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Chronic Venous Disease (CVD) is a common medical condition affecting up to 80% of the general population. Clinical manifestations can range from mild to more severe signs and symptoms that contribute to the impairment of the quality of life (QoL) of affected patients. Among treatment options, venoactive drugs such as diosmin are widely used in the symptomatic treatment in all clinical stages. The aim of this study is to determine the effectiveness of a new formulated diosmin in relieving symptoms and improving QoL in patients suffering from CVD. In this randomized, double-blind, placebo-controlled, multicenter clinical study, CVD patients with a Clinical-Etiology-Anatomy-Pathophysiology (CEAP) classification system between C2 and C4 were randomized to receive a bioavailable diosmin (as μsmin® Plus) 450 mg tablet once daily or a placebo for 8 weeks. Clinical symptoms and QoL were monitored using the measurement of leg circumference, visual analogue scale (VAS) for pain, Global Index Score (GIS) and Venous Clinical Severity Score (VCSS). A total of 72 subjects completed the study. From week 4, leg edema was significantly decreased in the active group (p &lt, 0.001). An improvement in the VAS score was observed in the active group compared to placebo at the end of treatment (p &lt, 0.05). GIS and VCSS scores were significantly improved in the active group at week 8 (p &lt, 0.001). No treatment related-side effects were recorded. The results of this study showed that the administration of low-dose μsmin® Plus was safe and effective in relieving symptoms and improving QoL in subjects with CVD.

Omalizumab is a humanized monoclonal antibody which binds to human immunoglobulins E (IgE), thus preventing their interactions with both high affinity and low affinity IgE receptors. Therefore, omalizumab is currently recommended for add-on biological therapy of uncontrolled allergic asthma, mainly characterized by type 2 airway eosinophilic inflammation. Because omalizumab has been the first, and for a long time the only available monoclonal antibody for add-on treatment of type 2 asthma, some long-term studies have been published which provide a clear evidence of the therapeutic effectiveness of the anti-IgE pharmacological strategy. Within this context, the present single-centre observational study refers to 15 patients with severe allergic asthma, treated with omalizumab for at least 5 years at the Respiratory Unit of “Magna Græcia” University Hospital located in Catanzaro, Italy. In these asthmatic subjects we observed significant increases in asthma control test (ACT) score, with respect to baseline (14.60 ± 2.97), after 1 year (19.20 ± 2.98; p < 0.0001) and 5 years (21.67 ± 2.38; p < 0.0001) of add-on treatment with omalizumab. More importantly, omalizumab significantly lowered the number of annual asthma exacerbations (baseline: 3.66 ± 2.01) after 1 year (0.83 ± 1.14; p < 0.0001) and 5 years (0.63 ± 0.99; p < 0.0001), respectively. This excellent therapeutic outcome made it possible to drastically decrease the daily oral intake of prednisone (baseline: 22.50 ± 5.17 mg) after 1 year (1.83 ± 4.06 mg; p < 0.0001), as well as after 5 years (1.66 ± 3.61 mg; p < 0.0001). With regard to lung function, omalizumab significantly and persistently enhanced FEV 1 (baseline: 1636 ± 628.4 mL) after 1 year (2000 ± 679.7 mL; p < 0.05) and 5 years (1929 ± 564.8 mL; p < 0.05), respectively. Such relevant clinical and functional improvements were associated with reductions of blood eosinophil counts (baseline: 646.0 ± 458.9 cells/μl), already detectable after 1 year (512.7 ± 327.8 cells/μl; not significant), which reached the threshold of statistical significance after 5 years (326.0 ± 171.8 cells/μl; p < 0.05). Therefore, these real-life data referring to our single-centre observational investigation further corroborate the long-term therapeutic ability of omalizumab to improve several clinical, functional and haematological signatures of severe type 2 asthma.

