Retrospective analysis of adverse drug reactions induced by gemcitabine treatment in patients with non-small cell lung cancer.

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.

Effects of Ginko Biloba and caspase inhibitors on brain ischemia in the Mongolian Gerbil.

AIM: Data reported in previous studies and our own previous experience have led us to explore the mechanism of and the degree of protection afforded by Ginko Biloba in a model of cerebral ischemia in the Mongolian Gerbil evaluating histological and neurological effects in this rodent. METHODS: Mongolian Gerbils were divided into experimental groups: Group A consisted of animals subjected only to experimental ischemia; 5 minutes occlusion of the carotid arteries. Group B consisted of animals subjected to experimental ischemia and to a dose of Ginko Biloba, given intraperitoneally immediately before the surgical procedure. Group C consisted of animals subjected to experimental ischemia and to a dose of Ginko Biloba, given intraperitoneally immediately after the surgical procedure. Group D consisted of animals subjected to experimental ischemia and to a dose of the caspase inhibitors z-VAD.FMK and z-DEVD.FMK injected intracerebroventricularly through the right hemisphere before the surgical procedure. Group E consisted of animals subjected to experimental ischemia and to a dose of caspase inhibitors injected after the surgical procedure. Group F consisted of Sham-operated animals. Histological controls were done by H and E and the TUNEL method in the frontal cortex and caudate-putamen. RESULTS: The percentage of normal cells was not statistically significant at analysis with H and E, whereas the TUNEL method showed good protection with Ginko Biloba and caspase inhibitors, when the latter is given in the reperfusion phase. These data were in agreement with data obtained at neurological examination. CONCLUSION: We could say that cellular morphology is in itself an untrustworthy tool for judging the effects of ischemia and protective drugs; the TUNEL method may add important information about the different components of cellular death; the reperfusion phase may be critical for apoptotic phenomena; Ginko Biloba might protect neurons of the frontal cortex from both necrotic and apoptotic death in this model of ischemia.

Retrospective analysis of adverse drug reactions to bronchodilators observed in two pulmonary divisions of Catanzaro, Italy.

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.

Adverse drug reactions to antibiotics observed in two pulmonology divisions of catanzaro, Italy: a six-year retrospective study.

We retrospectively analysed adverse drug reactions (ADRs) associated with antibiotic therapy and reported over a 6-year period, from January 1995 to December 2000, in clinical notes of two Pulmonology Units of "Mater Domini" University Hospital and "Pugliese-Ciaccio" Hospital, both located in Catanzaro, Italy. Antibiotics were responsible for 92 (44.9%) out of 205 episodes of ADRs. In particular, 22 episodes (23.9%) were observed after penicillin G administration, 19 episodes (20.7%) following ceftazidime and cefotaxime administration, 16 episodes (17.4%) after therapy with ampicillin, and 35 reactions (38%) were further reported during treatments with other antibiotics. We determined that the drug-ADR relationship was certain in 63% of the reports; withdrawal of the suspected drug led to recovery in 95% of cases. In conclusion, this retrospective evaluation demonstrated that antibiotics are a common cause of ADRs in hospitalised patients and, therefore, drug surveillance can successfully identify targeted adverse events.

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.

Potential role of potassium channel openers in the treatment of asthma and chronic obstructive pulmonary disease.

Airway smooth muscle (ASM) cells express various types of potassium (K+) channels which play a key role in determining the resting membrane potential, a relative electrical stability and the responsiveness to both contractile and relaxant agents. In addition, K+ channels are also involved in modulation of neurotransmitter release from airway nerves. The most important K+ channels identified in airways include large and small Ca2+-activated, delayed-rectifier, and ATP-sensitive channels. These K+ channels are structurally and functionally different, thus playing distinct roles in airway electrophysiology and pharmacology. Many in vitro and in vivo studies, performed in both animals and humans, have shown that K+ channel openers are able to induce hyperpolarization of ASM cells, bronchodilation, suppression of airway hyperresponsiveness (AHR), and inhibition of neural reflexes. Therefore, airway K+ channels represent a suitable pharmacological target for the development of new effective therapeutic options in the treatment of asthma and chronic obstructive pulmonary disease (COPD).

