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Despite the wide number of studies investigating on drug-induced allergy, limited data focused on allergies associated with orally administered drugs are available. The aim of the study is to evaluate allergic drug reactions associated with oral drug use, using an Italian spontaneous reporting database of adverse drug reactions (ADRs). Spontaneous reports associated with oral drugs retrieved from seven Italian regions (GIF research group), collected from 1988 to 2006, were analysed. Association between drugs and allergic adverse reactions was assessed using the case/non-case method, calculating the ADR reporting odds ratio (ROR) as a measure of disproportionality. Overall, 27,175 reports of adverse reactions related to oral drug use were analysed; of these, 3143 (11.6%) were judged as allergy cases. Paediatric patients (

Statins have different effects beyond cholesterol reduction and stimulate angiogenesis. We investigated the effect of simvastatin in diabetes-related healing defects. An incisional skin wound model produced on the back of female diabetic mice (db(+)/db(+)) and their normoglycemic littermates (db(+)/(+)m) was used. Animals were treated daily either with simvastatin (5 mg/(kgi.p.)) or vehicle. Mice were killed on different days (3, 6 and 12 after skin injury) for measurement of vascular endothelial growth factor (VEGF) mRNA and protein expression, to assess histologically the healing process and to evaluate wound breaking strength and angiogenesis by CD31 immunostaining. Simvastatin administration in diabetic mice increased VEGF mRNA (simvastatin=4.8+/-0.6n-fold/beta-actin; vehicle=2.3+/-0.4n-fold/beta-actin) and protein expression (simvastatin=5+/-0.7 integrated intensity; vehicle=2.2+/-0.3 integrated intensity) and enhanced nitric oxide wound content at day 6. Additionally, the statin augmented breaking strength and PECAM-1 immunostaining at day 12. Finally, simvastatin administration restored the impaired wound healing process in diabetic mice. Similar results were obtained in normoglycaemic mice. Passive immunization with anti-VEGF antibody (10 microg/mouse) completely abrogated the beneficial effects of simvastatin on healing in diabetic mice. Simvastatin has potential application in diabetes-related wound healing disorders.

Diagnostic contrast media (CM) are a widely used class of drugs with poor information regarding their safety. Nevertheless, epidemiological studies showed that CM cause adverse reactions commonly considered unpreventable and unavoidable. Because spontaneous reporting is a valuable methodology for better defining the safety profile of drugs after their approval, we analyzed the spontaneous reports of suspected adverse reactions attributed to CM sent to the Sicilian Regional Centre for the Spontaneous Reporting of Adverse Drug Reactions (ADRs) during the period from 1996 to 2006, with the aim to identify their most important features. One hundred ADR reports out of 3471 involved CM (2.9%); 29 reports were serious, including 1 fatal case. Skin, respiratory system and gastrointestinal tract were most frequently affected sites. The majority of reports described hypersensitivity reactions with immediate onset. Iopromide (52.5%), iopamidol (13.9%) and iomeprol (11.9%) were the drugs with the highest number of reports. Case reports collected by the Sicilian Regional Centre showed that CM adverse reactions are not common or not commonly signalled; however, in agreement with previous published reports, analysis of data suggests that they are generally allergic-like reactions. Further investigations are needed within post-marketing surveillance to identify and prevent the consequences of CM adverse reactions and interactions. Awareness about CM safety should be promoted among all healthcare professionals.

Limited information is available on drug-induced neuropsychiatric disorders in general practice. The spontaneous reports of both neurological and psychiatric adverse drug reactions (ADRs) collected during a 2-year period in PharmaSearch database, an Italian database recording reports of ADRs from general practitioners (GPs), were examined. Between January 2002 and December 2003, 171 general practitioners sent to PharmaSearch a total of 1131 reports corresponding to 1892 ADRs. Of overall reports, 310 (27.4%) involved the central nervous system resulting in 440 neuropsychiatric reactions (specifically, 241 neurological and 199 psychiatric). In our survey, 40 reports were excluded because they were incomplete or contradictory and thus classified as 'unlikely' or 'unclassifiable'. Therefore, the present analysis was carried out on 270 reports with 391 neuropsychiatric reactions (213 neurological and 178 psychiatric, respectively). Vertigo (16.4%), confusion (10.7%) and headache (10.0%) were the reactions more commonly reported. Drugs indicated for the treatment of nervous system disorders (ATC 1 code=N) accounted only for 38.4% of neuropsychiatric reactions, while most of these reactions were related to drugs indicated for other than nervous system diseases. Non-steroidal anti-inflammatory drugs (NSAIDs), fluoroquinolones, antidepressant drugs, opioids, and drugs for peptic ulcer were the categories most frequently suspected for neuropsychiatric reactions. Of 391 neuropsychiatric reactions, 78 (19.9%) were unlabeled and 41 (10.5%) were serious. In conclusion, the present study carried out in general practice underlines the importance of neuropsychiatric ADRs and reminds GPs to pay attention to this kind of toxicity when they prescribe pharmacological agents to their patients.

Background: Oral anticoagulants (OAs) are recommended for many clinical problems and their use requires organised and knowledgeable medical support. Up to our knowledge, there is no data about both the reasons of treatment among OAs' users and the number of patients prescribed with OAs in Italy., Objectives: To describe the OA use, and the reasons of prescribing among Italian General Practitioners., Methods: We used the Health Search Database owned by the Italian College of General Practitioners to identify the clinical records of patients > or =20 years who had at least one prescription of OAs during the year 2002., Results: Among a study population of 448,495 patients, 3,649 subjects (0.81%) had received at least one OAs prescription. Applying such a proportion to the overall Italian population, on the basis of data from Italian Office for National Statistics (ISTAT), we estimated that 376,882 patients would have used OAs during the year 2002 in Italy. The most frequent clinical problem related to the use of OAs was atrial fibrillation (45.6%), followed by cardiac valve disease (14.6%), deep vein thrombosis (12.2%) and peripheral artery embolism (7.7%)., Conclusions: Approximately 370,000 patients are prescribed with OAs in Italy and for more than 50% of them life-long therapy is recommended. Atrial fibrillation is the most frequent reason for prescription.

