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S Tognella

Publications and source records attributed to S Tognella.

At least 19 recordsLinked to original sources
PubMed2006

Nasal and bronchial tolerability of Rofecoxib in patients with aspirin induced asthma.

UNLABELLED: Aspirin (ASA) and several other nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit cyclo-oxygenase (COX) enzyme both isoforms 1 and 2, and can precipitate asthmatic attacks in aspirin-induced asthmatics. Rofecoxib (R) is a novel and specific COX-2 inhibitor which is caracterized by an highly selective COX-2 inhibition, and can be presumed as non cross-reactive with ASA. Aim of the study was to assess the bronchial and the nasal response to R in AIA. MATERIALS AND METHODS: Nineteen subjects with AIA (21-54 years, 7 m, mean FEV1 85.1% pred. +/- 5.4 sd) performed two oral provocation tests: one with increasing doses of ASA and one other of R at a time interval of 2 weeks, according to a randomized, cross-over design. The bronchial and the nasal responses were measured by serial measures of FEV1, and of nasal resistences by acoustic rhinomanometry, respectively. STATISTICS: Anova for trends was used, and p<0.05 accepted. RESULTS: Mean ASA PD20 was 68.3 mg +/- 12.4 sd. ASA induced a significant broncho-constriction in all patients with AIA: basal FEV1 dropped from 88.9% pred. +/- 6.2sd to 70.1% pred. +/- 6.9sd after 60 min. (Anova p = 0.001). Despite ASA, R was well tolerated: basal FEV1 remained unchanged during the period of observation following the R 25mg ingestion. ASA also precipitated a significant nasal response with increased nasal resistances (anova p < 0.001) and reduced volumes (anova p < 0.001). The nasal function was unchanged following R 25mg. CONCLUSIONS: Despite ASA, Rofecoxib, largely due to its highly specificity for COX-2, proved a drug particularly safe in treating patients with AIA.

Adult↗
PubMed2006

Aspirin induced asthma (AIA) with nasal polyps has the highest basal LTE4 excretion: a study vs AIA without polyps, mild topic asthma, and normal controls.

UNLABELLED: Cysteinil Leukotrienes (LTs) are products of the arachidonic acid cascade which are synthetised by 5-lipoxigenase in inflammatory cells, particularly in eosinophils. Urinary leukotriene E4 concentration (LTE4), that reflects the whole body production of cysteinil-leukotrienes, is particularly increased in patients with aspirin-intolerant asthma (AIA). Aim of the present study was to assess basal urinary LTE4 levels from AIA patients with nasal polyps to those from AIA patients with only rhinitis (without polyps), and those from mild atopic asthmatics and normal controls. SUBJECTS & METHODS: 34 normal subjects (N; 19 - 57y, FEV1 = 102.1% pred. +/- 8.2 sd; negative MCh challenge; negative prick test); 39 mild-persistent atopic asthmatics (A; 18-66y, FEV1 = 92.1 %pred. +/- 14.6 sd; PD20 FEV1 = 380.7mcg +/- 481.2 sd); 24 subjects with AIA with rhinitis (AIA/R; 18 - 56y, FEV1 = 71.6%pred +/- 15.5 sd; reversibility = 15.1% bsln +/- 2.1 sd after salbutamol 200mg), and 10 subjects with AIA and nasal polyposis (AIA/NP; 22-49 y; FEV1 = 70.6%pred. +/- 7.1 sd; reversibility = 13.2% bsln +/- 1.6 sd after salbutamol 200 microg) were studied. After their informed consent, urine were collected in the morning for the LTE4 quantitative immunoenzimatic assay (pg/mg creatinine; Cayman Chemical, Ann Arbour, Mi, USA). STATISTICS: Wilcoxon signed rank test was used, and p<0.05 accepted as the lowest level of statistical significance. RESULTS: AIA/NP subjects had the highest levels of urinary LTE4 (432.3 pg/mg +/- 88.1 sd) compared to AIA/R (330.7 pg/mg +/- 72.3s, p < 0.01), to A (129.1 pg/mg +/- 74.8sd, p < 0.001), and to N controls (66.5 pg/mg +/- 20.6 sd, p < 0.001). Moreover, urinary LTE4 levels measured in AIA/R subjects proved significantly higher than those measured in A (p < 0.001) and in N controls (p<0.001), while LTE4 levels in A proved significantly higher than those in N controls (p<0.001). Furthermore, basal LTE4 levels seem inversely related to those of basal FEV1 (102.1 % pred. +/- 8.2sd in N, 92.1 % pred +/- 14.6 sd in A, 71.6 % pred. +/- 15.5 sd in AIA/R, 70.6 % pred +/- 7.1 sd in AIA/P, respectively). Respiratory function in the two sub-groups of AIA patients proved reduced than in atopic asthmatics (p<0.001) and in normal controls (p < 0.001), even though the difference between these two subgroups of subjects did not reach the statistical significance. CONCLUSIONS: Cys-LTs confirm their relevant pathogenetic role in AIA, but also in early stages of atopic asthma. Urinary LTE4 exexcretion proves directly proportional to the extent of nasal structural changes occurring in ASA-intolerant asthmatics, being subjects with nasal polyps those with the highest LTE4 values, immediately followed by those with hypertrophic rhinitis. Routinary measurements of urinary LTE4 should be regarded as a sensitive indicator in monitoring the clinical evolution of nasal involvement in AIA.

