Pirfenidone

185.22200

185.22

D7NLD2JX7U

748456

DTXSID4045183

C2635

White solid from hot water

L04AX05|L - Antineoplastic and immunomodulating agents

2933399090

22.00000

1.9

Off-White Solid

1.137 g/cm3

96-97ºC

329.1ºC at 760 mmHg

152.7ºC

1.592

DMSO: ≥10 mg/mL, soluble ;Solubule in methanol

Store at RT

3.68X10-5 mm Hg at 25 deg C (est)

Henry's Law constant = 9.16X10-8 at 25 °C (est)

Hydroxyl radical reaction rate constant = 5.12X10-12 cu cm/molecule-sec at 25 °C (est)|Ozone radical reaction rate constant = 5.26X10-17 cu cm/molecule-sec at 25 °C (est)

NONH for all modes of transport

3

R22

S36

UV1148200

Xn

Stable under recommended storage conditions.

P301 + P312 + P330

H302

SRP: Expired or waste pharmaceuticals shall carefully take into consideration applicable DEA, EPA, and FDA regulations. It is not appropriate to dispose by flushing the pharmaceutical down the toilet or discarding to trash. If possible return the pharmaceutical to the manufacturer for proper disposal being careful to properly label and securely package the material. Alternatively, the waste pharmaceutical shall be labeled, securely packaged and transported by a state licensed medical waste contractor to dispose by burial in a licensed hazardous or toxic waste landfill or incinerator.|Product: Offer surplus and non-recyclable solutions to a licensed disposal company; Contaminated packaging: Dispose of as unused product.

Incompatible materials: Strong oxidizing agents.

The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, including pirfenidone, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act.

|Warning|H302 (97.96%): Harmful if swallowed [Warning Acute toxicity, oral]|P264, P270, P301+P312, P330, and P501|Aggregated GHS information provided by 49 companies from 3 notifications to the ECHA C&L Inventory.|H302: Harmful if swallowed [Warning Acute toxicity, oral]

Eye/face protection: Safety glasses with side-shields conforming to EN166. Use equipment for eye protection tested and approved under appropriate government standards such as NIOSH (US) or EN 166(EU).|Skin protection: Handle with gloves.|Body Protection: Complete suit protecting against chemicals. The type of protective equipment must be selected according to the concentration and amount of the dangerous substance at the specific workplace.|Respiratory protection: For nuisance exposures use type P95 (US) or type P1 (EU EN 143) particle respirator. For higher level protection use type OV/AG/P99 (US) or type ABEK-P2 (EU EN 143) respirator cartridges. Use respirators and components tested and approved under appropriate government standards such as NIOSH (US) or CEN (EU).

Suitable extinguishing media: Use water spray, alcohol-resistant foam, dry chemical, or carbon dioxide.|Advice for firefighters: Wear self contained breathing apparatus for fire fighting if necessary.

ACCIDENTAL RELEASE MEASURES: Personal precautions, protective equipment and emergency procedures: Use personal protective equipment. Avoid dust formation. Avoid breathing vapors, mist or gas. Ensure adequate ventilation. Avoid breathing dust. Environmental precautions: Do not let product enter drains. Methods and materials for containment and cleaning up: Pick up and arrange disposal without creating dust. Sweep up and shovel. Keep in suitable, closed containers for disposal.

ACCIDENTAL RELEASE MEASURES: Personal precautions, protective equipment and emergency procedures: Use personal protective equipment. Avoid dust formation. Avoid breathing vapors, mist or gas. Ensure adequate ventilation. Avoid breathing dust. Environmental precautions: Do not let product enter drains.|Precautions for safe handling: Avoid contact with skin and eyes. Avoid formation of dust and aerosols. Provide appropriate exhaust ventilation at places where dust is formed. Normal measures for preventive fire protection.|Appropriate engineering controls: Handle in accordance with good industrial hygiene and safety practice. Wash hands before breaks and at the end of workday.|Gloves must be inspected prior to use. Use proper glove removal technique (without touching glove's outer surface) to avoid skin contact with this product. Dispose of contaminated gloves after use in accordance with applicable laws and good laboratory practices. Wash and dry hands.|SRP: Local exhaust ventilation should be applied wherever there is an incidence of point source emissions or dispersion of regulated contaminants in the work area. Ventilation control of the contaminant as close to its point of generation is both the most economical and safest method to minimize personnel exposure to airborne contaminants. Ensure that the local ventilation moves the contaminant away from the worker.

