Exploratory analysis of a phase III trial of pirfenidone identifies a subpopulation of patients with idiopathic pulmonary fibrosis as benefiting from treatment

<p>Abstract</p> <p>Background</p> <p>A phase III trial in Japan showed that pirfenidone is effective for idiopathic pulmonary fibrosis (IPF). To find out which patients specifically benefit from pirfenidone, we analyzed in an exploratory manner the data from the phase III trial.</p> <p>Methods</p> <p>The patients in the phase III trial were stratified by baseline percentage predicted vital capacity (%VC), arterial oxygen partial pressure (PaO₂), and the lowest oxygen saturation by pulse oximetry (SpO₂) during the 6-minute steady-state exercise test (6MET). In the subpopulations, changes in VC and subjective symptoms (cough and dyspnea on the Fletcher, Hugh-Jones [F, H-J] Classification scale) were evaluated in patients treated with high-dose (1800 mg/day) pirfenidone, low-dose (1200 mg/day) pirfenidone, and placebo at week 52.</p> <p>Results</p> <p>Significant efficacy of pirfenidone in reducing the decline in VC could be seen in a subpopulation having %VC ≥ 70% and SpO₂< 90% at baseline. This favorable effect was accompanied by categorical change in VC and progression-free survival time. In the subpopulation, pirfenidone significantly suppressed cough and dyspnea.</p> <p>Conclusions</p> <p>IPF patients having %VC ≥ 70% and SpO₂< 90% at baseline will most likely benefit from pirfenidone when evaluated using changes in VC (and %VC), and cough and dyspnea symptoms. This subpopulation could expect to benefit most from pirfenidone treatment.</p> <p>Trial Registration</p> <p>This clinical trial was registered with the Japan Pharmaceutical Information Center (JAPIC) on September 13th, 2005 (Registration Number: JAPICCTI-050121).</p

Characterization of lymphocyte populations in nonspecific interstitial pneumonia*

STUDY OBJECTIVES: Nonspecific interstitial pneumonia (NSIP) has been identified as a distinct entity with a more favorable prognosis and better response to immunosuppressive therapies than usual interstitial pneumonia (UIP). However the inflammatory profile of NSIP has not been characterized. DESIGN: Using immunohistochemistry techniques on open lung biopsy specimens, the infiltrate in NSIP was characterized in terms of T and B cells, and macrophages, and the T cell population further identified as either CD4 (helper) or CD8 (suppressor-cytotoxic) T cells. The extent of Th1 and Th2 cytokine producing cells was determined and compared to specimens from patients with UIP. RESULTS: In ten NSIP tissue samples 41.4 ± 4% of mononuclear cells expressed CD3, 24.7 ± 1.8% CD4, 19.1 ± 2% CD8, 27.4 ± 3.9% CD20, and 14.3 ± 1.6% had CD68 expression. Mononuclear cells expressed INFγ 21.9 ± 1.9% of the time and IL-4 in 3.0 ± 1%. In contrast, biopsies from eight patients with UIP demonstrated substantially less cellular staining for either cytokine (INFγ; 4.6 ± 1.7% and IL-4; 0.6 ± 0.3%). Significant populations of CD20 positive B-cells were also identified. CONCLUSION: The lymphocytic infiltrate in NSIP is characterized by an elevated CD4/CD8 T-cell ratio, and is predominantly of Th1 type, with additional populations rich in B-cells. Such features are consistent with the favorable clinical course observed in patients with NSIP compared to UIP

Isolation of cytoplasmic NADPH-dependent phenol hydroxylase and catechol-1,2-dioxygenase from Candida tropicalis yeast

The efficiencies of NADPH-dependent phenol hydroxylase (EC 1.14.13.7) and catechol 1,2-dioxygenase (EC.1.13.11.1) in biodegradation of phenol in the cytosolic fraction isolated from yeast Candida tropicalis were investigated. Enzymatic activities of both NADPH-dependent phenol hydroxylase and catechol 1,2-dioxygenase were detected in the cytosolic fraction of C. tropicalis grown on medium containing phenol. Using the procedure consisting of chromatography on DEAE-Sepharose, fractionation by polyethylene glycol 6000 and gel permeation chromatography on Sepharose 4B the enzyme responsible for phenol hydroxylation in cytosol, NADPH-dependent phenol hydroxylase, was isolated from the cytosolic fraction of C. tropicalis close to homogeneity. However, fractionation with polyethylene glycol 6000 lead to a decrease in catechol 1,2-dioxygenase activity. Therefore, another procedure was tested to purify this enzyme. Gel permeation chromatography of proteins of the eluate obtained by chromatography on a DEAE-Sepharose column was utilized to separate phenol hydroxylase and catechol 1,2-dioxygenase. Among gel permeation chromatography on columns of Sephadex G-100, Sephacryl S-300 and Sepharose 4B tested for their efficiencies to isolate phenol hydroxylase and catechol 1,2-dioxygenase, that on Sephacryl S-300 was found to be suitable for such a procedure. Nevertheless, even this chromatographic method did not lead to obtain catechol 1,2-dioxygenase in sufficient amounts and purity for its further characterization. The data demonstrate the progress in resolving the enzymes responsible for the first two steps of phenol degradation by the C. tropicalis strain