The polymorphic cytochrome P450 isoenzymes (CYPs) 2C9, 2C19 and 2D6 metabolise many important drugs, as well as other xenobiotics. Their polymorphism gives rise to important interindividual and interethnic variability in the metabolism and disposition of several therapeutic agents and may cause differences in the clinical response to these drugs. In this study, we determined the genotype profile of a random Italian population in order to compare the CYP2C9, CYP2C19 and CYP2D6 allele frequencies among Italians with previous findings in other Caucasian populations. Frequencies for the major CYP2C9, CYP2C19 and CYP2D6 mutated alleles and genotypes have been evaluated in 360 unrelated healthy Italian volunteers (210 males and 150 females, aged 19-52 years). Genotyping has been carried out on peripheral leukocytes DNA by molecular biology techniques (PCR, RFLP, long-PCR). CYP2C9, CYP2C19 and CYP2D6 allele and genotype frequencies resulted in equilibrium with the Hardy-Weinberg equation. One hundred and fourteen subjects (31.7%) carried one and 23 subjects (6.4%) carried two CYP2C9 mutated alleles. Sixty-eight (18.9%) volunteers were found to be heterozygous and six (1.7%) homozygous for the CYP2C19*2, while no CYP2C19*3 was detected in the evaluated population. Volunteers could be divided into four CYP2D6 genotypes groups: 192 subjects (53.3%) with no mutated alleles (homozygous extensive metabolisers, EM), 126 (35.0%) with one mutated allele (heterozygous EM), 12 (3.4%) with two mutated alleles (poor metabolisers, PM) and 30 (8.3%) with extracopies of a functional gene (ultrarapid metabolisers, UM). Frequencies of both CYP2C9 and CYP2C19 allelic variants, as well as CYP2D6 detrimental alleles, in Italian subjects were similar to those of other Caucasian populations. Conversely, the prevalence of CYP2D6 gene duplication among Italians resulted very high, confirming the higher frequency of CYP2D6 UM in the Mediterranean area compared to Northern Europe., (Copyright 2004 Elsevier Ltd.)

Biologic therapies, namely antibodies against tumor necrosis factor-alpha (TNF- alpha) or its receptors, have been recently introduced for the treatment of patients with inflammatory bowel disease (IBD). In the present study the effects of cloricromene, an agent with known antithrombotic actions and with demonstrated anti-TNF- alpha activity were investigated in a rat model of experimental colitis induced with dinitrobenzenesulphonic acid (DNB)/ethanol. We investigated three experimental groups: (i) sham-colitis with vehicle-treatment (controls, n = 6), (ii) colitis with vehicle-treatment (saline, 0.1 ml s.c., daily) (DNB-V, n = 7), (iii) colitis with cloricromene-treatment (10 mg/kg/day s.c.; DNB-C, n = 8). After 7 days, the weight gain, colon wet weight, macroscopic damage score, coagulation parameters, colon mucosal myeloperoxidase activity (MPO), and tissue concentrations of TNF- alpha and of macrophage inhibitory peptide-2 (MIP-2) were assessed. The macroscopic damage scores, colon wet weights, and tissue MIP-2 levels were significantly increased in untreated and in cloricromene-treated rats compared with controls. Cloricromene treatment was associated with a minor body weight loss (p < 0.025) and significantly reduced tissue concentrations of MPO and TNF-alpha (p < 0.02, both). Blood coagulation parameters were not affected by treatment. In the DNB-model treatment with cloricromene effectively reduces tissue levels of TNF- alpha and of myeloperoxidase, whereas MIP-2 concentrations were not influenced. Blood coagulation parameters remained unchanged indicating safety of treatment. Since biological therapies frequently fail to improve disease course of IBD, other therapies with similar targets should be further investigated.

Angiogenesis induced by growth factors may represent a rational therapy for patients with stroke. Vascular endothelial growth factor (VEGF) plays a pivotal role in angiogenesis and VEGF expression is enhanced in the post-ischemic brain. VEGF induced by brain hypoxia can lead to the growth of new vessels and may represent a natural protective mechanism improving survival after stroke. In the light of these findings we investigated changes of VEGF expression in different brain regions after intracerebroventricular injection of adeno-associated virus transferring gene for VEGF (rAAV-VEGF) in the gerbil, and after transient brain ischemic injury, we studied the effects of rAAV-VEGF injection on survival, brain edema, delayed neuronal death in the CA1 area and learning ability. Treatment with rAAV-VEGF 6 days or 12 days before ischemia significantly improves survival, brain edema and CA1 delayed neuronal death and post-ischemic learning evaluated by passive avoidance test. Animals treated with rAAV-VEGF showed in the thalamus and the cortex, a significant positive immunostaining for VEGF similar to those subjected to brain ischemia and not treated with rAAV-VEGF. These data represent a further contribution to a possible employment of gene therapy by using rAAV-VEGF in brain ischemia and indicate that thalamus and cortex may be targets for neuroprotective effects of VEGF.

Anthocyanins are a group of naturally occurring phenolic compounds as colorants in several plants, flowers and fruits. These pigments have a great importance as quality indicators, as chemotaxonomic markers and antioxidants. The content of blackberry (Rubus species) juice was investigated by HPLC/ESI/MS using narrow bore HPLC columns. Using this method we demonstrated that cyanidin-3-O-glucoside represents about 80% of the total anthocyanin contents in blackberry extract. Here we investigated antioxidant activity of the blackberry juice and cyanidin-3-O-glucoside on the endothelial dysfunction in cells and in vascular rings exposed to peroxynitrite. In human umbilical vein endothelial cells (HUVEC) in vitro, peroxynitrite caused a significant suppression of mitochondrial respiration (38 +/- 2.1% of control cells), as measured by the mitochondrial-dependent conversion of the dye MTT to formazan. Peroxynitrite caused DNA strand breakage (63 +/- 1.9% single strand vs 3 +/- 0.9% single strand in control cells), as measured by the alkaline unwinding assay, and caused an activation of PARS, as measured by the incorporation of radiolabeled NAD(+) to nuclear proteins. Blackberry juice (different dilutions that contained 80 ppm;40 ppm;14.5 ppm of cyanidin-3-O-glucoside) and cyanidin-3-O-glucoside (as chloride) (0.085 microM; 0.028 microM; 0.0085 microM) reduced the peroxynitrite-induced suppression of mitochondrial respiration, DNA damage and PARS activation in HUVECs. Vascular rings exposed to peroxynitrite exhibited reduced endothelium-dependent relaxant responses in response to acetylcholine as well as a vascular contractility dysfunction in response to norepinephrine. The development of this peroxynitrite-induced vascular dysfunction was ameliorated by the blackberry juice (different dilutions that contained 80 ppm;40 ppm;14.5 ppm of cyanidin-3-O-glucoside) and cyanidin-3-O-glucoside (as chloride) (0.085 microM;0.028 microM;0.0085 microM). In conclusion our findings clearly demonstrate that blackberry juice containing cyanidin-3-O-glucoside is a scavenger of peroxynitrite and that exert a protective effect against endothelial dysfunction and vascular failure induced by peroxynitrite.