Adult↗
PubMed2006

The therapeutic effects of inhaled long-acting beta2-adrenergics (LABA) and corticosteroids (ICS) are not affected by their inhalation sequence in moderate/persistent asthma.

UNLABELLED: Bronchial asthma is defined as "a chronic inflammatory disease of the airways involving many cells" and inhaled corticosteroids have therefore become the fundamental drugs for the long-term management of the disease. In moderate and severe persistent asthma the use of a long-acting bronchodilator is recommended in order to control symptoms and to enhance the efficacy of corticosteroids. Although not based on scientific evidence, it has been assumed that the, 2 adrenergic and the inhaled steroid should be administered in a strict inhalation sequence: the bronchodilatator first and then the steroid. The aim of the study was to assess the effects of this assumption experimentally, common indeed since long ago. MATERIALS AND METHODS: Twelve subjects with moderate-persistent asthma (7 males, aged 18-64, basal FEV1 = 65.59% pred. +/- 7.59 ds; reversibility = + 14.8% +/- 8.3 ds from baseline after Salbutamol 200mg), symptomatic despite the regular home treatment with Fluticasone p. 250mg bid and beta 2 short-acting prn for over 6 weeks, were initially treated with combined SM/FP 50/250mg bid from an unique Diskus" device, for 6 weeks. After this initial phase, the treatment continued according to a randomised, double-blind, cross-over design: all subjects received the same drugs, from two different Diskus" inhalers, and according to two different sequences of administration: 1) SM first and FP 20' later for 4 weeks, and then FP first and SM 20' later for a further 4 weeks; 2) vice versa. No wash-out period was included between these two phases of cross-over treatment. FEV1 (% pred.); morning PEF (L/min), the use of short-acting beta 2 as required (n/week); the number of awakenings at night (n/week), and the daytime asthma symptom score were measured. STATISTICS: The t paired test and anova (Duncan test) were used for statistical comparisons: a p<0.05 was accepted as the minimum level of significance. RESULTS: After the first six weeks of treatment with combined Salmeterol/Fluticasone, 50/250 mg FEV1 changed from 69.6% pred. +/- 7.59 ds to 79.8% pred. +/- 10.1 ds (p>0.005), whilst the morning PEF changed from 282.2 l/min : 64.1 ds to 333.4 l/min +/- 55.5 ds (p<0.02). Furthermore, the consumption of beta 2 adrenergic prn dropped from 4.4 (no./week) +/- 7.3 ds to 1.2 +/- 0.9 ds (p<0.001); the number of night-time awakenings decreased from 1.6 (no./week) +/- 0.2 ds to 0.2 +/- 0.3 ds (p<0.001), and the daytime symptom score changed from 3.4 +/- ds 0.8 to 1.9 +/- 0.7 ds (p<0.001). This therapeutic performance was maintained over the two subsequent 4-week periods of treatment from two distinct devices independently of the inhalation sequence. In particular, by both using salmeterol first or using fluticasone first, the therapeutic effects proved quite identical: FEV1: 80.7 % pred. +/- 9.5 ds and 80.3 +/- 7.4 ds; morning PEF: 336.5 l/min +/- 55.4 ds and 338.6 l/min +/- 67.1 ds; consumption of beta 2 adrenergic as required: 0.9 (no./week) +/- 0.6 ds and 0.9 (no./week) +/- 0.8 ds; number of awakenings: 0.3 (no./week) +/- 0.3 and 0.2 (no./week) +/- 0.3 ds; day-time/night-time symptom score: 1.7 +/- 0.5 ds and 1.8 +/- 0.6 ds, respectively (anova = ns). CONCLUSIONS: Both in terms of lung function and of clinical outcomes the efficacy of SM and FP administration proved completely independent of the particular sequence for their separate inhalation and quite superimposable to thatachieved b y their combined inhalation from an unique device.