Glucagon-like peptide-1 (GLP-1) is a hormone that can regulate several neuronal functions. The modulation of GLP-1 receptors emerged as a potential target to treat several neurological diseases, such as epilepsy. Here, we studied the effects of acute and chronic treatment with liraglutide (LIRA), in genetically epilepsy prone rats (GEPR-9s). We have also investigated the possible development of tolerance to antiseizure effects of diazepam, and how LIRA could affect this phenomenon over the same period of treatment. The present data indicate that an acute treatment with LIRA did not diminish the severity score of audiogenic seizures (AGS) in GEPR-9s. By contrast, a chronic treatment with LIRA has shown only a modest antiseizure effect that was maintained until the end of treatment, in GEPR-9s. Not surprisingly, acute administration of diazepam reduced, in a dose dependent manner, the severity of the AGS in GEPR-9s. However, when diazepam was chronically administered, an evident development of tolerance to its antiseizure effects was detected. Interestingly, following an add-on treatment with LIRA, a reduced development of tolerance and an enhanced diazepam antiseizure effect was observed in GEPR-9s. Overall, an add-on therapy with LIRA demonstrate benefits superior to single antiseizure medications and could be utilized to treat epilepsy as well as associated issues. Therefore, the potential use of GLP1 analogs for the treatment of epilepsy in combination with existing antiseizure medications could thus add a new and long-awaited dimension to its management.

In this work complexation of luteolin (H4Lu) with Al(III), Fe(III) and Cu(II) at 37 °C and in 0.16 M NaCl is discussed. To evaluate the competition of the ligand for the metal cations and H+, the protonation constant of luteolin was also determined under the same experimental conditions. Speciation profiles obtained by potentiometric titrations show that in aqueous solution a complexation occurs at 1:1 ligand-to-Al(III) ratio, and at 1:1 and 2:1 ligand-to-cation ratios for Fe(III) and Cu(II). The coordination sites of luteolin to the different metal ions were determined by a computational approach, displaying that copper ion shows no selective preference towards any of the complexation sites of luteolin, while the six-membered chelate ring of the 4–5 site (i.e., the 4-carbonyl-5-hydroxyl site of the A and C rings of the ligand) is the preferred one for aluminum and iron ions. Additionally, we have evaluated the antioxidant and anti-inflammatory properties of free luteolin and of the luteolin-metal ion complexes. The complex with iron was found to have a higher activity than the other complexes (i.e., Fe(III)-Lu > Cu(II)-Lu > Al(III)-Lu), and its DPPH radical scavenging ability was even higher than that of free luteolin. Finally, all luteolin metal complexes were found to significantly reduce lipopolysaccharide (LPS)-induced interleukin (IL)-6 levels in monocyte-derived macrophages with the following order: Fe(III)-Lu > Al(III)-Lu > Cu(II)-Lu > free Lu.

Functional studies indicate that essential cellular processes are controlled by Vitamin A derivatives. Among these the retinoic acid isoforms, all-trans- and 9-cis (9cRA), regulate the expression of various genes in both physiological and pathological conditions. Using several in vitro experimental models such as pancreatic β-cells, pre-adipocytes and breast cancer cells with different phenotypes, we demonstrated the capability of 9cRA to modulate myotrophin (Mtpn) and miR-375 expressions. The 9cRA effect in pancreatic β-cells line INS-1 832/13 point out a decreased expression of Mptn at both mRNA and protein levels associated to a concomitant increase of miR-375. We also studied the effect of this molecule on 3T3-L1 pre-adipocytes cells demonstrating a down-regulation of Mtpn and a dramatic increase of miR-375. Moreover, in the in vitro breast cancer model such as MDA-MB-231 and MCF-7 cells, 9cRA showed different effect on both Mtpn and miR-375 expression. In INS-1 832/13, 3T3-L1 pre-adipocytes and MCF-7 but not in MDA-MB-231, the effect of 9cRA on Mptn gene expression and its miR was under the control of RARs and RXRs receptors, as revealed by the exposure of these cell line to LE540 or HX603 receptor antagonists. In our findings 9cRA emerges has a hormone with a regulatory action on miR-375 that in most cases interfere with Mtpn expression.

Purpose To evaluate the efficacy of a low-cost preparation of platelet-rich plasma (PRP) eye drops in the treatment of persistent non-infectious corneal ulcer. Observations A 67-year-old female presented to our clinic with a wide corneal ulcer and severe paracentral corneal thinning refractory to medical therapy with antibiotics, lubricant and contact lens bandage. The patient received a novel preparation of PRP solution. After 15 days of therapy, we observed complete resolution of the corneal ulcer with regrowth of the epithelium and a reduction in corneal opacity. Conclusion and importance Although the low-cost PRP preparation gives a lower platelet concentration than standard procedures, our work shows this preparation to be effective in the treatment of refractory non-infectious corneal ulcer.

