Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0015672 (fatigue)
 51,768 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To determine which patients are prone to side effects from interferon beta-1b and which side effects are most troublesome, we studied 72 patients with clinically definite MS who were started on interferon beta-1b after its release and found that the side effects significantly associated with treatment included skin reactions, flu-like symptoms, fatigue, leukopenia, new or worsened depression, and new or worsened headache. Of these, only fatigue and depression were significantly associated with discontinuance of therapy. Moreover, the course of disease before initiation of treatment also had a significant impact on the likelihood of discontinuing medication. Thus, despite an apparently similar therapeutic benefit (as judged by the similarly reduced attack rate in each group), patients with a secondary chronic progressive course were more likely to discontinue treatment (63%) than patients with either a relapsing/progressive course (18%) or a remitting/relapsing course (7%). Indeed, in the final regression equation, the only factors significantly related (r = 0.875) to the discontinuance of therapy were fatigue (p < 0.0001), a fatigue-depression interaction (p < 0.0001), and a chronic progressive course of disease (p<0.0001). Thus, if future clinical trials are to provide useful information on the value of interferon beta-1b in progressive MS, the side effects of fatigue and depression will need to be ameliorated to limit the drop-out rate from such trials.
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PMID:Side effect profile of interferon beta-1b in MS: results of an open label trial. 861 31

Recombinant interferon beta-1b has been registered with the Swiss health authorities since August 1995. Due to a special arrangement with health insurances it has been possible to prescribe this medication since spring 1995. We report on our experience with the first 30 consecutively treated multiple sclerosis patients. Indication, adverse event profile and clinical response to treatment are described. The most common side effects were local injection site reactions (63%), influenza-like symptoms (50%) and fatigue (33%). As compared to the prestudy period we observed a 49% reduction in the exacerbation rate. Compliance was excellent, possibly due to strict selection and extensive information about possible effects and side effects.
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PMID:[Multiple sclerosis: therapy with recombinant beta-1b interferon: initial results with 30 multiple sclerosis patients in northwest Switzerland]. 892 50

Mice exercised to fatigue and exposed to herpes simplex virus type 1 (HSV-1) exhibit greater mortality than control mice. In this study, we examined lung macrophage resistance to HSV-1 after exercise in terms of both viral replication and interferon (IFN)-beta production. We utilized the reverse transcriptase-rapid polymerase chain reaction to measure the IFN-beta mRNA content in alveolar macrophages. IFN release was measured with a bioassay, and viral replication within the macrophage was assessed by plaque titration. Exercised (Ex) mice ran on a treadmill until fatigue while control (Con) mice remained in lanes above the treadmill. After exercise, alveolar macrophages were removed and incubated with HSV-1. Alveolar macrophage IFN-beta mRNA was greater in Ex than in Con mice. Culture supernatant from infected macrophages showed a higher degree of IFN release and a higher number of infectious viral particles in Ex vs. Con mice. It is likely that the increase in IFN-beta mRNA occurs in response to a higher degree of viral replication. These results suggest that macrophages from Ex mice are less resistant to infection with HSV-1.
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PMID:Exercise effects on IFN-beta expression and viral replication in lung macrophages after HSV-1 infection. 984 45

