Cutaneous adverse reactions to lenalidomide.

Lenalidomide is an immunomodulatory drug (IMiD) used principally in the treatment of multiple myeloma (MM), myelodysplastic syndromes (MS) and amyloidosis. Adverse reactions related to lenalidomide include myelosuppression (mainly neutropenia but also thrombocytopenia), gastrointestinal problems, skin eruption, atrial fibrillation and asthenia, decreased peripheral blood stem cell yield during stem cell collection, venous thromboembolism, and secondary malignances. In this review we focused our attention on the cutaneous adverse reactions to lenalidomide.

Oral adverse reactions due to cinnamon-flavoured chewing gums consumption.

Cinnamon-flavoured products (toothpaste, chewing gum, food, candy and mouthwash) can cause oral adverse reactions; among these, the most common is contact stomatitis (cinnamon contact stomatitis, CCS). Signs and symptoms of contact allergic reactions affecting the oral mucosa can mimic other common oral disorders, making diagnosis difficult. As CCS may be more prevalent than believed and its clinical features can frequently determine misdiagnosis, we reviewed case reports and case series of oral adverse reactions due to cinnamon-containing chewing gums, emphasizing clinical aspects, diagnostic and management procedures. We also proposed an algorithm to perform a diagnosis of CCS as in the previous published literature the diagnostic approach was not based on a harmonized and shared evidence-based procedure. Moreover, as patients can refer to different specialists as dentists, dermatologists and allergists, a multidisciplinary approach is suggested.

Rosmarinus officinalis L. as cause of contact dermatitis.

Because of the widespread use of botanicals, it has become crucial for health professionals to improve their knowledge about safety problems. Several herbal medicines contain chemicals with allergenic properties responsible for contact dermatitis. Among these, one is Rosmarinus officinalis L. (rosemary), a plant used since ancient times in folk medicine; at the present time it is used worldwide as a spice and flavouring agent, as a preservative and for medicinal and cosmetic purposes. The present article aims to revise and summarise scientific literature reporting cases of contact dermatitis caused by the use of R. officinalis as a raw material or as herbal preparations. Published case reports were researched on the following databases and search engines: PUBMED, MEDLINE, EMBASE, Google Scholar, Scopus. The used keywords were: R. officinalis and rosemary each alone or combined with the words allergy, contact dermatitis, allergic contact dermatitis, sensitisation and occupational dermatitis. The published case reports show that both rosemary extracts and raw material can be responsible for allergic contact dermatitis. Two cases related to contact dermatitis caused by cross-reactivity between rosemary and thyme were also commented. The diterpene carnosol, a chemical constituent of this plant, has been imputed as a common cause for this reaction. The incidence of contact dermatitis caused by rosemary is not common, but it could be more frequent with respect to the supposed occurrence. It seems plausible that cases of contact dermatitis caused by rosemary are more frequent with respect to the supposed occurrence, because they could be misdiagnosed. For this reason, this possibility should be carefully considered in dermatitis differential diagnosis.

Systemic nickel allergy: oral desensitization and possible role of cytokines interleukins 2 and 10.

Nickel ingested with food can elicit either systemic cutaneous or gastrointestinal symptoms causing a systemic nickel allergy syndrome (SNAS) that can be treated with tolerance by oral ingestion of the metal. It has been suggested that interleukins 2 (IL-2) and 10 (IL-10) are involved in the mechanisms underlying oral tolerance. We evaluated the clinical efficacy of oral desensitization therapy in SNAS consisting in the administration of nickel sulphate. Because nickel allergy prevalently affects women, only female subjects (N = 22) were recruited. Oral nickel desensitizing therapy was associated with low-nickel diet for three months. Before and after therapy, clinical conditions were evaluated, and circulating cytokines IL-2 and IL-10 were measured. After the two-year treatment, visual analogue scale (VAS) scores for symptoms were significantly reduced (P less than 0.001). Patients were released by either cutaneous or gastrointestinal symptoms and by tolerating nickel-containing food. At the end of the treatment, nickel oral challenge test was negative in 18 patients, and IL-2 level in the serum was significantly reduced while IL-10 was increased, although this datum was not statistically significant. Our study confirms the clinical efficacy of nickel oral immunotherapy and focuses on the mechanisms triggered by oral tolerance indicating that reduction of IL-2 can be associated with success of oral nickel desensitizing therapy.