The carotid body tumors (CBTs) are relatively rare neoplasms and may present into benign or life threatening malignant forms. Matrix metalloproteinases (MMPs) are often involved in vascular and cancer diseases. Objective of this study is to study the relationship between CBTs and MMPs.We performed a multicenter study on 14 patients with CBTs. All tumors were resected. For each patient, we evaluated the MMPs' levels in both plasma (enzyme-linked immunosorbent assay [ELISA] test) and tissue samples (Western blot analysis). These MMPs' plasma levels were compared with the MMPs' plasma levels of healthy patients.Eleven patients had benign CBTs, whereas 3 patients had malignant CBTs. ELISA findings revealed significant higher levels (P 0.01) of MMP-1, -2, -3, -8, and -9 in patients with paraganglioma with respect to healthy patients. Patients with malignant CBTs showed significantly higher levels (P 0.01) of MMP-1, -2, and -3 compared with patients with benign CBTs.Because this is an exploratory study, the experience on this casuistry showed that MMPs' evaluation may help clinicians and surgeons to formulate a more rapid and clear diagnosis on CBTs' behavior. However, other studies on a large group of patients may be useful to validate these observations.

Chronic venous disease (CVD) is a common and relevant problem affecting Western people. The role of estrogens and their receptors in the venous wall seems to support the major prevalence of CVD in women. The effects of the estrogens are mediated by three estrogen receptors (ERs): ERα, ERβ, and G protein-coupled ER (GPER). The expression of ERs in the vessel walls of varicose veins is evaluated.In this prospective study, patients of both sexes, with CVD and varicose veins undergoing open venous surgery procedures, were enrolled in order to obtain vein samples. To obtain control samples of healthy veins, patients of both sexes without CVD undergoing coronary artery bypass grafting with autologous saphenous vein were recruited (control group). Samples were processed in order to evaluate gene expression.Forty patients with CVD (10 men [25%], 30 women [75%], mean age 54.3 years [median 52 years, range 33-74 years]) were enrolled. Five patients without CVD (three men, two women [aged 61-73 years]) were enrolled as the control group. A significant increase of tissue expression of ERα, ERβ and GPER in patients with CVD was recorded (p .01), which was also related to the severity of venous disease.ERs seem to play a role in CVD; in this study, the expression of ERs correlated with the severity of the disease, and their expression was correlated with the clinical stage.

Introduction An association between arterial aneurysms and matrix metalloproteinases (MMPs) has been described previously. MMPs regulate extracellular structural proteins and tissue remodeling. Neutrophil gelatinase-associated lipocalin (NGAL) is involved in the regulation of MMP activity. The aim of this work was to study the relationship between the levels of MMPs and NGAL and arterial aneurysms. Methods In a multicenter, open-label, parallel groups, prospective study, patients with aneurysmal disease were divided into 2 groups: Group I (with ruptured aneurysm) and group II (with nonruptured aneurysm). Healthy volunteer patients were also enrolled and represented the control group (group III). Results We enrolled 307 patients (107 in group I and 200 in group II) with arterial aneurysm: 49 popliteal, 31 common femoral, 2 superficial femoral, 29 common iliac artery, 3 common carotid, and 193 abdominal aorta. Finally, 11 healthy volunteer patients (9 males and 2 females; age range, 40–70 years; median 56) were enrolled in group III. Enzyme-linked immunosorbent assay and Western blot analysis revealed greater levels of immunoreactive MMP-9 and NGAL in all patients with ruptured aneurysms, both central and peripheral aneurysms, and in the aneurismal vessels. Conclusion These results provide potentially important insights to the understanding of the natural history of arterial aneurysms. MMPs and NGAL play a role in development of arterial aneurysms and may represent molecular markers for the prevention of aneurysmal rupture.