Generally well tolerated with the most frequent side effects reported being photosensitivity rash and gastrointestinal symptoms.|IDENTIFICATION AND USE: Pirfenidone is a white solid. It is used as medication for the treatment of idiopathic pulmonary fibrosis. HUMAN EXPOSURE AND TOXICITY: Reports of angioedema (some serious) such as swelling of the face, lips and/or tongue which may be associated with difficulty breathing or wheezing have been reported with use of pirfenidone in the post-marketing setting. ANIMAL STUDIES: In a 24-month carcinogenicity study in rats, pirfenidone caused statistically significant dose-related increases of the combination of hepatocellular adenoma and carcinoma in male rats at doses of 750 mg/kg and above (AUC exposure approximately 1.9 times adult exposure at the MRDD). There were statistically significant increases of the combination of hepatocellular adenoma and carcinoma and the combination of uterine adenocarcinoma and adenoma at a dose of 1500 mg/kg/day (AUC exposure approximately 3.0 times adult exposure at the MRDD). In a 24-month carcinogenicity study in mice, pirfenidone caused statistically significant dose-related increases of the combination of hepatocellular adenoma and carcinoma and hepatoblastoma in male mice at doses of 800 mg/kg and above (AUC exposure approximately 0.4 times adult exposure at the MRDD). There were statistically significant dose-related increases of the combination of hepatocellular adenoma and carcinoma in female mice at doses of 2000 mg/kg and above (AUC exposure approximately 0.7 times adult exposure at the MRDD). Pirfenidone had no effects on fertility and reproductive performance in rats at dosages up to 1000 mg/kg/day (approximately 3 times the MRDD in adults on a mg/sq m basis). A fertility and embryo-fetal development study with rats and an embryo-fetal development study with rabbits that received oral doses up to 3 and 2 times, respectively, the maximum recommended daily dose (MRDD) in adults (on mg/sq m basis at maternal doses up to 1000 and 300 mg/kg/day, respectively) revealed no evidence of impaired fertility or harm to the fetus due to pirfenidone. In the presence of maternal toxicity, acyclic/irregular cycles were seen in rats at doses approximately equal to and higher than the MRDD in adults (on a mg/sq m basis at maternal doses of 450 mg/kg/day and higher). In a pre- and post-natal development study, prolongation of the gestation period, decreased numbers of live newborn, and reduced pup viability and body weights were seen in rats at an oral dosage approximately 3 times the MRDD in adults (on a mg/sq m basis at a maternal dose of 1000 mg/kg/day). Pirfenidone was not mutagenic or clastogenic in the following tests: mutagenicity tests in bacteria, a chromosomal aberration test in Chinese hamster lung cells, and a micronucleus test in mice. No genotoxic effects were observed neither in newborn rats transplacentally exposed to pirfenidone, or in two adult rodent models when pirfenidone was administered orally or topically.

In large randomized controlled trials, serum aminotransferase elevations more than 3 times the upper limit of normal (ULN) occurred in 4% of pirfenidone- compared to less than 1% of placebo-treated patients. The elevations were generally asymptomatic and short lived, resolving with or without dose modification and requiring drug discontinuation in approximately 1% of patients. Despite the frequency of serum enzyme elevations during therapy, clinically apparent liver injury was not reported in preregistration studies. Nevertheless, since the general availability of pirfenidone in the United States and during years of clinical use elsewhere, there have been isolated case reports of clinically apparent liver injury due to pirfenidone, some of which were severe and even fatal. The latency to onset ranged from one month to one year and the injury was usually hepatocellular or mixed. Immunoallergic features were not common.