Fatal hypersensitivity reaction to an oral spray of flurbiprofen: a case report.

WHAT IS KNOWN AND OBJECTIVE: Safety of the anti-inflammatory drug flurbiprofen is comparable with that of other non-steroidal anti-inflammatory drugs of the propionic acid class, which are commonly associated with gastrointestinal and renal side effects. Here we report a case of a fatal hypersensitivity reaction to an oral spray of flurbiprofen taken for sore throat. CASE SUMMARY: A 29-year-old man came to the emergency care unit reporting sore throat with an intense burning sensation associated with fever. Pharyngotonsillitis was diagnosed, and local treatment with oral flurbiprofen spray was prescribed. Immediately after using the spray, the patient experienced a severe reaction characterized by serious dyspnoea, followed by death. The cause of death was heart failure with acute asphyxia from oedema of the glottis. The cause of death was concluded to be hypersensitivity to flurbiprofen spray. WHAT IS NEW AND CONCLUSION: Oral propionic acid derivatives have been associated with a relatively high frequency of allergic reactions. However, allergy to flurbiprofen has rarely been documented. Scientific literature reports two relevant cases of hypersensitivity reaction to flurbiprofen: in one case, a patient presented with a maculopapular rash 48 h after having taken oral flurbiprofen followed by angio-oedema and hypotension. In another case, a single oral dose of flurbiprofen caused itching and swelling around the eyes, redness and increased lacrimation. We describe, for the first time, a fatal case of hypersensitivity reaction to flurbiprofen oral spray. Hypersensitivity reactions to flurbiprofen are infrequent; however, health professionals should be aware of potential adverse reactions, even during topical administration as oral spray.

Anaphylaxis caused by helminths: review of the literature.

BACKGROUND: Anaphylaxis is a severe, life-threatening, generalized or systemic hypersensitivity reaction. In many individuals with anaphylaxis a pivotal role is played by IgE and the high-affinity IgE receptor on mast cells or basophils. Less commonly, it is triggered through other immunologic mechanisms, or through nonimmunologic mechanisms. The human immune response to helminth infections is associated with elevated levels of IgE, tissue eosinophilia and mastocytosis, and the presence of CD4+ T cells that preferentially produce IL-4, IL-5, and IL-13. Individuals exposed to helminth infections may have allergic inflammatory responses to parasites and parasite antigens. AIM: To summarize the evidences about the role of helmiths in triggering anaphylaxis. MATERIALS AND METHODS: PubMed search was performed by combining the terms (anaphylaxis, anaphylactic, anaphylactoid) with each one of the etiological agents of human helminthiasis for the period January 1950 to September 2012. RESULTS: < The PubMed search identified 609 papers. Only four genera of helminths were associated with anaphylaxis. (Echinococcus spp, 302 papers; Anisakis spp, 73 papers; Taenia solium cysticercosis, 7 papers; and Ascaris spp., 243 papers). CONCLUSIONS: The risk of anaphylaxis in patients with helminthiasis can vary according to the pathogens, occurring more frequently during echinococcosis of after anisakis infestation and being extremely rare after other helminth infestations. However, physicians, allergist and parasitologist in particular, should be aware of a potential anaphylaxis caused by helminths.

Vigilance on use of drugs, herbal products, and food supplements during pregnancy: focus on fosfomycin.

PURPOSE: Urinary tract infection (UTI) is defined as a common bacterial infection that can lead to significant morbidity such as stricture, fistula, abscess formation, bacteremia, sepsis, pyelonephritis, and kidney dysfunction with a mortality rates reported of 1% in men and 3% in women because of development of pyelonephritis. UTIs are more common in women and the 33% of them require antimicrobials treatment for at least one episode by the age of 24 years. UTIs are the most common infections observed during pregnancy and up to 30% of mothers with not treated asymptomatic bacteriuria may develop acute pyelonephritis which consequently can be associated to adverse maternal and fetal outcomes. All bacteriuria in pregnancy should be treated with antimicrobial treatments being safe for both the mother and the fetus. Approximately one every four women receives prescription of antibiotic treatment during pregnancy, nearly 80% of all the prescription medications during gestation. The use of fosfomycin to treat cystitis in pregnancy generally considered safe and effective. Even though use on antibiotics for urinary tract infections is considered generally safe for the fetus and mothers, this opinion is not based on specific studies monitoring the relationship of among urinary infections, consumption of antibiotics, and pregnancy outcomes. MATERIALS AND METHODS: On this basis we decided to analyze data from the database of our multicenter study PHYTOVIGGEST, reporting data from 5362 pregnancies, focusing on use of fosfomycin. Principal outcomes of pregnancy in women treated with fosfomycin were taken into consideration. RESULTS: Women who have been treated with urinary antibiotics during the pregnancy were 183. With respect to the total number of pregnancies of our sample, these women represented the percentage of 3.49% (187/5362). Analysis of different outcomes of pregnancy such as gestational age, neonatal weight, and neonatal Apgar index did not show any significant difference. At the same time, analysis of data of pregnancy complicancies (such as urgent cesarean delivery, use of general anesthesia, need to induce labor) did not show any difference in women taking fosfomycin during pregnancy and those not taking it. CONCLUSIONS: Our data, based on a large number of pregnancies, confirm the safety use of fosfomycin use in pregnancy.