Administration, Inhalation↗
PubMed2004

Montelukast 10 mg improves nasal function and nasal response to aspirin in ASA-sensitive asthmatics: a controlled study vs placebo.

UNLABELLED: Aspirin-induced asthma (AIA) is a clinical syndrome characterized by acute airway reaction to aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDS). The most recent etiological hypothesises is that an overexpression of the enzyme LTC(4) synthase occurs in AIA, with the consequent production of sulfidopeptide leukotrienes (LTs). AIM: Aim of the present study was to assess the effect of Montelukast, a selective cys-LT receptor antagonist, on nasal function, nasal reactivity to ASA and blood markers of eosinophilic inflammation in mild-to-moderate AIA. MATERIAL AND METHOD: Thirty-six nonsmoker subjects with AIA (17 males, 22-52 years) performed a nasal provocation test (NPT) with lysine-aspirin (L-ASA) in baseline and after a 4-week Montelukast 10 mg or placebo treatment. Nasal function was assessed by the acoustic rhinomanometry, and they also performed a lung function test (forced expiratory volume in 1 s), and a blood sample for the eosinophil count and the eosinophil cationic protein (ECP) plasma measurements. After both treatments, all subjects repeated the NPT, the lung function, and the ECP and the eosinophil blood count. STATISTICAL ANALYSIS: t-Test was used to compare mean values +/- SD between groups, and P < 0.05 was assumed as the level for statistical significance. RESULTS: Airway patency was never affected by the NPT with L-ASA. In baseline, NPT with L-ASA precipitated a nasal reaction in all subjects, with a substantial increase in nasal resistance (calculated resistance [REQ]; from 0.89 +/- 0.18 to 2.2 +/- 0.17 cmH(2)O/l/min in group M, P < 0.001; and from 0.91 +/- 0.48 to 2.3 +/- 0.21 cmH(2)O/l/min in group P, P < 0.001); and a significant reduction in total nasal volume in at least one nostril (volume [VOL]; from 11.1 +/- 3.2 to 8.1 +/- 4.1 cm(3) in the group M, P < 0.001, and from 12.3 +/- 4.1 to 7.9 +/- 4.5 cm(3) in the group P, P < 0.001). The nasal reaction to L-ASA remained unchanged following placebo, but it was completely minimized following a 4-week treatment with Montelukast. Also nasal function, the nasal symptom score, and the markers of eosinophilic inflammation proved significantly affected and improved by the active drug only. CONCLUSIONS: Montelukast 10 mg daily for 4 weeks, but not placebo, improves nasal function and nasal response to Aspirin substantially in ASA-sensitive asthmatics.

Acetates↗
PubMed2003

Assessment of inhaled BDP-dose dependency of exhaled nitric oxide and local and serum eosinophilic markers in steroids-naive nonatopic asthmatics.

