Papers by Gioacchino Calapai
Atherosclerosis, 2000
Mycobacterium avium is a facultative intracellular opportunistic pathogen especially relevant in ... more Mycobacterium avium is a facultative intracellular opportunistic pathogen especially relevant in cases of people living with AIDS. The aim of this study was to evaluate the role of intercellular adhesion molecule 1 (ICAM-1) in the inflammatory response against M. avium infection. Mice deficient for ICAM-1 (ICAM KO) and infected with M. avium presented increased bacterial load in the spleen, liver and lungs compared to C57BL/6. Moreover, ICAM deficient mice presented reduced granuloma area in liver at 30 days post-infection with reduced numbers of lymphocytes and granulocytes. The assessment of in vitro cytokine production by ICAM KO spleen cells showed lower levels of IFN-g compared to C57BL/6, whereas TNF-a remained unaltered. Additionally, the production of IFN-g in liver and spleen tissues was also diminished in ICAM-1 KO mice. Interestingly, a persistent reduction in IFN-g production was observed in CD3 þ NK1.1 þ cells of ICAM-1 deficient mice compared to wild-type animals. Together, these results demonstrate the importance of ICAM-1 in the efficient control of M. avium infection and granuloma formation and highlights its role on CD3 þ NK1.1 þ cell population as important for IFN-g production during infection.
Life Sciences, 2000
We studied the effects of pre-treatment (15 days) with oral administration of Ginkgo biloba extra... more 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.
Journal of Pharmacological Sciences, 2005
We studied the long-term effects of repeated doses of nicotine, causing dependence, 120 days afte... more We studied the long-term effects of repeated doses of nicotine, causing dependence, 120 days after its withdrawal on feeding behavior and on brain nitric oxide (NO) formation in female mice. Nicotine dependence was induced by subcutaneous (s.c.) nicotine injection (2 mg/kg, four injections daily) for 14 days. Daily food intake was evaluated for the entire observational period (120 days). Moreover, 30, 60, and 120 days after nicotine withdrawal, we evaluated food intake, nitrite/nitrate levels, and nitric oxide synthase (NOS) activity and expression in the hypothalamus after food deprivation (24 h). In animals in which nicotine dependence was induced (NM), daily food intake was similar to that of controls (M). However, following food deprivation, NM mice showed i) a significant increase in food intake, ii) changes in weight gain and in hypothalamic nitrite/nitrate levels, and iii) enhancement of hypothalamic neuronal NOS (nNOS) activity. Results indicate that high doses of nicotine producing dependence induce long-term changes in feeding behavior consequent to food deprivation associated to alterations in the brain nitrergic system.
Journal of Neurosurgery: Spine, 2007
Journal of Neurochemistry, 2003
We investigated if IRFI 042, an analog of vitamin E, protects the brain against oxidative stress ... more We investigated if IRFI 042, an analog of vitamin E, protects the brain against oxidative stress induced by intraperitoneal administration of Kainic acid (KA) (10 mg/kg); sham brain injury rats were used as controls. Animals received either IRFI 042 (20 mg/kg) or its vehicle 30 min before KA injection and after 6 h were sacrificed to measure malonildyaldheide (MDA) and glutathione levels (GSH) in the diencephalon. Behavioral changes were also monitored. Intraperitoneal administration of IRFI decreased MDA (micromol/g wet tissue: KA + vehicle ¼ 22.5 ± 4.2; KA + IRFI ¼ 17.1 ± 1; P < 0.005) and prevented GSH loss (nmol/g wet tissue: KA + vehicle ¼ 0.41 ± 0.1; KA + IRFI ¼ 1.86 ± 0.2; P < 0.005) in the diencephalon. The latency of occurrence of behavioral signs increased from 39 ± 1 to 62 ± 6 min in IRFI 042 group. The data suggest that IRFI 042 might protect against KA-induced oxidative stress.
Journal of Clinical Investigation, 1999
The recent cloning of the mouse and human obesity genes and the characterization of their protein... more The recent cloning of the mouse and human obesity genes and the characterization of their protein product, leptin (1), has introduced a new era in the field of obesity research. Leptin is a hormone exclusively produced by the adipocytes that conveys information on the size of energy stores to the brain and activates hypothalamic centers that regulate energy intake and expenditure (2). This protein also regulates feeding behavior by reducing food consumption (3, 4).