Leptin increases serotonin turnover by inhibition of brain nitric oxide synthesis.

Leptin administration inhibits diencephalic nitric oxide synthase (NOS) activity and increases brain serotonin (5-HT) metabolism in mice. We evaluated food intake, body-weight gain, diencephalic NOS activity, and diencephalic content of tryptophan (TRP), 5-HT, hydroxyindoleacetic acid (5-HIAA), and 5-HIAA/5-HT ratio after intracerebroventricular (ICV) or intraperitoneal (IP) leptin injection in mice. Five consecutive days of ICV or IP leptin injections induced a significant reduction in neuronal NOS (nNOS) activity, and caused a dose-dependent increase of 5-HT, 5-HIAA, and the 5-HIAA/5-HT ratio. Diencephalic 5-HT metabolism showed a significant increase in 5-HT, 5-HIAA, and the 5-HIAA/5-HT ratio 3 hours after a single leptin injection. This effect was maintained for 3 hours and had disappeared by 12 hours after injection. After a single IP leptin injection, the peak for 5-HT, 5-HIAA, and the 5-HIAA/5-HT ratio was achieved at 6 hours. Single injections of ICV or IP leptin significantly increased diencephalic 5-HT content. Leptin-induced 5-HT increase was antagonized by the coadministration of L-arginine only when the latter was ICV injected, whereas D-arginine did not influence leptin effects on brain 5-HT content. Finally, in nNOS-knockout mice, the appetite-suppressant activity of leptin was strongly reduced, and the leptin-induced increase in brain 5-HT metabolism was completely abolished. Our results indicate that the L-arginine/NO pathway is involved in mediating leptin effects on feeding behavior, and demonstrate that nNOS activity is required for the effects of leptin on brain 5-HT turnover.

Immunolocalization and activation of nuclear factor-kappaB in the sciatic nerves of rats with experimental autoimmune neuritis.

Recent data support an important role played by nuclear factor kappa B (NF-kappaB) in peripheral neuropathies. We investigated expression and activation of NF-kappaB in experimental autoimmune neuritis (EAN) in rat sciatic nerves removed after 7, 14 and 21 days after immunization. Immunoreactivity for the activated form of NF-kappaB was found in the nuclei of T cells and macrophages at days 14 and 21, and also in the nuclei of few Schwann cells and of vascular endothelial cells at all time points, especially during the peak stage. Western blot showed a single band corresponding to 65 kDa in all EAN animals. NF-kappaB DNA-binding activity was revealed by electrophoretic mobility shift assay. Our results support NF-kappaB activation in EAN during the induction stage as well as in the disease remission.

Reduction of myocardial infarct size in rat by IRFI-048, a selective analogue of vitamin E.

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 x 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 x 10(-3)/g tissue to 1.8 +/- 0.5 U x 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).(ABSTRACT TRUNCATED AT 250 WORDS)

Evidence that nitric oxide modulates drinking behaviour.

