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71.
Bronchial hyperresponsiveness and quality of life in asthmatics 总被引:1,自引:0,他引:1
Riccioni G D'Orazio N Di Ilio C Della Vecchia R Ballone E Menna V Guagnano MT 《Respiration; international review of thoracic diseases》2003,70(5):496-499
BACKGROUND: Quality of Life (QoL) measurements are more responsive to clinically significant changes that are not evaluated by conventional clinical measures. OBJECTIVE: The objective of this study is to examine the relationship between bronchial hyperresponsiveness (BHR) and QoL in asthmatic patients. PATIENTS AND METHODS: 394 patients underwent clinical follow-up, pulmonary function tests and the methacholine challenge test (MCHt), and completed the Asthma Quality of Life Questionnaire (AQLQ). RESULTS: 200 patients had a positive MCHt and in 194 it was negative. For all 32 items, asthmatic patients had a median value of 4.7 (4.2-5.9) compared to 5.6 (4.7-6.3) in patients with negative MCHt (p < 0.01). For physical activities, patients with positive MCHt showed a median value of 5.0 (4.5-6.0) compared to 5.7 (4.8-6.3) in patients with negative MCHt (p < 0.05). Median scores of 12 items of symptoms and 5 items of emotions were significantly lower in patients with positive MCHt [4.5 (3.7-5.8) and 5.1 (4.2-6.1)] than in patients with negative MCHt [5.5 (4.4-6.1) and 6.3 (5.2-6.9), respectively, (p < 0.01)]. For items of environmental stimuli the median score was 4.7 (3.7-5.9) in patients with positive MCHt, being significantly lower than in patients with negative MCHt [5.4 (4.2-6.4), p < 0.05]. Patients with positive MCHt had lower values of QoL than patients with negative MCHt. CONCLUSIONS: QoL changes may be more sensitive than evaluation of BHR. The measurement of Qol may be important because it enables us to characterize patients who could be candidates eventually to a pharmacological treatment for BHR because they have an impaired QoL. 相似文献
72.
Antonio Lombardo Sergio Scavino Giovanni Scornavacca Giuseppe Oliva Costantino Sipione Rossella Cacciola Luciano Motta 《Acta diabetologica》1986,23(1):1-12
Summary The authors report data obtained from a 3-year study of CSII and humanized insulin (semi-synthetic human insulin) administered
to 18 insulin-dependent subjects in the outpatient clinic. The aim of this study was to evaluate the validity of insulin pumps
in long-term treatment. Metabolic parameters were significantly improved (p<0.001) in the first month and remained so with
only slight alterations throughout treatment. The authors underline some metabolic problems (ketosis) caused by malfunctioning
of the insulin pumps, by the difficulties with the infusion sytem or by nodular skin lesions at the infusion site. Only these
lesions called for treatment to be discontinued in 4 patients. The highest incidence of nodular skin lesions was seen after
one year’s uninterrupted treatment and they seem connected to the duration of treatment rather than to the patients’ negligence
(inadequate hygiene, delayed needle substitution). The authors conclude that CSII treatment is valid over short-term periods,
whereas it presents drawbacks over long-term administration. 相似文献
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Florenzo Iannone Elisa Gremese Gaia Gallo Piercarlo Sarzi-Puttini Costantino Botsios Francesco Trotta Stefania Gasperini Mauro Galeazzi Silvano Adami Fabrizio Cantini Marco Sebastiani Roberto Gorla Antonio Marchesoni AnnaRita Giardina Rosario Foti Angiola Mele Eleonora Bruschi Gianluca Bagnato Gian Luca Erre Giovanni Lapadula 《Clinical rheumatology》2014,33(1):31-37
The aim of this study was to evaluate the clinical outcomes of etanercept in rheumatoid arthritis (RA) patients with moderate or severe disease activity. We analyzed data from the Italian biologics register Gruppo Italiano Studio Early Arthritides (GISEA) to investigate the rate of disease remission and functional improvement, based on the 28-Joint Disease Activity Score (DAS28) and the (Health Assessment Questionnaire (HAQ) score in RA patients with moderate or severe disease activity beginning etanercept therapy. Disease was defined as severe (H-RA) with DAS28 ≥5.1 and moderate (M-RA) with DAS28 ≥3.2 to 5.1 at baseline. Patients were considered in remission if DAS28 was ≤2.6, and HAQ ≤0.5 defined normal function. We enrolled 953 RA patients, 320 with M-RA and 633 H-RA. Age and disease duration were similar in the two cohorts, but H-RA patients had significantly more comorbidities (p?<?0.01) and took significantly more disease-modifying antirheumatic drugs (p?<?0.001) than M-RA patients. After 1 year, the percentage of patients achieving disease remission and normal function (DAS28 ≤2.6 plus HAQ ≤0.5) was higher in M-RA (21.4 %) than in H-RA patients (14.8 %, p?=?0.007), regardless of the disease duration. Additionally, female gender (p?=?0.006) and H-RA class (p?=?0.002) negatively predicted disease remission at 1 year. However, the drug survival rate did not differ between the two subsets. This study confirms that etanercept was effective in the treatment of active RA, but best response, in terms of disease remission and normal function ability, was greater and easier to attain in M-RA patients. These findings may aid clinicians to choose the best strategy to treat RA. 相似文献
76.