We used a molecular genetics approach to investigate the role of nuclear factor-kappaB (NF-kappaB) in neointimal hyperplasia induced by flow interruption of carotid artery in mice. Wild type mice (WT mice) and mice rendered deficient in p105, the precursor of p50, one of the components of the multimeric transcription factor NF-kappaB (NF-kappaB knockout mice; KO mice), were subjected to a complete ligation of the left common carotid artery. Morphometric analysis of the structural alteration caused by the disruption of the arterial blood flow was performed 14 days after surgery. Furthermore the expression of intercellular adhesion molecule-1 (ICAM-1) in injured arteries was evaluated 4 days after artery ligation by the means of reverse transcriptase polymerase chain reaction (RT-PCR) and quantification of the ICAM-1 protein levels. In a separate experiment normal mice were randomly assigned to receive a recombinant adeno-associated virus (rAAV) encoding the gene for the NF-kappaB inhibitory protein IkappaBalpha (rAAV-IkappaBalpha), or the beta-galactosidase gene (rAAV-LacZ), both at a dose of 10(11) copies and 2 weeks later were subjected to the complete ligation of the left carotid artery. NF-kappaB activity (studied by means of electrophoretic mobility shift assay-EMSA), IkappaBalpha expression (evaluated by Western blot analysis) ICAM-1 evaluation (RT-PCR and quantification of the protein levels) and a morphometric analysis were evaluated in the injured arteries. Disruption of the arterial blood flow caused a marked neointimal hyperplasia. The mean intimal area was 0.023+/-0.002 mm(2) in wild type mice compared with 0.002+/-0.001 mm(2) in NF-kappaB knockout mice. ICAM-1 expression was 1.7+/-0.8 relative amount of ICAM-1 mRNA in wild type mice compared with 0.4+/-0.06 relative amount of ICAM-1 mRNA in NF-kappaB knockout mice. ICAM-1 protein levels were also significantly reduced in NF-kappaB knockout mice. Injured arteries treated with rAAV-IkappaBalpha had a greater expression of IkappaBalpha and lower NF-kappaB activity, when compared with vessels treated with rAAV-LacZ. Furthermore, ICAM-1 expression was markedly attenuated by the treatment with rAAV-IkappaBalpha (rAAV-LacZ=1.6+/-0.8 relative amount of ICAM-1 mRNA; rAAV-IkappaBalpha=0.55+/-0.04 relative amount of ICAM-1 mRNA). ICAM-1 protein levels were also significantly decreased in rAAV-IkappaBalpha treated mice. Finally the mean intimal area was 0.028+/-0.003 mm(2) in left carotid arteries treated with rAAV-LacZ whereas it was 0.003+/-0.004 mm(2) in vessels treated with rAAV-IkappaBalpha. Our data indicate that NF-kappaB plays a crucial role in neointimal hyperplasia induced by flow cessation in the mouse carotid artery, and in addition suggest that rAAV-mediated gene transfer of IkappaBalpha might represent a novel therapeutic approach to the treatment of restenosis.

In the present study, by comparing the responses in wild-type mice (iNOSWT) and mice lacking (iNOSKO) the inducible (or type 2) nitric oxide synthase (iNOS), we investigated the correlation between endogenous nitric oxide (NO) and prostaglandin (PG) generation in carrageenan-induced pleurisy. The inflammatory response in iNOSKO mice was significantly reduced in respect to iNOSWT animals, as demonstrated by the exudate volume (-63%) and numbers of infiltrating cells (-62%). The levels of NOx in the pleural exudate from carrageenan-treated mice were significantly (p < 0.01) decreased in iNOSKO mice (16 +/- 7.6 nmoles/mice) compared to iNOSWT animals (133 +/- 9 nmoles/mice). Similarly, the amounts of PGE2 in the pleural exudates of carrageenan-treated animals were significantly (p < 0.01) lower in iNOSKO compared to iNOSWT mice (120 +/- 20 pg/mice vs. 308 +/- 51 pg/mice). Also the amounts of 6-keto-PGF(1 alpha) produced by lungs from carrageenan-treated iNOSKO mice (1.01 +/- 0.10 ng/tissue mg) were significantly (p < 0.01) reduced compared to iNOSWT carrageenan-treated mice (2.1 +/- 0.09 ng/tissue mg). In conclusion our results confirm, by the use of iNOSKO mice that in carrageenan-induced pleurisy NO positively modulates PG biosynthesis.

The phytoestrogen genistein improves endothelial dysfunction in ovariectomized rats through a nitric oxide-dependent mechanism. We investigated whether genistein alters the balance between the nitric oxide products and endothelin-1 and influences endothelium-dependent vasodilation in postmenopausal women. Sixty healthy postmenopausal women were enrolled in the study. A double-blind, placebo controlled, randomized design was employed. After a 4-week stabilization on a standard fat-reduced diet, participants to the study were randomly assigned to receive either genistein (n=30; 54 mg/day) or placebo (n=30). Flow-mediated, endothelium-dependent vasodilation of the brachial artery, plasma nitric oxide breakdown products and endothelin-1 levels were measured at baseline and after 6 months of genistein therapy. The mean baseline level of nitrites/nitrates was 22+/-10 micromol/l and increased to 41+/-10 micromol/ml after 6 months of treatment. The mean baseline plasma endothelin-1 level was 14+/-4 pg/ml and decreased to 7+/-1 pg/ml following 6 months of treatment with genistein. The mean baseline ratio of nitric oxide to endothelin also significantly increased at the end of treatment. Flow-mediated, endothelium-dependent vasodilation of the brachial artery was 3.9+/-0.8 mm at baseline and increased to 4.4+/-0.7 mm after 6 months of treatment. Placebo-treated women showed no changes in plasma nitrites/nitrates, endothelin-1 levels and flow-mediated vasodilation. Genistein therapy improves flow-mediated endothelium dependent vasodilation in healthy postmenopausal women. This improvement may be mediated by a direct effect of genistein on the vascular function and could be the result of an increased ratio of nitric oxide to endothelin.

We carried out a multicentre community-based study in order to describe the antibiotic therapeutic approach of paediatricians from two different areas of Italy in the treatment of respiratory tract infection (RTIs), and to assess which factors are involved in a possible variability of prescribing habits. Forty paediatricians participated in the study between October 1998 and April 1999. They had to complete a questionnaire for each therapeutic intervention resulting in an antibiotic prescription. A logistic regression model was used to identify possible predictors in choosing parenteral antibiotics for the treatment of RTIs. In 2 975 questionnaires of antibiotic treatment, RTIs represented 90.2% of the total antibiotics used. Upper respiratory tract infections were the most commonly treated diagnostic group (59.6%), followed by lower respiratory tract infections (20.4%), and middle ear infections (19.8%). Statistically significant differences between northern and southern Italy were reported in the antibiotic prescription profile and the duration of the therapy. Another marked difference was reported in the frequency of laboratory analysis requests. The logistic regression model indicated that the use of parenteral antibiotics appears significantly related to the type of infections [lower RTIs: (OR: 3.99; 95% CI: 2.49-6.37)], the geographic location [northern Italy: (OR: 0.20; 95% CI: 0.20-0.39)], and the presence of concurrent diseases (OR: 3.21; 95% CI: 1.46-7.02). The lack of adherence to clinical guidelines and the marked variability of antibiotic prescription rates between different areas of the country appear to be related to factors other than bacterial resistance, and highlight the importance of carrying out educational programmes targeted at the national level for improving the antibiotic prescription habits for the treatment of RTIs.