Overlapping symptomatologies between Chronic Fatigue Syndrome (CFS) and Chemical Sensitivity have been observed by different investigators. Therefore, it is of great importance to develop biomarker(s) for possible differentiation between viral induced CFS (without sensitivity to chemicals) versus chemically induced CFS. Since interferon induced proteins 2-5A Synthetase and Protein Kinase RNA (PKR) have been implicated in the viral induction of CFS, the objective of this study was to utilize 2-5A and PKR activity for differentiation between CFS induced by either viruses or chemicals. Based on the CDC definition and criteria, twenty CFS patients who were positive for viral genome(s) (mainly HHV6; HTLVII, EBV, and CMV) and did not have any history of exposure to toxic chemicals were included in this study. As a comparison, the second group of patients consisted of twenty individuals from the same geographical area who were negative for viral genomes but had been exposed to methyl tertiary-butyl ether concentration of up to 70 ppb and benzene concentration up to 14 ppb. All patients complained of fatigue and other symptoms overlapping between the two groups. From all 40 patients, blood was drawn, leukocyte extract was prepared and assayed for 2-5A Synthetase and PKR activity. Clinical specimens which were positive for viral genomes showed from 2.2-38.7 fold increase in 2-5A activity and 1.3-13.5 fold increase in PKR activities over the background of the healthy controls. Similarly, the second group (negative for viral genomes, but exposed to chemicals) showed a 1.1-29.2 fold increase for 2-5A Synthetase and a 1.3-11.6 fold increase for PKR when they were compared to healthy subjects. To elucidate mechanisms involved in viral versus chemical induction of 2-5A Synthetase and PKR, MDBK cell lines were cultured either in the presence or absence of HHV6, MTBE, or Benzene, heat shock proteins and interferon-beta. 2-5A and PKR activities were measured in all the above conditions. A clear induction of 2-5A and PKR was observed when MDBK cells were exposed to HHV6, MTBE, and Benzene. This induction was more significant with HSP90, HSP70, and IFN-beta indicating their involvement in the mechanism of action. However, when MDBK cells were incubated either with MTBE + Benzene or HHV6 in the presence or absence of anti IFN-beta or anti-HSP-70, the activities of both 2-5A and PKR in HHV6 infected cells were inhibited by more than 90% due to addition of anti IFN-beta, and only 20% by addition of anti-HSP70. While in MTBE + Benzene exposed cells anti IFN-beta reduced the activity of these enzymes by 40% and anti-HSP70 by more than 90%. This variation in the induction of 2-5A and PKR by anti-HSP70 or IFN-beta indicates involvement of IFN-beta in viral induction 2-5A and PKR, and HSP involvement in chemical induction of these enzymes. We conclude that 2-5A and PKR are not only biomarkers for viral induction of CFS, but biomarkers to other stressors that include MTBE and Benzene.
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PMID:Interferon-induced proteins are elevated in blood samples of patients with chemically or virally induced chronic fatigue syndrome. 1031 75

To evaluate the safety, toxicity, and maximum tolerated dose (MTD) of IFN beta-1a (Rebif, Serono Laboratories, Inc.) in patients with malignant diseases unresponsive to standard therapies and to assess the pharmacodynamics and pharmacokinetics associated with IFN beta-1a administration, an open-label, single-center phase I study was designed. Thirty-four patients were enrolled and treated with IFN beta-1a. All had measurable solid neoplasms or evaluable hematological malignancies. All patients received a single i.v. bolus dose of IFN-beta-1a on day 1, followed 7 days later by daily s.c. injections for 28 consecutive days. Successive groups of three patients received increasingly higher doses (in geometric progression from 1.5 million international units (MIU)/m2 to 24 MIU/m2) until dose-limiting toxicities were noted. Pharmacokinetic and biological studies, including measurement of the activity of 2',5'-oligoadenylate synthetase (2',5'-OAS) in peripheral blood mononuclear cells and serum levels of soluble Tac (CD 25) and beta-2 microglobulin, were performed on patients who agreed to participate. i.v. and s.c. doses of IFN beta-1a up to 24 MIU/m2 were administered. The most frequent adverse events (AEs) were constitutional symptoms. Grade III AEs during i.v. dosing included fever, elevation of bilirubin, and infection unrelated to therapy. No grade IV events were seen. AEs noted during continuous s.c. therapy included fever, liver transaminase increase, albuminuria, fatigue, nausea, myalgia, and rigors. Dose-limiting toxicities were encountered during s.c. dosing at the 24-MIU/m2 and 18-MIU/m2 dose levels and included gastrointestinal toxicity, elevations of aspartate aminotransferase and alanine aminotransferase, and albuminuria. The s.c. MTD was determined to be 12 MIU/m2, although there was great variability in the individual patient's ability to tolerate IFN beta-1a. 2',5'-OAS activity, thought to be indicative of IFN activity, increased within hours after i.v. and s.c. dosing, with the level remaining persistently elevated during the s.c. daily injections. The highest peak level was attained in the 6-MIU/m2 group. There was no evidence that the increase in 2',5'-OAS activity decayed with repetitive dosing, nor was there evidence of accumulation in this pharmacodynamic marker. Serum beta-2-microglobulin levels showed a modest time- and dose-dependent increase after s.c. administration of IFN beta-1a, with the largest increase seen at the 24-MIU/m2 dose level. There were no clear dose-dependent responses noted in soluble Tac serum levels. IFN beta-1a was well-tolerated when administered by a single i.v. bolus injection at doses up to and including 24 MIU/m2. Daily s.c. injections for at least 28 days were well-tolerated at doses up to and including 12 MIU/m2, with some patients tolerating doses twice as high as this. The MTD for the i.v. route could not be clearly determined according to the guidelines of the protocol. However, i.v. bolus doses up to 24 MIU/m2 were relatively well-tolerated. For the s.c. route, the MTD was determined to be 12 MIU/m2, but there was great interpatient variability, with some patients able to tolerate higher doses.
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PMID:A phase I study of recombinant interferon-beta in patients with advanced malignant disease. 1063 30