Journal of Cardiovascular Pharmacology, 1992
Splanchnic artery occlusion (SAO) shock was induced in anesthetized rats by clamping the celiac t... more Splanchnic artery occlusion (SAO) shock was induced in anesthetized rats by clamping the celiac trunk and the superior mesenteric artery for 45 min. The arteries were then released and survival rate, mean survival time, mean arterial blood pressure (MAP), plasma levels of thromboxane B2 (TxB2) and 6-keto-PGF1 alpha, and the phagocytotic activity of peritoneal macrophages were evaluated. Shocked animals died within 89 +/- 10 min, while all sham-shocked rats survived greater than 3 h. SAO shock produced relevant changes in MAP, significantly increased plasma levels of TxB2 and 6-keto-PFG1 alpha, and decreased peritoneal macrophage phagocytotic activity. The administration of G 619, a dual thromboxane synthase inhibitor/thromboxane A2 receptor antagonist (50 mg/kg, 15 min before SAO shock) significantly increased survival time (190 +/- 13 min) and survival rate, reduced plasma levels of TxB2, and partially restored the impairment in peritoneal macrophage phagocytosis. Finally, the administration of G 619 had beneficial effects on changes in MAP-induced bay SAO shock. These data further confirm the involvement of TxA2 in SAO shock and suggest that G 619 may have positive effects in low-flow states.
Inhalation Toxicology, 2009
Two groups of 20 healthy volunteers with cigarettes of different tar yield were compared with a g... more Two groups of 20 healthy volunteers with cigarettes of different tar yield were compared with a group of 20 never smokers over 24 h for several biomarkers. All groups were of similar mean ages and the smokers had smoked for a homogeneous period of approximately 10 yr. The groups were assessed using routine medical parameters as well as biomarkers of recent smoke exposure and other biomarkers that were under evaluation as possible markers of risk for smoking-associated diseases. All biomarkers of exposure-carbon monoxide, nicotine plus its five major metabolites, and 4-(methylnitrosamine)-1-(3-pyridyl)-1-butanol (NNAL)-were significantly elevated in smokers. For biomarkers of potential risk evaluated in the blood, white cells and immunoglobulin (Ig) G showed a decrease related to smoking status (p < .01). Interleukin 6 levels were higher in smoker groups compared to never smokers, with a significant increasing trend across the groups (p < .05). Among the urinary biomarkers studied, 11-deydrothromboxane B2, 2,3-dinor-thromboxane B2, and thymidine glycol showed significant increasing trends across the groups (p < .01). The results suggest that after the first decade or less of smoking, changes in inflammatory, immunological, and cardiovascular function can be observed. However, further studies on larger groups will be required to better understand the kinetics of these subtle effects observed early in smokers and their relationship with the potential risk of subsequent smoking-associated disease.
Free Radical Biology and Medicine, 1994
The effects of IRFI-048 (2,3-dihydro-5-methoxy-4,6,7-trimethyl-2-benzofuranyl acetic acid), a sel... more The effects of IRFI-048 (2,3-dihydro-5-methoxy-4,6,7-trimethyl-2-benzofuranyl acetic acid), a selective analogue of Vitamin E, on myocardial tissue injury were examined in anaesthetized rats subjected to 60-min occlusion of the left coronary artery followed by 60-min reperfusion. Infarct size (Evan's blue and tetrazolium stain), serum creatinphosphokinase (CPK), plasma malonaldehyde (MAL), cardiac myeloperoxidase (MPO) activity, and ST-segment of electrocardiogram (ECG) and survival rate were evaluated. Postischaemic reperfusion produced severe cardiac necrosis, caused neutrophil (PMNs) infiltration (evaluated by MPO activity) in the jeopardized tissue, increased serum CPK and plasma MAL, raised ST-segment of ECG, and decreased survival rate. IRFI-048, (200 and 400 mg/kg o.s.) given to the rats 6 h before occlusion, caused a reduction of necrotic area expressed as a percentage of either the area at risk or the total left ventricle, decreased MPO activity both in the area at risk (from 3.2 +_ 0.3 U × 10-3/g tissue to 1.1 _+ 0.4 U x 10-3/g tissue; p < .005) and in the necrotic area (from 5.7 + 0.9 U × 10-a/g tissue to 1.8 + 0.5 U × 10-3/g tissue; p < .001), attenuated the rise of ST-segment of ECG (from 0.51 _+ 0.14 mV in the vehicle group to 0.28 + 0.11 mV in the treated group; p < .005), reduced the increase of plasma MAL and serum CPK during reperfusion (from 42 +_ 5.3 nmol/ml to 15 _+ 3.1 nmol/ml and 139 _ 13 IU/100 ml to 58 -+ 7.5 IU/100 ml, respectively; p < .001). Finally, IRFI-048 enhanced survival rate evaluated at the end of experiment. The results indicate that IRFI-048 significantly reduces myocardial infarct size and emphasize the beneficial action of analogues of vitamin E on the prevention of lipid peroxidation.