Soft tissue sarcomas (STS) are rare tumors with mesenchymal origin, accounting for 1% of all human cancer. Local control of STS can be obtained through the use of surgery and radiotherapy. In about 40% of these patients, disease will recur at distant sites, and of these more than 90% will die because of this aggressive malignancy. In advanced and/or metastatic STS patients treated with anthracycline-based regimen the median overall survival is about 12 months, and it has remained unchanged during the last 20 years. Clearly, this strongly suggests the need for discover more active compounds in STS, such as imatinib in GIST or dermatofibrosarcoma patients. In this paper we describe the crucial role of angiogenesis mechanisms in sarcomas development and progression. Consequentially, we focus on pazopanib, a novel multitargeted tyrosine kinase inhibitor with anti-angiogenic activity, mainly due to VEGFR2 pathway interference. We also analyze principal completed trials leading pazopanib approval in sarcomas pretreated patients.

It is known that the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) are effective in both the primary and the secondary prevention of ischemic heart disease. Increasing evidence indicates that statins have protective effects in several neurological diseases including stroke, cerebral ischemia, Parkinson disease, multiple sclerosis, traumatic brain injury and epilepsy. The aim of the present research was to evaluate the effects of some HMG-CoA reductase inhibitors (i.e. lovastatin, simvastatin, atorvastatin, fluvastatin and pravastatin) commonly used for the treatment of hypercholesterolemia in the DBA/2 mice, an animal model of generalized tonic-clonic seizures. Furthermore, the co-administration of these compounds with some antiepileptic drugs (AEDs; i.e. carbamazepine, diazepam, felbamate, gabapentin, lamotrigine, levetiracetam, oxcarbazepine, phenobarbital, phenytoin, topiramate and valproate) was studied in order to identify possible positive pharmacological interactions. Simvastatin only was active against both the tonic and clonic phase of audiogenic seizures, whereas the other statins tested were only partially effective against the tonic phase with the following order of potency: lovastatin>fluvastatin>atorvastatin; pravastatin was completely ineffective up to the dose of 150mg/kg. The co-administration of ineffective doses of all statins with AEDs generally increased the potency of the latter reducing their ED50 values. In particular, simvastatin was the most active in potentiating the activity of AEDs and the combinations of statins with carbamazepine, diazepam, felbamate, lamotrigine, topiramate and valproate were the most favorable, whereas, the co-administrations with the other AEDs studied was in most cases neutral. The increase in potency was generally associated with an enhancement of motor impairment (TD50); however, the therapeutic index (TD50/ED50) of combined treatment of AEDs with statins was predominantly more favorable than control. Statins administration did not significantly affect the total plasma but, in some cases, it increased the free plasma levels and the brain concentrations of some of the AEDs studied (i.e. carbamazepine, diazepam, phenytoin and valproate); however, these alterations where not statistically significant. Therefore, with the exception of the latter compounds, we might exclude pharmacokinetic interactions and conclude that for the most of AEDs, potentiation was of pharmacodynamic nature. In conclusion, simvastatin, fluvastatin, lovastatin and atorvastatin showed an additive anticonvulsant effect when co-administered with some AEDs, most notably carbamazepine, diazepam, felbamate, lamotrigine, topiramate and valproate, implicating a possible therapeutic relevance of such drug combinations. The present results suggest that statins, besides the beneficial cardiovascular effects, might be able to affect brain areas, which might participate in the regulation of seizure susceptibility.

