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)

Fludarabine phosphate is the 2-fluoro, 5'-monophosphate derivative of vidarabine (ara-A) with the advantages of resistance to deamination by adenosine deaminase (ADA) and improved solubility. The mechanism of cytotoxic action of the compound appears to involve metabolic conversion to the active triphosphate. Fludarabine phosphate has substantial activity against lymphoid malignancies, particularly chronic lymphocytic leukemia (CLL) and low-grade non-Hodgkin's lymphoma (NHL). Its single-agent activity in CLL appears at least comparable to those of other conventional combination regimens. Its activity in Hodgkin's disease, mycosis fungoides, and macroglobulinemia, although suggestive, needs to be further defined and clinical trials are warranted in hairy cell leukemia, prolymphocytic leukemia, and previously untreated myeloma. The compound does not appear active against most common solid tumors. Early clinical trials indicated significant myelosuppression and the potential for severe neurotoxicity. Toxicity on the currently used low-dose schedules includes transient and reversible myelosuppression, nausea and vomiting, diarrhea, somnolence/fatigue, and elevations of liver enzymes and/or serum creatinine. Possible pulmonary toxicity has been suggested in several patients. The currently used low-doses of fludarabine phosphate, even with repeated administration, are well tolerated and appear safe with a negligible risk for severe neurotoxicity. Based on its single-agent activity and tolerability, the Food and Drug Administration recently granted group C designation of the drug for the treatment of patients with refractory CLL outside the clinical trials setting. The use of fludarabine phosphate in combination regimens and its impact on the natural history of the lymphoid malignancies is yet to be determined. Fludarabine phosphate may well occupy a pivotal role in the management of CLL and low-grade NHL.
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PMID:Fludarabine phosphate: a synthetic purine antimetabolite with significant activity against lymphoid malignancies. 170 43

Relapse continues to be a problem after bone marrow transplantation (BMT) for hematologic malignancies, particularly in recipients of autologous or T-cell-depleted allogeneic grafts and in patients with advanced disease. Interferon (IFN) has shown antiproliferative activity in several malignant hematologic diseases and potentially may be of benefit when administered early after BMT when the number of residual cells is minimal. We tested in a phase I study the maximum tolerated daily dose of recombinant IFN alpha-2b in patients who had received a transplant for a disease at high risk for relapse (acute myeloid leukemia or non-Hodgkin's lymphoma beyond first remission, advanced myelodysplastic syndrome, acute lymphoblastic leukemia at any stage, chronic myeloid leukemia in accelerated or blast phase. Recombinant IFN alpha-2b was started at a dose of 0.5 x 10(6) IU/m2 and escalated by 0.5 x 10(6) IU/m2 in groups of three or four patients. The intention was to administer IFN as soon as stable engraftment after BMT was achieved (defined as an absolute neutrophil count of greater than 2.0 x 10(9)/L and platelet count greater than 100 x 10(9)/L for 5 consecutive days) and continued for 2 months. A total of 14 patients were enrolled after autologous (n = 3) or allogeneic (n = 11) BMT. Dose-limiting toxicity was myelosuppression. Significant (grade 2 to 4) neutropenia and thrombocytopenia led to discontinuation or dose reduction in five of eight patients receiving 1.5 x 10(6) or 2 x 10(6) IU/m2 IFN. Mild to moderate (grade 1 or 2) anorexia, weight loss, and fatigue occurred in the majority of patients independent of the IFN dose. De novo acute GVHD responsive to steroid treatment developed in 3 of 11 allograft recipients. Natural killer (NK) cell function was low before IFN treatment and was not improved with the cytokine. Conversely, interleukin-2-activated NK cells showed normal function even before starting IFN and no change was seen during IFN treatment. Clonogenic hematopoietic progenitor studies showed depression of all progenitor lines (colony-forming unit [CFU]-granulocyte, erythroid, monocyte, megakaryocyte, CFU granulocyte-macrophage, burst-forming unit-erythroid) by IFN at all dose levels except at 0.5 x 10(6) IU/m2. Considering this result and the incidence and severity of marrow depression seen at doses greater than 1.0 x 10(6) IU/m2, we would consider this the maximum dose safely tolerated if IFN alpha-2b is administered in this setting for a prolonged course on a daily basis.
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PMID:Treatment with recombinant interferon (alpha-2b) early after bone marrow transplantation in patients at high risk for relapse [corrected]. 174 91