There is limited evidence that inhibition of the activity of the protease calpain I reduces inflammation. Here we investigate the effects of calpain inhibitor I in animal models of acute and chronic inflammation (carrageenan-induced pleurisy and collagen-induced arthritis). We report here for the first time that calpain inhibitor I (given at 5, 10, or 20 mg/kg i.p. in the pleurisy model or at 5 mg/kg i.p every 48 hours in the arthritis model) exerts potent anti-inflammatory effects (eg, inhibition of pleural exudate formation, mononuclear cell infiltration, delayed the development of the clinical signs and histological injury) in vivo. Furthermore, calpain inhibitor I reduced (1) the staining for nitrotyrosine and poly (ADP-ribose) polymerase (immunohistochemistry) and (2) the expression of inducible nitric oxide synthase and cyclooxygenase-2 in the lungs of carrageenan-treated rats and in joints from collagen-treated rats. Thus, prevention of the activation of calpain I reduces the development of acute and chronic inflammation. Inhibition of calpain I activity may represent a novel therapeutic approach for the therapy of inflammation.

We studied the effects of pre-treatment (15 days) with oral administration of Ginkgo biloba extract (Ph-Gb 37.5-150 mg/kg) on brain malonildialdehyde (MDA), brain edema, brain nitrite and nitrate and delayed neuronal death following transient cerebral ischemia in the Mongolian gerbil. Survival was not modified, however, pre-treatment with Ginkgo biloba significantly and in a dose-dependent way reduced post-ischemic brain MDA levels and post-ischemic brain edema. Delayed neuronal death in the CA1 of the hippocampus was attenuated by the highest dose of the extract. Increase of nitrite and nitrate was observed after cerebral ischemia in the hippocampus and it was dose-dependently reduced in animals pretreated with Ph-Gb, thus suggesting that neuroprotective effects of Ginkgo biloba may be due to an inhibitory action on nitric oxide formation.

We investigated the effects of tyrophostin AG 556, a tyrosine kinase inhibitor, on the phenomenon of leukocyte accumulation during ischaemia and reperfusion of the myocardium. Male anaesthetized rats were subjected to total occlusion (45 min) of the left main coronary artery followed by 5 h reperfusion (MI/R). Sham myocardial ischaemia-reperfusion rats (Sham MI/R) were used as controls. Myocardial necrosis, myocardial myeloperoxidase activity (MPO), serum creatinine phosphokinase activity (CPK) serum Tumor Necrosis Factor (TNF-alpha) and Interleukin 6 (IL-6), cardiac intercellular adhesion molecule-1 (ICAM-1) and TNF-alpha expression and myocardial contractility (left ventricle dP/dt(max)) were evaluated. Myocardial ischaemia plus reperfusion in untreated rats produced marked myocardial necrosis, increased serum CPK activity (196.5 +/- 19 U/100 ml, at the end of reperfusion) and myeloperoxidase activity (MPO, a marker of leukocyte accumulation) both in the area-at-risk (4.5 +/- 0.5 U/g/tissue) and in necrotic area (8.2 +/- 1.2 U/g/tissue), reduced myocardial contractility (1,706 +/- 52 mmHg/s, at the end of reperfusion) and induced a marked increase in the serum levels of TNF-alpha (1,950 +/- 97 pg/ml, at 1 h of reperfusion) and IL-6 (998 +/- 16 U/ml, at the end of reperfusion). Finally, myocardial ischaemia-reperfusion injury also increased cardiac mRNA for TNF-alpha and ICAM-1 in the myocardium-at risk. Tyrphostin AG 556 (0.5, 1 and 2 mg/kg subcutaneously 5 min after the onset of reperfusion) lowered myocardial necrosis and myeloperoxidase activity in the area-at-risk (1.5 +/- 0.2 U/g/tissue, following the highest dose) and in necrotic area (2.9 +/- 0.3 U/g/tissue following the highest dose), decreased serum CPK activity (96 +/- 9 U/100 ml, at the end of reperfusion), lowered serum TNF-alpha and IL-6, increased myocardial contractility (2,096 +/- 88 mmHg s, at the end of reperfusion) and reduced cardiac mRNA levels for TNF-alpha and ICAM-1. The present data suggest that tyrosine kinase inhibitors protect against myocardial ischaemia-reperfusion injury by reducing leukocyte accumulation to the ischaemic myocardium.

Protein tyrosine kinases help to regulate the expression of many genes that play important roles in inflammation. Here we investigate the effects of the tyrosine kinase inhibitor tyrphostin AG126 in two animal models of acute and chronic inflammation, carrageenan-induced pleurisy and collagen-induced arthritis. We report here that tyrphostin AG126 (given at 1, 3, or 10 mg/kg i.p. in the pleurisy model or 5 mg/kg i.p. every 48 hours in the arthritis model) exerts potent anti-inflammatory effects in animal models of acute and chronic inflammation in vivo. These include the inhibition of pleural exudate formation and mononuclear cell infiltration (pleurisy model) and the development of clinical signs and tissue injury (arthritis model). Furthermore, tyrphostin AG126 reduced the staining for nitrotyrosine and poly (ADP-ribose) polymerase (by immunohistochemistry) and the expression of inducible nitric oxide synthase and cyclooxygenase-2 in the lungs of carrageenan-treated rats and in the joints from collagen-treated rats. Thus, we provide the first evidence that prevention of the activation of protein tyrosine kinases reduces the development of acute and chronic inflammation, and that inhibition of the activity of certain tyrosine kinases may represent a novel approach for the therapy of inflammation.

The survey was carried out, between September 1995 and May 1996, in order to describe the prescriptive behaviour among Sicilian general practitioners (GPs) in choosing an empirical antibiotic regimen for LRTIs in adult patients and begin an educational process which involves the same GPs in decisions regarding their prescriptions and in performing local guidelines. Each practitioner filled out a questionnaire for each therapeutic intervention which ended with an antibiotic prescription. The questionnaire also enquired into the patient's characteristics, diseases to be treated and drug prescription. Doctors were asked to give an opinion about the severity assessment of the infectious disease before choosing the antibiotic treatment, in order to evaluate the prescriptive behaviour of physicians related to the patient's symptoms. Of all Sicilian GPs approached, 76 physicians from 25 Sicilian towns, with a patient population of 96,630, agreed to participate. The GPs used 49 different molecules and six different associations of two antibiotics. The most frequently used antibacterial agents were cephalosporins (55.0%). Penicillins (11.7%), fluoroquinolones (11. 4%), macrolides (10.1%) and combinations of penicillins with beta-lactamase inhibitors (7.9%), together, represented 41.1% of the remaining antibiotic prescriptions. The choice of the route of administration was significantly influenced by age of the patients, by symptoms and signs of the disease and by the presence of concurrent diseases rather than by bacteria suspected of causing the disease. The rather marked variation in antibiotic prescribing pattern for LRTIs among Sicilian GPs reflects lack of availability or knowledge of any local or national guidelines about the management of these diseases., (Copyright 1999 Academic Press.)