Concomitant use of pirfenidone and CYP1A2 inducers may result in decreased exposure to and reduced efficacy of pirfenidone. The manufacturer of pirfenidone recommends that potent CYP1A2 inducers be avoided during pirfenidone therapy.|Concomitant use of pirfenidone with agents or a combination of agents that are potent or moderate inhibitors of both CYP1A2 and one or more other CYP isoenzymes involved with pirfenidone metabolism (i.e., CYP2C9, 2C19, 2D6, and 2E1) should be avoided.|Concomitant administration of a single dose of pirfenidone with the potent CYP1A2 inhibitor fluvoxamine (initially 50 mg daily, titrated upward to 150 mg daily for 10 days) in nonsmokers and smokers increased pirfenidone exposure approximately fourfold in nonsmokers and sevenfold in smokers.|Concomitant administration of pirfenidone (single 801-mg dose on day 6) with the moderate CYP1A2 inhibitor ciprofloxacin (750 mg twice daily on days 2-7) increased the systemic exposure to pirfenidone by 81%. Pirfenidone dosage should be reduced if used concomitantly with ciprofloxacin at a dosage of 750 mg twice daily. No initial dosage adjustment is recommended if pirfenidone is used concomitantly with ciprofloxacin at a dosage of 250 or 500 mg once daily; however, patients receiving such concomitant therapy should be monitored closely for adverse effects.|For more Interactions (Complete) data for Pirfenidone (8 total), please visit the HSDB record page.

Esbriet should be used with caution in patients with mild (CLcr 50-80 mL/min), moderate (CLcr 30-50 mL/min), or severe (CLcr less than 30 mL/min) renal impairmen. Monitor for adverse reactions and consider dosage modification or discontinuation of Esbriet as needed. The safety, efficacy, and pharmacokinetics of Esbriet have not been studied in patients with end-stage renal disease requiring dialysis. Use of Esbriet in patients with end-stage renal diseases requiring dialysis is not recommended.|Esbriet should be used with caution in patients with mild (Child Pugh Class A) to moderate (Child Pugh Class B) hepatic impairment. Monitor for adverse reactions and consider dosage modification or discontinuation of Esbriet as needed. The safety, efficacy, and pharmacokinetics of Esbriet have not been studied in patients with severe hepatic impairment. Esbriet is not recommended for use in patients with severe (Child Pugh Class C) hepatic impairment.|Cigarette smoking reduces peak plasma concentrations and systemic exposure to pirfenidone by 32 and 54%, respectively. The manufacturer recommends that patients be encouraged to stop smoking prior to initiation of pirfenidone and to avoid smoking during therapy.

Pirfenidone is 50-58% protein-bound in plasma, primarily to albumin.

For the treatment of idiopathic pulmonary fibrosis (IPF).|Esbriet is indicated in adults for the treatment of mild to moderate idiopathic pulmonary fibrosis.|Idiopathic Pulmonary Fibrosis (in adults)

Pirfenidone is an orally available pyridinone derivative that inhibits collagen formation and is used to treat idiopathic pulmonary fibrosis. Elevations in serum enzyme levels during pirfenidone therapy are not uncommon, but it has yet to be implicated in cases of clinically apparent liver injury with jaundice.