A polyethylene glycol conjugate of L-asparaginase (PEGLA) was administered to 21 patients with refractory non-Hodgkin's lymphoma. The dose given was 2,000 mu/m2 intramuscularly every 2 weeks. Eligibility required at least one prior trial of chemotherapy and ambulatory performance status. At entry, all patients had measurable lesions and documented disease progression. The median age of the patients was 61 years; 18 (86%) were ambulatory with minimal symptoms, 12 patients (57%) had 3 or more prior regimens, and 13 (62%) had stage IV disease. Histologic subtype was low grade in 11 patients (52%), intermediate in 7 (33%), high grade in 2 (10%) and unclassifiable in one (5%). There were two partial responses (11%) noted (95% confidence interval of response of 1-30%). Eleven patients (52%) were removed from study due to disease progression. Nine patients (43%), required removal for toxicity (7 for protracted nausea and vomiting and 2 for confusion). One patient died of sepsis while on study but this was not considered drug related. Almost one third of patients complained of fatigue or loss of appetite. Nausea and vomiting occurred in approximately half the patients and was moderate to severe in 9. Diarrhea and abdominal pain were also noted in one-third of those treated. Changes in the partial thromboplastin time and fibrinogen were noted in most patients but resulted in no bleeding complications. In this trial, PEGLA displayed modest activity in a heterogenous group of patients with progressive non-Hodgkin's lymphoma.
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PMID:A phase II trial of PEG-L-asparaginase in the treatment of non-Hodgkins lymphoma. 234 67

The effects and toxicities of interferon alfa are described, and the role of the pharmacist in making decisions and providing education about biologic response modifiers (BRMs) is discussed. Interferons have both direct antitumor activity and extensive effects on the immune system. Two recombinant interferon alfa products--interferon alfa-2a and interferon alfa-2b are available commercially. Indications in FDA-approved labeling for interferon alfa include the treatment of hairy-cell leukemia, acquired immunodeficiency syndrome-related Kaposi's sarcoma, and genital warts; however, it also is being used successfully against early chronic myelogenous leukemia, low-grade non-Hodgkin's lymphoma, cutaneous T-cell lymphoma, and previously untreated multiple myeloma. Other malignancies that respond to treatment with interferon alfa are malignant melanoma, ovarian carcinoma, and renal cell carcinoma. The toxic pattern of interferon alfa consists of flu-like symptoms, which are seen at all doses, on all schedules, and in virtually all patients. After repeated dosing, the chronic toxicities of anorexia, weight loss, and malaise and fatigue may develop. Myelosuppression, central nervous system toxicity, increased hepatic enzyme concentrations, nausea and vomiting, and cardiovascular toxicity also are possible. Serum neutralizing antibodies may be formed during therapy; this phenomenon may affect the clinical outcome. Numerous BRMs are being investigated for clinical use, and pharmacists must become conversant in the issues that surround these agents. Areas in which pharmacist involvement and knowledge are important include overall cost, product similarities and differences, dosing and scheduling, drug delivery systems, ways to minimize waste, adverse effects and their management, drug interactions, storage requirements, differences in production and purification techniques among manufacturers, and education of patients and staff.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Biologic response modifiers: the interferon alfa experience. 248 96

Patients treated for Hodgkin's disease and non-Hodgkin's lymphoma have a better prognosis than other patients with cancer so may have a lower prevalence of psychological and social morbidity. Trained interviewers used standardised methods to assess 90 patients at a mean of 32 months after the diagnosis of Hodgkin's disease or non-Hodgkin's lymphoma. Chemotherapy and radiotherapy had commonly caused adverse effects including hair loss, vomiting, nausea, and loss of appetite. Although most patients were free of disease and not receiving treatment at follow up, some still suffered from a lack of energy (31 patients), loss of libido (19), irritability (22), and tiredness (19); 30 patients complained of continued impairment of thinking or disturbance of short term memory. After diagnosis 21 patients had suffered from an anxiety state or depressive illness, or both, while 27 had experienced borderline anxiety or depression, or both. Mood disturbance was positively correlated with adverse effects of treatment, particularly those affecting the gastrointestinal tract. Social adjustment was less affected, but failure to return to work, or a long delay in returning to work, and a persistent lack of interest in leisure activities gave cause for concern. These findings of substantial psychiatric and social morbidity in patients with Hodgkin's disease and non-Hodgkin's lymphoma prompted a prospective study of these patients to determine their nature and duration.
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PMID:Psychological problems associated with diagnosis and treatment of lymphomas. I: Retrospective study. 311 23

A prospective study of 120 patients newly diagnosed as having Hodgkin's disease and non-Hodgkin's lymphoma was conducted to determine the nature, extent, and timing of the psychiatric and social morbidity associated with the diagnosis and treatment. Patients were interviewed at diagnosis and two, six, and 12 months later by trained interviewers using standardised questionnaires. Psychiatric morbidity was greatest in the three months before treatment, but new episodes of anxiety and depression developed throughout the year of follow up. Altogether 39 patients suffered a depressive illness or anxiety state, or both, and a further 37 experienced borderline anxiety or depression, or both, during the 15 months of assessment. The most common adverse effects of treatment were hair loss, nausea, vomiting, sore mouth, and changes in perception of taste. Toxicity of treatment was associated with psychiatric morbidity. Conditioned responses to chemotherapy were experienced by 32 patients. Social morbidity was low, although difficulties in returning to work and to previous levels of leisure activity were noted. Although most patients were no longer receiving treatment and were free of disease at the one year follow up, 51 patients continued to complain of loss of energy, 24 of loss of libido, 38 of tiredness, 23 of irritability, 18 of poor concentration, and 23 of memory impairment. These results confirm our retrospective study and suggest that a high price is paid for long term survival by a substantial proportion of patients receiving treatment for Hodgkin's disease and non-Hodgkin's lymphoma.
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PMID:Psychological problems associated with diagnosis and treatment of lymphomas. II: Prospective study. 311 24