The aim of the present study was to assess the dose-dependency from inhaled steroids of changes of airways inflammation [eosinophils count and eosinophil cationic protein (ECP)] measures in induced sputum and in serum, as well as that of exhaled nitric oxide. Twenty steroid-naive patients with nonatopic asthma of mild to moderate degree [forced expiratory volume in 1 s (FEV1) = 70% of predicted] and with negative response to the standard tests for allergy were selected; after a 1-week run-in period they were randomized to receive a 12-week treatment period of inhaled beclomethasone dipropionate dry powder given with the Pulvinal inhaler (Clenil P, Chiesi Farmaceutici S.p.A., Parma, Italy) in two different dose regimens, 400 microg bid (high dose) or 200 microg bid (low dose), over a double blind, parallel groups design. The following outcome measures were assessed in baseline and after 1, 6 and 12 weeks of treatment: FEV1 (l), eosinophils count in sputum (%), is ECP (microg/l), serum eosinophils count (%), serum ECP (microg/l) and exhaled NO (ppb). The results showed that all the considered parameters improved in both groups: the increase over baseline of FEV1 and the decrease of NO were significant at any time in the high-dose group and only at week 12 in the low-dose group (NS between groups), whereas the markers of eosinophilic activity showed more consistent reductions in the high-dose than in the low-dose group when measured in induced sputum (P < 0.05 between groups after 6 and 12 weeks for eosinophils count and after 12 weeks for ECP). Decreases over baseline of markers measured in serum were more rapid in the high-dose group, without differences between groups. A marked trend towards a negative correlation was found between FEV1 and ECP, (r = -0.72, P < 0.05), between FEV1 and eosinophils in sputum (r = -0.31, NS) and between FEV1 and exhaled NO (r = -0.38, NS), all of them only in the high-dose group. The results of the study demonstrate that changes of levels of eosinophilic activity in the airways are dependent from the daily dose of inhaled steroids when measured in induced sputum and that the local assessment can therefore represent a practical and noninvasive method to monitor the extent of airways inflammation.

Administration, Inhalation↗
PubMed2002

Cost-of-illness of lung disease in the TriVeneto Region, Italy: the GOLD Study.

Lung diseases imply a high consumption of healthcare resources representing a burden for patients and their families as well as for the society. The aim of the Global Outcomes in Lung Diseases (GOLD) study was to perform a cost-of-illness analysis of three pathologies affecting the lower respiratory tract: community-acquired pneumonia (CAP), chronic obstructive pulmonary disease (COPD) and bronchial asthma (BA). This observational study was conducted in a large region of northeast Italy, Triveneto, between 1999 and 2000. Patients of both sexes and aged > or = 14 years, were randomly selected from 28 identified centres of pneumology; patients were considered eligible if they had been visited at least twice at the centre during the observational period. Study periods were different for the three pathologies: for BA and COPD the recruitment period lasted 8 weeks and the follow-up period 12 months; for CAP, given the acute nature of the disease, two recruitment periods (May and November) were identified with a follow-up lasting 6 months. After collecting information for each patient (age, sex, risk factors, severity of the disease, occupation), data were recorded by each centre in a dedicated software program and then sent to a central database where final results were analysed. Cost-of-illness analysis was conducted within the framework of the National Healthcare System (NHS). Consumption of medical resources used during the follow-up period was valued according to market prices and published official tariffs. A total number of 1068 patients (596 men and 458 women) were selected: 42.5% were affected by BA, 46.3% by COPD, and 11.2% by CAP. Mean cost per patient/year for patients affected by BA and COPD ranged from Euro 608 to 2457 and from Euro 1500 to 3912, respectively, depending on illness severity. Mean cost per episode of CAP was Euro 1586. This study confirms the findings of other studies published in the international literature, demonstrating that asthma and COPD are often misdiagnosed and mistreated and so their management, especially for the most severe patients, becomes complex and highly expensive. The use of preventive, specialised care could help in achieving early diagnosis and treatment of these patients.

Aged↗
PubMed2001

Evidence of adequacy of the performance of the Pulvinal by measuring through-device peak inspiratory flow rate in severe airways obstruction in adults and children.