Interferon-beta-1b (IFN-beta-1b) has been shown to reduce the relapse rate in patients with relapsing-remitting multiple sclerosis (MS) and disease progression in patients with secondary progressive MS. While acute administration of IFN-beta-1b is known to cause flu-like symptoms, chronic medication has been suggested to cause mood alterations and anxiety attacks, and secondary to this neuropsychological deficits that may impair daily life. It is unknown, however, whether the latter symptoms are induced by acute IFN-beta-1b administration. Therefore, we examined the impact of a single subcutaneous injection of IFN-beta-1b in 8 healthy males. In a crossover design, each subject was injected subcutaneously with either 8 million IU IFN-beta-1b or placebo (NaCl) at 8:00 h. Flu-like symptoms (body temperature, heart rate, blood pressure), mood status ['profile of mood states', Befindlichkeitsskala (BFS)] and neuropsychological performance (trail marking test, verbal memory test, d2 attention test) and were assessed at baseline, 4, 8 and 24 h after injection. IFN-beta-1b increased body temperature, heart rate and fatigue. Nevertheless, acute IFN-beta-1b injection did not impair any parameters of neuropsychological performance. Thus, although IFN-beta-1b produces physiological symptoms indicative of sickness behavior, these data suggest that IFN-beta-1b administration does not have an impact on the cognitive capacity following acute administration.
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PMID:Neuropsychological performance and mood states following acute interferon-beta-1b administration in healthy males. 1209 9

Recombinant interferon beta-1b (INF-beta-1b) has been proven to be an effective means of treating relapsing-remitting multiple sclerosis (MS). Adverse reactions to interferon therapy have been well documented. The most common side effects are transient influenza-like symptoms, including fever, fatigue, nausea, and myalgia. Cutaneous necrosis has occasionally been reported, mostly involving small and limited lesions. This article describes an MS patient who developed multiple large, deep cutaneous ulcers on INF-beta-1b injection sites, which subsequently required surgical treatment. Vessel thrombosis in the subcutaneous fatty layer and the clinical appearance of livedoid erythema beside the ulcers indicated that INF-3-1b may have caused skin necrosis through its vascular effects.
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PMID:Skin necrosis following a recombinant interferon-beta-1b injection. 1255 67

