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)

Kaposi's sarcoma (KS) is a malignant neoplasm that develops in 20% to 30% of all acquired immunodeficiency syndrome (AIDS) cases. Kaposi's sarcoma primarily involves the skin, but can progress to involve the lungs, gastrointestinal tract, and liver. alpha-Interferon alone or in combination with zivoduvine has activity in acquired immunodeficiency syndrome-related KS, especially in patients with limited disease and CD4 lymphocyte counts over 400/mm3. Patients with progressive or symptomatic visceral disease, however, can be treated more effectively with cytotoxic chemotherapy. We have used a combination of doxorubicin, bleomycin, and vincristine (ABV) and have achieved response rates of over 80%. Discontinuation of therapy, however, is associated with relapse shortly after response (2 to 3 months). Thus, we have begun studies to define a safe and effective maintenance therapy. Such therapies should include antiretroviral agents since most patients succumb to other human immunodeficiency virus complications, and since human immunodeficiency virus directly, through viral proteins, and indirectly, through the induction of cellular genes, induces KS growth. Additionally, agents with antitumor activity and possible antiviral activity, such as alpha-interferon, may be potentially effective in maintenance therapies. We recently studied 21 patients in a phase I study of recombinant interferon alpha-2b (INTRON-A, Schering-Plough Corp, Kenilworth, NJ) alone following ABV chemotherapy. A dose of 10 million units, given in daily subcutaneous injections, was the maximal tolerated dose; higher doses were associated with intolerable fatigue, diarrhea, and fevers. We are currently conducting a phase I/II trial studying the combination of zivoduvine (500 mg/d) and recombinant interferon alpha-2b (5, 10, and 15 million units) as maintenance in patients with advanced or progressive KS.
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PMID:Phase I/II trials of alpha-interferon alone or in combination with zidovudine as maintenance therapy following induction chemotherapy in the treatment of acquired immunodeficiency syndrome-related Kaposi's sarcoma. 171 42

The interferons (IFN) act too slowly to arrest acute viral infections, but interferon-alpha (IFN alpha) preparations have proved useful in some chronic infections and will clearly be used increasingly in these in the future. In the preparations derived from human leucocytes or cultured B lymphoblastoid cells, which are in routine clinical use, mixtures of a number of distinct subtypes of human IFN alpha have been identified. There are also 3 slightly different versions of the same single subtype, IFN alpha-2, made by recombinant DNA procedures in bacteria. IFN alpha preparations are injected intramuscularly or subcutaneously. Dose-related side effects are common but usually tolerable, but prolonged treatment may cause increasing fatigue and depression. Some patients form neutralising antibodies which block the effects of the IFN; these appear to be relatively more common after recombinant IFN alpha-2 than after IFN derived from human cells. Given intranasally, IFN alpha can prevent a subsequent experimental rhinovirus infection, or the spread of natural colds within a family. Repeated administration progressively damages the nasal mucosa, so that long term prophylaxis is not possible. IFN alpha has proved useful in patients with papillomavirus warts of the larynx, ano-genital region (condyloma acuminata) and skin (common warts). Treatment regimens remain to be optimised and are likely to include surgery or other treatments. IFN alpha and zidovudine (azidothymidine) synergistically inhibit the growth of HIV in vitro, and combination are on trial in patients with early AIDS. Very large doses of IFN alpha are effective against Kaposi's sarcoma in some AIDS patients. In chronic hepatitis B, continuing virus replication may lead to cirrhosis or primary liver cancer. Earlier clinical trials with IFN alpha gave inconclusive results, but recent large studies have confirmed that 25 to 40% of patients obtain benefit; this probably results from both the antiviral and the immunomodulatory effects of IFN alpha. In patients with chronic hepatitis C, the biochemical markers usually improve rapidly during IFN alpha administration, but relapse if treatment is stopped after only a few months; to increase the chances of sustained cure, the treatment period is now being prolonged.
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PMID:The use of interferon-alpha in virus infections. 172 72