The involvement of the L-arginine-nitric oxide (NO) pathway in brain, in the regulation of drinking behaviour, has been evaluated by injecting L-arginine and N omega-nitro-L-arginine methyl ester (L-NAME) into the lateral cerebral ventricle (i.c.v.). L-Arginine (5 and 10 micrograms/rat), but not D-arginine, was antidipsogenic when administered to 24 hr water-deprived rats but did not change the intake of water in normally hydrated rats. However, L-NAME (5 and 10 micrograms/rat) did antagonize the effect of L-arginine in water-deprived animals but, by itself, did not increase thirst. L-Arginine (100 ng), when injected into the preoptic area significantly reduced water deprivation-induced drinking. The same dose was unaffective when given intraventricularly. Finally, L-arginine (5 and 10 micrograms/rat, i.c.v.) inhibited drinking induced by intraventricular injection of angiotensin II (250 ng/rat). The effect was dose-dependent. The results indicate that: (1) NO acts as an inhibitory mechanism when thirst is stimulated by water deprivation or by angiotensin II; (2) the preoptic area might be one of the central sites of antidipsogenic action of NO and (3) nitric oxide synthase might be inhibited during water deprivation.

Food deprivation increases brain nitric oxide synthase and depresses brain serotonin levels in rats.

We studied nitric oxide (NO) synthase activity and serotonin content in the diencephalon of 24 hr food deprived rats. NO synthase activity was significantly increased whereas serotonin levels together with those of tryptophan and 5-hydroxyindoleacetic acid (5-HIAA) were reduced in food deprived rats when compared to control rats. NG-Nitro-L-arginine (L-NO Arg), an inhibitor of NO synthase, was used as a tool to study the role of NO in food deprivation. Twenty-four hr food deprived male Sprague-Dawley rats were intraperitoneally (i.p.) administered L-NO Arg (12.5, 25 and 50 mg/kg) before food presentation. Control rats received a NaCl (0.9%) solution. Food consumption was monitored 1 and 2 hr after food presentation. L-NO Arg administration produced a dose-dependent reduction in food intake. Pretreatment with metergoline (2 mg/kg) but not with ritanserin (1 mg/kg) antagonized the anorectic effect of L-NO Arg. Moreover, in the diencephalon L-NO Arg significantly reduced NO synthase activity whereas it increased serotonin levels. Our data indicate that NO might have a physiological role in the regulation of food intake and suggest that brain NO may modulate the central serotoninergic system.

Mediation by nitric oxide formation in the preoptic area of endotoxin and tumour necrosis factor-induced inhibition of water intake in the rat.

1. Drinking was induced in rats by 24 h of water deprivation. Water intake (ml) was evaluated for a 1 h period. 2. NG-nitro-L-arginine methyl ester (L-NAME, 5-10 micrograms, i.c.v., 50-100 ng into the preoptic area (POA)), an inhibitor of nitric oxide (NO) synthase, and methylene blue (50-100 ng into POA), an inhibitor of guanylate cyclase activation, antagonized the inhibition of drinking induced by E. coli endotoxin (LPS, 640 micrograms kg-1, i.v.) and tumour necrosis factor (TNF alpha, 40 ng, i.c.v.) in 24 h water-deprived rats. 3. L-Arginine (25, 50 and 100 ng), the precursor amino acid of NO, but not the stereoisomer D-arginine (100 ng), inhibited drinking induced by water deprivation when injected into the POA 30 min before water presentation (74.4% of inhibition with the highest dose). A dose of 12.5 ng L-arginine into the POA did not exhibit antidipsogenic effects. 4. TNF alpha (20 and 40 ng, i.c.v.; 1.25, 2.5 and 5 ng into the POA) showed a dose-dependent and powerful inhibition of drinking behaviour in water-deprived rats (70.4% and 80.8%, i.c.v. and into POA, with the highest doses, respectively). A dose of 10 ng of TNF alpha given i.c.v. had no effect on the intake of water. 5. LPS and TNF alpha, given at doses (160 micrograms kg-1, i.v. and 10 ng, i.c.v., respectively) that did not influence drinking in water-deprived rats, exhibited a strong antidipsogenic effect in water-deprived rats treated with a dose of L-arginine (12.5 ng, into the POA) which did not modify drinking by itself. (LPS + L-arginine:53.6% of inhibition; TNFalpha + L-arginine: 52.0% of inhibition).6. These results suggest that NO into the POA: (1) acts as an inhibitory mechanism on thirst and (2)plays a role in the antidipsogenic effect of LPS and TNFalpha.

Effects of intracerebroventricular leptin administration on food intake, body weight gain and diencephalic nitric oxide synthase activity in the mouse.