Effects of non-bronchoconstrictive doses of inhaled propranolol on airway responsiveness to methacholine.

OBJECTIVES: The aim of this study was to evaluate the effects of non-bronchoconstrictive doses of propranolol on airway hyperresponsiveness to methacholine. METHODS: Double increasing concentrations (from 0.03 to 64 micrograms/ml) of inhaled propranolol were administered to a study population which included ten patients with mild asthma, ten rhinitics, and ten healthy control subjects. After the baseline bronchial responses to propranolol and methacholine, expressed as the cumulative provocative dose producing a 20% fall in forced expiratory volume in 1 s (PD20FEV1), were assessed, methacholine challenge was repeated after pretreatment with non-bronchoconstrictive doses of propranolol. RESULTS: The pharmacologically induced beta-blockade did not cause any effect in normal individuals, but it worsened airway responsiveness to methacholine in all asthmatics (geometric mean PD20 FEV1: 257 and 87 micrograms, respectively) and some rhinitics (geometric mean PD20 FEV1: 724 and 446 micrograms, respectively). CONCLUSION: Asthmatic patients were extremely sensitive to beta-blockers, whereas we observed a variable response to propranolol within the group of rhinitic subjects. This variability in the latter group is possibly because these individuals had different degrees of airway inflammation, increased parasympathetic activity, and beta-adrenoceptor dysfunction.

Audiogenic seizures susceptibility in transgenic mice with fragile X syndrome.

PURPOSE: To evaluate their susceptibility to audiogenic seizures, five groups of knockout mice with various forms of fragile X genetic involvement [hemizygous males (n = 46), and homozygous (n = 38) and heterozygous females (n = 45), and their normal male (n = 45) and female (n = 52) littermates] were studied. METHODS: All mouse groups were tested at ages 17, 22, 35, and 45 days. Audiogenic seizure susceptibility was scored, and the analysis of variance was used for the evaluation of the effects of age and genetic condition on seizure severity score (SSS). RESULTS: All groups of knockout fragile X mice exhibited SSSs significantly higher than those observed in their wild-type littermates; among knockout mice, hemizygous males and homozygous females showed the highest SSSs. Hemizygous males showed higher SSSs with increasing age, from 17 to 45 days; homozygous females showed a peak at age 22 days, followed by a decrease; finally, heterozygous females had their highest SSSs at age 17 days. CONCLUSIONS: This study demonstrates that an increased susceptibility to audiogenic seizures is present in fragile X knockout mice at all the ages tested. These results support the validity of this animal model also for epilepsy and seizures in the human fragile X syndrome.

Epilepsy and EEG findings in males with fragile X syndrome.

PURPOSE AND METHODS: One hundred and ninety-two fragile X male patients were investigated for seizures and EEG findings, 168 in a retrospective and 24 in another prospective study, to characterize the natural history of seizures, epilepsy, and EEG abnormalities in males with this syndrome. RESULTS: Seizures were documented in 35 (18.2%) of 192 patients; they never started before the age of 2 years or after the age of 9 years. Seizures were frequently of the complex partial type and less frequently of the partial motor and generalized type. Seizures involving frontal and temporal lobes were commonly seen and were usually well controlled by anticonvulsants. In the majority of young fragile X patients studied, an age-related paroxysmal EEG pattern was found, which showed neurophysiologic characteristics very similar to those of the centrotemporal spikes. CONCLUSIONS: These findings confirm that fragile X syndrome can be considered a genetic model of epilepsy.

Bactericidal activity of lansoprazole and three macrolides against Helicobacter pylori strains tested by the time-kill kinetic method.

The bactericidal activities of macrolides (clarithromycin, roxithromycin and azithromicyn) and lansoprazole, alone and in combination, against Helicobacter pylori strains were evaluated. It was found that the association of lansoprazole and clarithromycin resulted in a marked synergism, while the combination of roxithromycin or azithromycin with lansoprazole had synergistic and additive effects.