Pulvinal is a novel DPI designed to deliver inhaled drugs to the airways. Previous in vitro and in vivo data has suggested that the peak inspiratory flow rate (PIFR), measured through Pulvinal, does not depend on the severity of expiratory airflow obstruction and that the lowest PIFR values seem sufficient to deliver an effective bronchodilator dose. To study this further, we have investigated through-Pulvinal PIFR in categories of patients who are likly to generate low inspiratory flow rates. Three different patients' groups were selected (severe asthmatics, n = 52, including elderly) patients with severe chronic obstructive pulmonary disease (COPD, n = 21) and children with asthma (n = 16). This study aimed to measure the through-device PIFR and also to assess whether this correlated with measures of expiratory flow rate. Inspiratory flow measurements were made with a Pulvinal inhaler inserted into the adapted mouthpiece of a pneumotochograph. No significant correlations were seen between through-device PIFR and expiratory volumes or flow rates when expressed as percent predicted normal (forced expiratory volume in 1 sec [FEV1] and peak expiratory flow rate [PEFR]) in any of the three studied populations. A significant correlation was present for FEV1 (when expressed in liters) and through-device PIFR in the adult asthmatic and COPD study groups. In spite of the disease severity in adult populations and the age of children, the lowest generated PIFR values were within the range producing adequate performance of Pulvinal DPI (>20 L/min). We conclude that inspiratory flow rates generated through the Pulvinal inhaler can be adequate in asthma and COPD, including patients at the extremes of severity and age, who may theoretically have a limitation in their inspiratory flow.

Adolescent↗
PubMed1999

A novel charged trinuclear platinum complex effective against cisplatin-resistant tumours: hypersensitivity of p53-mutant human tumour xenografts.

Multinuclear platinum compounds were rationally designed to bind to DNA in a different manner from that of cisplatin and its mononuclear analogues. A triplatinum compound of the series (BBR 3464) was selected for preclinical development, since, in spite of its charged nature, it was very potent as cytotoxic agent and effective against cisplatin-resistant tumour cells. Anti-tumour efficacy studies were performed in a panel of human tumour xenografts refractory or poorly responsive to cisplatin. The novel platinum compound exhibited efficacy in all tested tumours and an impressive efficacy (including complete tumour regressions) was displayed in two lung carcinoma models, CaLu-3 and POCS. Surprisingly, BBR 3464 showed a superior activity against p53-mutant tumours as compared to those carrying the wild-type gene. The involvement of p53 in tumour response was investigated in an osteosarcoma cell line, SAOS, which is null for p53 and is highly sensitive to BBR 3464, and in the same cells following introduction of the wild-type p53 gene. Thus the pattern of cellular response was investigated in a panel of human tumour cells with a different p53 gene status. The results showed that the transfer of functional p53 resulted in a marked (tenfold) reduction of cellular chemosensitivity to the multinuclear platinum complex but in a moderate sensitization to cisplatin. In addition, in contrast to cisplatin, the triplatinum complex was very effective as an inducer of apoptosis in a lung carcinoma cell line carrying mutant p53. The peculiar pattern of anti-tumour activity of the triplatinum complex and its ability to induce p53-independent cell death may have relevant pharmacological implications, since p53, a critical protein involved in DNA repair and induction of apoptosis by conventional DNA-damaging agents, is defective in several human tumours. We suggest that the peculiar DNA binding properties of the triplatinum complex may contribute to the striking profile of anti-tumour efficacy. Taken together, the available information supports that anti-tumour activity of the novel compound is mediated by a mechanism different from that of conventional platinum complexes, and compounds of this series could represent a new class of promising anti-tumour agents.

Animals↗
PubMed1996

Antitussive activity of moguisteine enantiomers in guinea-pigs and rats.

The antitussive effect of the R-(+)- and S-(-)-enantiomers of moguisteine were evaluated in comparison with the racemate in cough induced by 7.5% citric acid and 30 microM capsaicin aerosol in conscious guinea-pigs. No difference in potency was observed between moguisteine and the enantiomers. The oral ED50 values (with 95% confidence limits) for moguisteine, R-(+)- and S-(-)-enantiomers were respectively: 20.4 (12.9-26.6), 20.9 (14.9-26) and 21.6 (11.8-30.0) mg/kg-1 in cough provoked by citric acid and 17.7 (12.5-29.8), 18.9 (14.1-30.1) and 20.5 (15.1-36.6) mg/kg-1 in cough induced by capsaicin. The acute oral and intraperitoneal toxicities of the enantiomers and moguisteine in the rat are very similar. These findings suggest that the use of either enantiomer does not offer any advantage over the racemate.