Fitoterapia, 1999
The effects of repeated oral administration of 2.5–20 mg/kg of two Citrus aurantium fruit extract... more The effects of repeated oral administration of 2.5–20 mg/kg of two Citrus aurantium fruit extracts standardized to different concentrations of synephrine (4 and 6%, respectively) on food intake, body weight gain, arterial blood pressure, electrocardiogram (ECG) and mortality have been investigated in the rat. C. aurantium administration significantly reduced food intake and body weight gain. However, mortality (not observed in controls) was present in all C. aurantium treated groups. Arterial blood pressure was not modified, but ECG alterations (ventricular arhythmias with enlargement of QRS complex) were evident in animals treated with both extracts. Our data indicate that, in the rat, antiobesity effects of C. aurantium are accompanied by toxic effects probably due to cardiovascular toxicity.
Experimental Neurology, 2004
Brain injury was induced by intraperitoneal administration of kainic acid (KA, 10 mg/kg). Animals... more Brain injury was induced by intraperitoneal administration of kainic acid (KA, 10 mg/kg). Animals were randomized to receive either IRFI 042 (20 mg/kg i.p.), a lipid peroxidation inhibitor, or its vehicle (NaCl 0.9% DMSO 10% 1 ml/kg i.p.) 30 min before KA administration.
Evidence-Based Complementary and Alternative Medicine, 2007
The increase of herbal medicine use led many scientists to contribute to the research in this fie... more The increase of herbal medicine use led many scientists to contribute to the research in this field. Also a few pharmacologists, after an initial phase of correct criticisms, today recognize the possibility of investigating the scientific value of medicinal products composed essentially of vegetable extracts. However, it is logical to pose the questions: (i) is there a role for the pharmacologist in herbal medicine (or phytotherapy)? (ii) can we do without pharmacologists'? First, two worlds-drug researchers (pharmacologists) and herbal medicines-yesterday appearing in opposition, are today closer and it is not unusual to read scientific works describing herbal extracts in journals traditionally dedicated to the study of synthetic drugs. Second, clinical application of herbal medicines is evaluable through the methods of modern clinical pharmacology. Efficacy and safety of medicinal plants represent naturally the object of interest for the pharmacologist and it is surely this aspect which gives the most important information on herbal medicine use. Many plants have been studied and results published showing, one time good or another poor, efficacy. Safety aspects of some of the most frequently used plants are now well known. For example, today we learn to use hypericum and we do not give it to patients taking other drugs because the interactions of hypericum with them. Contraindications of other plants, often represented by interactions with drugs, are finally known (Ginkgo biloba and drugs acting on blood coagulation). In conclusion, antagonistic behavior of pharmacologists versus herbal medicines is not useful. On the contrary, modern phytotherapy needs the contribution of researchers usually trained to evaluate efficacy and safety of medicinals.