In a 12-month follow-up study, we evaluated 27 patients (18 F and 9 M) with relapsing-remitting (RR) multiple sclerosis (MS), who had started treatment with interferon beta-1a (IFNbeta-1a) (Avonex), 30 microg i.m. once weekly, 6-18 months (median 10 months) before study entry. Quality of life (QOL), disability, independence, cognitive performances, symptoms of depression and anxiety, and fatigue were assessed at baseline, 6 months and 12 months. The frequency and severity of the side effects of treatment, at hours 0-12, 13-48 and 49-168 after the injection, were self-reported weekly in a structured questionnaire. QOL did not change significantly during the follow-up. The percentage of patients who reported side effects after the injection of IFNbeta-1a remained constant during the 52 weeks. The mean number of side effects increased significantly from the 6th to the 12th month. The general linear model analysis of variance disclosed significant changes over time for almost all side effects, but we did not find any correlation between QOL and number of side effects. In conclusion, 1-year treatment with IFNbeta-1a did not significantly change patient's QOL. Disability progression correlated with patient's QOL. Side effects, which were mild, did not diminish over time, did not induce treatment discontinuation and did not interfere with QOL.
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PMID:A longitudinal study of quality of life and side effects in patients with multiple sclerosis treated with interferon beta-1a. 1460 12

Functional imaging studies have demonstrated a relationship between fatigue and altered cerebral activation patterns in multiple sclerosis patients, but no relationship between fatigue and brain atrophy has been demonstrated. We hypothesized that the subjective complaint of fatigue would predict the severity of destructive brain pathology. We assessed the relationship between fatigue and brain atrophy longitudinally in a cohort of 134 patients previously enrolled in a 2-year clinical trial of interferon beta-1a and re-evaluated 8 years after randomization into the trial. Brain atrophy was measured using the brain parenchymal fraction (BPF), and disability was measured using the Multiple Sclerosis Functional Composite at baseline, year 2 and year 8. Fatigue was measured using the Sickness Impact Profile's Sleep and Rest Scale (SIPSR) at baseline, year 2 and year 8. Linear regression analyses were used to assess the relationship between changes in fatigue and atrophy progression. Worsening fatigue on the SIPSR during the initial 2 years was significantly associated with progressive brain atrophy over the subsequent 6 years. The relationships between fatigue and brain atrophy were independent of changes in disability, mood, or other MRI characteristics. This suggests that the subjective complaint of fatigue is linked to destructive pathologic processes in RRMS patients.
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PMID:Association of fatigue and brain atrophy in multiple sclerosis. 1569 98

A woman with a menstrual cycle-dependent fever (more than 38 degrees C) and severe fatigue that disrupted her ability to work was referred to our hospital. Six years ago, the patient received interferon beta injections (6,000,000 IU day-1x48 days) for the treatment of hepatitis C virus. Although the treatment was successful against the virus, the symptomatic fever occurred monthly since the third year after receiving the treatment. The symptoms occurred a few days after ovulation in every menstrual cycle. When the ovarian function was suppressed by GnRH agonist (GnRHa), the symptoms disappeared. While in anovulation, the patient received estrogen followed by estrogen with progestogen, which resembles the sex hormone milieu of a normal menstrual cycle without the LH surge; this treatment did not induce the symptoms. When human CG (hCG) was injected on the beginning day of estrogen with progestogen following treatment with estrogen alone, the previous symptoms reappeared. However, the hCG injection without estrogen priming did not induce the symptoms. These studies indicated that the LH surge after estrogen priming induced the symptoms. Changes in serum inflammatory cytokine levels (interleukin-1, interleukin-6, and tumor necrosis factor-alpha) were examined during the ovulatory cycle and the interleukin-1 levels during the treatment. There were no significant changes on these levels in the febrile period. The patient experienced normal menstrual cycles after finishing the five-month GnRHa treatment. Although her symptoms still occur, they are mild and do not require further medical treatment.
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PMID:A case of ovulatory cycle-dependent symptoms in woman with previous interferon beta therapy. 1600 34


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