The aim of this study was to investigate the spontaneous reports of suspected adverse drug reactions, observed in elderly patients (over 65 years of age) in Sicily (Italy) during the period from 1 January 1995 to 31 December 1997. Of 1307 reports, the geriatric ADRs were 284 (21.7%); 92 (32.4%) of these were serious. There was a correlation between the reporting rates of ADRs and the increase of age. Similar trends are seen in the number of serious ADR reports. Old-older patients result most frequently affected by serious ADRs. The antimicrobial and musculo-skeletal drugs were responsible for 48. 3% of the whole suspected geriatric ADRs. The commonest ADRs reported for the elderly, affected skin and the gastrointestinal system. There was probably a correlation between multi-drug consumption, comorbidity and seriousness of ADRs. A higher percentage of serious ADRs originated from university hospitals (57. 1%)., (Copyright 1999 Academic Press.)

The aim of the present study was to investigate the effect of two inhibitors (3-aminobenzamide and nicotinamide) of poly (ADP-ribose) synthetase on the production of the inflammatory mediator prostaglandins in a model of acute inflammation, carrageenan-induced pleurisy, where prostaglandins are known to play a crucial role. The results show that the poly (ADP-ribose) synthetase inhibitors, 3-aminobenzamide (2.5, 5 and 10 mg/kg) and nicotinamide (12.5, 25 and 50 mg/kg), inhibit the inflammatory response (pleural exudate formation, polymorphonuclear cell infiltration and prostaglandin production). The present results demonstrate that inhibition of poly (ADP-ribose) synthetase exerts potent anti-inflammatory effects. Part of these anti-inflammatory effects may be related to a reduction of prostaglandin production during the inflammatory process.

The aim of the present study was to investigate the role of poly (ADP-ribose) synthetase (PARS) in a model of acute local inflammation (zymosan-activated plasma (ZAP)-induced paw edema), in which the oxyradicals, nitric oxide and peroxynitrite, are known to play a crucial role. Injection of zymosan-activated plasma (ZAP) into the rat paw induced edema formation. The maximal increase in paw volume was observed at three hours after administration (maximal in paw volume: 1.29+/-0.09 ml). At this time point, there was a marked increase in neutrophil infiltration in the paw, as measured by an increase in myeloperoxidase (MPO) activity in the paw tissue (260+/-25 mU/100 mg wet tissue). However, ZAP-induced paw edema was significantly reduced in a dose-dependent manner by treatment with 3-aminobenzamide (3-AB) or nicotinamide (NIC), two inhibitors of PARS, at 1, 2, 3, 4 hours after ZAP injection. PARS inhibition also caused a significant reduction of MPO activity. The paw tissues were also examined immunohistochemically for the presence of nitrotyrosine (a footprint for peroxynitrite formation). At 3 h following ZAP injection, staining for nitrotyrosine were also found to be localised within discrete cells in the inflamed paw tissue. Treatment with PARS inhibitor prevented the appearance of nitrotyrosine in the tissues. Our results suggest that in paw edema induced by ZAP, inhibition of PARS exert potent anti-inflammatory effects.

Experimental studies have shown that intrapulmonary leukocyte sequestration and activation is implicated in the pathogenesis of acute lung injury during endotoxemia. Selectins are involved in the adhesion of leukocyte to the endothelium. Sulfatide is recognized by P selectin and blocks this adhesion molecule. We studied the effects of sulfatide on endotoxin-induced lung damage in rats. Endotoxin shock was produced in male rats by a single intravenous (i.v.) injection of 20 mg/kg of Salmonella enteritidis lipopolysaccharide (LPS). LPS administration reduced survival rate (0%, 72 h after endotoxin challenge) decreased mean arterial blood pressure (MAP), produced leukopenia (Controls = 11,234+/-231 cells/mL, LPS = 4,567+/-123 cells/mL) and increased lung myeloperoxidase activity (MPO; a marker of leukocyte accumulation) in the lung (Controls = 0.35+/-0.1 U/g/tissue; LPS = 10+/-1.2 U/g/tissue). Furthermore LPS administration markedly impaired the concentration-response curves for acetylcholine and sodium nitroprusside in isolated pulmonary arterial rings. There was also an increased staining for P-selectin in the pulmonary arteries. Sulfatide treatment (10 mg/kg, 30 min. after LPS challenge), significantly protected against LPS-induced lethality (90% survival rate and 70% survival rate 24 h and 72 h after LPS injection), reduced LPS induced hypotension, reverted leukopenia (8,895+/-234 cells/ml) and lowered lung MPO activity (1.7+/-0.9 U/g/tissue). Furthermore sulfatide restored to control values the LPS-induced impairment in arterial pulmonary vasorelaxation and reduced P-selectin immunostaining. Our data indicate that sulfatide attenuates LPS-induced lung injury and protects against endotoxin shock.

Acute otitis media (AOM) is one of the most common diseases of childhood, but it is less common in adults. Usually, in clinical practice therapy cannot wait until the laboratory report and the choice of an antibiotic prescription is initiated on an empirical basis. Moreover, several studies have shown great variability in antibiotic prescription for AOM. The study was carried out in order to describe the antibiotic prescribing pattern and the prescriptive behaviour among Sicilian general practitioners (GPs) in choosing an empirical antibiotic regimen for treatment of AOM. Each GP completed a questionnaire for each therapeutic intervention which ended with an antibiotic prescription. Diagnoses and drugs were classified according to the International Classification of Diseases (ICD-10) and to the Anatomical Therapeutic Chemical (ATC) classification system, respectively. Antibiotics, issued for AOM, accounted for 11.1% of total antimicrobial therapy in paediatrics and 3.4% in adults. The commonest therapeutic groups were: cephalosporins (44.1%), macrolides (26.1%), extended spectrum penicillins (16.1%), combination of penicillins and beta-lactamase inhibitors (11.4%). The route of administration appeared to be influenced by age of the patients, by a subjective clinical assessment of disease severity and by the presence of concurrent diseases. The diagnostic criteria and the marked variation in antibiotic prescribing pattern for AOM among Sicilian GPs reflects a lack of knowledge of any local or national guidelines., (Copyright 1998 The Italian Pharmacological Society.)

During inflammation nitric oxide reacts at near diffusion limited rates with superoxide to form the strong oxidant peroxynitrite. Nitration on the ortho position is a major product of peroxynitrite attack on proteins. In the present study we investigated whether immunohistochemical detection of nitrotyrosine (footprint of peroxynitrite) can be associated with human hepatitis. Paraffin-embedded liver tissue biopsies from patients with chronic active hepatitis, chronic active hepatitis plus cirrhosis and chronic persistent hepatitis exhibit significant specific immunostaining with the antibody to nitrotyrosine. Positive staining was found in 57% and 72% of tissue specimens from patients with chronic hepatitis and cirrhosis, respectively. Immunohistochemical staining of nitrotyrosine residues was found in the hepatocytes and Kuppffer cells of the necrotic area. The presence of nitrotyrosine indicates that oxidants derived from nitric oxide such as peroxynitrite are generated in human hepatitis and may be involved in its pathogenesis.