Pulmonary Fibrosis Agents

/CLINICAL TRIALS/ ClinicalTrials.gov is a registry and results database of publicly and privately supported clinical studies of human participants conducted around the world. The Web site is maintained by the National Library of Medicine (NLM) and the National Institutes of Health (NIH). Each ClinicalTrials.gov record presents summary information about a study protocol and includes the following: Disease or condition; Intervention (for example, the medical product, behavior, or procedure being studied); Title, description, and design of the study; Requirements for participation (eligibility criteria); Locations where the study is being conducted; Contact information for the study locations; and Links to relevant information on other health Web sites, such as NLM's MedlinePlus for patient health information and PubMed for citations and abstracts for scholarly articles in the field of medicine. Pirfenidone is included in the database.|Esbriet is indicated for the treatment of idiopathic pulmonary fibrosis (IPF). /Included in US product label/|/EXPL THER/ Left ventricular remodeling is a frequent complication of hypertension with no therapeutic treatment available for the subsequent onset of myocardial fibrosis. Pirfenidone is an antifibrotic small-molecular-size drug with anti-inflammatory properties that is used as a treatment for fibrotic diseases, but its effects on hypertension-induced myocardial fibrosis are unknown. Therefore, we tested whether pirfenidone could ameliorate hypertension-induced left ventricular remodeling and whether hypertension-induced NLRP3 (Nod-like receptor pyrin domain containing 3), a critical protein in NLRP3 inflammasome formation, is involved in the therapeutic mechanism. A TAC-induced mouse model of hypertension and left ventricular hypertrophy was treated with pirfenidone, and survival, collagen deposition by histopathologic examination, heart function by echocardiography, concentrations of fibrosis-related inflammatory cytokines TGF-beta1, IL-1beta in heart homogenate and in vitro cell cultures by ELISA, levels of ROS and inflammatory cells by flow cytometry, and levels of NLRP3 by Western blotting and immunohistochemistry were measured. Pirfenidone increased the survival rate and attenuated myocardial fibrosis and inflammatory mediators in the TAC-induced hypertension-complicated left ventricular remodeling mouse model. The inhibition of NLRP3 expression by pirfenidone attenuated the expression of IL-1beta and IL-1beta-induced inflammatory and profibrotic responses. Pirfenidone may be useful in the treatment of hypertension-induced myocardial fibrosis by inhibiting NLRP3-induced inflammation and fibrosis.|/EXPL THER/ Systemic sclerosis (SSc)-associated interstitial lung disease (SSc-ILD) has become the leading SSc-related cause of death. Although various types of immunosuppressive therapy have been attempted for patients with SSc-ILD, no curative or effective treatment strategies for SSc-ILD have been developed. Therefore, management of patients with SSc-ILD remains a challenge. Here, we report a Chinese, female, SSc-ILD patient who was negative for Scl-70 and showed an excellent response to pirfenidone without obvious adverse effects. She had been suffered from dry cough and exertional dyspnea for 2 months. The chest computed tomography manifestation was consistent with a pattern of fibrotic nonspecific interstitial pneumonia. The pulmonary function test showed isolated impaired diffusion. After 11 weeks of administration of pirfenidone, the dry cough and dyspnea had disappeared. Both of the lung shadows and the pulmonary diffusion function were improved. Pirfenidone might be an effective option for early SSc-ILD treatment. A well-controlled clinical trial is expected in the future.

Elevations in serum transaminase (ALT and/or AST) concentrations exceeding 3 times the upper limit of normal (ULN) have occurred in patients receiving pirfenidone; concomitant elevations in bilirubin concentrations have been reported rarely. ALT or AST elevations of at least 3 times the ULN were reported in 3.7% of patients receiving pirfenidone compared with 0.8% of patients receiving placebo in clinical studies; ALT or AST elevations of 10 times the ULN or greater occurred in 0.3% of pirfenidone-treated patients. Increases in liver enzymes were reversible following dosage modification or interruption of therapy. No cases of liver transplant or death due to liver failure related to pirfenidone use have been reported to date; however, the manufacturer states that the combination of transaminase elevations and hyperbilirubinemia without evidence of obstruction is generally recognized as an important predictor of severe liver injury possibly resulting in death or the need for liver transplant in some patients. Liver function tests including ALT, AST, and bilirubin concentrations should be performed prior to initiation of pirfenidone therapy, monthly for the first 6 months, and then every 3 months thereafter. Interruption of therapy and/or dosage reduction may be necessary in patients experiencing liver enzyme elevations.|Cigarette smoking reduces peak plasma concentrations and systemic exposure to pirfenidone by 32 and 54%, respectively. The manufacturer recommends that patients be encouraged to stop smoking prior to initiation of pirfenidone and to avoid smoking during therapy.|There are no adequate and well-controlled studies of Esbriet in pregnant women. Pirfenidone was not teratogenic in rats and rabbits. Because animal reproduction studies are not always predictive of human response, Esbriet should be used during pregnancy only if the benefit outweighs the risk to the patient.|Adverse effects reported in 10% or more of patients receiving pirfenidone and at an incidence greater than with placebo include nausea, rash, abdominal pain, upper respiratory tract infection, diarrhea, fatigue, headache, dyspepsia, dizziness, vomiting, anorexia, gastroesophageal reflux disease (GERD), sinusitis, insomnia, decreased weight, and arthralgia.|For more Drug Warnings (Complete) data for Pirfenidone (16 total), please visit the HSDB record page.