In 1981, the National Cancer Institute undertook Phase II trials of interferon alfa-2a in patients with non-Hodgkin's lymphoma (including cutaneous T-cell lymphoma [CTCL]) and chronic lymphocytic leukemia (CLL). A dose of 50 X 10(6) U/m2, three times per week, was used initially, then adjusted downward as dictated by toxic effects. A 54% response rate was achieved among 24 patients with low-grade non-Hodgkin's lymphomas, and the median duration of response was 8 months. Less encouraging results emerged from studies in patients with intermediate- or high-grade disease. Responses were noted in only two of six patients in the former group, and only one of seven in the latter group. Results have likewise been disappointing in patients with CLL. Of 18 individuals treated, only two exhibited brief, partial responses. In CTCL, on the other hand, alpha interferon may be the most effective single agent. Among 20 patients with advanced disease who had failed previous therapies, 45% responded. The primary dose-limiting toxicity in all these trials has been flu-like symptoms, particularly fever and fatigue. Fever has generally resolved as treatment has been continued, but dosage reductions are usually necessary to alleviate fatigue. Future studies are likely to focus on the use of alpha interferon in combination with chemotherapeutic agents or other biologic response modifiers, such as monoclonal antibodies.
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PMID:Interferon therapy of non-Hodgkin's lymphoma. 349 59

Alpha interferons are biological response modifiers that regulate immune function, slow cell proliferation, and inhibit virus replication. Large supplies of purified preparations are now available for clinical trials. Common toxicity includes an influenza-like syndrome to which tolerance occurs after several doses, and chronic fatigue and anorexia that may be dose-limiting. Myelosuppression is mild. Alpha interferons have established clinical activity against several human cancers, including melanoma, Kaposi's sarcoma, multiple myeloma, non-Hodgkin's lymphoma, hairy cell leukemia, and renal cell carcinoma. These data and alpha interferon nomenclature are summarized in table form. Intranasal alpha interferon is effective in prophylaxis of common viral upper respiratory tract infections, although toxicity in long-term use is prohibitive. Short-term administration to high risk populations may be most useful. Optimal doses and schedules need to be determined for all indications.
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PMID:The new alpha interferons. 391 Mar 84

A phase I study of VP was undertaken using the methods of a single (40 cases; range of dose levels 30-540 mg/m2) and 5-day (41 cases; range of dose levels 40-140 mg/m2/day) intravenous administration. The dose-limiting toxicity of VP was moderate to severe leukopenia. MTD was estimated to be 540 mg/m2 for a single and 140 mg/m2/day for 5-day administration. The median days to WBC nadir from the start of therapy and to recovery from reaching the nadir were 10 and 10.5 for single, and 15 and 7 for 5-day administration, respectively. Thrombocytopenia was less frequent and less pronounced than leukopenia. Mild gastrointestinal disturbances and alopecia were frequently observed. Transient hepatic dysfunction, fever, headache, fatigue, dyspnea, hypotension, and pain along the vein were also encountered in a small number of patients. There were no cases with renal, neurologic or cardiac toxicity. Objective tumor regression was seen in one case each of IBL(CR), bladder cancer, non-Hodgkin's lymphoma and ATL (PR). The post-infusion plasma decay of VP in 4 cases given 80-120 mg/m2 by a single administration was biphasic with t1/2 alpha ranging from 0.13 to 0.39 h and t1/2 beta ranging from 3.33 to 4.85 h. No accumulation of VP was found in plasma after five repeated daily doses. Doses of 360-480 mg/m2 by single and 80-100 mg/m2/day by 5-day administration repeated every 3 to 4 weeks can therefore be recommended for phase II studies in good-risk patients.
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PMID:[A phase I study of VP-16-213 (VP, etoposide) by single and 5-day intravenous administration]. 394 9

Forty-nine patients with non-Hodgkin's lymphoma or Hodgkin's disease were entered into a multi-institutional phase II trial to evaluate the antitumor activity of human interferon alpha, prepared from buffy coats. Interferon alpha was administered intramuscularly in doses of 1 X 10(6) u, 3 X 10(6) u or 9 X 10(6) u daily for 30 days. Objective partial responses were seen in 3 of 18 patients with nodular lymphoma, all at the 9 X 10(6) u dose. Interferon alpha was not observed to be of therapeutic benefit in the other subtypes of non-Hodgkin's lymphoma or Hodgkin's disease. The major toxicities consisted of fatigue, fever, myalgias and weight loss. Serum interferon levels obtained 3 to 4 hours after injection varied widely, even among patients treated at the same dose level. Despite the relatively low doses of interferon used and the brief period of administration, this study extends the earlier observations of the antitumor effect of interferon in nodular lymphoma. These results are discussed in relation to the cumulative experience in human lymphoma using alpha interferons induced in human leukocytes and those produced in bacteria by recombinant DNA techniques.
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PMID:Human interferon alpha in malignant lymphoma and Hodgkin's disease. Results of the American Cancer Society trial. 402 69


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