In a series of studies, recombinant interferon-alpha 2a (rIFN alpha 2a, Roferon-A) was administered alone (273 men) or combined with vinblastine (91 men) to patients with acquired immunodeficiency syndrome (AIDS)-related Kaposi's sarcoma (KS). Patients were treated with daily doses of rIFN alpha 2a ranging from 3 to 54 million international units (I.U.) administered intramuscularly. A dose of 36 million I.U. daily for approximately 10 weeks followed by a three times weekly maintenance schedule with the same dose resulted in the best overall therapeutic benefit. An escalating-dose regimen of 3, 9, and 18 million I.U. daily, each for 3 days, followed by 36 million I.U. daily, produced equivalent therapeutic benefit with amelioration of acute toxicity in some patients. Response was more likely in patients without a history of opportunistic infection or B symptoms (fever, night sweats, or weight loss). Response rate increased with increasing baseline CD4 lymphocyte count and was 45.5% in patients with a CD4 count of greater than 400/mm3. Responding patients with a CD4 count of greater than 200/mm3 had a distinct survival advantage over patients who had similar CD4 counts but whose tumors did not regress with therapy. The addition of vinblastine increased toxicity and did not improve the response rate or prolong survival. Side effects included fatigue, fever, chills, myalgias, headaches, anorexia, nausea, diarrhea, and dizziness. Mild abnormalities in hematologic and liver function tests occurred in some patients. Most adverse effects diminished or resolved with continued therapy. We conclude that rIFN alpha 2a offers important therapeutic benefit in a select group of patients with AIDS-related KS.
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PMID:Interferon-alpha 2a in the treatment of acquired immunodeficiency syndrome-related Kaposi's sarcoma. 182 54

A combination of oral zidovudine (250 mg twice daily) and subcutaneous interferon-alpha (10 x 10(6) units daily) was evaluated for clinical, antiretroviral, and immunological efficacy and for side effects in 17 patients with AIDS-related Kaposi's sarcoma. Fifteen patients were evaluable. During the study period of 12 weeks, tumor responses were complete in two patients and partial in two patients (27% major response rate). Minimal responses were seen in two patients (40% overall response rate). An anti-HIV effect (reduction of serum p24 antigen by 70% or more) was observed in seven of ten evaluable patients who were initially antigenemic. CD4 lymphocyte counts remained unchanged. In six patients who had either a tumor response or a marked decline of HIV antigenemia, the treatment was continued between 12 and 59 weeks beyond the study period. Two of four patients with tumor regression at 12 weeks had an additional tumor response in this period despite prior dose reduction of interferon due to toxicity. Late progression of KS was eventually observed in four of six patients on prolonged treatment. The responsiveness of Kaposi's sarcoma seen in this study in patients with low CD4 counts and prior constitutional symptoms (fever, weight loss) was unexpected and needs further confirmation by larger patient groups. Dose-limiting toxicities were bone marrow depression (severe anemia in four and neutropenia with anemia in two patients), subjective adverse experiences (fever, fatigue, myalgia; four patients) and both (two patients).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Combined treatment with zidovudine and lymphoblast interferon-alpha in patients with HIV-related Kaposi's sarcoma. 190 99