Aripiprazole (APZ) is regarded as a first-line atypical antipsychotic used for the treatment of first and multiple episodes of schizophrenia to improve positive- and negative-symptoms. Its therapeutic indications were extended to acute manic and mixed episodes associated with bipolar disorder. In addition, APZ was approved as an adjunct therapy for major depressive disorder in 2007. Compared to other antipsychotic drugs, APZ has a unique pharmacological profile. It is a partial agonist at D₂ dopamine receptors and serotonin 5-HT(1A) and 5-HT₇ receptors, whereas it is an antagonist at serotonin 5-HT(2A) and 5-HT₆ receptors. Since epilepsy is often accompanied with neurological comorbidities such as depression, anxiety and cognitive deficits caused by both the disease and/or drug treatment, we wished to examine the effects of a sub-chronic treatment (>14 consecutive days) with APZ (0.3, 1 and 3 mg/kg; i.p.) on both absence seizures and WAG/Rij rat's behavior using different standard paradigms: Open field (OF) test, elevated plus maze (EPM) test, forced swimming (FS) test, sucrose consumption (SC) test and Morris water maze (MWM). WAG/Rij rats represent a validated genetic animal model of absence epilepsy with mild-depression comorbidity, also including other behavioral alterations. APZ treatment showed some anti-absence properties and regarding the behavioral comorbidity in this rat strain, we observed that APZ possesses clear antidepressant effects in the FS and SC tests also increasing memory/learning function in the Morris water maze test. In the two anxiety models used, APZ showed only minor effects. In conclusion, our results indicate that APZ might actually have a potential in treating absence seizures or as add-on therapy but more interestingly, these effect might be accompanied by positive modulatory actions on depression, anxiety and memory which might be also beneficial in other epileptic syndromes. This article is part of a Special Issue entitled 'Cognitive Enhancers'.

Background: Improvement of fatigue in patients with multiple sclerosis (MS) who were given bupropion has been previously reported, but scales for lethargy and depression were not used. Objective: This letter describes the course of chronic fatigue in a patient with MS who received off-label treatment with bupropion. Methods: A 47-year-old white woman (weight, 56 kg) with a 7-year history of relapsing-remitting MS (Expanded Disability Status Scale score of 3), without previous use of medication for MS, presented with a complaint of irritability and chronic fatigue. The Fatigue Severity Scale (FSS) documented the presence of fatigue related to MS (score of 7). The Beck Depression Inventory scale excluded an association between depression and fatigue (score of 8; possible range, 0–24); both the Pittsburgh Sleep Quality Index (score of 4; possible range, 0–21) and the Epworth Sleepiness Scale (score of 6; possible range, 0–24) excluded nighttime and daytime sleep disturbances. The patient was started on amantadine (100 mg/d), with an increase to 100 mg every 12 hours 2 weeks later, for the persistence of fatigue. Three months later, the absence of clinical response was noted (FSS score of 7). Amantadine was discontinued and bupropion therapy was initiated at 300 mg/d. Results: A repeat clinical evaluation conducted after 3 months of bupropion treatment indicated an improvement in fatigue (FSS score of 4) without changes in Beck Depression Inventory, Pittsburgh Sleep Quality Index, or Epworth Sleepiness Scale scores. The discontinuation and reinitiation of bupropion confirmed the effectiveness of bupropion for improving chronic fatigue in this patient. At the time of writing this report, 13 months after the resumption of bupropion treatment, the patient had experienced no further episodes of fatigue, and no adverse events had been reported. Conclusion: This patient with relapsing-remitting MS experienced improvements in chronic fatigue (as measured by FSS) after treatment with bupropion, but properly designed, randomized, active- and placebocontrolled clinical trials are needed to evaluate the efficacy and safety of bupropion in more patients with MS and fatigue. (Clin Ther. 2010;32:2030–2034) ©

Drug-induced delirium is a common matter in the elderly and anticholinergics, together with a number of different drugs, may significantly contribute to the delirium onset, especially in demented people. We report a case of a probable anticholinergic drug-induced delirium in an elderly patient. An 80-year-old man with Alzheimer's dementia presented with wandering, depressed mood with crying, somatic worries, anedonism and suicide recurrent ideas. A first external psychiatric assessment led to the diagnosis of melancholic depression and therapy with haloperidol 2mg/day, orphenadrine 100mg daily, amitriptyline 40 mg/day, lorazepam 2mg/day was started. Two weeks later patient suddenly developed delirium, characterized by nocturnal agitation, severe insomnia, daytime sedation, confusion, hallucinations and persecutory delusions. These symptoms progressively worsened, with the consequent caregiver's stress. A geriatric consultation excluded the main causes of delirium, therefore both Operative Units of Pharmacovigilance and Psychiatry were activated, for a clinical pharmacological and psychiatric assessment. Haloperidol, amitriptyline and orphenadrine were promptly dismissed. The patient began a treatment with quetiapine 25mg/day for two days, then twice a day, and infusion of saline 1000 ml/day for two days; psychiatric symptoms gradually diminished and therapy with galantamine was begun. We postulate that this clinical report is suggestive for an anticholinergic drug- induced delirium since the Naranjo probability scale indicated a probable relationship between delirium and drug therapy. In conclusion, a complete geriatric, pharmacological, and psychiatric evaluation might be necessary in order to reduce the adverse drug reactions in older patients treated with many drugs.