Administration, Oral↗
PubMed1996

Effects of moguisteine, a peripheral nonnarcotic antitussive agent, on airway inflammation in guinea-pigs in vivo.

Cough is a common symptom of respiratory diseases associated with irritation or inflammation of the airways, and symptomatic antitussive drugs are frequently prescribed to control an abnormal cough reflex. Our aim was to evaluate the effects of moguisteine, a novel, peripheral, nonnarcotic antitussive agent, on airway inflammation induced in guinea-pigs with a variety of stimuli. These stimuli included exposure to tobacco smoke for 10 min, to elicit airway hyperreactivity, eosinophil recruitment in bronchoalveolar lavage (BAL), airway epithelial damage and plasma exudation; graded platelet-activating factor (PAF) infusion (600 ng.kg-1 over one h), to induce airway hyperreactivity; 2% ovalbumin (OA) aerosol challenge in 1% OA-sensitized animals, to induce late-phase (17 and 72 h) airway leucocyte accumulation. We also assessed the activity of moguisteine on plasma leakage induced by capsaicin, on bronchoconstriction induced by acetylcholine (ACh), histamine (H) and PAF, and on leukotriene mediated allergic bronchospasm in OA-sensitized guinea-pig. Moguisteine (p.o. and i.m.) and dexamethasone (p.o. and i.m.) dose-dependently reduced tobacco smoke-induced bronchial hyperreactivity. Moguisteine and dexamethasone abolished eosinophil recruitment in BAL, prevented the sloughing of the epithelium and significantly reduced airway microvascular leakage. Both agents were also highly effective in reducing bronchial hyperreactivity elicited by PAF infusion. In addition, moguisteine was active in inhibiting airway neutrophil and eosinophil accumulation in BAL observed 17 and 72 h after OA challenge in sensitized guinea-pigs. In contrast to dexamethasone, moguisteine did not prevent capsaicin-induced plasma leakage. It was also ineffective against bronchoconstriction as induced by ACh, H, and PAF and failed to inhibit leukotriene-dependent bronchospasm. Our data suggest that moguisteine represents an antitussive compound endowed with interesting airway anti-inflammatory properties in guinea-pigs in vivo. Its mechanism of action remains to be elucidated.

Acetylcholine↗
PubMed1995

Characterization of cisplatin-glutathione adducts by liquid chromatography-mass spectrometry. Evidence for their formation in vitro but not in vivo after concomitant administration of cisplatin and glutathione to rats anc cancer patients.

After incubation of equimolar amounts of cisplatin (CDDP) and glutathione (GSH) in phosphate buffer pH 7.4 at 37 degrees C, we detected two CDDP-GSH adducts whose structures, characterized by LC-MS, corresponded to cis-[Pt(NH3)2Cl(SG)] and cis-([Pt(NH3)2Cl]2(mu-SG))+. The latter is a new CDDP-GSH adduct, which was postulated but never structurally characterized so far. Rats and patients were given a 15-min intravenous infusion of CDDP (10 mg/kg to rats and 25 mg/m2 to patients) preceded by a GSH intravenous administration (200 mg/kg to rats as a bolus and 1.5 g/m2 to patients as a 15-min infusion). After the administrations, CDDP-GSH adducts were absent in rat and human plasma ultrafiltrates. The discrepancy between in vitro and in vivo findings can be explained based on pharmacokinetic considerations.

Animals↗
PubMed1995

N-acyl-2-substituted-1,3-thiazolidines, a new class of non-narcotic antitussive agents: studies leading to the discovery of ethyl 2-[(2-methoxyphenoxy)methyl]-beta-oxothiazolidine-3-propanoate.