Peroxynitrite, a potent cytotoxic oxidant formed by the reaction of nitric oxide with superoxide anion, is an important mediator of reperfusion injury. In a rodent model of mesenteric ischemia and reperfusion injury we evaluated the contribution of the constitutive and/or inducible nitric oxide synthase (cNOS or iNOS) in the formation of peroxynitrite. Splanchnic artery occlusion (SAO) shock was induced in rats by clamping both the superior mesenteric artery and the celiac trunk for 45 min, followed by release of the clamps (reperfusion). A significant peroxynitrite production was found in the plasma of the splanchnic occlusion shocked rats at 60 minutes after reperfusion. Immunohistochemical examination demonstrated a marked increase in the immunoreactivity to nitrotyrosine, a specific "footprint" of peroxynitrite, in the necrotic ileum and the aorta of shocked rats. No change in plasma levels of nitrate/nitrite, tissue iNOS expression (by western blotting detection) or iNOS activity was found in the intestine at 60 minutes after reperfusion. On the contrary, activity of the cNOS was reduced (approximately 50%) in the reperfused ischemic intestinal tissue. Treatment with NG-nitro-L-arginine methyl ester, a non selective inhibitor of nitric oxide synthase (given at 3 mg/kg i.v., 5 min prior to reperfusion), significantly reduced plasma level of peroxynitrite and the immunohistochemical staining for nitrotyrosine in the ileum and aorta. Our results suggest that during splanchnic artery occlusion shock peroxynitrite formation is likely to be correlated with nitric oxide production from constitutive nitric oxide synthase activation rather than from the inducible isoform enzyme.

Peritoneal administration of zymosan in the rat induced a severe inflammatory process characterised by an increase in the plasma levels of nitrite and nitrate, stable metabolites of nitric oxide (NO) and in the levels of peroxynitrite, as measured by the oxidation of the fluorescent dye dihydrorhodamine 123, at 18 hours zymosan challenge. Immunohistochemical examination demonstrated a marked increase in the immunoreactivity to nitrotyrosine, a specific "footprint" of peroxynitrite, in the aorta of zymosan-shocked rats. In ex vivo experiments, thoracic aorta rings of zymosan-treated rats showed a reduced contraction to noradrenaline and reduced responsiveness to the relaxant effect to acetylcholine (vascular hyporeactivity and endothelial dysfunction, respectively). Treatment of zymosan-shocked rats with 3-aminobenzamide or Nicotinamide, inhibitors of poly ADP-ribosil synthetase (PARS) activity reduced the production of peroxynitrite and significantly prevented the cardiovascular dysfunction. Our data suggest that peroxynitrite and PARS activation play a role in the zymosan-induced cardiovascular derangements in the rat.

The extent and clinical significance of the pharmacokinetic interaction between fluoxetine and haloperidol was studied in 13 schizophrenic patients with prominent negative symptoms. Patients stabilized on chronic low-dose haloperidol (3-8 mg day-1) received additional fluoxetine (20 mg day-1) for 12 consecutive weeks. Mean plasma concentrations of haloperidol increased significantly from 6.5 +/- 2.4 nmol l-1 at baseline to 8.8 +/- 3.6 nmol l-1 (P < 0.01) at week 12 of fluoxetine treatment, but this effect was not associated with an increase in mean extrapyramidal side effects score on the Simpson and Angus Scale. The improvement in negative symptomatology, as measured by the Scale for Assessment of Negative Symptoms, did not correlate significantly with the increase in plasma haloperidol levels. Though our findings confirm that fluoxetine impairs haloperidol clearance, this interaction is unlikely to have adverse clinical consequences, at least in patients chronically stabilized on a low dosage of haloperidol. As fluoxetine is a potent inhibitor of cytochrome P450 (CYP) 2D6, these results also provide indirect evidence for an involvement of CYP2D6 in the metabolism of haloperidol.

Interleukin-1 beta (IL-1 beta) causes inhibition of drinking behaviour. Moreover it induces formation of prostaglandins (PGs) and nitric oxide (NO). Both PGs and NO are able to inhibit drinking stimulated by water deprivation or by intracerebroventricular (i.c.v.) administration of angiotensin II. In this study, we studied in the preoptic area (POA) the possible role of PGs and NO in the antidipsogenic action induced by IL-1 beta. IL-1 beta was injected in the lateral cerebral ventricle (i.c.v.) (2.5, 10, 20, and 40 ng/rat) or into POA (0.625, 1.25, 2.5, and 10 ng/rat). L-arginine (12.5, 25, 50, and 100 ng/rat), the precursor of NO, or NG-nitro-L-arginine methyl ester (L-NAME) (25, 50, and 100 ng/rat), an inhibitor of nitric oxide synthase (NOS), were injected only into POA. Drinking behaviour was induced by water deprivation (24 h). IL-1 beta injected either i.c.v. or into POA caused dose dependent inhibition of drinking. In the POA a treatment with acetylsalicylic acid (ASA) (33, 66, and 135 micrograms/rat), but not with L-NAME, antagonized the inhibition of drinking behaviour induced by the highest doses of IL-1 beta in the POA. In the POA, a treatment with ASA or L-NAME antagonized the inhibition of drinking behaviour caused by injection of the highest doses of L-arginine. Our data suggest that the central inhibition of drinking behaviour of IL-1 beta is mediated through the formation of PGs, but not NO, in the POA.

Injection of zymosan-activated plasma into the rat paw induced oedema formation. Subplantar injection of the non isoform- selective inhibitors of nitric oxide (NO) synthase, N(G)-nitro-L-Arginine methyl ester and N(G)-methyl-L-Arginine, and of a scavenger of NO, haemoglobin, inhibited the early phase of oedema development. Inhibition of cyclooxygenase activity by indomethacin reduced the late increase in paw volume after the injection of zymosan-activated plasma. Methylene blue, an inhibitor of the soluble guanylate cyclase, had no effect. Our results suggest that in paw oedema induced by zymosan-activated plasma, the inflammatory response is dependent on NO (for the early phase) and prostaglandins (for the late phase). The effect of NO is likely to be mediated by a pathway which does not involve cyclic GMP.