Structure-activity relationships of 2-aryl-2,5-dihydropyridazino [4,3-b]indol-3(3H)-ones at the benzodiazepine receptor.

A large series of 2-aryl-2,5-dihydropyridazino[4,3-b]indol-3(3H)ones (PIs) carrying properly selected substituents at the indole and N2-phenyl rings was prepared and tested as central benzodiazepine receptor (BZR) ligands and potential (anti)convulsant agents. Stereoelectronic requirements for high receptor affinity were detected by means of 2-D and 3-D QSAR analyses. BZR affinities and pharmacological profiles of the compounds were examined in comparison with some other pyridazinoindolones recently described by us and with pyrazoloquinoline (PQ) analogues. An anticonvulsant activity greater than PQs was generally observed for PIs. Notably, in the test of audiogenically induced seizures, one compound showed a potency comparable to that of diazepam.

Comparative epileptogenic properties of two monobactam derivatives in C57, Swiss and DBA/2 mice.

The behavioural and electrocortical effects of two monobactam derivatives were studied after intraperitoneal (ip) administration in DBA/2 mice, a strain genetically susceptible to sound-induced seizures, and in C57 and Swiss mice, two strains not prone to seizure. DBA/2 mice were more susceptible than Swiss and C57 mice to seizures induced by aztreonam or carumonam. No significant differences were observed between seizures elicited by aztreonam and carumonam in animals (DBA/2 only) administered intracerebroventricularly or ip. Although the main mechanism for seizure-like activity of monobactams cannot be easily determined, we believe that several mechanisms may be involved. An increased excitation of the central nervous system (CNS) by inhibition of GABA binding to receptors and a slow clearance of aztreonam and carumonam from the CNS may be postulated.

Functional preservation of benzodiazepine receptors of the primary somatosensory cortex in Creutzfeldt-Jakob disease: a pharmacologic-evoked potential study.

In previous studies, we demonstrated that the benzodiazepine (BZP) receptors of the visual system are functionally preserved in Creutzfeldt-Jakob disease (CJD). We hypothesized that such a functional preservation is not confined to the visual system. In a 74-year-old woman suffering from CJD, three consecutive recording sessions of somatosensory cortical evoked potentials (SEPs) by right median nerve stimulation were carried out: (a) basal condition, without any pharmacologic treatment; (b) 1 min after i.v. administration of 10 mg diazepam (DZP); (c) 2.5 min after i.v. administration of 3 mg FMZ, a high-affinity receptor benzodiazepine antagonist. DZP greatly decreased the amplitude of SEP early components, whereas flumazenil (FMZ) reversed such an effect. The results of this study, paralleling our previous findings on the visual system in CJD, demonstrated functional preservation of BZP receptors in the somatosensory pathways as well.

Relationship between structure and convulsant properties of some beta-lactam antibiotics following intracerebroventricular microinjection in rats.

The epileptogenic activities of several beta-lactam antibiotics were compared following their intracerebroventricular administration in rats. Different convulsant potencies were observed among the various beta-lactam antibiotics tested, but the epileptogenic patterns were similar. The patterns consisted of an initial phase characterized by wet-dog shakes followed by head tremor, nodding, and clonic convulsions. After the largest doses of beta-lactam antibiotics injected, clonus of all four limbs and/or the trunk, rearing, jumping, falling down, escape response, transient tonic-clonic seizures, and sometimes generalized seizures were observed, followed by a postictal period with a fatal outcome. At a dose of 0.033 mumol per rat, cefazolin was the most powerful epileptogenic compound among the drugs tested. It was approximately three times more potent than benzylpenicillin in generating a response and much more potent than other cephalosporins, such as ceftriaxone, cefoperazone, and cefamandole. No epileptogenic signs were observed with equimolar doses of cefotaxime, cefonicid, cefixime, and ceftizoxime in this model. The more convulsant compounds (i.e., cefazolin and ceftezole) are both characterized by the presence of a tetrazole nucleus at position 7 and show a marked chemical similarity to pentylenetetrazole. Imipenem and meropenem, the two carbapenems tested, also showed epileptogenic properties, but imipenem was more potent than meropenem, with a convulsant potency similar to those of ceftezole and benzylpenicillin. In addition, the monobactam aztreonam possessed convulsant properties more potent than those of cefoperazone and cefamandole. This suggest that the beta-lactam ring is a possible determinant of production of epileptogenic activity, with likely contributory factors in the substitutions at the 7-aminocephalosporanic or 6-aminopenicillanic acid that may increase or reduce the epileptogenic properties of the beta-lactam antibiotics. While the structure-activity relationship was also investigated, there seem to be no convincing correlations among the rank order of lipophilicities and the convulsant potencies of the compounds studied. The lack of marked convulsant properties of cefixime, cefonicid, cefuroxime, and cephradine suggests that these antibiotics may interact with a binding site which is different from that by which the beta-lactam antibiotics exert their convulsant effects or may demonstrate a reduced affinity for the relevant site(s).

