Interferon administration

The formation and release of interferon by viral and other pathological stimulation has resulted in a search for chemical inducers of endogenous interferon. Administration of a wide range of compounds has resulted in induction of interferon production. However, no clinically useful compounds have been found for humans, although tilorone is effective in inducing interferon in mice. 

Depending on the timing of exposure, interferon alfa may adversely affect the pharmacokinetic and hematological effects of cyclophosphamide. In 10 patients with multiple myeloma, interferon alfa given 2 hours before cyclophosphamide infusion significantly reduced cyclophosphamide clearance and produced less exposure to its metabolite 4-hydroxycyclophosphamide compared with interferon administration 24 hours after cyclophosphamide (406). This resulted in a significantly greater fall in white blood cell count in patients who received interferon alfa after cyclophosphamide. 

Castro A, Suarez D, Inglada L, CarbaUo E, Dominguez A, Diago M, Such J, Del Olmo JA, Perez-Mota A, Pedreira J, Quiroga JA, Carreno V (1997) Multicenter randomized, controlled study of intramuscular administration of interferon-beta for the treatment of chronic hepatitis C. J Interferon Cytokine Res 17 27-30... 

Pegylated interferon is interferon that is attached to a polyethylene glycol molecule that increases the half-life of the drug, thus allowing once-weekly dosing versus thrice-weekly administration required for the unmodified formulation. Pegylated interferon is well tolerated and is superior in efficacy to unmodified interferon for the treatment of chronic hepatitis B.26... 

Dosing and Administration Dose, frequency, and route of administration differ between the beta interferon products (see Table 26-3). 0 Dose-response curves have been observed with the beta interferons. However, it is not known if the total weekly dose or the frequency of administration is most important.37... 

Interferon-a2b is approved by the Food and Drug Administration (FDA) as adjuvant therapy for high-risk melanoma. 

Interferon-a2b has diverse mechanisms of action, including antiviral activity, impact on cellular metabolism and differentiation, and antitumor activity.42 The antitumor activity is due to a combination of direct antiproliferative effect on tumor cells and indirect immune-mediated effects.42 Interferon-a2b is currently approved by the Food and Drug Administration (FDA) as adjuvant therapy for patients who are free of disease after curative surgical resection but are at high risk of MM recurrence. This includes patients with bulky disease or regional lymph node involvement such as stage IIB, IIC, or III disease.43 It is controversial if interferon-a2b (IFN) should be offered as adjuvant therapy for every high-risk MM patient. The reason is because clinical trials with different doses of IFN have not proved definitively that IFN improves overall patient survival. 

Fever, rigors, chills, malaise headaches, myalgia Nausea, emesis Neutropenia Hepatic enzyme elevation Cutaneous—alopecia, transient, mild rashlike reaction Acetaminophen (APAP). NSAID if APAP is not effective. Meperidine for severe chills and rigors. Bedtime administration. 5-HT3 antagonist, prochlorperazine, metoclopramide, fluids Weekly complete blood count reduce dose by 30-50% Liver function tests (LFTs) weekly withhold treatment until LFTs normalize restart at 30-50% dose reduction reversible on dose reduction or cessation. Interferon is contraindicated in patients with psoriasis because exacerbation of psoriasis has been noted during IFN therapy. 

To study the effects of iron overloading on inflammatory cells, Muntane et al. [186] investigated the effect of iron dcxtran administration on the acute and chronic phases of carrageenan-induced glanuloma. It was found that iron dcxtran increased the iron content in plasma and stores, and enhanced lipid peroxidation and superoxide production by inflammatory cells. At the same time, iron dcxtran had a beneficial effect on recovery from the anemia of inflammation. It has been suggested that iron overload may affect nitric oxide production in animals. For example, alveolar macrophages from iron-overloaded rats stimulated with LPS or interferon-7 diminished NO release compared to normal rats [187]. 

PEGylated interferons Covalent attachment of PEG increases interferon half-life from 3 h to some 24 h, thereby generating a product whose dosage schedule requires once-weekly as opposed to daily administration 8... 

Clinical trials have shown the recombinant interferons to be effective in the treatment of various cancer types, with rhIFN-a2a and -a2b both approved for treatment of hairy cell leukaemia. This is a rare B-lymphocyte neoplasm for which few effective treatments were previously available. Administration of the recombinant interferons promotes significant regression of the cancer in up to 90 per cent of patients. 

Like most drugs, administration of interferons can elicit a number of unwanted side effects. Unfortunately, in some instances the severity of such effects can limit the maximum recommended therapeutic... 

Prediction of the range or severity of side effects noted after administration of any interferon preparation is impossible. Careful monitoring of the patients, particularly in the earliest stages of treatment, soon reveals the onset of any side effects that might warrant suspension of treatment. 

Younes, H. and Amsden, B. 2002. Interferon-gamma therapy evaluation of routes of administration and delivery systems. Journal of Pharmaceutical Sciences 91(1), 2-17. 

Aso and coworkers described the induction of interferon by oral administration of Ge-13223. The metabolic fate of Ge-132 was investigated by Kagoshima and Onishi24. 

Alimena, G. et al., Interferon alpha-2b as therapy for Ph -positive chronic myelogenous leukemia A study of 82 patients treated with intermittent or daily administration, Blood, 72, 642, 1988. 

Based upon recent controlled studies, there is considerable evidence that opioids such as morphine induce substantial effects on immune status. For example, it has been shown that morphine administration is associated with alterations in a number of immune parameters, such as natural-killer cell activity [12,13], proliferation of lymphocytes, [13, 14] antibody production [15,16], and the production of interferon [17]. Studies in our laboratory have shown that acute morphine treatment in rats suppresses splenic lymphocyte proliferative responses to both T- and B-cell mitogens, splenic natural-killer cell activity, blood lymphocyte mitogenic responsiveness to T-cell mitogens, and the in vitro production of the cytokines interleukin-2 and interferon-y [18-22], Furthermore, the immune alterations induced by morphine are dose-dependent and antagonized by the opioid-receptor antagonist, naltrexone (e.g., [22]). 

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. 

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