European Journal of Pharmacology, 2000
Erythropoietin prevents in vitro glutamate-induced neuronal death and could play a role in the ce... more Erythropoietin prevents in vitro glutamate-induced neuronal death and could play a role in the central nervous system. We investigated Ž . Ž the in vivo effects of recombinant human erythropoietin after intraperitoneal i.p.; 25-100 U or intracerebroventricular i.c.v.; 0.25-25
European Journal of Pharmacology, 1992
1 The aim of the present study was to investigate the eects of cloricromene, a coumarine derivati... more 1 The aim of the present study was to investigate the eects of cloricromene, a coumarine derivative, in rats subjected to collagen-induced arthritis. 2 Collagen-induced arthritis (CIA) was induced in Lewis rats by an intradermal injection of 100 ml of the emulsion (containing 100 mg of bovine type II collagen) (CII) and complete Freund's adjuvant (CFA) at the base of the tail. On day 21, a second injection of CII in CFA was administered.
European Journal of Pharmacology, 1994
The effects of NG-nitro-L-arginine, an inhibitor of brain nitric oxide (NO) synthase, on central ... more The effects of NG-nitro-L-arginine, an inhibitor of brain nitric oxide (NO) synthase, on central serotoninergic system were studied in male obese Zucker rats and in their lean age-matched controls (FA/?; FA/FA), both groups aged 14 weeks. Acute injection of N~-nitro-L-arginine (50 mg/kg i.p.) or repeated administration of NG-nitro-L-arginine (50 mg/kg i.p. daily, for 7 days) reduced food intake and body weight in obese rats. Acute administration of N~-nitro-L-arginine reduced food intake in lean rats. However, lean rats showed tolerance to the N6-nitro-L-arginine effects after repeated administration. NG-Nitro-Larginine administration significantly increased serotonin metabolism in the cortex, diencephalon and medulla-pons of obese Zucker rats after either acute or repeated administration of NG-nitro-L-arginine. In contrast, N~-nitro-L-arginine increased serotonin metabolism in lean rats only after acute administration, and the appearance of tolerance to NG-nitro-L-arginine anorectic effects paralleled the failure of NG-nitro-L-arginine to increase serotonin metabolism. The present data extend our previous findings indicating that NG-nitro-L-arginine possesses anorectic activity in obese Zucker rats, and clearly suggest that the central serotoninergic system mediates the anorexia induced by inhibitors of brain NO synthase.
European Journal of Pharmacology, 1997
In 24 h water deprived rats we have evaluated the effects of melatonin on the inhibition of thirs... more In 24 h water deprived rats we have evaluated the effects of melatonin on the inhibition of thirst and on fever induced by Escherichia Ž . Ž . coli lipopolysaccharide. Intraperitoneal i.p injection of lipopolysaccharide 0.32, 0.64 and 0.96 mgrkg alone induced, a dose-dependent and significant inhibition of water intake as well as fever. In addition, lipopolysaccharide at the same concentrations increased urinary prostaglandins and serum cytokines levels. On the contrary, lipopolysaccharide treatment had no effects on cerebral brain nitric oxide Ž synthase activity. All lipopolysaccharide effects were reverted by a prior, concomitant and subsequent i.p. treatment with melatonin 2, 4 . and 6 mgrkg , whereas they were still present when melatonin was injected in combination with the melatonin receptor antagonist Ž . luzindole 15, 30 and 60 mgrkg, i.p. . We suggest that melatonin could exert its dipsogenic effects through a reduction of the free radical Ž P . nitric oxide NO whereas it may reduce body temperature by preventing an excessive formation of prostaglandins and cytokines. q 1997 Elsevier Science B.V.
European Journal of Pharmacology, 2000
To ascertain in vivo whether recombinant human erythropoietin has a neuroprotective effect on the... more To ascertain in vivo whether recombinant human erythropoietin has a neuroprotective effect on the cortex during subarachnoid hemorrhage, 56 rabbits were divided into the following groups: Group 1 control sham operated plus placebo (n=14; saline solution - NaCl 0.9%); Group 2 control sham operated plus recombinant human erythropoietin (n=14); Group 3 subarachnoid hemorrhage plus placebo (n=14); Group 4 subarachnoid hemorrhage plus recombinant human erythropoietin (n=14; intraperitoneal administration of recombinant human erythropoietin immediately after inducing subarachnoid hemorrhage). In none of the Groups 1 and 2 animals was subarachnoid hemorrhage induced. In Group 3 rabbits, an increase in locomotor activity (open field apparatus) was observed 24, 48 and 72 h after surgery, and the mortality rate was 42.9% within 72 h after surgery, and, no increase in locomotor activity was observed in Group 4 rabbits, which survived for at least 72 h. Our findings suggest that recombinant human erythropoietin may be of benefit in the treatment of subarachnoid hemorrhage.