A prospective phase I clinical trial with recombinant interferon-alpha-2b as maintenance therapy after cytotoxic chemotherapy was conducted. Twenty-one homosexual and bisexual males with extensive mucocutaneous or visceral epidemic acquired immunodeficiency syndrome (AIDS)-Kaposi's sarcoma (KS) were studied. After a complete response (6 patients) or partial response (15 patients) from chemotherapy consisting of Adriamycin (20 mg/m2), bleomycin (10 U/m2), and vincristine (1.4 mg/m2; 2 mg maximum), patients were given interferon-alpha (IFN-alpha) in an attempt to prolong disease-free survival. Three dose levels of daily IFN-alpha were tested: 5, 10, and 15 million U. The maximum tolerated dose was 10 million units. Dose-limiting toxicities included recurrent grade 3 fatigue, diarrhea, and fever, which resulted in the termination of therapy in eight patients (38%). Hematologic toxicities were infrequent (four patients; 19%). Responses were observed in two patients on IFN-alpha, both at the 10-million-U dose level. The median duration of response on IFN-alpha therapy following chemotherapy was 8 weeks (range, 3-11). We conclude that the duration of IFN-alpha maintenance response following cytotoxic chemotherapy is short with response to residual disease observed in a minority of cases at this dose and schedule. Additional trials of maintenance therapy in patients with advanced AIDS-KS combining antiretroviral agents are in progress.
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PMID:Interferon-alpha maintenance therapy after cytotoxic chemotherapy for treatment of acquired immunodeficiency syndrome-related Kaposi's sarcoma. 225 62

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

A Phase I study of recombinant interferon-gamma (rIFN-gamma) was conducted to determine the toxicity and pharmacokinetics of this lymphokine in acquired immunodeficiency syndrome (AIDS) patients with Kaposi's sarcoma (KS). Sixteen patients with AIDS/KS were entered into a fixed-dose trial at either 0.001, 0.01, 0.1, or 1.0 mg/m2 of rIFN-gamma. rIFN-gamma was initially administered either as a single 24-hr continuous iv infusion or as a single im injection, followed 4 days later by a 10-day course of daily therapy by the same route. Following a 1-week washout period, this sequence of administration was then repeated, with the drug given by the alternate route. Pharmacokinetic analysis of the 1.0-mg/m2 group revealed that peak serum levels of up to 153 U/ml occurred 2-4 hr after im injection and that steady-state levels of up to 40 U/ml were reached approximately 7-12 hr after beginning iv infusion. Dose-related toxicities in this trial included fever, headache, fatigue, nausea, and hepatitis, all of which were most severe at the two highest doses. Dose-dependent depression of the total white blood-cell (WBC) count, affecting both granulocytes and lymphocytes, was the most common laboratory abnormality. Natural killer (NK)-cell activity was slightly enhanced at a dose of 0.1 mg/m2 but suppressed at 1.0 mg/m2 of drug; monocyte-mediated cytotoxicity, in contrast, was significantly increased only at the highest dose. No dose-related changes were noted in KS lesions, HLA-DR expression by peripheral blood mononuclear cells, lymphocyte blastogenesis, or the ability to culture cytomegalovirus (CMV) from body fluids. We conclude that a maximally tolerated dose (MTD) for this drug is in the range of 0.1-1.0 mg/m2 and that at least modest evidence of systemic immunomodulation may be seen when rIFN-gamma is given at doses at or near this MTD.
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PMID:A phase I trial of recombinant human interferon-gamma in patients with Kaposi's sarcoma and the acquired immunodeficiency syndrome (AIDS). 254 86

rTNF was administered to 28 patients with advanced metastatic cancers by continuous intravenous infusion for 5 consecutive days every 2 weeks. The dose levels were 30, 40, 70, 110, 180 and 290 micrograms/M2/day. Groups of 3 patients were started at each successive dose level and then on subsequent courses treated with the next dose level through 4 escalations as tolerated. Tumor types were: colon cancer 14; adenocarcinoma of unknown primary, 2; renal cancer, 2; leiomyosarcoma, 2; lung cancer, 1; prostate cancer, 1; thymona, 1; bladder cancer; 1; parotid, 1; Kaposi's sarcoma 2; ovarian 1. Toxicities included fever and chills (usually within the first 8 hours of infusion), fatigue, headache, decreased performance status, hypotension and CNS. All patients experienced leukopenia and thrombocytopenia within 24 hours or less after start of infusion with return of baseline by 72 hours after rTNF was stopped. The fall in these counts averaged 50% and was not dose related. No major changes in liver or renal function, coagulation or blood lipids were seen. Major dose limiting toxicities were fatigue, confusion, thrombocytopenia, seizures, hypotension and decreased performance status. NK cell activity measured against K562 target cells was augmented from about 30% target cell lysis to about 70% target cell lysis over the first 7 days of treatment. Two patients, both with metastatic colon cancer showed transient, objective tumor regression which did not qualify as a partial response. One patient with ovarian cancer had a stable partial response but progressed after 13 courses of treatment. Continuous infusion of TNF can be safely administered to patients with a maximum tolerated dose of only between 30 and 40 micrograms/M2/day.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:A phase I trial of recombinant tumor necrosis factor (rTNF) administered by continuous intravenous infusion in patients with disseminated malignancy. 264 24