The aim of this work was to study whether a G-protein regulates lipopolysaccharide (LPS) induced TNF-alpha production in tumour-bearing rat peritoneal macrophages differently to in normal rats. We also investigated whether a state of 'early endotoxin tolerance' affects LPS induced TNF-alpha release via a G-protein-mediated phenomenon. LPS-stimulated (50 micrograms ml-1 of Salmonella enteritidis LPS) TNF-alpha release was investigated in peritoneal macrophages harvested from both normal rats and tumour-bearing rats. Cholera toxin (10, 100 and 1000 ng ml-1) did not significantly modify LPS-induced TNF-alpha release. In contrast pertussis toxin (0.1, 1.0 and 10 ng ml-1) significantly increased LPS-induced TNF-alpha release and inhibited LPS-stimulated prostaglandin E2 (PGE2) production in both normal rat macrophages and tumour-bearing rat macrophages. Pertussis toxin effects on these LPS responses were correlated with a pertussis-toxin-mediated ADP-ribosylation of a 41 kDa protein(s). The LPS-mediated responses were significantly greater in macrophages from tumour-bearing rats than in macrophages from normal rats. PGE2 (10(-9), 10(-8) and 10(-7) M) suppressed LPS-induced TNF-alpha production in a dose-dependent fashion. A state of 'early endotoxin tolerance' was then induced in tumour-bearing rats by a single intravenous injection of 125 micrograms rat-1 of LPS, and experiments were performed on peritoneal macrophages harvested 24 h after LPS injection. In tolerant macrophages pertussis toxin induced an increase in LPS-stimulated TNF-alpha release and an inhibition in LPS-stimulated PGE2 release significantly lower than in macrophages harvested from non-tolerant tumour bearing rats. Our results suggest that a pertussis-toxin-sensitive G-protein may serve to regulate the synthesis of TNF-alpha in rat peritoneal macrophages and that the activity of this pertussis-sensitive G-protein is increased in macrophages from tumour-bearing rats. Furthermore, our experiments would indicate that a 'state of endotoxin tolerance', caused by altering the function of presumably a Gi-protein, may exert beneficial effects on the functions of macrophages in tumour-bearing rats.

The aim of our study was to examine the mechanism of E-selectin production and leukocyte accumulation in myocardial ischaemia-reperfusion injury. Myocardial injury was induced in anaesthetized rats by the clamping of the left main coronary artery followed by reperfusion. After thoracotomy a silk suture was placed under the left coronary artery. The ligature was tied for a period of 1 h and after this period it was untied and the ischaemic myocardium was reperfused for 1 h (MI/R rats) or removed (SHAM MI/R rats). Myocardial ischaemia plus reperfusion in untreated rats decreased survival rate, produced a marked myocardial necrosis, enhanced cardiac myeloperoxidase activity (a marker enzyme commonly used to assess polymorphonuclear leukocyte infiltration) and increased serum creatinephosphokinase (CPK) activity, serum levels of tumour necrosis factor-alpha (TNF-alpha) and serum levels of soluble E-selectin (sE-selectin). Furthermore, MI/R rats had an increased pressure rate index studied as a quantitative means for assessing myocardial oxygen demand. Administration of cloricromene, an inhibitor of TNF-alpha, reduced TNF-alpha production, significantly lowered serum sE-selectin levels, blunted leukocyte accumulation in the ischaemic myocardium and protected the myocardium from injury due to ischaemia and reperfusion. The results of the present study show an involvement of E-selectin in vivo in the pathogenesis of myocardial ischaemia and reperfusion and suggest that TNF-alpha may induce in vivo the production of a specific adhesion mechanism which sustains leukocyte infiltration.

The present study was designed to investigate the effects of BAY U 3405, a new thromboxane A2 (TxA2) receptor antagonist, in endotoxin shock. Endotoxin shock (ES) was induced in male rats by an i.v. injection of Salmonella enteritidis lipopolysaccharide (LPS; 20 mg kg-1). LPS administration caused animal death (survival = 0%, 48 h after endotoxin challenge), systemic hypotension, depressed phagocytosis and increased blood levels of TNF-alpha, TxB2 and 6-keto-PGF1 alpha, reduced white blood cell (WBC) count (ES = 5.9 +/- 1 x 10(3) mm-3; CTRL = 13.4 +/- 5 x 10(3) mm-3) and enhanced myeloperoxidase (MPO) activity, studied as a quantitative means for assessing leukocyte accumulation, in the ileum (ES = 0.24 +/- 0.7 U g-1 fresh tissue; CTRL = 0.13 +/- 0.04 U g-1 fresh tissue), in the heart (ES = 0.41 +/- 0.1 U g-1 fresh tissue; CTRL = 0.16 +/- 0.08 U g-1 fresh tissue) and in the lung (ES = 0.68 +/- 0.11 U g-1 fresh tissue; CTRL = 0.19 +/- 0.05 U g-1 fresh tissue). Furthermore, endotoxin administration produced characteristic damage of the gastric mucosa consisting of haemmorrhagic infiltrates. BAY U 3405 (30 mg kg-1 i.v., 30 min before endotoxin challenge) increased survival rate (45% survival rate 48 h after endotoxin challenge), reduced hypotension, decreased TNF-alpha levels in serum, enhanced phagocytic activity (ES = 25.6 +/- 1.9%, BAY U 3405 = 45.9 +/- 0.4%, P < 0.001) and lowered MPO activity in the ileum (0.14 +/- 0.05 U g-1 fresh tissue), in the heart (0.18 +/- 0.08 U g-1 fresh tissue) and in the lung (0.44 +/- 0.09 U g-1 fresh tissue). Finally, the gastric alterations were significantly reduced in rats pretreated with BAY U 3405. These data suggest that this thromboxane receptor antagonist might be a useful drug in shock conditions.

The distribution of the oxidation polymorphism related to cytochrome CYP2D6 (debrisoquine type) was determined in 246 healthy Italian volunteers. Phenotyping was based on HPLC determination of the dextrometorphan/dextrorphan concentration ratio (metabolic ratio) in urine samples collected over an 8 h interval following a single oral 30 mg dose of dextromethorphan hydrobromide. Urinary excretion of dextromethorphan showed a wide interindividual variability, ranging from < or = 0.04 to 3.9% and from 0.5 to 79.6% of the dose, respectively. Metabolic ratios ranged from < or = 0.001 to 6.6. Eleven of the 246 subjects showed a metabolic ratio greater than 0.30, indicating that 4.5% of the population could be ascribed to the poor metabolizer status. The frequency of the poor metabolizer phenotype in this population is within the range described for other Caucasian ethnic groups.