Pirfenidone is a novel agent with anti-inflammatory, antioxidant, and antifibrotic properties. It may improve lung function and reduce the number of acute exacerbations in patients with idiopathic pulmonary fibrosis (IPF).

Compounds capable of relieving pain without the loss of CONSCIOUSNESS. (See all compounds classified as Analgesics.)|Anti-inflammatory agents that are non-steroidal in nature. In addition to anti-inflammatory actions, they have analgesic, antipyretic, and platelet-inhibitory actions.They act by blocking the synthesis of prostaglandins by inhibiting cyclooxygenase, which converts arachidonic acid to cyclic endoperoxides, precursors of prostaglandins. Inhibition of prostaglandin synthesis accounts for their analgesic, antipyretic, and platelet-inhibitory actions; other mechanisms may contribute to their anti-inflammatory effects. (See all compounds classified as Anti-Inflammatory Agents, Non-Steroidal.)|Substances that inhibit or prevent the proliferation of NEOPLASMS. (See all compounds classified as Antineoplastic Agents.)

Rapidly absorbed following oral administration.|The steady-state volume of distribution following oral administration is approximately 70L.|Esbriet binds to human plasma proteins, primarily to serum albumin, in a concentration-independent manner over the range of concentrations observed in clinical trials. The overall mean binding was 58% at concentrations observed in clinical studies (1 to 10 ug/mL). Mean apparent oral volume of distribution is approximately 59 to 71 liters.|After single oral-dose administration of 801 mg Esbriet, the maximum observed plasma concentration (Cmax) was achieved between 30 minutes and 4 hours (median time of 0.5 hours). Food decreased the rate and extent of absorption. Median Tmax increased from 0.5 hours to 3 hours with food. Maximum plasma concentrations and AUC0-inf decreased by approximately 49% and 16% with food, respectively.|Pirfenidone is excreted predominantly as metabolite 5-carboxy-pirfenidone, mainly in the urine (approximately 80% of the dose). The majority of Esbriet was excreted as the 5-carboxy metabolite (approximately 99.6% of that recovered).|/MILK/ A study with radio-labeled pirfenidone in rats has shown that pirfenidone or its metabolites are excreted in milk. It is not known whether Esbriet is excreted in human milk.|... This study aimed to evaluate the pharmacokinetics and urinary excretion of pirfenidone and its major metabolite 5-carboxy-pirfenidone in healthy Chinese subjects under fed conditions. 20 healthy subjects of either sex were recruited in this randomized, single-center, and open-label, single ascending doses (200, 400, and 600 mg) and multiple doses (400 mg, 3 times daily) study. Safety was assessed by adverse events, ECGs, vital signs, and clinical laboratory parameters. Blood and urine samples were analyzed with a validated LC/MS method. Pirfenidone was safe and well tolerated. After single-dose administration, pirfenidone was rapidly absorbed with a mean Tmax of 1.8-2.2 hr and a mean half life of 2.1-2.4 hr. 5-carboxy-pirfenidone was rapidly formed with a mean Tmax of 1.5-2.2 hr and a mean half life of 2.1-2.6 hr. Cmax and AUC for both parent and metabolite were dose proportional over the 200-600 mg dose range. No gender effect was found. In the steady state, the accumulation index (R) estimated for the 3 dosing intervals ranged from 1.1 to 1.5 for both pirfenidone and 5-carboxy-pirfenidone, indicating that the exposure of pirfenidone and 5-carboxy-pirfenidone increased slightly with repeated dosing, but half life and CL/F remained unchanged. Metabolism is the primary mechanism of drug clearance of pirfenidone. About 87.76% of the administered pirfenidone was excreted in urine in the form of 5-carboxy-pirfenidone, while only 0.6159% of the administered pirfenidone was detected as the unchanged form in urine.

