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Interferons play an important role in the first line of defense against viral infections. They are part of the non-specific immune systemand are induced at an early stage in viral infection before the specific immune system has had time to respond. Interferons are made by cells in response to an appropriate stimulus, and are released into the surrounding medium; they then bind to receptors on target cells and induce transcription of approximately 20-30 genes in the target cells, and this results in an anti-viral state in the target cells. TYPES OF INTERFERON: TYPE I interferon: Interferon-alpha (leukocyte interferon) is produced by virus-infected leukocytes, etc Interferon-beta (fibroblast interferon) is produced by virus-infected fibroblasts, or virus-infected epithelial cells, etc Interferon response Interferon-a (a family of about 20 related proteins) and interferon-b are particularly potent as antiviral agents. They are not expressed in normal cells, but viral infection to an acute virus of a cell causes interferons to be made and released from the cell (that cell will often infection eventually die as a result of the infection). The interferon binds to target cells and induces an antiviral state. Both DNA and RNA viruses induce interferon but RNA viruses tend to induce higher levels. Double-stranded RNA produced during viral infection may be an important inducing agent. Other stimuli will also cause these interferons to be made: e.g. exogenous double-stranded RNA, lipopolysaccharide, other components of certain bacteria. TYPE II inteferon Interferon-gamma (immune interferon) is produced by certain activated Tcells and NK cells. Interferon-gamma is made in response to antigen (including viral antigens) or mitogen stimulation of lymphocytes.
INTERFERON-alpha AND INTERFERON-beta (TYPE I INTERFERONS) These interferons induce about 20-30 proteins, and the function of many of these is not fully understood. However, three of the proteins that appear to play an important
Effects of interferon role in the induction of the anti-viral state have been intensively studied. Expression of one of these proteins (25 oligo A synthase) results in activation of the second of these proteins (a ribonuclease) which can break down mRNA, and expression of the third protein (a protein kinase) results in inhibition of the initiation step of protein synthesis. These activities target viral protein synthesis, but also result in inhibition of host protein synthesis. Thus it is important that these proteins are only made and activated when needed. Interferon treatment induces the synthesis of the inactive form of these proteins in the target cell. Double-stranded RNA is needed for activation of these proteins. It directly activates 25 oligo A synthase and protein kinase R, and indirectly activates ribonuclease L (since this needs 2'5'oligo A, the product of 25 oligo A synthase, for activation). Thus, these potentially toxic pathways are only activated in the interferontreated cell if double-stranded RNA is made, this will usually only happen if virus infection actually occurs. The activation of these proteins may sometimes result in the death of the cell, but at least the progress of the infection is prevented.
OTHER EFFECTS OF INTERFERONS The pathway described above is by no means the only way that interferons protect cells against viruses and other pathogens. All three interferons increase expression of class I MHC molecules and thus promote recognition by cytotoxic T cells. All three interferons can activate NK cells which can then kill virus-infected cells. Interferon-gamma increases expression of class II MHC molecules on antigenpresenting cells and thus promotes presentation of antigens to helper T cells. Interferon-gamma can also activate the ability of macrophages to resist viral infection (intrinsic antiviral activity) and to kill other cells if they are infected (extrinsic antiviral activity). Interferons have many other effects on gene expression, not all of which are understood. THERAPEUTIC USES OF INTERFERONS Interferons-alpha and -beta have been used to treat various viral infections. One currently approved use for various types of interferon-a is in the treatment of certain cases of acute and chronic hepatitis C and chronic hepatitis B. Interferon-gamma has been used to treat a variety of disease in which macrophage activation might play an important role in recovery, eg. lepromatous leprosy, leishmaniasis, toxoplasmosis.
Since interferons have anti-proliferative effects, they have also been used to treat certain tumors such as melanoma and Kaposis sarcoma.
SIDE EFFECTS OF INTERFERONS Common side effects of interferons: fever, malaise, fatigue, muscle pains High levels of interferons can cause kidney, liver, bone marrow and heart toxicity.
VIRAL DEFENSES AGAINST THE NON-SPECIFIC AND SPECIFIC IMMUNE SYSTEMS Not surprisingly, some viruses have developed defenses against the interferoninduced antiviral response and other aspects of the immune defense system. For example, viruses may code for proteins which block interferon binding to cells, inhibit the action of the interferon-induced protein kinase, inhibit NK function, interfere with cell surface expression of MHC, block complement activation, prevent the host cell committing apoptosis, etc.
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Interferon
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Pharmacy Author: Omudhome Ogbru, PharmD Medical and Pharmacy Editor: Jay W. Marks, MD
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What are interferons and how do they work? For what conditions are interferons used? Are there any differences among the different types of interferons? What are the side effects of interferons? With which drugs do interferons interact? What are the available interferons?
Interferons are a family of naturally-occurring proteins that are made and secreted by cells of the immune system (for example, w and epithelial cells). Three classes of interferons have been identified: 1. alpha, 2. beta, and 3. gamma.
Each class has many effects, though their effects overlap. Commercially available interferons are human interferons manufacture mechanism of action of interferon is complex and is not well understood. Interferons modulate the response of the immune syste substances that invade the body. Interferons do not directly kill viral or cancerous cells; they boost the immune system response a regulating the action of several genes that control the secretion of numerous cellular proteins that affect growth.
Interferon alfa-2a (Roferon-A) is FDA-approved to treat hairy cellleukemia, AIDS-related Kaposi's sarcoma, and chronic my
Interferon alfa-2b is approved for the treatment of hairy cell leukemia, malignant melanoma, condylomata acuminata, AIDS-r and chronic hepatitis B.