Homocysteine (Hcy) is a thyol amino acid resulting from de-methylation of methionine, an essential amino acid derived from dietary proteins. It is metabolized through two pathways: re-methylation and transsulfuration, which use as cofactors folate, vitamin B6 and vitamin B12. Hyperhomocysteinemia has been identified as a risk factor for cerebrovascular disease, dementia, impaired cognitive function and depression. Several drugs may interfere with metabolic pathways of Hcy, leading to an alteration of plasma Hcy levels. Lipid-lowering agents, used to reduce the risk of cerebral venous thrombosis or occlusive vascular disease in patients with high levels of plasmatic lipids, can increase plasma Hcy levels. Hyperhomocysteinemia has been also documented in Parkinson disease patients treated with levodopa and in epileptic patients after chronic treatment with antiepileptic drugs. In contrast, vitamins supplementations may be warranted in patients treated with lipid-lowering agents, levodopa and antiepileptic drugs in order to maintain normal plasma Hcy values. In contrast, higher doses of vitamins can induce dysfunctions in central and peripheral nervous system; therefore excessive supplements should be avoided.

We report for the first time the lack of therapeutic effects after the switch from a brand formulation of allopurinol to a generic one. A 56-year-old man, with a 5 years history of well-treated gout arthropathy with allopurinol (Zyloric ® 300 mg/die), developed acute gout arthropathy after the switch from the brand formulation of allopurinol to a generic one. Clinical evaluation and laboratory findings confirmed the diagnosis of acute gout arthropathy. Generic formulation of the drug was dismissed and Zyloric ® was administered with an improvement of both clinical symptoms and laboratory findings. In conclusion, even if generic formulations are considered to have the same effects in comparison to the brand one, more data are necessaries in order to well define their effectiveness and rationale use.

Genetic factors play a key role in determining the widely heterogeneous response to pharmacological treatment detectable among asthmatics. In particular, polymorphisms of the genes encoding relevant anti-asthma drug targets contribute significantly to such a variability. Therefore, it is very important to characterize asthmatic patient's genotypes and the related phenotypic patterns, in order to predict the individual therapeutic outcome. This pharmacogenetic approach will eventually help clinicians to optimize and personalize anti-asthma treatment, and will also provide useful information with regard to pre- and post-marketing evaluation of both effectiveness and side effects of newly introduced drugs.

Non-small cell lung cancer (NSCLC) is the leading cause of cancer death in the world. Traditional chemotherapy for advanced NSCLC is often considered excessively toxic. Recent clinical trials documented that gemcitabine may represent a good therapeutical option in patients with NSCLC. Aim of our research was to retrospectively evaluate the adverse effects induced by gemcitabine in patients with NSCLC from 1 January 1997 to 31 December 2002, in clinical records of Oncology Divisions of "S. Giovanni di Dio" Hospital of Crotone, "Ospedali Riuniti" Hospital of Reggio Calabria, Hospital of Paola, and in Pneumological Oncology Division of "Mariano Santo" Hospital of Cosenza, Italy. Clinical records of patients treated with gemcitabine (1000mgm(-2) on days 1 and 8) were reviewed and following data were obtained: sex and age of the patients, histologic diagnosis and disease stage, World Health Organisation (WHO) performance status and toxic effects induced by gemcitabine. We reported that 71.6% of NSCLC patients (age range 48-77 years; 135 males, 27 females; performance status 0=53, 1=109) were eligible for our study. Side effect of gemcitabine involved gastrointestinal system (nausea, vomiting and diarrhoea) and only in the last cycles (VIII-XI) emopoiethic system (leukopenia, neutropenia, thrombocytopenia and anemia). Grade IV vomiting occurred in three patients, thrombocytopenia in two. Grade III leukopenia was observed in three patients. Other toxicities were mild. None of the patients died during chemotherapy. In conclusion, these data showed that gemcitabine present a very good tolerability in patients with NSCLC. Therefore, it could be considered as a new therapeutic agents to use as first line therapy for this disease.