Pirfenidone is excreted predominantly as metabolite 5-carboxy-pirfenidone, mainly in the urine (approximately 80% of the dose). The majority of Esbriet was excreted as the 5-carboxy metabolite (approximately 99.6% of that recovered).|In vitro profiling studies in hepatocytes and liver microsomes have shown that Esbriet is primarily metabolized in the liver by CYP1A2 and multiple other CYPs (CYP2C9, 2C19, 2D6, and 2E1). Oral administration of Esbriet results in the formation of four metabolites. In humans, only pirfenidone and 5-carboxy-pirfenidone are present in plasma in significant quantities. The mean metabolite-to-parent ratio ranged from approximately 0.6 to 0.7. No formal radiolabeled studies have assessed the metabolism of pirfenidone in humans. In vitro data suggests that metabolites are not expected to be pharmacologically active at observed metabolite concentrations.

2-2.5 hours|The mean terminal half-life is approximately 3 hours in healthy subjects.|... This study aimed to evaluate the pharmacokinetics and urinary excretion of pirfenidone and its major metabolite 5-carboxy-pirfenidone in healthy Chinese subjects under fed conditions. 20 healthy subjects of either sex were recruited in this randomized, single-center, and open-label, single ascending doses (200, 400, and 600 mg) and multiple doses (400 mg, 3 times daily) study. ... After single-dose administration, pirfenidone was rapidly absorbed with a mean ... half life of 2.1-2.4 hr. 5-carboxy-pirfenidone was rapidly formed with ... a mean half life of 2.1-2.6 hr. ...