Ribavirin combined with interferon alfa-2b, interferon alfacon-1 (Infergen), pegylated interferon alfa-2b, or pegylated interfe chronic hepatitis C. Interferon beta-1b (Betaseron) and interferon beta-1a (Avonex) are approved for the treatment of multiple sclerosis.
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Interferon alfa-n3 (Alferon-N) is approved for the treatment of genital and perianal warts caused by human papillomavirus (H
Interferon gamma-1B (Actimmune) is approved for the treatment of chronic granulomatous disease, and severe, malignant os
Although interferons are very similar they affect the body differently. Therefore, different interferons are used for different condi cancers and viral infections; interferon betas are used for treating multiple sclerosis; and interferon gamma is used for treating ch
Flu-like symptoms following each injection (fever, chills, headache, muscle aches and pains, malaise) occur with all of the interf and occur in up to half of all patients. The symptoms tend to diminish with repeated injections and may be managed with analges antihistamines such as diphenhydramine (Benadryl).
Deaths
Suicide: Patient 148 was a 42 year-old woman on PEG-IFN 0.5pg/kg for 25 weeks who
died by self-inflicted gunshot wound. Of note is the lack of history of depression. No symptoms or signs of depression were noted by the patient's physicians.
Suicide, murder, paranoid reaction in the post-treatment period: Patient 598 was a 41 year-old man on IFN for 1 year and a history of depression,
antisocial behavior, and drug abuse.
ideation, attempt, or completed suicide, was commonly (but by no means invariably) associated with a previous history of depression or other psychiatric diagnoses. Depression and other psychiatric disorders occurred both during the interferon-treatment period and in the post-treatment period. Abuse of illicit drugs or ethanol was reported. Very frequently drug abuse represented a relapse of drug addiction and was often associated with development of depression. Overdoses of illicit drugs were also reported. These events did not appear to be a manifestation of suicidal behavior.
Suicide attempt: Patient 057 was a 49 year-old woman who completed PEG-IFN 1.5
pg/kg for 1 year and attempted suicide (venisection and intake of 24 g of acetaminophen) in the post-treatment period. The patient had a history of depression and anxiety.
Suicidal gesture, depression, anxiety, agitation: Patient 053 was a 53year-old man on PEG-IFN 1 pg/kg for 1 year and a history of depression and drug abuse.
Suicidal ideation, depression: Patient 012 was a 39 year-old man. PEG-IFN was
discontinued after 42 weeks for severe depression and suicidal thoughts. There was no previous history of depression.
Suicidal ideation: Patient 288 was a 39 year-old woman on PEG-IFN 1.5pg/kg and no
previous history of depression. The event resolved with treatment and IFN was continued.
Depression: Patient 084 was a 37 year-old man on PEG-IFN 0.5 pg/kg for 9 months and
a history of depression and drug abuse.
Depression, drug abuse: Patient 086 was a 34 year-old woman who completed
PEG-IFN 1.5 pg/kg treatment. Depression developed and was followed by use of illicit drugs. The patient had a history of depression.
Depression: Patient 089 was a 59 year-old woman on IFN for 2 months who developed
severe depression, fatigue and somnolence; previous history of depression.
Depression: Patient 638 was a 43 year-old man who completed one year of treatment
with PEG-IFN 0.5 pg/kg. Depression began within 1 month of treatment and waxed and waned in severity. In the post-treatment period the patient was hospitalized for severe depression.
Addiction relapse/overdose, depression, agitation, hypothyroidism:Patient 517 was a 47 year-old man on PEG-IFN 0.5 pg/kg for 37
weeks. He became depressed, agitated, irritable and overdosed on diazepam (#50 10 mg tabs), hydrocodone and dalmane. He developed hypothyroidism requiring treatment. There was a previous history of depression and drug abuse.
Substance abuse, injury accidental: Patient 097 was a 47 year-old man who
completed PEG-IFN 0.5 pg/kg treatment. The patient sustained a crush injury with pelvic and rib fractures and bladder injury. During hospitalization for the multiple trauma he developed ethanol withdrawal syndrome.
Addiction relapse: Patient 107 was a 31 year-old man on IFN for 11 months. The
patient had history of drug abuse and depression and was hospitalized for detoxification from benzodiazepines.
Addiction relapse: Patient 297 a 35 year-old man discontinued IFN treatment after 6
weeks later.
lnfections
Because of the bone marrow suppressive effect of interferons alfa, serious infections were reviewed for unusual clinical manifestations or outcomes. The following events were described. Two cases of pneumonias presumed to be bacterial; one case of each of the following: appendicitis; peri-appendiceal abscess with peritonitis; retrouterine abscess in the presence of an IUD; oral abscess following dental extractions; labial abscess associated with controlled diabetes; tonsillitis presumed to be bacterial; erysipelas originating from a wound in the popliteal fossa; aseptic meningitis. The adverse events were not associated with clinically significant decreases in neutrophil counts and patients appeared to recover with treatment. An unusual finding was the presence (in patient 206 on PEG-IFN 0.5 yglkg) of necrotizing epithelioid granulomas in the post-treatment liver biopsy. A diagnosis of mycobacterium infection was considered but was not confirmed.
Hearing loss: Patient 068 was a 36 year-old woman who completed 1 year treatment
with PEG-IFN 1.5 yglkg. The patient complained of hearing loss and an audiogram showed a bilateral 30% loss of hearing (30 dB in the 1000 and 2000 Hz frequencies) that remained stable on continued IFN treatment.
Generalized urticaria: Patient 318 was a 54 year-old woman on PEG-IFN 0.5 pg/kg
who developed injection site erythema after the third dose. With the fourth dose the patient developed urticaria that began at the injection site and became generalized. IFN was discontinued and the patient was treated with corticosteroids.