The effects of cloricromene, a coumarine derivative, were studied in an anaesthetized rat model of coronary artery ligation (60 min) followed by reperfusion (60 min; MI/R). Sham operated rats were used as controls (Sham MI/R). Myocardial ischaemia-reperfusion injury produced a marked myocardial injury (necrotic area/area-at-risk = 68 +/- 4%; necrotic area/total area = 48 +/- 3%) high serum creatinphosphokinase activity (Sham MI/R = 29 +/- 8 U/ml; MI/R = 205 +/- 11 U/ml) and elevated myocardial myeloperoxidase activity (investigated as an index of leukocyte adhesion and accumulation), in the area-at-risk (6.3 +/- 0.2 U x 10(-3)/g tissue) and in necrotic area (6.5 +/- 0.5 U x 10(-3)/g tissue). Furthermore, serum TNF-alpha was undetectable during the occlusion period, but upon the release of the coronary artery significantly increased. At the end of reperfusion, macrophage TNF-alpha was also enhanced. The administration of cloricromene (2 mg/kg, 5 minutes after the onset of reperfusion) significantly reduced myocardial injury (necrotic area/area-at-risk 30 +/- 1.3%; necrotic area/total area = 25 +/- 1.5) blunted the increase in serum creatinphosphokinase activity (92 +/- 5 U/ml) and lowered myeloperoxidase activity in area-at-risk (2.5 +/- 0.2 U x 10(-3)/g tissue) and in necrotic area (2.2 +/- 0.3 U x 10(-3)/g tissue) and decreased the serum and macrophage levels of TNF-alpha. These data indicate that cloricromene exerts beneficial effects on myocardial ischaemia/reperfusion injury. Finally, since we measured increased serum levels of TNF-alpha that were blunted by the cloricromene treatment, our data are consistent with an involvement of TNF-alpha in the reperfusion injury induced by myocardial ischaemia.

This study was designed to assess the role of leukocytes in rats subjected to splanchnic artery occlusion for 45 min followed by reperfusion (SAO shock). Leukopenia was induced by an intravenous injection of vinblastine (1 mg/kg) 72 h before SAO shock. Survival rate (within 6 h), plasma levels of thromboxane B2 (TxB2), serum levels of tumour necrosis factor (TNF-alpha), and histological alteration of the intestinal tract were investigated. Control rats [white blood cells (WBC) = 10362 +/- 630/mm3] died within 2 h following ischaemia and reperfusion. Leukopenic (WBC = 1263 +/- 311/mm3) animals which underwent SAO shock survived more than 2 h and 50% of them were still alive after 6 h. Plasma TxB2 levels significantly increased in WBC count normal rats subjected to SAO shock (8.4 +/- 2.1 ng/ml), compared to sham animals (0.4 +/- 0.08 ng/ml); however SAO shock raised TxB2 levels significantly less (2.1 +/- 1.1 ng/ml) in leukopenic rats. Serum TNF-alpha, undetectable in sham-shocked rats (either with normal WBC count or without), rose up to 150 +/- 12 U/ml in shocked rate and to 45 +/- 5 U/ml (P < 0.01) in shocked animals with leukopenia. SAO shock induced a massive necrosis of the intestinal tract in rats with normal WBC count. Leukopenia prevented ileum necrosis in SAO shock. These data indicate that leukocytes play an important role in splanchnic artery occlusion and reperfusion.

The debrisoquine oxidation phenotype was assessed in 137 healthy Italian volunteers and in 41 drug-free schizophrenic patients. A bimodal distribution of the urinary debrisoquine/4-hydroxydebrisoquine metabolic ratio was observed in healthy volunteers. Ten subjects were identified as poor metabolizers, yielding a frequency of 7.3% which is similar to that reported in other European countries. The prevalence of the poor metabolizer phenotype was 9.8% among schizophrenic patients. This indicates that there is no association between polymorphic drug oxidation and schizophrenic disorder. Treatment with chlorpromazine (100 or 150 mg daily) significantly increased the debrisoquine metabolic ratio in nine patients (P less than 0.01). These results confirm that neuroleptics of the phenothiazine class inhibit the oxidative metabolism of debrisoquine.

Intravenous (640 micrograms/kg) or intracerebroventricular (0.5 and 1 microgram) injection of Escherichia coli endotoxin (LPS) causes inhibition of water intake induced by 24 hour period of water deprivation in the rat. Tumor necrosis factor alpha (TNF-alpha; 20 and 40 ng/rat) given into the lateral cerebral ventricle (i.c.v.) causes effects similar to those observed after LPS. Cloricromene, given either intravenously (1 and 2 mg/kg) or i.c.v. (250 and 500 ng), abolished the antidipsogenic effect induced by LPS (administered both i.v. and i.c.v.). Cloricromene (2 mg/kg, i.v. or 500 ng/rat, i.c.v.), on the contrary, did not modify the antidipsogenic effects induced by TNF-alpha. These data indicate that peripherally injected cloricromene (as well as that i.c.v. injected) antagonizes the effects of mediators of LPS on sites regulating thirst and suggest that cloricromene's action may be due to inhibition of brain TNF-alpha formation induced by LPS.

Activation of cholinergic neurons in specific brain regions evokes a hypernatriuretic response, which appears to be atropine-sensitive and, perhaps, independent from the renal innervation. However the role of cholinergic neurons in central control of renal function is not well understood. The purpose of this study was to further investigate whether brain acetylcholine stores are able to influence kaliuresis and natriuresis in conscious rats. Therefore, the renal response to cholinergic drugs was examined in Wistar rats which underwent to a 0.15 M NaCl solution (saline) load administered by gavage. Central injection of arecoline, a muscarinic agonist, produced a dose-dependent reduction in water diuresis and a highly significant increase in sodium excretion within two hours from the oral saline load. An intracerebroventricular (ICV) injection of methylatropine completely blocked both the antidiuretic and the natriuretic response induced by arecoline. Hemicholinium-3 (HC), centrally administered at a dose (34.8 nmol) known to be capable of inducing a maximal depletion of brain acetylcholine, elicited a time-dependent antidiuretic effect accompanied by a highly significant reduction in potassium and sodium urinary excretion. Therefore, we suggest that brain cholinergic neurons are involved in the regulation of the electrolyte balance.

Intravenous (i.v. 320 and 640 micrograms/kg) and intracerebroventricular (i.c.v.; 1 microgram/rat) injection of Escherichia coli lipopolysaccharide (LPS) powerfully inhibited drinking induced by 24 h water deprivation. Pretreatment with acetylsalicylic acid (ASA) into the preoptic area (POA) completely abolished the effect induced by i.v. LPS, but did not modify that elicited by i.c.v. LPS. Intraperitoneal ASA injections significantly reduced the antidipsogenic effect of i.c.v. LPS. Electrolytic ablation of the subfornical organ (SFO) did not modify the effect induced by either i.v. or i.c.v. LPS. Present findings indicate that: (1) the antidipsogenic effect of i.v. LPS is mediated by prostaglandin synthesis into the POA, (2) the SFO is not involved in this effect, and (3) prostaglandins in other brain areas, besides POA, modulate the effect of i.c.v. LPS. It is suggested that at least two different brain sites, inside the blood-brain barrier, might be involved in the antidipsogenic effect of LPS.

The new calcium antagonist Nimodipine has been shown to have more powerful dilator action on cerebral than peripheral vessels. The effect of the drug on cerebral metabolism was studied in conscious rats using the /14C/-2-deoxyglucose quantitative autoradiographic technique. Intravenous injection of Nimodipine, 2 mcg/Kg, determined significant increases in local cerebral glucose utilization that appeared to be homogeneous in magnitude and anatomic distribution throughout the brain. This study raises the question whether Nimodipine affects brain functions by other mechanisms than an increase in cerebral blood flow.