1. Intracranial administration of leptin reduces both food intake and body weight gain in the mouse. Inhibitors of nitric oxide (NO) synthase produce similar effects. 2. To investigate the role of the brain L-arginine/NO pathway in mediating this effect of leptin, we have evaluated food intake and body weight gain after daily (5 days) intracerebroventricular (i.c.v.) administration of leptin (0.5-2 microg) alone or in association with L-arginine (10 microg). Moreover, we measured diencephalic nitric oxide synthase (NOS) activity after a single i.c.v. leptin (0.25-2 microg) injection and after consecutive doses of leptin (0.25-2 microg) over 5 days. The time course of the effect of leptin on NOS activity was also evaluated. 3. I.c.v. injected leptin (1 and 2 microg) significantly and dose-dependently reduced food intake and body weight gain with respect to vehicle (food intake: 5.97+/-0.16 g 24 h(-1) and 4.27+/-0.18 g 24 h(-1), respectively, vs 8.05+/-0.34 g 24 h(-1), P<0.001, n=6 for each group; body weight gain: -10.7+/-0.46% and -15.7+/-0.65%, respectively, vs 5.14+/-0.38%, P<0.001, n=6 for each group). This effect was antagonized by L-arginine (food intake: 7.90+/-0.37 g 24 h; body weight gain: 5.11+/-0.31%, n=6). Diencephalic NOS activity was significantly reduced by the highest doses of leptin with respect to vehicle (vehicle: 0.90+/-0.04 nmol citrulline min(-1) g(-1) tissue; leptin 1 microg: 0.62+/-0.03 nmol citrulline min(-1) g(-1) tissue, P<0.001; leptin 2 microg: 0.44+/-0.03 nmol citrulline min(-1) g(-1) tissue, P<0.001, n=6 for each group). Similar results were obtained in animals treated with daily consecutive doses of leptin. The inhibitory effect appeared rapidly (within 30 min) and was long lasting (up to 12 h). 4. Our results suggest that the brain L-arginine/NO pathway may be involved in the central effect of leptin on feeding behaviour and body weight gain in mice.

Contribution of intercellular adhesion molecule 1 (ICAM-1) to the pathogenesis of splanchnic artery occlusion shock in the rat.

1. It has been suggested that leukocytes play a key role in the pathogenesis of splanchnic artery occlusion shock. Intercellular adhesion molecule 1 (ICAM-1) is an adhesion molecule of crucial importance in the phenomenon of leukocyte accumulation. 2. We investigated the involvement of ICAM-1 in the pathogenesis of splanchnic artery occlusion shock. Splanchnic artery occlusion (SAO) shock was induced in anaesthetized rats by clamping splanchnic arteries for 45 min. Sham-operated animals were used as controls. Survival time, serum tumour necrosis factor-alpha (TNF-alpha), white blood cell (WBC) count, mean arterial blood pressure, myeloperoxidase activity (MPO; studied as a quantitative means to assess leukocyte accumulation) and the responsiveness to acetylcholine of aortic rings were investigated. SAO shocked rats had a decreased survival time (90 +/- 9.5 min, while sham-shocked rats survived more than 4 h), reduced mean arterial blood pressure, increased serum levels of TNF-alpha (201 +/- 10 mu ml-1) and MPO activity in the ileum (0.15 +/- 0.03 mu x 10(-3) per g tissue) and in the lung (1.9 +/- 0.8 mu x 10(-3) per g tissue), leukopenia and reduced responsiveness to acetylcholine (ACh, 10 nM-10 microM) of aortic rings. 3. Administration of monoclonal antibody raised against rat ICAM-1 significantly increased survival time (225 +/- 9 min), reduced leukopenia and MPO activity both in the ileum (0.031 +/- 0.003 mu x 10(-3) per g tissue) and in the lung 0.23 +/- 0.03 mu x 10(-3) per g tissue), improved the cardiovascular changes and restored the responsiveness to ACh of aortic rings. 4. Our findings are consistent with an involvement of adhesion mechanisms in vivo in the pathogenesis of SAO shock and suggest that specific adhesion mechanisms, which support leukocyte accumulation,may represent potentially important therapeutic targets in circulatory shock.

Cardioprotection by the phytoestrogen genistein in experimental myocardial ischaemia-reperfusion injury.

