correlate with duration of gluten intake. Early exposure to gluten may modify the immunological response. Gluten withdrawal does not protect patients with a late diagnosis from autoimmune diseases.
Adolescent↗
Diagnostic accuracies for celiac disease of four tissue transglutaminase autoantibody tests using human antigen.
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Adult↗
The effects of 1-year gluten withdrawal on bone mass, bone metabolism and nutritional status in newly-diagnosed adult coeliac disease patients.
OBJECTIVES: To evaluate the impact of a 1-year gluten-free diet on bone metabolism and nutritional status in coeliac disease. METHODS: Bone mineral density, serum indices of bone remodelling, clinical and biochemical nutritional assessment were evaluated in 86 consecutive newly-diagnosed, biopsy proven, coeliac disease patients (untreated). A complete reevaluation, including intestinal biopsy, was repeated within 1 year of dietary treatment (treated). RESULTS: Untreated: according to WHO criteria, 34% of patients had a normal bone mineral density, 40% had osteopenia and 26% osteoporosis. Between males and females there were no statistical differences in bone metabolism or in most of the nutritional indices, while, between fertile and postmenopausal women, bone mineral density and several bone metabolism markers were significantly different. Compared to subjects with a normal bone mineral density, osteopenics had higher bone specific alkaline phosphatase (BAP) and Bone-Gla-protein (BGP) values. In patients with a concomitant BAP increase and 25OH vitamin D serum level reduction, bone mineral density and several bone turnover markers were statistically different compared to patients without such a serological pattern. Treated: notwithstanding intestinal biopsy which showed a mucosal recovery in only 57%, gluten-free diet led, even in postmenopausal women, to a significant improvement in bone mineral density, bone metabolism and nutrition, except for folic acid, albumin and pre-albumin serum levels which persisted as abnormal in patients with obdurate mucosal impairment. CONCLUSIONS: Coeliac disease patients are at high risk for developing a low bone mineral density and bone turnover impairment. A gluten-free diet can improve this situation even in postmenopausal women and in patients with incomplete mucosal recovery.
Adult↗
Determination of thiamphenicol residues in albumin and yolk of hen eggs.
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Administration, Oral↗
Effects of angiotensin II blockade on nitric oxide blood levels in IgA nephropathy.
BACKGROUND: The effects of renin-angiotensin system blockade on nitric oxide (NO), especially in pathological conditions, are far from being established. The influence of kinins and angiotensin type 2 receptor are largely speculative and based mainly on animal studies. This study was aimed to address these aspects in humans. METHODS: Eight IgA nephropathy patients with documented clinical and histological indicators of poor prognosis were given 50 mg of losartan, 10 mg of enalapril, and 40 mg of the NO donor isosorbide 5 mononitrate (as a control of NO generation) in randomized order for 7 days each. Treatment periods were separated by washout periods of 7 days each. Laboratory investigations were performed before and after each study period. Seven healthy controls received losartan and enalapril according to the same study design. RESULTS: Glomerular filtration rate remained stable while effective renal plasma flow increased with each treatment (P<0.05). Under losartan and enalapril, filtration fraction fell (P=0.02), plasma renin activity increased (P<0.05) and urinary aldosterone concentration decreased (P=0.02). Angiotensin-converting enzyme activity was reduced to the limit of detection under enalapril (P<0.001). Blood NO, detected as nitrosylhaemoglobin by a recently developed technique of spin-trap electron paramagnetic resonance, increased significantly, as expected, during treatment with isosorbide 5 mononitrate (P=0.01), with enalapril (P<0.05), and also with losartan (P<0.05). Unlike losartan, enalapril significantly reduced albuminuria (P=0.01) in this short-term period. In the seven healthy controls, neither enalapril nor losartan were able to increase blood NO levels significantly. CONCLUSIONS: Blood levels of nitrosylhaemoglobin, a surrogate marker of NO, increased under blockade of the renin-angiotensin system in patients with IgA nephropathy, but not in healthy volunteers. This increase could contribute to changes of effective renal plasma flow in renal disease states.
Adult↗
BTA quantitative assay and NMP22 testing compared with urine cytology in the detection of transitional cell carcinoma of the bladder.
