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

Gravitational Chern-Simons Lagrangians and black hole entropy

We analyze the problem of defining the black hole entropy when Chern-Simons terms are present in the action. Extending previous works, we define a general procedure, valid in any odd dimensions both for purely gravitational CS terms and for mixed gauge-gravitational ones. The final formula is very similar to Wald's original formula valid for covariant actions, with a significant modification. Notwithstanding an apparent violation of covariance we argue that the entropy formula is indeed covariant.Comment: 39 page

Black Holes in Gravity with Conformal Anomaly and Logarithmic Term in Black Hole Entropy

We present a class of exact analytic and static, spherically symmetric black hole solutions in the semi-classical Einstein equations with Weyl anomaly. The solutions have two branches, one is asymptotically flat and the other asymptotically de Sitter. We study thermodynamic properties of the black hole solutions and find that there exists a logarithmic correction to the well-known Bekenstein-Hawking area entropy. The logarithmic term might come from non-local terms in the effective action of gravity theories. The appearance of the logarithmic term in the gravity side is quite important in the sense that with this term one is able to compare black hole entropy up to the subleading order, in the gravity side and in the microscopic statistical interpretation side.Comment: Revtex, 10 pages. v2: minor changes and to appear in JHE

Logarithmic correction to BH entropy as Noether charge

We consider the role of the type-A trace anomaly in static black hole solutions to semiclassical Einstein equation in four dimensions. Via Wald's Noether charge formalism, we compute the contribution to the entropy coming from the anomaly induced effective action and unveil a logarithmic correction to the Bekenstein-Hawking area law. The corrected entropy is given by a seemingly universal formula involving the coefficient of the type-A trace anomaly, the Euler characteristic of the horizon and the value at the horizon of the solution to the uniformization problem for Q-curvature. Two instances are examined in detail: Schwarzschild and a four-dimensional massless topological black hole. We also find agreement with the logarithmic correction due to one-loop contribution of conformal fields in the Schwarzschild background.Comment: 14 pages, JHEP styl

Warped black holes in 3D general massive gravity

We study regular spacelike warped black holes in the three dimensional general massive gravity model, which contains both the gravitational Chern-Simons term and the linear combination of curvature squared terms characterizing the new massive gravity besides the Einstein-Hilbert term. The parameters of the metric are found by solving a quartic equation constrained by an inequality that imposes the absence of closed timelike curves. Explicit expressions for the central charges are suggested by exploiting the fact that these black holes are discrete quotients of spacelike warped AdS(3) and a known formula for the entropy. Previous results obtained separately in topological massive gravity and in new massive gravity are recovered as special cases.Comment: 38 pages, 7 figures. v2: minor changes, added refs and an appendix on self-dual and null z-warped black hole

Oral Pirfenidone in patients with chronic fibrosis resulting from radiotherapy: a pilot study

<p>Abstract</p> <p>Background</p> <p>Fibrosis is a common side effect after treatment with ionizing radiation. Several methods to ameliorate debilitating fibrosis have been employed but without consistent results. The goal of this pilot study is to determine if Pirfenidone, a novel regulator of cytokine gene expression, has the potential to ameliorate established radiation-induced fibrosis.</p> <p>Methods</p> <p>Open label, prospective pilot study of 800 mg three times/day, orally administered Pirfenidone was administered to enrolled patients who were had completed radiation therapy and who had established radiation-induced fibrosis. Range of motion (ROM) was assessed using standard measures, and subjective measures of pain, fatigue, disability and global health were measured every three months.</p> <p>Results</p> <p>Seven patients were enrolled of whom 3 had ROM assessments of 1 site and 2 had ROM assessments of 2 sites. Of these assessments, 6 revealed increased ROM during drug intervention while 1 revealed a decreased ROM. There was an overall improvement in the mental composite score of the SF36 while physical composite score was decreased and the vitality score was unchanged. Two patients were removed from the study because of syncopal episodes.</p> <p>Conclusion</p> <p>Several patients experienced improved function of at least 25% and reported subjective improvement. Pirfenidone may benefit patients with radiation-induced fibrosis and is worthy of a larger well controlled trial.</p

Logarithmic Corrections to Extremal Black Hole Entropy from Quantum Entropy Function

We evaluate the one loop determinant of matter multiplet fields of N=4 supergravity in the near horizon geometry of quarter BPS black holes, and use it to calculate logarithmic corrections to the entropy of these black holes using the quantum entropy function formalism. We show that even though individual fields give non-vanishing logarithmic contribution to the entropy, the net contribution from all the fields in the matter multiplet vanishes. Thus logarithmic corrections to the entropy of quarter BPS black holes, if present, must be independent of the number of matter multiplet fields in the theory. This is consistent with the microscopic results. During our analysis we also determine the complete spectrum of small fluctuations of matter multiplet fields in the near horizon geometry.Comment: LaTeX file, 52 pages; v2: minor corrections, references adde

In Vitro Effects of Pirfenidone on Cardiac Fibroblasts: Proliferation, Myofibroblast Differentiation, Migration and Cytokine Secretion

Cardiac fibroblasts (CFs) are the primary cell type responsible for cardiac fibrosis during pathological myocardial remodeling. Several studies have illustrated that pirfenidone (5-methyl-1-phenyl-2-[1H]-pyridone) attenuates cardiac fibrosis in different animal models. However, the effects of pirfenidone on cardiac fibroblast behavior have not been examined. In this study, we investigated whether pirfenidone directly modulates cardiac fibroblast behavior that is important in myocardial remodeling such as proliferation, myofibroblast differentiation, migration and cytokine secretion. Fibroblasts were isolated from neonatal rat hearts and bioassays were performed to determine the effects of pirfenidone on fibroblast function. We demonstrated that treatment of CFs with pirfenidone resulted in decreased proliferation, and attenuated fibroblast α-smooth muscle actin expression and collagen contractility. Boyden chamber assay illustrated that pirfenidone inhibited fibroblast migration ability, probably by decreasing the ratio of matrix metalloproteinase-9 to tissue inhibitor of metalloproteinase-1. Furthermore, pirfenidone attenuated the synthesis and secretion of transforming growth factor-β1 but elevated that of interleukin-10. These direct and pleiotropic effects of pirfenidone on cardiac fibroblasts point to its potential use in the treatment of adverse myocardial remodeling

Gravitational Chern-Simons terms and black hole entropy. Global aspects

We discuss the topological and global gauge properties of the formula for a black hole entropy due to a purely gravitational Chern-Simons term. We study under what topological and geometrical conditions this formula is well-defined. To this end we have to analyze the global properties of the Chern-Simons term itself and the quantization of its coupling. We show that in some cases the coupling quantization may interfere with the well-definiteness of the entropy formula.Comment: 37 pages, a few comments and references adde