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61.
Armin Hatzelmann Esteban J. Morcillo Giuseppe Lungarella Serge Adnot Shahin Sanjar Rolf Beume Christian Schudt Hermann Tenor 《Pulmonary pharmacology & therapeutics》2010,23(4):235-256
After more than two decades of research into phosphodiesterase 4 (PDE4) inhibitors, roflumilast (3-cyclopropylmethoxy-4-difluoromethoxy-N-[3,5-di-chloropyrid-4-yl]-benzamide) may become the first agent in this class to be approved for patient treatment worldwide. Within the PDE family of 11 known isoenzymes, roflumilast is selective for PDE4, showing balanced selectivity for subtypes A–D, and is of high subnanomolar potency. The active principle of roflumilast in man is its dichloropyridyl N-oxide metabolite, which has similar potency as a PDE4 inhibitor as the parent compound. The long half-life and high potency of this metabolite allows for once-daily, oral administration of a single, 500-μg tablet of roflumilast.The molecular mode of action of roflumilast – PDE4 inhibition and subsequent enhancement of cAMP levels – is well established. To further understand its functional mode of action in chronic obstructive pulmonary disease (COPD), for which roflumilast is being developed, a series of in vitro and in vivo preclinical studies has been performed.COPD is a progressive, devastating condition of the lung associated with an abnormal inflammatory response to noxious particles and gases, particularly tobacco smoke. In addition, according to the Global Initiative for Chronic Obstructive Lung Disease (GOLD), significant extrapulmonary effects, including comorbidities, may add to the severity of the disease in individual patients, and which may be addressed preferentially by orally administered remedies. COPD shows an increasing prevalence and mortality, and its treatment remains a high, unmet medical need.In vivo, roflumilast mitigates key COPD-related disease mechanisms such as tobacco smoke-induced lung inflammation, mucociliary malfunction, lung fibrotic and emphysematous remodelling, oxidative stress, pulmonary vascular remodelling and pulmonary hypertension. In vitro, roflumilast N-oxide has been demonstrated to affect the functions of many cell types, including neutrophils, monocytes/macrophages, CD4+ and CD8+ T-cells, endothelial cells, epithelial cells, smooth muscle cells and fibroblasts. These cellular effects are thought to be responsible for the beneficial effects of roflumilast on the disease mechanisms of COPD, which translate into reduced exacerbations and improved lung function. As a multicomponent disease, COPD requires a broad therapeutic approach that might be achieved by PDE4 inhibition. However, as a PDE4 inhibitor, roflumilast is not a direct bronchodilator.In summary, roflumilast may be the first-in-class PDE4 inhibitor for COPD therapy. In addition to being a non-steroid, anti-inflammatory drug designed to target pulmonary inflammation, the preclinical pharmacology described in this review points to a broad functional mode of action of roflumilast that putatively addresses additional COPD mechanisms. This enables roflumilast to offer effective, oral maintenance treatment for COPD, with an acceptable tolerability profile and the potential to favourably affect the extrapulmonary effects of the disease. 相似文献
62.
A O Hopper L K Kwong D K Stevenson S M Shahin A D'Harlingue K K Tsuboi R L Ariagno 《The Journal of pediatrics》1983,102(3):415-418
We designed an in vitro assay to detect the presence of lactose in the tracheal aspirates of premature, ventilator-dependent infants. This method was employed to identify recurrent, unrecognized aspiration, which could prolong the requirements for ventilator support and contribute to the development of chronic lung disease. One hundred five determinations of lactose were performed on the tracheal fluid obtained from 42 ventilator-dependent infants who were receiving enteral feedings. There was a wide range of lactose levels (0 to 3,270 nmol lactose/ml tracheal aspirate). Six infants had samples that were highly suggestive of aspiration (greater than 200 nmol lactose/ml tracheal aspirate). Twenty infants had questionably positive samples (25 to 200 nmol lactose/ml tracheal aspirate), and 16 infants had samples that were considered negative for aspiration (less than 25 nmol lactose/ml tracheal aspirate). 相似文献
63.