PURPOSE: Both BTA TRAK and NMP22 urine concentrations have shown a sensitivity superior to urine cytology in the detection of bladder cancer. We compared these tumor markers with urine cytology performed on 3 consecutive samples and evaluated by an expert cytopathologist. PATIENTS AND METHODS: The investigations were conducted on 94 patients undergoing a diagnostic cystoscopy for a high suspicion of bladder cancer (group 1) and on 102 patients with previous history of transitional cell carcinoma awaiting a follow-up cystoscopy (group 2). Biopsy specimens were obtained also from tumor negative patients. Immunoassays for BTA TRAK and NMP22 were carried out according to standard methods. The choice of the cut-off was based on the ground of sensitivity and specificity curves intersection. Urine cytology results were expressed as positive, negative and 'dubious'. RESULTS: Overall sensitivity was 56% for NMP22 (cut-off 11 U/ml) and 57% for BTA TRAK (cut-off 60 U/ml). When dubious results were considered as positive cases, urine cytology achieved a sensitivity of 73.3%. Assuming dubious cases as negative results, urine cytology sensitivity resulted 59.3%. When the 2 groups of patients were evaluated separately with different cut-off, there was no significant gain in sensitivity for BTA TRAK and NMP22 over urine cytology. CONCLUSIONS: Urine cytology performed on 3 samples showed the highest sensitivity and specificity. The diagnostic advantage of urine cytology over BTA TRAK and NMP22 was maintained when patients were stratified by tumor grade.
Aged↗
Absorption kinetics and bioavailability of cephalexin in the dog after oral and intramuscular administration.
The pharmacokinetics of cephalexin, a first generation cephalosporin, were investigated in dogs using two formulations marketed for humans, but also often employed by practitioners for pet therapy. Cephalexin was administered to five dogs intravenously and intramuscularly as a sodium salt and by the oral route as a monohydrate. The dosage was always 20 mg/kg of active ingredient. A microbiological assay with Sarcina lutea as the test organism was adopted to measure cephalexin concentrations in serum. The mean residence time (MRT) median values after intravenous (i.v.), intramuscular (i.m.) and oral administration (p.o.) were 86 min, 200 min, and 279 min, respectively. After i.m. and oral dosing the peak serum concentrations (24.2 +/- 1.8 micrograms/mL and 20.3 +/- 1.7 micrograms/mL, respectively) were attained at 90 min in all dogs and bioavailabilities were 63 +/- 10% and 57 +/- 5%, respectively. The time course of the cephalexin serum concentrations after oral administration was best described by a model incorporating saturable absorption kinetics of the Michaelis-Menten type: thus in the gastrointestinal tract of dogs a carrier mediated transport for cephalexin similar to that reported in humans, may exist. The predicted average serum concentrations of cephalexin after repeated i.m. and oral administration indicated that, in order to maintain the therapeutic concentrations, the 20 mg/kg b.w. dosage should be administered every 6-8 h.
Absorption↗
Disposition of antimony and aminosidine combination after multiple subcutaneous injections in dogs.
The disposition of a combination of antimony (Sbv) (12.8 mg/kg) and aminosidine (AM) (10 mg/kg) in 10 healthy Beagle dogs after multiple subcutaneous injections is described. Sbvplasma concentrations were determined by atomic absorption spectrometry, and AM by ion-pair liquid chromatography, using a fluorimetric detector. Sbvreached Cmaxat 60 min, and for about 1 h plasma levels were homogeneously stabilized between 10.78 and 11.76 microgram/mL; by 12 h, Sbvplasma concentrations were close to the detection limit (0.3 microgram/mL). AM Cmaxvalues were recorded after 1 h (30.6+/-3.11 microgram/mL, mean +/- SD), and plasma levels reached values close to the detection limit (0.15 microgram/mL) between 7 and 8 h after injection. Sbvkinetic parameters did not appear modified by the presence of AM. Moreover, repeated injections of the combination did not modify the kinetic behaviour of the two drugs and did not alter the renal function of the animals. The superimposition analysis of the Sbvdata suggests that a twice daily injection of the metal at a dose of 12.8 mg/kg would be sufficient to maintain inhibitory Sbvconcentrations similar to those recorded in humans.
Amebicides↗