1. Soybean phytoestrogens have no oestrogen agonist effects on the reproductive system and therefore it is reasonable to explore the potential of these naturally occurring plant oestrogens in the cardiovascular pathology. We therefore investigated the effects of genistein in a rat model of myocardial ischaemia-reperfusion injury. 2. Anaesthetized rats were subjected to total occlusion (45 min) of the left main coronary artery followed by 5 h reperfusion (MI/R). Sham operated rats were used as controls. Myocardial necrosis, myocardial myeloperoxidase activity (MPO), serum creatinine phosphokinase activity (CPK), serum and macrophage Tumour Necrosis Factor-alpha (TNF-alpha), cardiac intercellular adhesion molecule-1 (ICAM-1) immunostaining, cardiac mRNA for ICAM-1 evaluated by the means of reverse transcriptase polymerase chain reaction (RT - PCR), ventricular arrhythmias and myocardial contractility (left ventricle dP/dt(max)) were evaluated. 3. Myocardial ischaemia and reperfusion in untreated rats produced marked myocardial necrosis, increased serum CPK activity and MPO activity both in the area-at-risk and in the necrotic area, reduced myocardial contractility, caused ventricular arrhythmias and induced a marked increase in serum and macrophage TNF-alpha. Furthermore myocardial ischaemia-reperfusion injury increased ICAM-1 expression in the myocardium. 4. Administration of genistein (1 mg kg(-1), i.v., 5 min after coronary artery occlusion) lowered myocardial necrosis and MPO activity in the area-at-risk and in the necrotic area, decreased serum CPK activity, increased myocardial contractility, decreased the occurrence of ventricular arrhythmias, reduced serum and macrophages levels of TNF-alpha and blunted ICAM-1 expression in the injured myocardium. Finally genistein added in vitro to peritoneal macrophages collected from untreated rats subjected to myocardial ischaemia-reperfusion injury significantly reduced TNF-alpha production. 5. Our data suggest that genistein limits the inflammatory response and protects against myocardial ischaemia-reperfusion injury.

Multiple organ failure following zymosan-induced peritonitis is mediated by nitric oxide.

In the present study we tested the hypothesis that nitric oxide may play a role in the pathogenesis of multiple organ failure induced by peritoneal injection of zymosan in the rat. A severe inflammatory response characterized by peritoneal exudation, high plasma and peritoneal levels of nitrate/ nitrite (breakdown products of nitric oxide), prostaglandin E2 and leukocyte infiltration into peritoneal exudate was induced by zymosan administration. This inflammatory process started within 3 h of administration and onset occurred at 18 h, coinciding with damage of lung, small intestine and liver, as assessed by histological examination and by increase of myeloperoxidase activity, indicative of neutrophil infiltration. Furthermore, at 18 h after zymosan-induced peritonitis, expression of inducible nitric oxide synthase enzyme was found mainly in the macrophages of inflamed lungs. Subcutaneously administration of a nonisoform selective nitric oxide synthase inhibitor, NG-nitro-L-arginine methyl ester, reduced formation of peritoneal exudate fluid, blocked plasma and peritoneal nitrate/nitrite accumulation, and attenuated the elevated release of peritoneal prostaglandin E2. In addition, nitric oxide synthase inhibition was effective in preventing the development of organ failure since tissue injury and neutrophil infiltration, by myeloperoxidase evaluation, was reduced in lung, small intestine, and liver. In conclusion, major findings of our study are that nitric oxide exerts a proinflammatory role in the development of multiple organ failure and nitric oxide synthase inhibition is an effective antiinflammatory therapeutic tool, since inhibits not only nitric oxide but also prostaglandin production and cellular infiltration in inflamed organs.

Inhibition of nitric oxide formation reduces voluntary ethanol consumption in the rat.

Brain nitric oxide is involved in the mechanisms that regulate ingestive behavior. To test whether this compound plays a role in alcohol preference, we studied the effects of different doses of NG-nitro-L-arginine (L-NO arg), an inhibitor of nitric oxide synthase (NOS), on voluntary consumption of ethanol and on blood alcohol levels produced by a single intraperitoneal dose of alcohol in the rat. L-NO arg produced a significant and dose-dependent reduction of ethanol intake (P < 0.001) without influencing total fluid consumption or feeding behavior. L-NO arg did not influence the kinetics of alcohol. Our data show that inhibition of nitric oxide formation accompanies reduction of ethanol intake and suggest a possible role for nitric oxide in ethanol self-administration.