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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2013/05/10 15:40:37」(JST)

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Pegylated interferon alfa-2b is a treatment for hepatitis C developed by Schering-Plough, brand name is PegIntron.

It was approved in January 2001.

It has also been approved as treatment for melanoma with nodal involvement after surgical resection, under the brand name Sylatron by Merck in April 2011.

PEG-interferon alpha is a pegylated interferon composed of 165 amino acids. The PEG (polyethylene glycol) protects the molecule from proteolytic breakdown and increases the biological half-life of the interferon protein. It is also used in patients with neurofibromatosis to shrink neurofibromas. Pegylated Interferon Alpha 2b is also used in the treatment of Myeloproliferative Neoplasms.^[2]

Mechanism of Action [edit]

One of the major mechanisms of PEG-interferon alpha-2b utilizes the JAK-STAT signaling pathway. The basic mechanism works such that PEG-interferon alpha-2b will bind to its receptor, interferon-alpha receptor 1 and 2 (IFNAR1/2). Upon ligand binding the Tyk2 protein associated with IFNAR1 is phosphorylated which in turn phosphorylates Jak1 associated with IFNAR2. This kinase continues its signal transduction by phosphorylation of signal transducer and activator of transcription (STAT) 1 and 2 via Jak 1 and Tyk2 respectively. The phosphorylated STATs then dissociate from the receptor heterodimer and form an interferon transcription factor with p48 and IRF9 to form the interferon stimulate transcription factor-3 (ISGF3). This transcription factor then translocates to the nucleus where it will transcribe several genes involved in cell cycle control, cell differentiation, apoptosis, and immune response.^[3]^[4]

PEG-interferon alpha-2b acts as a multifunctional immunoregulatory cytokine by transcribing several genes, including interleukin 4 (IL4). This cytokine is responsible for inducing T helper cells to become type 2 helper T cells. This ultimately results in the stimulation of B cells to proliferate and increase their antibody production. This ultimately allows for an immune response, as the B cells will help to signal the immune system that a foreign antigen is present.^[5]

Another major mechanism of type I interferon alpha (IFNα) is to stimulate apoptosis in malignant cell lines. Previous studies have shown that IFNα can cause cell cycle arrest in U266, Daudi, and Rhek-1 cell lines.^[6]

A follow-up study researched to determine if the caspases were involved in the apoptosis seen in the previous study as well as to determine the role of mitochondrial cytochrome c release. The study confirmed that there was cleavage of caspase-3, -8, and -9. All three of these cysteine proteases play an important role in the initiation and activation of the apoptotic cascade. Furthermore, it was shown that IFNα induced a loss in the mitochondrial membrane potential which resulted in the release of cytochrome c from the mitochondria. Follow-up research is currently being conducted to determine the upstream activators of the apoptotic pathway that are induced by IFNα.^[7]

Host genetic factors influencing treatment response [edit]

For genotype 1 hepatitis C treated with pegylated interferon-alfa-2a or pegylated interferon-alfa-2b (brand names Pegasys or PEG-Intron) combined with ribavirin, it has been shown that genetic polymorphisms near the human IL28B gene, encoding interferon lambda 3, are associated with significant differences in response to the treatment. This finding, originally reported in Nature,^[8] showed that genotype 1 hepatitis C patients carrying certain genetic variant alleles near the IL28B gene are more likely to achieve sustained virological response after the treatment than others. A later report from Nature^[9] demonstrated that the same genetic variants are also associated with the natural clearance of the genotype 1 hepatitis C virus.

References [edit]

^ http://www.fda.gov/downloads/Drugs/DrugSafety/UCM133677.pdf See line 27
^ http://www.ncbi.nlm.nih.gov/pubmed/16219569
^ Ward A. et al. "The Jak-Stat pathway in normal and perturbed hematopoiesis". BLOOD. January 2000; VOL 95, Number 1, 19-26
^ PATHWAYS :: IFN alpha
^ Thomas H. et al. "Mechanisms of Action of Interferon and Nucleoside Analogues". Journal of hepatology.2004 Feb; 40(2):364.
^ Sangfel O, Erickson S, et al. (1997). Cell Growth Differ.,8;343-352
^ Thyrell et al. “Mechanisms of Interferon-alpha induced apoptosis in malignant cells”. Oncogene: Nature Publishing Group. 2002. 21; 1251-1262
^ Ge D, Fellay J, Thompson AJ, et al. (2009). "Genetic variation in IL28B predicts hepatitis C treatment-induced viral clearance". Nature 461 (7262): 399–401. doi:10.1038/nature08309. PMID 19684573.
^ Thomas DL, Thio CL, Martin MP, et al. (2009). "Genetic variation in IL28B and spontaneous clearance of hepatitis C virus". Nature 461 (7265): 798–801. doi:10.1038/nature08463. PMC 3172006. PMID 19759533.