Drug Safety, 2008
Aim To describe and evaluate spontaneous reports of suspected adverse reactions (ARs) associated ... more Aim To describe and evaluate spontaneous reports of suspected adverse reactions (ARs) associated with herbal laxatives received by the Italian Medicines Agency and the Italian National Institute of Health between April 2002 and January 2011. Methods Spontaneous reports of suspected ARs were individually analyzed by a multidisciplinary group of experts, and a causality assessment was performed. Results Twenty-six reactions were reported during the study period. Of these, eight were associated with herbal medicinal products and 18 were related to herbal food supplements. Almost 80% of the reports on ARs involved women. The ARs, classified by System Organ Class, were associated with gastrointestinal, skin and subcutaneous tissue, and hepatobiliary disorders. Fifty percent of the reactions were serious, with the patients requiring hospitalization; of these, one was lifethreatening. Most of the herbal remedies associated with the reported ARs contained liquorice, dandelion, and/or plants containing anthraquinones. Possible causes of the ARs were long-term use, idiosyncratic reactions or hypersensitivity, and interaction with other treatments. All of these factors and the presence of a large number of components in the same product increased the unpredictability of the final effect. Conclusions The total number of 26 ARs recorded in 8 years is limited; however, the an under-reporting effect cannot be excluded. Moreover, taking into account the seriousness of the reported ARs, the low number of reports does not represent a guarantee of safety. To reduce the risk of an adverse outcome, herbal laxatives should be used only over the short term.
Drug Safety, 2009
The Internet may play a crucial role in the prompt provision of updated drug safety information. ... more The Internet may play a crucial role in the prompt provision of updated drug safety information. Nevertheless, limited knowledge of the English language among healthcare professionals or suboptimal search skills constitute barriers to widespread and appropriate use of the Internet for this purpose in Italy. In order to provide accurate information on drug safety and to promote the reporting of adverse drug reactions, in 1999 the clinical section of the Italian Society of Pharmacology created the website www.farmacovigilanza.org, financially supported by a non-profit foundation. The website promptly and independently provides news published in the international literature on drug safety, translated into Italian. The site also contains specific sections dedicated to adverse reactions to herbal products and cosmetic preparations. The aim of this paper was to describe the number and characteristics of users and the most intensively visited sections of the website. Furthermore, in September 2006, 300 registered users who had accessed a registered users area aimed specifically at health professionals more than 20 times in the preceding 12 months received a ten-item multiple choice questionnaire via e-mail, to assess satisfaction with the accuracy and promptness of information provided, text comprehension and other information sources for drug-related issues. We hereby describe the results of the survey, after careful analysis of the questionnaires. Up until July 2007, the site had over 600 000 direct accesses and 9760 healthcare professionals registered to use the site. A total of 108 responses to the e-mailed questionnaire were received (response rate = 36%), of which 103 were analysed; five were excluded due to missing information. Overall, the majority of responders judged the information on the site as objective and understandable. More than 85% of participants declared that the site has influenced their opinion and attitudes toward the safety of medicines. In particular, responders said that they pay more attention to drug interactions and to the safety profile of newly marketed drugs, and spend more time on communicating the risks of drugs used by their patients. Specifically, responders stated that they pay more attention to drug interactions (87.7%), newly marketed drugs (68.5%), herbal remedies (56.2%), drugs in patients at increased risk (42.5%), drugs in pregnant women (42.5%) and cosmetics (13.7%). The website www.farmacovigilanza.org appears to be an effective tool that provides users of the site with independent, relevant and reliable safety information. It was found to influence (and possibly improve) the quality of prescribing of a large proportion of the general practitioners who responded to our questionnaire, and our results indicate a high appreciation of the information found on the website. Moreover, the survey disclosed that there is a substantial need for such information in the national language by healthcare professionals. We think that our approach can serve as a model for similar initiatives in countries elsewhere in the world.
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Papers by Gioacchino Calapai