Adjuvant interferon gamma in patients with drug – resistant pulmonary tuberculosis: a pilot study

BACKGROUND: Tuberculosis (TB) is increasing in the world and drug-resistant (DR) disease beckons new treatments. METHODS: To evaluate the action of interferon (IFN) gamma as immunoadjuvant to chemotherapy on pulmonary DR-TB patients, a pilot, open label clinical trial was carried out in the Cuban reference ward for the management of this disease. The eight subjects existing in the country at the moment received, as in-patients, 1 × 10(6 )IU of recombinant human IFN gamma intramuscularly, daily for one month and then three times per week up to 6 months as adjuvant to the indicated chemotherapy, according to their antibiograms and WHO guidelines. Sputum samples collection for direct smear observation and culture as well as routine clinical and thorax radiography assessments were done monthly. RESULTS: Sputum smears and cultures became negative for acid-fast-bacilli before three months of treatment in all patients. Lesion size was reduced at the end of 6 months treatment; the lesions disappeared in one case. Clinical improvement was also evident; body mass index increased in general. Interferon gamma was well tolerated. Few adverse events were registered, mostly mild; fever and arthralgias prevailed. CONCLUSIONS: These data suggest that IFN gamma is useful and well tolerated as adjunctive therapy in patients with DR-TB. Further controlled clinical trials are encouraged

A Structure-Based Approach for Mapping Adverse Drug Reactions to the Perturbation of Underlying Biological Pathways

Adverse drug reactions (ADR), also known as side-effects, are complex undesired physiologic phenomena observed secondary to the administration of pharmaceuticals. Several phenomena underlie the emergence of each ADR; however, a dominant factor is the drug's ability to modulate one or more biological pathways. Understanding the biological processes behind the occurrence of ADRs would lead to the development of safer and more effective drugs. At present, no method exists to discover these ADR-pathway associations. In this paper we introduce a computational framework for identifying a subset of these associations based on the assumption that drugs capable of modulating the same pathway may induce similar ADRs. Our model exploits multiple information resources. First, we utilize a publicly available dataset pairing drugs with their observed ADRs. Second, we identify putative protein targets for each drug using the protein structure database and in-silico virtual docking. Third, we label each protein target with its known involvement in one or more biological pathways. Finally, the relationships among these information sources are mined using multiple stages of logistic-regression while controlling for over-fitting and multiple-hypothesis testing. As proof-of-concept, we examined a dataset of 506 ADRs, 730 drugs, and 830 human protein targets. Our method yielded 185 ADR-pathway associations of which 45 were selected to undergo a manual literature review. We found 32 associations to be supported by the scientific literature

Effects of pirfenidone on transforming growth factor-

ABSTRACT This study was undertaken to investigate whether treatment with the antifibrotic drug pirfenidone (PD) down-regulates the bleomycin (BL)-induced overexpression of transforming growth factor (TGF)-␤ gene in the lungs. Hamsters were intratracheally instilled with SA or BL (6.5 U/kg/4 ml) under anesthesia. They were fed a diet containing 0.5% PD or the same control diet (CD) without the drug 2 days before and throughout the study. After the animals were sacrificed, their lungs were appropriately processed. The BL treatment elevated the total influx of inflammatory cells, including macrophages, by severalfold at different days in bronchoalveolar lavage fluid (BALF) from hamsters in BL ϩ CD groups, relative to the corresponding SA ϩ CD control groups. Treatment with PD significantly (P Յ .05) suppressed the influx of inflammatory cells and macrophages at day 7 in the BL ϩ PD groups, relative to the corresponding BL ϩ CD groups. In addition, the levels of TGF-␤ in BALF from hamsters in BL ϩ CD groups were elevated by 2.6-to 4.5-fold at different days, relative to the corresponding SA ϩ CD groups. Treatment with PD significantly (P Յ .05) reduced the TGF-␤ protein in BALF from BL ϩ PD groups at 14 and 21 days, when compared with the corresponding BL ϩ CD groups. The intratracheal instillation of BL significantly (P Յ .05) elevated the TGF-␤ mRNA at 7, 14, and 21 days in BL ϩ CD groups, relative to the corresponding SA ϩ CD groups, and treatment with PD significantly (P Յ .05) suppressed the TGF-␤ gene expression in BL ϩ PD groups at these times, when compared with the corresponding BL ϩ CD groups. Nuclear runoff studies revealed that PD suppressed the BL-induced increase in TGF-␤ gene transcription by 33%. It was concluded that one of the mechanisms for antifibrotic effect of PD is its ability to suppress the BLinduced overexpression of TGF-␤ gene at the transcriptional level