The characteristics and clinical uses of recombinant colony-stimulating factors (CSFs) are described, and the pharmacist's role as a consultant and educator on biotherapeutic substances is discussed. CSFs stimulate the formation and differentiation of the erythrocytes, neutrophils, eosinophils, basophils, monocytes, and platelets that compose the blood cell population. Recombinant CSFs represent a means by which the numbers of hematopoietic cells can be modulated, thus making these agents potentially useful in treating hematologic and immunologic deficiencies. CSFs also can increase the ability of neutrophils and monocyte-macrophages to protect the body against foreign invasion. Granulocyte macrophage colony-stimulating factor (GM-CSF) has increased host defenses in acquired immunodeficiency syndrome patients with Kaposi's sarcoma; increased neutrophil, platelet, and erythrocyte counts in preleukemic patients; and increased neutrophil counts in patients with aplastic anemia. GM-CSF and granulocyte colony-stimulating factor (G-CSF) have appeared to alleviate the drastic decrease in neutrophil counts associated with cytotoxic chemotherapy. G-CSF also has shown promise in stimulating neutrophil production in patients with transitional cell carcinoma, congenital agranulocytosis, and hairy-cell leukemia. Mild adverse effects such as fever, chills, rash, fatigue, myalgia, and bone pain are associated with GM-CSF therapy; G-CSF therapy is associated mostly with mild to moderate bone pain. Areas of education for pharmacists working with biotherapeutic substances include stability, storage temperature, drug interactions, novel drug-delivery systems such as monoclonal antibodies or liposomes, variations in biologic activity, and the evolving nature of the information about these investigational drugs. The pharmacist can anticipate an increasing role as a consultant on the use of CSFs and other biotherapeutic substances.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Colony-stimulating factors and tomorrow's pharmacy: why we must be ready. 269 Jun 7

Seventy-four sequential lymph node biopsies from 30 acquired immunodeficiency syndrome (AIDS)/AIDS-related complex (ARC) patients showed temporal histologic progression from explosive follicular hyperplasia (EFH) to mixed follicular hyperplasia/involution (mixed) to follicular involution (FI) to lymphocyte depletion (LD). This histologic progression correlated with symptoms, development of opportunistic infections (OI), and mortality. At initial biopsy, only 50% of the AIDS/ARC patients with EFH/mixed compared to 100% with FI/LD were symptomatic with weight loss, night sweats, diarrhea, fever, or fatigue. 31% of ARC patients with EFH and 63% with FI developed an OI in a median of 69 months and 5 months, respectively; 86% with LD had a concurrent or previous OI. Ninety percent of ARC patients progressing to FI/LD died; 85% of those persisting with EFH/mixed remained alive 18 to 50 months after initial biopsy. AIDS patients with EFH lived twice as long as those with FI/LD. Progressive histology did not correlate with lymphoma. The number of ARC patients developing Kaposi's sarcoma was too small to draw definitive conclusions.
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PMID:Progressive lymph node histology and its prognostic value in patients with acquired immunodeficiency syndrome and AIDS-related complex. 272 79


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