G. De Sarro

Anti-epileptic effects of focal micro-injection of excitatory amino acid antagonists.

The role of excitatory synaptic activity at various brain regions in the development and spread of seizure activity has been investigated by the focal microinjection of 2-amino-7-phosphono-heptanoate (2-APH), a selective antagonist at the N-methyl-D-aspartate preferring receptor, orγ-D-glutamylaminomethyl sulphonate (GAMS), a partially selective antagonist at the kainate receptor. In genetically epilepsy prone rats the seizure response to a loud sound is most effectively suppressed by focal injections of 2-APH, 0.1–1.0 nmol, in the inferior colliculus. Protection is also seen after injections of 2-APH, 25 nmoles, in the substantia nigra (pars reticulata) or the midbrain reticular formation. Motor limbic seizures induced by pilocarpine, 380 mg/kg intraperitoneally, are prevented by prior injection into the substantia nigra, pars reticulata, or the entopeduncular nucleus, of 2-APH, 10 nmol or 10 pmol, respectively. Similar protection follows the injection of 2-APH, 1–5 pmol in the piriform cortex. The convulsant effects of pilocarpine are also blocked by the focal injection of GAMS, 10 nmol in the entopeduncular nucleus. This experimental approach can indicate critical sites at which seizure activity is initiated in particular models (e.g., inferior colliculus in sound-induced seizures, and piriform cortex in limbic seizures) and the pathways controlling seizure expression, such as the basal ganglia outputs. It also identifies specific receptors at which anticonvulsant drugs may operate.

Retrospective Evaluation of Adverse Drug Reactions Induced by Nonsteroidal Anti-Inflammatory Drugs

AbstractBackground and objective: Nonsteroidal anti-inflammatory drugs (NSAIDs) are among the most widely prescribed drugs, and their use can be complicated by the development of adverse drug reactions (ADRs). The aim of this study was to assess the frequency of NSAID-induced ADRs in hospitalised patients in the Clinical Divisions of the Catanzaro and Cosenza hospitals. Methods: We retrospectively analysed NSAID-induced ADRs after evaluating all ADRs recorded by the Clinical Divisions of the Catanzaro and Cosenza hospitals over a 10-year period, from January 1995 to December 2004. Results: NSAIDs were found to be responsible for 55.2% of the episodes of ADRs overall. Diclofenac and aspirin (acetylsalicylic acid) were the drugs most frequently involved in the development of ADRs, while the skin was the body system most susceptible to NSAID-induced ADRs (43%). We determined that the drug-ADR relationship was probable in 62% of the reports; withdrawal of NSAID therapy led to a resolution of the clinical features of ADRs in 86% of episodes. Conclusion: NSAID therapy represents a common cause of ADRs in hospitalised patients. Their use should be carefully considered, especially in the presence of polydrug therapy.

Antiepileptic drugs for central post-stroke pain management.

Antiepileptic drugs (AEDs) are commonly prescribed for a wide range of disorders other than epilepsy, including both neurological and psychiatric disorders. AEDs play also a role in pharmacological management of neuropathic pain. Central post-stroke pain (CPSP) is a disabling morbidity occurring in 35% of patients with stroke. The pathophysiology of CPSP is not well known but central disinhibition with increased neuronal excitability has been suggested. AEDs include many different drugs acting on pain through several mechanisms, such as reduction of neuronal hyperexcitability. To our knowledge conclusive evidence has not been published yet. The aim of this review is to delineate efficacy and safety of AEDs in CPSP.

Synthesis and pharmacological properties of new 3-ethoxycarbonyl-11H-[1,2,4]triazolo[4,5-c][2,3]benzodiazepines

A series of new 3-ethoxycarbonyl-11H-[1,2,4]triazolo[4,5-c][2,3]benzodiazepines was synthesized starting from the corresponding bicyclic 1-aryl-3,5-dihydro-7,8-dimethoxy-4H-2,3-benzodiazepin-4-ones (CFMs), previously described as noncompetitive AMPA-type glutamate receptor antagonists, more potent than GYKI 52466. New synthesized compounds proved to be able to protect against seizures induced by means of auditory stimulation in DBA/2 mice and compound 8f the most active of the series showed anticonvulsant properties comparable to GYKI 52466.

The mTOR signaling pathway and neuronal stem/progenitor cell proliferation in the hippocampus are altered during the development of absence epilepsy in a genetic animal model

Hyperactivation of mammalian target of rapamycin (mTOR) signaling pathway occurs after an epileptogenic insult and, its inhibition prevents the development of spontaneous seizures. We have recently demonstrated that mTOR’s inhibition by rapamycin (started before seizure onset), permanently reduces the development of spontaneous absence seizures in WAG/Rij rats, an animal model of absence epilepsy; furthermore, mTOR phosphorylation was increased in adult WAG/Rij rats’ cortex, but not other brain areas. However, it was not clear whether this hyperphosphorylation was a cause or a consequence of absence seizure. Here, we have addressed this issue by analyzing immunohistochemically: (1) the brain levels of total and phosphorylated mTOR in young (before seizures) and adult WAG/Rij rats; (2) the proliferation of hippocampal neuronal stem/progenitor cells assessed by BrdU analysis at different ages. WAG/Rij rats have higher levels of total mTOR in several brain areas than Wistar rats; phospho-mTOR staining is higher in young WAG/Rij rats than control and adult WAG/Rij rats. Finally, the age-related decline in hippocampal neural progenitor cell proliferation rate was slower in WAG/Rij than Wistar rats. Our results support a role for persistent mTOR activation and consequent change in hippocampal progenitor cell proliferation during the epileptogenic process leading to the development of absence seizures in WAG/Rij rats.

