Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027947 (neutropenia)
 17,527 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Zidovudine, a nucleoside analog, was the first agent proved to be effective in the management of human immunodeficiency virus type 1 (HIV-1) infection. After demonstration of zidovudine's in-vitro activity against HIV-1 in 1985, the drug was rapidly evaluated in phase I and phase II clinical trials and was found to be effective in decreasing both mortality and the incidence of opportunistic infections in patients with the acquired immunodeficiency syndrome (AIDS) and advanced AIDS-related complex; the drug was also found to have a substantial but tolerable toxicity profile. Since the licensure of zidovudine in 1987, an intensive clinical research effort has established the drug's efficacy in the prevention of disease progression in asymptomatic and mildly symptomatic HIV-infected persons and has established the success of lower-dose therapy in patients at all stages of disease. The current recommendation is to use zidovudine at a dose of 500 to 600 mg/d in both symptomatic and asymptomatic persons with CD4 counts of less than 500/mm3. The major toxicities of anemia and neutropenia are less frequent at the lower doses presently used and can be managed by dose reduction or by use of hematopoietic growth factors. The inexorable disease progression seen despite zidovudine therapy and the isolation of clinical strains of HIV-1 resistant to zidovudine in vitro highlight the limitations of prolonged monotherapy with this agent. Although alternative dideoxynucleoside agents (for example, didanosine [dideoxyinosine and zalcitabine dideoxycytidine]) are available for the management of HIV-infected persons, zidovudine remains the cornerstone of antiretroviral therapy. Current research efforts are directed at elucidating the clinical relevance of zidovudine resistance and studying regimens in which zidovudine is used in combination with other agents. This latter approach holds great promise for improving efficacy, limiting toxicity, and perhaps preventing the emergence of viral resistance. For the forseeable future, zidovudine will continue to play a role in the development and in our understanding of antiretroviral therapy.
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PMID:Zidovudine: five years later. 844 32

Anemia, thrombocytopenia, and neutropenia have been observed in patients with acquired immune deficiency syndrome (AIDS) and AIDS-related complex. To investigate whether red cells (RBCs) of patients with human immunodeficiency virus infection were coated with IgG and/or complement (C3), blood samples of 239 patients were tested. The prevalence of a positive direct antiglobulin test on RBCs was 16.7 percent. By use of an enzyme-linked antiglobulin test (ELAT) to measure more accurately the number of IgG molecules per RBC in a group of 67 patients, 30 of the 67 individuals were observed to have increased numbers (mean, 155) compared to normal controls and to patients with hypergammaglobulinemia due to multiple myeloma or chronic liver disease. Hemoglobin level was correlated with the number of IgG molecules per RBC (p = 0.008), but no correlation could be demonstrated between those numbers and serum immunoglobulin (p = 0.10) or circulating immune complexes (p = 0.38). Our results with ELAT suggest that some AIDS patients may have specific binding of IgG on the surface of their RBCs, rather than nonspecific uptake; further clinical correlations are necessary to confirm these findings.
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PMID:Quantitation of red cell-bound IgG by an enzyme-linked antiglobulin test in human immunodeficiency virus-infected persons. 162 45

Adverse effects stemming from the therapeutic use of dideoxynucleoside derivatives continue to occur in patients with AIDS or AIDS-related complex. For example, the continued use of 3'-azido-3'-deoxythymidine (AZT) and 2',3'-didoxycytidine (ddC), both of which confer clinical benefits in AIDS patients, may be complicated by anemia, neutropenia and thrombocytopenia and ddC also causes peripheral neuropathy. Subsequently, the National Toxicology Program (NTP) has undertaken efforts to define and characterize the toxicities associated with currently employed and potential AIDS therapeutics in experimental animals, with particular emphasis on the hematopoietic and immune systems. In addition to AZT and ddC, 2',3'-dideoxyadenosine (ddA), 2',3'-dideoxyinosine (ddI) and 2',3'-didehydrodideoxythymidine (d4T) have been examined. The present studies describe: (1) the development of a poorly regenerative macrocytic anemia in mice exposed to AZT or ddC. This anemia demonstrates a rapid and progressive time course of toxicity and reversibility after cessation of treatment; (2) the selective suppression of erythroid progenitor cells in mice exposed to d4T without concomitant effects on myeloid stem cells. Myelotoxicity appears to show metabolism-dependent strain-specificity and is more evident following in vitro exposure than in vivo exposure; and (3) the immunosuppressive effects following subchronic (30-day) exposure. Of the nucleoside derivatives studied, only ddA and ddI altered immune function and these changes were confined to suppression of antibody responses. It can be concluded that the overall similarities in the hematopoietic and immune system effects between rodents and humans indicate that such animal toxicology studies provide important information relevant to the toxicity of these drugs.
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PMID:Experimental studies of the hematologic and immune system toxicity of nucleoside derivatives used against HIV infection. 166 55