We retrospectively analysed the adverse drug reactions (ADRs) associated with bronchodilator therapy and reported over a 7-year period, from January 1995 to December 2001, in clinical notes of two Pulmonary division of "Mater Domini" University Hospital and "Pugliese-Ciaccio" Hospital, both located in Catanzaro, Italy. Bronchodilators were responsible for 45 (18.5%) out of 243 episodes of ADRs. Theophylline was the drug most involved in ADRs (53.4%), and skin was the body system most susceptible to ADRs induced by all bronchodilators (47.7%). We determined that the drug-ADR relationship was certain in 73% of the reports; withdrawal of the suspected drug led to recovery in 86% of cases. In conclusion, this retrospective evaluation demonstrated that bronchodilators are a common cause of ADRs in hospitalised patients and, therefore, drug surveillance can successfully identify adverse events related with drug administration in hospitalised patients.

The anticonvulsant activity of riluzole against sound-induced seizures was studied in the DBA/2 mouse model. Riluzole (0.1-4 mg kg(-1), intraperitoneal (i.p.)) produced dose-dependent effects with ED(50) values for the suppression of tonic, clonic and wild running phases of 0.72, 1.38 and 2.71 mg kg(-1), respectively. Riluzole also protected DBA/2 mice from seizures induced by an intracerebroventricular (i.c.v.) injection of N-methyl-D-aspartate (NMDA) with ED(50) values of 3.03 and 5.0 mg kg(-1) for tonus and clonus, respectively. Pretreatment with glycine, an agonist to the glycine/NMDA receptors, shifted the dose-response effect of riluzole to the right (ED(50)=6.53 against tonus and 9.34 mg kg(-1) vs. clonus). Similarly, D-serine, an agonist at the glycine site, shifted the ED(50) of riluzole against the tonic component of audiogenic seizures from 0.72 to 1.97, and that against clonus from 1.38 to 2.77 mg kg(-1). Riluzole was also potent to prevent seizures induced by administration of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), an AMPA/kainate receptor agonist (ED(50)=1.80 and 3.35 mg kg(-1), against tonus and clonus, respectively). Pretreatment with aniracetam, a positive allosteric modulator of AMPA/kainate receptors, shifted the dose-response curve of riluzole to the right (ED(50)=1.78 against tonus and 2.58 mg kg(-1) vs. clonus). The data indicate that riluzole is an effective anticonvulsant drug in the genetic model of seizure-prone DBA/2 mice. Our findings suggest that the anticonvulsant properties of riluzole depend upon its interaction with neurotransmission mediated by both the glycine/NMDA and the AMPA/kainate receptor complex.

Gabapentin (1-50 mg/kg, intraperitoneally (i.p.)) was able to antagonize audiogenic seizures in Dilute Brown Agouti DBA2J (DBA/2) mice in a dose-dependent manner. Gabapentin at dose of 2.5 mg/kg i.p., which per se did not significantly affect the occurrence of audiogenic seizures in DBA/2 mice, potentiated the anticonvulsant activity of carbamazepine, diazepam, felbamate, lamotrigine, phenytoin, phenobarbital and valproate against sound-induced seizures in DBA/2 mice. The potentiation induced by gabapentin was greatest for diazepam, phenobarbital and valproate, less for felbamate and phenytoin and least for carbamazepine and lamotrigine. The increase in anticonvulsant activity was associated with a comparable increase in motor impairment. However, the therapeutic index of combined treatment of the above drugs + gabapentin was more favourable than that of the same drugs + saline. Since gabapentin did not significantly influence the total and free plasma levels of the anticonvulsant drugs studied, we suggest that pharmacokinetic interactions, in terms of total or free plasma levels, are not probable. However, the possibility that gabapentin can modify the clearance from the brain of the anticonvulsant drugs studied can not be excluded. In addition, gabapentin did not significantly affect the hypothermic effects of the anticonvulsants tested. In conclusion, gabapentin showed an additive effect when administered in combination with certain classical anticonvulsants, most notably diazepam, phenobarbital, felbamate, phenytoin and valproate.