A phase I/II trial of rAd/p53 (SCH 58500) gene replacement in recurrent ovarian cancer 总被引:4,自引:0,他引:4
Buller RE Runnebaum IB Karlan BY Horowitz JA Shahin M Buekers T Petrauskas S Kreienberg R Slamon D Pegram M 《Cancer gene therapy》2002,9(7):553-566
PURPOSE: To determine the safety, gene transfer, host immune response, and pharmacokinetics of a replication-deficient adenovirus encoding human, recombinant, wild-type p53 (SCH 58500) delivered into the peritoneal cavity (i.p.) alone and sequentially in combination with platinum-based chemotherapy, of patients with recurrent ovarian, primary peritoneal, or fallopian tube cancer containing aberrant or mutant p53. METHODS: SCH 58500 was administered i.p. to three groups of patients with heavily pretreated recurrent disease. Group 1 (n=17) received a single dose of SCH 58500 escalated from 7.5 x 10(10) to 7.5 x 10(12) particles. Group 2 (n=9) received two or three doses of SCH 58500 given alone for one cycle, and then with chemotherapy for two cycles. The SCH 58500 dose was further escalated to 2.5 x 10(13) particles/dose in group 2. A third group (n=15) received a 5-day regimen of SCH 58500 given at 7.5 x 10(13) particles/dose per day i.p. alone for cycle 1 and then with intravenous carboplatin/paclitaxel chemotherapy for cycles 2 and 3. RESULTS: No dose-limiting toxicity resulted from the delivery of 236/287 (82.2%) planned doses of SCH 58500. Fever, hypotension abdominal complaints, nausea, and vomiting were the most common adverse events. Vector-specific transgene expression in tumor was documented by RT-PCR in cells from both ascitic fluid and tissue biopsies. Despite marked increases in serum adenoviral antibody titers, transgene expression was measurable in 17 of 20 samples obtained after two or three cycles of SCH 58500. Vector was detectable in peritoneal fluid by 24 hours and persisted for as long as 7 days whereas none was detected in urine or stool. There was poor correlation between CT scans and CA125 responses. CA125 responses, defined as a greater than 50% decrement in serum CA125 from baseline, were documented in 8 of 16 women who completed three cycles of the multidose regimen. CONCLUSION: CT scans are not a valid measure of response to i.p. SCH 58500 due to extensive adenoviral-induced inflammatory changes. Intraperitoneal SCH 58500 is safe, well tolerated, and combined with platinum-based chemotherapy can be associated with a significant reduction of serum CA125 in heavily pretreated patients with recurrent ovarian, primary peritoneal, or fallopian tube cancer. 相似文献
64.
Régnauld K Nguyen QD Vakaet L Bruyneel E Launay JM Endo T Mareel M Gespach C Emami S 《Oncogene》2002,21(25):4020-4031
The heterotrimeric G-protein subunits Galpha and Gbetagamma are involved in cellular transformation and tumor development. Here, we report the expression of Galpha(olf) in human digestive and urogenital epithelial cells using RT-PCR and Western blot. When the constitutively activated form of Galpha(olf)Q214L (AGalpha(olf)) was stably transfected in canine kidney MDCKts.src and human colonic HCT-8/S11 epithelial cells, it induced cellular invasion in collagen gels. AGalpha(olf)-mediated invasion was abrogated by agonists of platelet activating factor receptors (PAF-R) and protease-activated receptors -1 (PAR-1), pharmacological inhibitors of PI3'-Kinase (wortmannin), protein kinase C (G?6976 and GF109203X), Rho GTPase (C3T exoenzyme), but was independent of protein kinase A. Accordingly, the invasive phenotype induced by AGalpha(olf) in HCT-8/S11 cells was reversed by the RhoA antagonist RhoD (G26V). Although AGalpha(olf) protected MDCKts.src cells against serum starvation-mediated apoptosis via a Rho-independent pathway, both AGalpha(olf) and Rho inhibition by C3T induced neuroendocrine-like differentiation linked to extensive neurite outgrowth and parathyroid hormone-related protein expression in human prostatic LNCaP-AGalpha(olf) cells. Since prostate tumors with a larger neuroendocrine cell population display increased invasiveness, persistent activation of the G-protein alpha(olf) may exert convergent adverse effects on cellular invasion and survival in solid tumors during the neoplastic progression towards metastasis. doi:10.1038/sj.onc.1205498 相似文献
65.