The synthesis of a novel class of antitussive agents is described. The compounds were examined for antitussive activity in guinea pig after cough induction by electrical or chemical stimulation. Ethyl 2-[(2-methoxyphenoxy)methyl]-beta-oxothiazolidine-3-propanoate (BBR 2173, moguisteine, 7) and other structurally related compounds showed a significant level of activity, comparable to that of codeine and dextromethorphan. The compounds presented in this paper are characterized by the N-acyl-2-substituted-1,3-thiazolidine moiety, which is a novel entry in the field of antitussive agents. The serendipitous discovery of the role played by the thiazolidine moiety in determining the antitussive effect promoted extensive investigations on these structures. This optimization process on N-acyl-2-substituted-1,3-thiazolidines led to the initial identification of 2-[(2-methoxypheoxy)methyl]-3-[2-(acetylthio)acetyl]- 1,3-thiazolidine (18a) as an interesting lead compound. The careful study of the rapid and very complicated metabolism of 18a provided further insights for the design of newer related derivatives. The observation that the metabolic oxidation on the lateral chain's sulfur of 18a to sulfoxide maintained the antitussive properties suggested the introduction of isosteric functional groups with respect to the sulfoxide moiety. Subsequent structural modifications showed that hydrolyzable malonic residues in the 3-position of the thiazolidine ring were able to assure high antitussive activity. This optimization ultimately led to the selection of moguisteine (7) as the most effective and safest representative of the series. Moguisteine is completely devoid of unwanted side effects (such as sedation and addiction), and its activity was demonstrated also in clinical studies.

Animals↗
PubMed1994

Intrapleural administration of interleukin-2 and LAK cells in locally advanced non-small-cell lung cancer. A case report.

AIMS AND BACKGROUND: The systemic administration of recombinant interleukin-2 (rIL-2) and lymphokine-activated killer (LAK) cells is ineffective in non-small-cell lung cancer (NSCLC). However, there is some evidence that their intrapleural administration could be effective, since it increases the concentrations of the cytokine and the effector cells in the tumor area, thereby obtaining greater antitumor activity. STUDY DESIGN: We report the case of a patient affected by a locally advanced lung adenocarcinoma with pleural effusion (T4 N0 M0-stage IIIb) treated with repetitive courses consisting of a priming continuous i.v. infusion (48 h) of rIL-2 (18 MIU/m2/day) intraplural administration of LAK cells (3-9 x 10(9)/day), in a single daily bolus, for 3 consecutive days and concomitant administration of rIL-2 (1.8-7.2 x 10(6) IU/day), for 5 days. RESULTS: We observed early disappearance of neoplastic cells in the pleural effusion, progressive decrease until disappearance of the pleural effusion, cavitation of the primary lesion during the treatment, and its stabilization for 9 months until progression. Radiologic changes were accompanied by a marked eosinophilia (up to 50 x 10(9)/L), and the intrapleural route of administration of rIL-2 induced a relevant increase in eosinophil count in peripheral blood. Immunologic changes in lymphocyte subpopulation phenotypes were also observed. The performance status of the patient improved, and she was still alive and eupnoic 25 months from the diagnosis and 23 months from the start of treatment. CONCLUSIONS: This case suggests a therapeutic role for intrapleural rIL-2, and we believe that the relationship among intrapleural administration of rIL-2 and LAK cells, the development of peripheral eosinophilia, and clinical response should be further investigated.

Carcinoma, Non-Small-Cell Lung↗
PubMed1994

Treatment of advanced renal cell cancer with sequential intravenous recombinant interleukin-2 and subcutaneous alpha-interferon.