Although the precise mechanism of action of pirfenidone and its specific molecular targets have yet to be elucidated, the molecule has demonstrated anti-fibrotic, anti-inflammatory, and antioxidant activity. One vital anti-fibrotic mechanism involves suppression of TGF-β1 (transforming growth factor-β1), a key cytokine involved in fibrogenesis and extracellular matrix production. There is also evidence to suggest that pirfenidone has the ability to downregulate the expression of potent pro-inflammatory cytokines including TNF-α, interleukin-1, and interferon gamma. In animal models, pirfenidone can inhibit both the influx of inflammatory cells and the increased pulmonary vascular permeability induced by bleomycin.|Dysfunctional mitochondria participate in the progression of chronic kidney disease (CKD). Pirfenidone is a newly identified anti-fibrotic drug. However, its mechanism remains unclear. Mitochondrial dysfunction is an early event that occurs prior to the onset of renal fibrosis. In this context, we investigated the protective effect of pirfenidone on mitochondria and its relevance to apoptosis and oxidative stress in renal proximal tubular cells. A remnant kidney rat model was established. Human renal proximal tubular epithelial cells (HK2) using rotenone, a mitochondrial respiratory chain complex I inhibitor were further investigated in vitro to examine the mitochondrial protective effect of pirfenidone. Pirfenidone protected mitochondrial structures and functions by stabilizing the mitochondrial membrane potential, maintaining ATP production and improving the mitochondrial DNA (mtDNA) copy number. Pirfenidone decreased tubular cell apoptosis by inhibiting the mitochondrial apoptotic signaling pathway. Pirfenidone also reduced oxidative stress by enhancing manganese superoxide dismutase (Mn-SOD) and inhibiting intracellular reactive oxygen species (ROS) generation, which suggested that the anti-oxidant effects occurred at least partially via the mitochondrial pathway. Pirfenidone may be effective prior to the onset of renal fibrosis because this drug exerts its anti-fibrotic effect by protection of mitochondria in renal proximal tubular cells.|Pirfenidone is a drug recently approved for idiopathic pulmonary fibrosis but its mechanisms of action are partially unknown. We have previously demonstrated that the airways of patients with idiopathic pulmonary fibrosis contain procoagulant microparticles that activate coagulation factor X to its active form, Xa, a proteinase that signals fibroblast growth and differentiation, thus potentially contributing to the pathogenesis of the disease. We also reported that in vitro exposure of human alveolar cells to H2O2 causes microparticle generation. Since p38 activation is involved in microparticle generation in some cell models and p38 inhibition is one of the mechanisms of action of pirfenidone, we investigated the hypothesis that H2O2-induced generation of microparticles by alveolar cells is dependent on p38 phosphorylation and is inhibited by pirfenidone. H2O2 stimulation of alveolar cells caused p38 phosphorylation that was inhibited by pirfenidone. The drug also inhibited H2O2 induced microparticle generation as assessed by two independent methods (solid phase thrombin generation and flow cytometry). The shedding of microparticle-bound tissue factor activity was also inhibited by pirfenidone. Inhibition of p38-mediated generation of procoagulant microparticle is a previously unrecognized mechanism of action of the antifibrotic drug, pirfenidone.|Recent studies indicate that pirfenidone (PFD) may have anti-fibrotic effects in many tissues, but the potential molecular mechanism remains unknown. The purpose of this study is to investigate the potential effects of PFD on epithelial-to-mesenchymal transition (EMT) and renal fibrosis in a unilateral ureteral obstruction (UUO) rat model and the involved molecular mechanism related to cultured human renal proximal tubular epithelial cells (HK-2). Sixty rats were randomly divided into three groups: sham-operated, vehicle-treated UUO, and PFD-treated UUO. Kidney specimens were collected at day 7 or 14 after UUO. PFD treatment was also performed for human HK-2. The tubulointerstitial injury, interstitial collagen deposition, and expression of type I and III collagen, a-SMA, S100A4, fibronection and E-cadherin were assessed. In addition, extracellular signal regulated kinase (ERK1/2), p38 MAPK (p38), and c-Jun N-terminal kinase/stress-activated protein kinase (JNK) were also detected. In vitro, PFD significantly attenuated TGF-beta1-induced EMT and extracellular matrix (ECM) synthesis, as determined by reducing expression of a-SMA, type I and III collagen, S100A4, fibronection, and increased expression of E-cadherin. PFD treatment attenuated TGF-beta1-induced up-regulation of phosphorylation of ERK1/2, p38 and JNK. In vivo, PFD reduced the degree of tubulointerstitial injury and renal fibrosis, which was associated with reduced expression of TGF-beta1, type III collagen, a-SMA, S100A4, fibronection, and increased expression of E-cadherin. These results suggest that pirfenidone is able to attenuate EMT and fibrosis in vivo and in vitro through antagonizing the MAPK pathway, providing a potential treatment to alleviate renal tubulointerstitial fibrosis.|Pirfenidone is a novel anti-fibrotic and anti-inflammatory agent that inhibits the progression of fibrosis in animal models and in patients with idiopathic pulmonary fibrosis (IPF). We previously showed that pirfenidone inhibits the over-expression of collagen type I and of heat shock protein (HSP) 47, a collagen-specific molecular chaperone, in human lung fibroblasts stimulated with transforming growth factor (TGF)-beta1 in vitro. The increased numbers of HSP47-positive type II pneumocytes as well as fibroblasts were also diminished by pirfenidone in an animal model of pulmonary fibrosis induced by bleomycin. The present study evaluates the effects of pirfenidone on collagen type I and HSP47 expression in the human alveolar epithelial cell line, A549 cells in vitro. The expression of collagen type I, HSP47 and E-cadherin mRNAs in A549 cells stimulated with TGF-beta1 was evaluated by Northern blotting or real-time PCR. The expression of collagen type I, HSP47 and fibronectin proteins was assessed by immunocytochemical staining. TGF-beta1 stimulated collagen type I and HSP47 mRNA and protein expression in A549 cells, and pirfenidone significantly inhibited this process. Pirfenidone also inhibited over-expression of the fibroblast phenotypic marker fibronectin in A549 cells induced by TGF-beta1. We concluded that the anti-fibrotic effects of pirfenidone might be mediated not only through the direct inhibition of collagen type I expression but also through the inhibition of HSP47 expression in alveolar epithelial cells, which results in reduced collagen synthesis in lung fibrosis. Furthermore, pirfenidone might partially inhibit the epithelial-mesenchymal transition.|Polarized T helper type 2 (Th2) response is linked with fibrosis. Here, we evaluated the effect of the anti-fibrotic agent pirfenidone on Th type 1 (Th1) and Th2 responses. For in vivo testing; Wistar rats were made cirrhotic by intraperitoneal administration of thioacetamide. Once hepatic damage was established, pirfenidone was administered intragastrically on a daily basis during three weeks. Gene expression of Th marks was evaluated by RT-PCR and Western blot assays from liver homogenates. Pirfenidone therapy induced down-regulation of Th2 transcripts and proteins (GATA3 and IL-4), without affecting significantly Th1 genes expression (T-bet and IFN-gamma). We found that the activated form of p38 MAPK (identified by Western blot) was reduced by pirfenidone treatment, which is consistent with the anti-Th2 activity observed. Pirfenidone reduced GATA3 nuclear localization without modifying its DNA binding activity (evaluated by electrophoretic mobility shift assay). For in vitro testing; human naive CD4+ T cells were cultured in either Th1 or Th2 polarizing conditions in the presence of pirfenidone and flow cytometric analysis of intracellular synthesis of IFN-gamma and IL-4 was conducted. Pirfenidone impaired development of Th2 subpopulation. In conclusion, pirfenidone is capable of impairing Th2 differentiation and limits Th2 profibrogenic response. The mechanism involves p38 inhibition and regulation of GATA3 expression and translocation.