Alessio Moriconi Thiago M. Cunha Guilherme R. Souza Alexandre H. Lopes Fernando Q. Cunha Victor L. Carneiro Larissa G. Pinto Laura Brandolini Andrea Aramini Cinzia Bizzarri Gianluca Bianchini Andrea R. Beccari Marco Fanton Agostino Bruno Gabriele Costantino Riccardo Bertini Emanuela Galliera Massimo Locati Sérgio H. Ferreira Mauro M. Teixeira Marcello Allegretti 《Proceedings of the National Academy of Sciences of the United States of America》2014,111(47):16937-16942
Chronic pain resulting from inflammatory and neuropathic disorders causes considerable economic and social burden. Pharmacological therapies currently available for certain types of pain are only partially effective and may cause severe adverse side effects. The C5a anaphylatoxin acting on its cognate G protein-coupled receptor (GPCR), C5aR, is a potent pronociceptive mediator in several models of inflammatory and neuropathic pain. Although there has long been interest in the identification of C5aR inhibitors, their development has been complicated, as for many peptidomimetic drugs, mostly by poor drug-like properties. Herein, we report the de novo design of a potent and selective C5aR noncompetitive allosteric inhibitor, DF2593A, guided by the hypothesis that an allosteric site, the “minor pocket,” previously characterized in CXC chemokine receptors-1 and -2, is functionally conserved in the GPCR class. In vitro, DF2593A potently inhibited C5a-induced migration of human and rodent neutrophils. In vivo, oral administration of DF2593A effectively reduced mechanical hyperalgesia in several models of acute and chronic inflammatory and neuropathic pain, without any apparent side effects. Mechanical hyperalgesia after spared nerve injury was also reduced in C5aR−/− mice compared with WT mice. Furthermore, treatment of C5aR−/− mice with DF2593A did not produce any further antinociceptive effect compared with C5aR−/− mice treated with vehicle. The successful medicinal chemistry strategy confirms that a conserved minor pocket is amenable for the rational design of selective inhibitors and the pharmacological results support that the allosteric blockade of the C5aR represents a highly promising therapeutic approach to control chronic inflammatory and neuropathic pain.Inflammatory and neuropathic pain are the most prevalent types of pathological pain and represent important health problems. Whereas inflammatory pain is one of the classic symptoms of the inflammatory process, neuropathic pain arises from any of multiple nerve lesions or diseases, with symptoms including hyperalgesia or allodynia (1, 2). Some of the most powerful painkillers, including opioids and nonsteroidal anti-inflammatory drugs, are only partially effective and prolonged exposure can cause unwanted effects (3, 4). As a result, there is continuous effort to identify novel therapeutics for pain control with alternative biological mechanisms and that elicit fewer side effects.Inflammatory mediators, including cytokines/chemokines, play a critical role in the pathogenesis of inflammatory and neuropathic pain (5, 6). Emerging evidences suggest that C5a, the anaphylatoxin produced by complement activation, has potent nociceptive activity in several models of inflammatory and neuropathic pain by interacting with its selective receptor C5aR (7, 8). C5aR belongs to the class A subfamily of the seven-transmembrane (TM) G protein-coupled receptors (GPCR) (9) and is widely expressed in immune cells, including neutrophils (polymorphonuclear cells, PMN), monocytes, microglia, and in nonimmune cells, including neurons in the CNS and dorsal root ganglia (10, 11).Evidence for a role of C5a in nociception sensitization has been obtained in several models of inflammatory pain. For example, C5a was produced at the inflammatory sites and elicited mechanical hyperalgesia by activating the C5aR on infiltrated PMN (7). Direct intraplantar injection of C5a in mice elicited both heat and mechanical hyperalgesia by sensitizing primary afferent C-nociceptors (12, 13). Local activation of C5aR has been also implicated in the pathogenesis of postsurgical pain, a model of postoperative pain (13). Finally, local administration of PMX-53, a C5aR antagonist, attenuated mechanical hyperalgesia induced by carrageenan, zymosan, or lipopolysaccharide (7). In addition to the peripheral role of C5a/C5aR in inflammatory pain, up-regulated levels of C5 and C5aR have been found in spinal cord microglia in animals subjected to spared nerve injury (SNI), a model of neuropathic pain (8). Indeed, C5-null mice or the infusion of PMX-53 into the intrathecal space reduced neuropathic pain hypersensitivity in the SNI model (8). Collectively, these data suggest that a neuroimmune interaction in the periphery and spinal cord through activation of the complement cascade and the production of C5a contributes to the genesis of both inflammatory and neuropathic pain.As for other peptidergic GPCRs, the efforts to identify small molecular weight C5aR antagonists have led to a limited number of molecules, mostly lacking adequate potency and selectivity (14). The most promising candidate so far described, PMX-53, is a cyclic peptidomimetic antagonist designed to mimic the C-terminal portion of C5a (15). Despite the encouraging results obtained in preclinical studies, as for many peptide drugs, the development of PMX-53 has been limited by its short half-life and unfavorable bioavailability (16). In the present study, we report the successful design of a nonpeptidic C5a allosteric small molecular weight inhibitor driven by the structural information on a minor pocket spanning between TM1, -2, -3, -6, and -7 that is highly conserved across the GPCR family and that has been recently proposed as a key motif for the intracellular activation process. Reparixin was previously reported as a neutral allosteric inhibitor of CXCR1 and CXCR2 that binds the TM in a region that overlaps the minor pocket (17, 18). Combining the information from independent sources on structural and functional features of allosteric sites in homologous chemokine receptors, this paper intends to provide what is, to our knowledge, the first example of de novo design of a new class of allosteric small molecular weight inhibitors of a GPCR not belonging to the chemokine receptor family, C5aR. The preclinical candidate, DF2593A, is a potent and orally active C5a noncompetitive allosteric inhibitor with significant antinociceptive effects in a wide range of inflammatory and neuropathic pain models. 相似文献
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