Interferon toxicity

Renal function impairment- In patients with end-stage renal disease requiring hemodialysis, dose reduction to 135 meg peginterferon alfa-2a is recommended. Closely monitor for signs and symptoms of interferon toxicity. Do not use ribavirin in patients with creatinine clearance less than 50 mL/min. 

Renal function impairment Closely monitor patients with impairment of renal function for signs and symptoms of interferon toxicity and adjust doses of peginterferon alfa-2b accordingly. Use peginterferon alfa-2b with caution in patients with Ccr less than 50 mL/min. 

The frequency and severity of toxicity seen with HDI in the adjuvant setting and the lack of overall survival benefit has raised several important questions (1) Are the toxicities associated with HDI treatment worth the potential benefits for patients (2) What are the mechanism(s) and best standard(s) of care for patients who experience interferon toxicity (3) Is the regimen/schedule of interferon used in the initial positive trial (HDI) necessary to achieve the benefits seen in this study Aggressive toxicity evaluation and individnalized management is essential to help preserve quality of life in those individuals receiving interferon therapy. 

Each interferon preparation was ultracentrifuged at 20,000 revolutions per minute for one hour to remove tissue debris and inactivated virus. The supernatant was dialyzed against distilled water (1 400) for 24 hours at4°C. The material was then freeze-dried. The dried product was reconstituted in one-tenth of the original volume in distilled water and dispensed into ampoules. Reconstituted solutions were assayed for interferon activity, examined for toxicity, and tested for sterility. 

Potentially, interferon is an ideal anhviral agent in that it acts on many different vimses and is not toxic to host cells. However, the exploitation of this agent in the treatment of viral infechons has been delayed by a number of factors. For example, it has proved to be species-specific and interferons raised in animal sources offered little protechon to human cells. Human interferon is thus needed for the treatment of human infechons and the produehon and purificahon of human interferon on a large scale has proved difficult. The inserhon of human genes for interferon into E. coli has resolved the produehon problems (Chapter 24). Clinical trials have demonstrated that interferon prevents rhinovirus infeehon and has a beneficial effect in herpes, cytomegalovims and hepahtis B vims infechons. 

Prior to the introduction of imatinib, the combination of interferon-alfa and low dose cytarabine was the nontransplant treatment of choice for patients in chronic phase CML. The precise mechanism of action of interferon-alfa remains unknown. The addition of cytarabine to interferon-alfa improves the response compared with interferon alone. This combination produces cytogenetic response rates of 30%, much lower than imatinib.13 One of the major drawbacks, in addition to the low response rates, is interferon s toxicity,... 

Kirkwood JM, Bender C, Agarwala S, et al. Mechanisms and management of toxicities associated with high dose interferon-a2b therapy. J Clin Oncol 2002 20 3703-3718. 

Ongoing clinical trials continue to assess the efficacy of recombinant interferon preparations in treating a variety of cancers. Some trials suggest that treatments are most effective when administered in the early stages of cancer development. rhIFN-as have also proven effective in the treatment of various viral conditions, most notably viral hepatitis. Hepatitis refers to an inflammation of the liver. It may be induced by toxic substances, immunological abnormalities, or by viruses (infectious hepatitis). The main viral causative agents are ... 

IFN-x is currently generating considerable clinical interest. It induces effects similar to type I interferon, but it appears to exhibit significantly lower toxicity. Thus, it may prove possible to use this interferon safely at dosage levels far greater than the maximum dosage levels applied to currently used type I interferons. This, however, can only be elucidated by future clinical trials. 

Jonasch, E. and Haluska, F. 2001. Interferon in oncological practice review of interferon biology, clinical applications and toxicities. Oncologist 6(1), 34-55. 

The basic structure of carboxyethylgermanium sesquioxide, a low-toxicity y-interferon inducing agent, consists of a 12-membered ring containing six Ge tetrahedra bridged by oxygen atoms. 

Leonard, J.R et al., Effects of single-dose interleukin-12 exposure on interleukin-12-as-sociated toxicity and interferon-gamma production, Blood, 90, 2541, 1997. 

While rDNA techniques offer exciting possibilities, there are many unanswered questions about the potential toxicity that each new product represents. For example, acute clinical toxicities of interferons (IFNs) include flu-like syndrome, fever, chills, malaise, anorexia, fatigue, and headache. Chronic dose-limiting toxicities include neutropenia, thrombocytopenia, impairment of myeloid maturation, reversible dose-related hepatotoxicity, some neurological toxicity (stupor, psychosis, peripheral neuropathy) and gastrointestinal toxicity. Some of these toxicities would be difficult to ascertain in rodents, and, in fact, may be species-specific. 

A particular toxicity associated with the administration of interferon to humans and experimental animals has been depression of the cytochrome P-450 monooxygenase (MFO) metabolizing enzymes. As a consequence of MFO inhibition following treatment with IFN, the sleep-time of mice treated with hexabarbital is increased, as is the toxicity of acetaminophen (Stebbing and Week, 1984). Possible effects on the metabolism of chemotherapeutic agents or other drugs processed by the P-450 MFOs should be anticipated. 

This approach appears somewhat irrational and without much scientific merit, since many of these new molecules are minimally toxic or nontoxic by this sort of acute evaluation. As in the case of interferons or monoclonal antibodies, the toxic effects observed in humans might not be predicted from safety assessments in rodents. An appropriate test species should be selected. Is the rat or mouse the appropriate species to evaluate a species-specific rDNA protein such as human growth hormone or interferons, or would nonhuman primates be more suitable Does the nonhuman primate really offer any advantages There is some consensus that the nonhuman primate may be a more appropriate species for testing some rDNA human proteins. 

The synthetic polymeric components as well as their combinations with proteins such as human serum albumin (HSA), bovine serum albumin (BSA), human serum albumin/a-interferon mixtures (HSA-IFNa) and myoglobin (MYO) did not give any negative response to in vitro and in vivo biocompatibility tests, such as platelet aggregation, complement activation, acute toxicity, and acute thromboembolic potential. 

Bone marrow toxicity Peginterferon alfa-2a suppresses bone marrow function and may result in severe cytopenias. Ribavirin may potentiate the neutropenia and lymphopenia induced by alpha interferons including peginterferon alfa-2a. Alpha interferons may be associated with aplastic anemia very rarely. 

Combination regimens utilizing standard chemotherapy as a single modality have been attempted with increased toxicities reported but impressive overall and complete response rates as high as 27% for patients with recurrent and metastatic disease (74). Schrijvers and colleagues concluded that the addition of interferon a-2b (IFN-a) as a biomodulator of 5-FU and cisplatin in the recurrent or metastatic setting offered no benefit (75). One hundred twenty-two patients were randomized to cisplatin (100 mg/m2, d 1) and continuous infusion 5-FU (1000 mg/m2, d 1-4) with or without the addition of IFN-a. The overall response rates (47.1% vs 38.4%, p > 0.50) and median survival (6.3 vs 6 mo, p = 0.49) with and without the addition of INF-a, respectively were similar in both arms and were not statistically significant. 

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