Acute Renal Failure Probably Induced by Prulifloxacin in an Elderly Woman A First Case Report

1 Clinical Pharmacology and Pharmacovigilance Unit, Department of Experimental and ClinicalMedicine, Faculty of Medicine and Surgery University ‘Magna Graecia’ of Catanzaro, ‘MaterDomini’ University Hospital, Catanzaro, Italy2 Department of Experimental and Clinical Medicine, Chair of Respiratory Diseases, Faculty ofMedicine and Surgery University ‘Magna Graecia’ of Catanzaro, ‘Mater Domini’ UniversityHospital, Catanzaro, Italy

Efficacy and safety of bevacizumab in glioblastomas.

Glioblastoma multiforme (GBM) is a common and malignant primary brain tumor arising from glial precursors the survival of which is estimated to be about 14 months after diagnosis despite current standard care with radiotherapy, surgery, and chemotherapies. Therapeutic approaches were greatly improved in the last years; however, GBM still represents the most lethal subtype of glioma. Actually, it has been estimated that only about 3.4% of patients will survive at the most five years when obtaining the best outcome from treatment; however, this depends on tumor resistance, which is generally related to repairing radiation injury, and self- improving cell growth repair and survival. All GBMs recur after initial therapy, limiting patients � survival at 20-25% within 1 year after diagnosis of recurrent disease. Moreover, for recurrent GBM response rates are less than 10% (ranging from 5% to 9%), and progression free survival at 6-month (PFS-6) rates ranges between 9% and 28% (median 15%). The development of targeted therapy based on tumor vascular blockade led to the approval of bevacizumab for recurrent or progressive glioblastoma, since it was proven that this offers a new opportunity for patients suffering from this malignancy. Bevacizumab is a recombinant antivascular monoclonal antibody binding to circulating Vascular Endothelial Growth Factor (VEGF) preventing this cytokine from reaching its receptors (VEGFR1 and VEGFR2) on endothelium, resulting in an inhibition of cells proliferation and vessels sprouting. The aim of this review is to address bevacizumab mode of action in malignant gliomas and provide a summary on currently available data on efficacy and safety.

Effects of piracetam alone and in combination with antiepileptic drugs in rodent seizure models

Summary.The nootropic drug piracetam was investigated in various experimental models of epilepsy. Generally, piracetam exhibits no or only moderate anticonvulsant properties against generalized tonic or clonic seizures. However, in many cases it did increase the anticonvulsant effectiveness of conventional antiepileptics, as shown in the maximal electroshock seizure (MES) threshold test, the traditional MES test or in DBA/2 mice. A pharmacokinetic interaction does not seem to be responsible for this effect. In lethargic mice, a model of absence seizures, piracetam significantly decreased the incidence and duration of spike-wave discharges. Furthermore, in the cobalt-induced focal epilepsy model piracetam reduced the number of spikes/min and in the hippocampal stimulation model it increased the anticonvulsant potency of phenobarbital and phenytoin after single and repeated administration. In conclusion, the well tolerated piracetam itself did not show marked anticonvulsant effects in most screening tests, however, its co-medication with antiepileptic drugs improved seizure protection in various models which may bear potential clinical significance.

VALPROATE-INDUCED DELIRIUM IN A DEMENTED PATIENT

In this study we report a case of valproate-induced delirium in a patient affected with Alzheimers disease (AD). A 75-year-old woman with AD presented moderate cognitive impairment associated to behavioral disorders, characterized by aggression, agitation, severe insomnia. She was treated with galantamine, promazine, acetylsalicylic acid and pantoprazole. Since behavioral disorders worsened more and more, home neurological consultation was asked. The neurologist prescribed a mood stabilizer, sodium valproate 500 mg daily for the first week and then, twice a day and stopped promazine. After an apparent initial benefit, about 16 days later, patient suddenly developed hyperactive delirium. It was characterized by worsening of insomnia and agitation, severe confusion, delusions, visual hallucinations alternated to sedation. She became progressively unable to walk and completely dependent in daily living activities. An urgent geriatric consultation was performed at patients home; physical examination showed mild dehydration, normal blood pressure. Oxygen saturation and electrocardiogram were normal. Sodium valproate was immediately stopped and rehydration was performed. The patient was admitted to a Geriatric Unit, where organic and metabolic damages were excluded. During the hospital stay the patient was agitated, aggressive, confused; intramuscular haloperidol 5mg and saline intravenous infusion 1500 cc daily were performed, they were partly successful. Three days after she was discharged and continued treatment with oral haloperidol 5mg daily. One week later the patient recovered and she is at present healthy. This is a case report of valproate-induced delirium. The Naranjo scale scored 7, classifying this drug-related event as probable. The present case report suggests the need for minimizing the use of psychoactive drugs in elderly demented patients, whether possible; age-related changes in pharmacokinetics and pharmacodynamics suggest the opportunity of a careful evaluation and a slow titration of treatments in these patients.

Generalised Dermatitis Induced by Pegylated Interferon-α-2b in a Patient Infected with Genotype-1 Hepatitis C Virus

Treatment with interferon (IFN) alone is general- We report a case of generalised exfoliative der-ly associated with a sustained virological responsematitis and intense pruritus during PEG-IFNα-2bin <20% of patients with hepatitis C virus (HCV)therapy in a patient with chronic HCV infection.infection.