Starting from in vitro studies suggesting synergistic antitumour activity against renal cell cancer (RCC) of recombinant interleukin-2 (rIL-2) and alpha-interferon (IFN), a phase II trial was initiated to test the clinical activity of this combination. The two cytokines were administered sequentially, with the aim of reducing the risk of additive toxicity and enhancing the immunological reaction against the tumour. The original treatment schedule consisted of rIL-2 18 x 10(6) U/m2/day by continuous intravenous infusion for 120 h days 1-5, and alpha-IFN 2b, at a flat dose of 9 x 10(6) U by subcutaneous or intramuscular injection thrice in a week, from day 8 to 28. Treatment was planned to be continued for six or more 28-day cycles, depending on clinical response. 12 patients were treated according to this schedule; as some cardiovascular toxicity was experienced in this set of patients, 11 further patients were treated with half-dose rIL-2 (i.e. 9 x 10(6) U/m2/day). 17 out of 23 enrolled patients completed at least one cycle of treatment and were evaluated for response. We observed six major responses [one complete response (CR) + five partial responses (PR)] for an objective response rate of 35% [95% confidence interval (CI) 17-59%]. 5 additional patients achieved stabilisation of disease; one of them reached CR after surgical extirpation of a lung mass. Sites of response included lung, nodes and bone. Duration of response is 12+ months for CR; 17, 16, 12+, 9 and 9 months for PRs. Median survival is 16 months. Response was not significantly different between full-dose and half-dose rIL-2. Considering stable disease (SD) as responses, there seemed to be a higher chance of response for patients with smaller tumour burden (P = 0.032). The toxicity of rIL-2 treatment, mainly cardiovascular, was substantial; 9 patients experienced severe cardiotoxicity, consisting of major arrhythmias, myocardial ischaemia, reduction of ejection fraction measured with heart radionuclide scan, and were excluded from continuing treatment. Other rIL-2-related toxicities forcing exclusion from the study were severe thrombocytopenia (1 case), and generalised exfoliative dermatitis requiring steroids (1 case). Otherwise, treatment was well tolerated; rIL-2-related toxicities promptly recovered after rIL-2 discontinuation in the majority of cases, and no treatment-related deaths were reported. The half-dose rIL-2 regimen was significantly less toxic in terms of hypotension (P = 0.014), fever (P = 0.014), oliguria (P = 0.042), serum creatinine elevation (P = 0.009) and prothrombin time elongation (P = 0.038).(ABSTRACT TRUNCATED AT 400 WORDS)

Adult↗
PubMed1994

Moguisteine: a novel peripheral non-narcotic antitussive drug.

1. The antitussive effects of moguisteine have been compared with codeine in several experimental models of cough in guinea-pigs and dogs. 2. Moguisteine and codeine dose-dependently (respective ED50 values are given in parentheses) inhibited cough induced in guinea-pigs by 7.5% citric acid aerosol (25.2 and 29.2 mg kg-1, p.o.), by 30 microM capsaicin aerosol (19.3 and 15.2 mg kg-1, p.o.), by mechanical stimulation (22.9 and 26.4 mg kg-1, p.o.) and by tracheal electrical stimulation (12.5 and 13.9 mg kg-1, p.o.). 3. Moguisteine was effective against cough induced by tracheal electrical stimulation in dogs (ED50 17.2 mg kg-1, p.o.); codeine was not tested because of its emetic effect. 4. After repeated dosing (12-15 days), moguisteine did not induce tolerance in either guinea-pigs or dogs. 5. Moguisteine did not interact with opiate receptors, since it did not show affinity for [3H]-naloxone binding sites and furthermore naloxone (5 mg kg-1, s.c.) did not antagonize its antitussive effects. 6. Moguisteine had no antitussive effect after i.c.v. administration (20 micrograms), whilst codeine (2-10 micrograms) and dextromethorphan (2.5-20 micrograms) were highly effective. 7. Our findings demonstrate that moguisteine is a novel peripherally acting non-narcotic antitussive agent, the mode of action of which remains to be elucidated fully.

Aerosols↗
PubMed1994

General toxicology of the new antitussive moguisteine.

Moguisteine (R,S(+/-)-2-(2-methoxyphenoxy)-methyl-3-ethoxycarbonylacetyl- 1,3-thiazolidine, CAS 119637-67-1), a new oral non-narcotic peripherally acting antitussive drug, was submitted to toxicological evaluation. The oral (gavage) and intraperitoneal routes in mice and rats and the oral route in rabbits produce very low acute toxicity. Administered by oral route, moguisteine proved to be well tolerated for 26 consecutive weeks and did not induce any general or local effect at up to the respective doses of 240 and 60 mg/kg/day for rats and dogs. In oral (dietary) carcinogenicity studies, moguisteine did not exhibit any carcinogenic effect in mice and rats treated for 87 and 104 weeks, respectively, at up to the dose of 600 mg/kg/day. These results are supported by the absence, both in vitro and in vivo, of mutagenic potential. Considering the overall results of the toxicological studies, it can be affirmed that moguisteine enjoys reliable tolerability, as also shown by a wide safety margin calculated on the basis of the animal and human exposures.

Animals↗