Scott Wadler Kenji Tai L. Rao Chervu Shahin Rafii Leon Landau M. Donald Blaufox Peter H. Wiernik 《European journal of nuclear medicine and molecular imaging》1989,15(2):108-110
There is a well documented relationship between small cell carcinoma of the lung and the amine precursor uptake and decarboxylation system of endocrine cells (APUD). We attempted to exploit this association by employing the unique radiopharmaceutical,131I-MIBG, which is recognized and taken up by the APUD system to monitor disease activity in patients with small cell carcinoma of the lung. A total of eight patients with biopsy proven, metastatic small cell carcinoma of the lung were studied.131I-MIBG was synthesized in our laboratory by reacting metaiodobenzylamine synthesized in our laboratory by reacting metaiodobenzylamine hydrochloride with cyanamide with subsequent solid phase radioiodination. A dose of 0.5 mCi radiopharmaceutical was injected and images obtained on a large field of view gamma camera with a high energy parallel hole collimator at 2, 24, and either 48 or 72 h. Images were compared with known focal areas of metastatic disease demonstrable on computed tomographic scan, chest roentgenogram or bone scan. We were unable to detect reproducible correlations between the images produced by conventional radiographic techniques and the images produced by our radiopharmaceutical. We conclude that this agent will probably not be useful for localization of metastatic small cell lung carcinoma.This work was supported by a Pilot Research Grant from the Education and Research Foundation of the Society of Nuclear Medicine 相似文献
66.
Summary The authors report their experience of isotope cisternography and ventriculography with I131 or Tc99m labelled albumin. Eighty-nine patients with different neurosurgical diseases responsible for alterations of the C.S.F. circulation and absorption were studied during a twenty months' period. The codition studied included; communicating hydrocephalus, obstrucsive hydrocephalus, pseudotumor cerebri, hemispherectomy, alteration of C.S.F. circulation following neurosurgical procedures, and C.S.F. rhinorrhoea.Presented at the IX. Symposium Neuroradiologicum, Göteborg, 24–29 August 1970. 相似文献
67.
68.
OBJECTIVES: There is controversy about whether all nasal polyps removed at operation should be sent for histopathologic examination. The primary aim of this study was to assess the incidence of unsuspected clinically relevant diagnoses in a large series of patients undergoing nasal polypectomy. A review of the literature on the frequency of this event was also performed. STUDY DESIGN: Retrospective study and review. METHODS: Data from patients undergoing nasal polypectomy over a 14 year period were reviewed. All adult patients undergoing first surgical removal of bilateral nasal polyps were included. Monolaterality and presence of suspicious looking lesions were exclusion criteria. RESULTS: A total of 2,147 patients were recruited. Eight cases of clinically relevant unexpected diagnoses were identified, corresponding to a frequency of 0.37% (95% confidence interval 0.16-0.73%). Inverted papilloma occurred in seven cases, neoplasia in one case. Affected patients tended to be older. Four previous smaller studies on this topic were identified. The reported incidence of unsuspected clinically relevant diagnoses varied between 0.00% and 0.92%. CONCLUSIONS: Although rare, unexpected clinically relevant findings may be identified during routine histologic examination of nasal polyps specimens. Future cost effectiveness analyses are required to clarify whether routine histology is a cost effective strategy. 相似文献
69.
We investigated whether N1 and P2 auditory-evoked responses are modulated by the spectral complexity of musical sounds in pianists and non-musicians. Study participants were presented with three variants of a C4 piano tone equated for temporal envelope but differing in the number of harmonics contained in the stimulus. A fourth tone was a pure tone matched to the fundamental frequency of the piano tones. A simultaneous electroencephalographic/magnetoencephalographic recording was made. P2 amplitude was larger in musicians and increased with spectral complexity preferentially in this group, but N1 did not. The results suggest that P2 reflects the specific features of acoustic stimuli experienced during musical practice and point to functional differences in P2 and N1 that relate to their underlying mechanisms. 相似文献
70.