Chlorpromazine versus sleep deprivation in activation of EEG in adult-onset partial epilepsy.

We prospectively compared the activating effect of chlorpromazine (CHLP, 50 mg, i.m.) versus sleep deprivation (SD) in 41 patients with a clinical diagnosis of partial epilepsy. Patients were selected on the basis of both seizure onset in adulthood and normal interictal awake EEG recordings. Twenty out of 41 patients (group A) were not yet treated because of either recent onset of epilepsy or misdiagnosis. The remaining 21 patients (group B) were treated with antiepileptic drugs (AED). A control group consisted of 18 healthy, volunteers (group C). All EEG recordings were scored by one observer according to a fixed protocol. In group A, SD and CHLP activated sleep EEG in 12 (60%) and 19 (95%) patients, respectively. This difference reached the limit of statistical significance (P = 0.05, McNemar test). In group B, SD and CHLP activated sleep EEG in 12 (57%) and 13 (62%) patients respectively. There was a significant (P < 0.02, exact Fisher test) intergroup difference (95% vs 62%) with respect to the activating effect of CHLP. No false-positive results were found in 18 control subjects. SD or CHLP activating procedures did not provoke any epileptic seizures in any of the groups. In conclusion, EEG activation by either SD or CHLP is highly specific in the diagnosis of adult-on-set partial epilepsy. Moreover, CHLP is more sensitive than SD in untreated patients, whereas the activating effect of CHLP may be partially attenuated by AED.

Increased cardiovascular responsiveness to central cholinergic stimulation in the genetically epilepsy-prone rat.

We sought to determine whether differences in cardiovascular responsiveness to central stimulation of the cholinergic system existed between the genetically epilepsy-prone and outbred Sprague-Dawley rats. We treated the unanaesthetized, restrained rats with the indirect cholinergic agonist physostigmine (25, 50, 100 and 200 micrograms kg-1, i.v.) and the direct muscarine agonist arecoline (50, 100 and 200 micrograms kg-1, i.v.). Blood pressure and heart rate were evaluated. Genetically epilepsy-prone rats demonstrated to be more susceptible to the action of physostigmine than the outbred Sprague-Dawley rats. Conversely, we did not note any difference between the two strains in the extent of the pressor response induced by arecoline. Moreover, we treated both strains with hemicholinium-3 (34.8 nmol, i.c.v.) to deplete endogenous stores of acetylcholine. This treatment did not affect the pressor response to arecoline, whereas it greatly reduced the response to physostigmine. The present results support an increased cardiovascular responsiveness to central cholinergic stimulation in the genetically epilepsy-prone rat which appears to be related to a pre-synaptic rather than a post-synaptic component.

2-Aryl-2,5-dihydropyridazino[4,3-b]indol-3(3H)-ones: novel rigid planar benzodiazepine receptor ligands.

A series of 2-aryl-2,5-dihydropyridazino[4,3-b]indol-3(3H)-ones 5 were prepared and evaluated for their ability to inhibit radioligand binding to BZR, and to prevent sound and pentylenetetrazole (PTZ) induced seizures in mice. The biological and pharmacological results are discussed in the light of some recently proposed pharmacophore models and compared through molecular orbital and molecular modeling studies to those obtained from the close pyrazoloquinoline analogs 6.