/SRP:/ Immediate first aid: Ensure that adequate decontamination has been carried out. If patient is not breathing, start artificial respiration, preferably with a demand valve resuscitator, bag-valve-mask device, or pocket mask, as trained. Perform CPR if necessary. Immediately flush contaminated eyes with gently flowing water. Do not induce vomiting. If vomiting occurs, lean patient forward or place on the left side (head-down position, if possible) to maintain an open airway and prevent aspiration. Keep patient quiet and maintain normal body temperature. Obtain medical attention. /Poisons A and B/|/SRP:/ Basic treatment: Establish a patent airway (oropharyngeal or nasopharyngeal airway, if needed). Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with 0.9% saline (NS) during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 mL/kg up to 200 mL of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poisons A and B/|/SRP:/ Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in severe respiratory distress. Positive-pressure ventilation techniques with a bag valve mask device may be beneficial. Consider drug therapy for pulmonary edema ... . Consider administering a beta agonist such as albuterol for severe bronchospasm ... . Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start IV administration of D5W TKO /SRP: "To keep open", minimal flow rate/. Use 0.9% saline (NS) or lactated Ringer's (LR) if signs of hypovolemia are present. For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam or lorazepam ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poisons A and B/|In the event of a suspected overdosage, appropriate supportive medical care should be provided, including monitoring of vital signs and observation of the clinical status of the patient.

/SIGNS AND SYMPTOMS/ Reports of angioedema (some serious) such as swelling of the face, lips and/or tongue which may be associated with difficulty breathing or wheezing have been received in association with use of Esbriet in the post-marketing setting.|/OTHER TOXICITY INFORMATION/ Elevations in serum transaminase (ALT and/or AST) concentrations exceeding 3 times the upper limit of normal (ULN) have occurred in patients receiving pirfenidone; concomitant elevations in bilirubin concentrations have been reported rarely. ALT or AST elevations of at least 3 times the ULN were reported in 3.7% of patients receiving pirfenidone compared with 0.8% of patients receiving placebo in clinical studies; ALT or AST elevations of 10 times the ULN or greater occurred in 0.3% of pirfenidone-treated patients. Increases in liver enzymes were reversible following dosage modification or interruption of therapy. No cases of liver transplant or death due to liver failure related to pirfenidone use have been reported to date; however, the manufacturer states that the combination of transaminase elevations and hyperbilirubinemia without evidence of obstruction is generally recognized as an important predictor of severe liver injury possibly resulting in death or the need for liver transplant in some patients. Liver function tests including ALT, AST, and bilirubin concentrations should be performed prior to initiation of pirfenidone therapy, monthly for the first 6 months, and then every 3 months thereafter. Interruption of therapy and/or dosage reduction may be necessary in patients experiencing liver enzyme elevations.

1-phenyl-5-(trideuteriomethyl)-1,2-dihydropyridin-2-one

Oral: capsules, 267 mg, Esbriet (InterMune)

HPLC determination in plasma.

Human drugs -> Esbriet -> EMA Drug Category|Other immunosuppressants, Immunosuppressants -> Human pharmacotherapeutic group|Human drugs -> Rare disease (orphan)|Human Drugs -> EU pediatric investigation plans|Human Drugs -> FDA Approved Drug Products with Therapeutic Equivalence Evaluations (Orange Book) -> Active Ingredients