External links [edit]

"FDA Approval Information"
"Peg Intron Website"
"Medicines patent loophole 'found'" at bbc.co.uk
[1] "Related Deaths from this Drug"*

UpToDate Contents

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1. 遺伝子2型および3型慢性C型肝炎の治療レジメン treatment regimens for chronic hepatitis c virus genotypes 2 and 3
2. 悪性黒色腫に対する補助免疫療法 adjuvant immunotherapy for melanoma
3. 慢性C型肝炎ウイルス感染に対するペグインターフェロンおよびリバビリンによる治療後に認められる持続性ウイルス陰性化の予測因子 predictors of a sustained virologic response following treatment with peginterferon and ribavirin for chronic hepatitis c virus infection
4. 成人における急性C型肝炎の臨床症状、診断、および治療 clinical manifestations diagnosis and treatment of acute hepatitis c in adults
5. 腎機能障害を有する成人における慢性C型肝炎感染症の治療 treatment of chronic hepatitis c infection in adults with renal impairment

English Journal

Combination immunotherapy for high-risk resected and metastatic melanoma patients.

Riker AI1, Rossi GR2, Masih P2, Alsfeld LC3, Denham F4, Tennant L2, Ramsey WJ2, Vahanian NN2, Link CJ2.
The Ochsner journal.Ochsner J.2014 Summer;14(2):164-74.
BACKGROUND: Patients with advanced melanoma have a poor outcome. We hypothesize that combination immunotherapy can synergistically activate host immunity to generate an effective treatment for patients with high-risk, resected stage 3, recurrent, refractory, or stage 4 melanoma.METHODS: We conducted
PMID 24940124

A pilot study of add-on oral hypoglycemic agents in treatment-naïve genotype-1 chronic hepatitis C patients receiving peginterferon alfa-2b plus ribavirin.

Hsu CS1, Hsu SJ2, Lin HH1, Tseng TC1, Wang CC1, Chen DS3, Kao JH4.
Journal of the Formosan Medical Association = Taiwan yi zhi.J Formos Med Assoc.2014 Jun 25. pii: S0929-6646(14)00178-8. doi: 10.1016/j.jfma.2014.05.007. [Epub ahead of print]
BACKGROUND/PURPOSE: Insulin resistance (IR) affects sustained virological response (SVR) to peginterferon alfa plus ribavirin (PR) in patients with chronic hepatitis C (CHC). Whether add-on oral hypoglycemic agents (OHAs) to PR improve SVR remains unclear; therefore, we conducted a prospective, rand
PMID 24974131

Simeprevir with pegylated interferon alfa 2a or 2b plus ribavirin in treatment-naive patients with chronic hepatitis C virus genotype 1 infection (QUEST-2): a randomised, double-blind, placebo-controlled phase 3 trial.

Manns M1, Marcellin P2, Poordad F3, de Araujo ES4, Buti M5, Horsmans Y6, Janczewska E7, Villamil F8, Scott J9, Peeters M10, Lenz O10, Ouwerkerk-Mahadevan S11, De La Rosa G12, Kalmeijer R12, Sinha R10, Beumont-Mauviel M10.
Lancet.Lancet.2014 Jun 3. pii: S0140-6736(14)60538-9. doi: 10.1016/S0140-6736(14)60538-9. [Epub ahead of print]
BACKGROUND: Pegylated interferon (peginterferon) alfa 2a or 2b plus ribavirin regimens were the standard of care in patients with hepatitis C virus (HCV) infection, but the sustained virological response can be suboptimum in patients with HCV genotype 1 infection. The efficacy, safety, and tolerabil
PMID 24907224

Japanese Journal

Genotype1b・C型慢性肝炎に対するPeginterferon α-2b/Ribavirin/Telaprevir3剤併用療法のRapid virological responseに寄与する因子の検討 : 多施設共同試験

島田紀朋,厚川正則,坪田昭人 [他]
肝臓 53(10), 627-632, 2012-10
NAID 40019457067

PEG-IFN/Ribavirin/Telaprevir三剤併用療法に伴う腎機能低下

小関至,木村睦海,荒川智宏 [他]
肝臓 53(7), 425-428, 2012-07
NAID 40019350671

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リンク元	「ペグインターフェロンアルファ-2b」
関連記事	「alfa」

「ペグインターフェロンアルファ-2b」

Peginterferon alfa-2b
Systematic (IUPAC) name
	PEGylated human interferon alpha 2b
Clinical data
AHFS/Drugs.com	Consumer Drug Information
MedlinePlus	a605030
Pregnancy cat.	contraindicated
Legal status	?
Pharmacokinetic data
Half-life	22-60 hrs
Identifiers
CAS number	99210-65-8
ATC code	L03AB10
DrugBank	DB00022
UNII	G8RGG88B68
KEGG	D02745
ChEMBL	CHEMBL1201561
Chemical data
Formula	C860H1353N229O255S9
Mol. mass	19269.1 g/mol
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