The efficacy of recombinant human granulocyte colony-stimulating factor (rhG-CSF) on neutropenia was evaluated in 14 patients with AIDS and AIDS-related complex (ARC). In all patients, including 11 neutropenic patients, 100 or 200 micrograms/m2 of rhG-CSF significantly increased the neutrophil counts. The response was greater in patients with higher neutrophil counts before the treatment, and was also dose-dependent. Although the effect seemed to be less potent, the agent also increased the neutrophil counts even when zidovudine (azidothymidine, AZT) and other myelosuppressive antiviral agents were administered simultaneously. These observations indicate that rhG-CSF may be beneficial in preventing and treating some secondary infections, and will make it easier to continue therapy with antiviral agents in patients with AIDS or ARC.
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PMID:Efficacy of recombinant human granulocyte colony-stimulating factor on neutropenia in patients with AIDS. 170 65

Twenty-two patients with acquired immunodeficiency syndrome (AIDS) or severe AIDS-related complex and multilineage hematopoietic defects were treated with recombinant granulocyte colony-stimulating factor (G-CSF) and erythropoietin (EPO) in a phase I/II trial. All patients were neutropenic and anemic after withdrawal of all bone marrow-suppressive drugs. Daily, G-CSF was subcutaneously self-administered until an absolute neutrophil count (ANC) greater than 6,000/microL was achieved and maintained for 2 weeks. Subcutaneous EPO was added to the regimen and the dose increased until an increase of 15 g/L of hemoglobin was observed. Groups of patients were administered increasing doses of zidovudine to determine their tolerance. G-CSF and EPO therapy was continued with dose modification to maintain an ANC greater than 1,500/microL and hemoglobin greater than 100 g/L. The dose of zidovudine was not altered. All 22 patients responded to G-CSF with a mean 10-fold increase in neutrophils occurring in less than 2 weeks. Significant increases in CD4 and CD8 cell number, lymphocyte proliferative response, and bone marrow cellularity were seen. EPO therapy increased hemoglobin in all 20 evaluable patients within 8 weeks. Sixteen patients received 1,000 mg and four patients received 1,500 mg of zidovudine per day. The reinstitution of zidovudine resulted in a decline in reticulocytes and hemoglobin and the reappearance of transfusion requirements in eight of the 20 patients, six of whom had the study medications stopped. No patient had the study medications stopped because of neutropenia or thrombocytopenia. Toxicities were mild and did not require dose modifications. Limiting dilution plasma and lymphocyte co-cultures for HIV as well as serum p24 antigen levels did not change significantly during G-CSF or combined G-CSF and EPO therapy. HIV p24 antigen decreased significantly with zidovudine therapy. Opportunistic infections occurred in 14 patients but were successfully treated with myelosuppressive antimicrobial agents, including ganciclovir, without the development of neutropenia. These results suggest that combined therapy with G-CSF and EPO may improve the neutropenia and anemia of AIDS. Combined therapy may allow the resumption of full-dose zidovudine in most patients intolerant of the hematologic effects of zidovudine without apparent alteration of HIV expression or the efficacy of zidovudine.
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PMID:Combined therapy with recombinant granulocyte colony-stimulating factor and erythropoietin decreases hematologic toxicity from zidovudine. 170 68

Twelve male patients, eight with the acquired immunodeficiency syndrome (AIDS) and four with AIDS related complex (ARC), who had zidovudine associated neutropenia (less than 1 x 10(9) neutrophils/l) were treated with recombinant human granulocyte colony-stimulating factor (G-CSF) in a phase I/II study. Treatment consisted of daily subcutaneous injections with G-CSF in a weekly increasing dose of 0.4, 2, 5 or 10 micrograms/kg body weight until a neutrophil count of more than 3 x 10(9) neutrophils/l was observed. This effective dose was continued for up to 4 weeks, followed by 4 weeks observation period without G-CSF treatment. Two patients (both with ARC) reached target neutrophil counts at the lowest G-CSF dose, whereas nine patients needed 2 micrograms/kg. One patient discontinued treatment before he reached target neutrophil counts. Mean (+/- SD) neutrophil counts before and after 1 and 4 weeks of effective dose treatment were 0.65(+/- 0.188) x 10(9), 6.016(+/- 2.595) x 10(9) and 5.54(+/- 4.237) x 10(9)/l respectively (P less than 0.01). The number of monocytes increased from 0.171(+/- 0.113) to 0.501(+/- 0.274) and 0.474(+/- 0.374) x 10(9)/l after 1 and 4 weeks of treatment (P less than 0.01). Other haematologic parameters did not change significantly. Two weeks post-treatment the numbers of neutrophils and monocytes had returned to pre-treatment values. Mild side effects consisting of bone, joint or muscle pain were observed in three patients. Two patients (both with AIDS) did not complete the study. One patient stopped treatment because of fever and malaise, attributable to a generalized cytomegalovirus (CMV) infection and one patient had to stop zidovudine treatment because of severe thrombocytopenia. We conclude that G-CSF increases the number of circulating neutrophilic granulocytes in zidovudine-treated patients at relatively low doses and with few side-effects.
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PMID:Effects of recombinant human granulocyte colony-stimulating factor on leucopenia in zidovudine-treated patients with AIDS and AIDS related complex, a phase I/II study. 171 56

To evaluate the effect of recombinant granulocyte-macrophage colony-stimulating factor (GM-CSF) on patients with acquired immunodeficiency syndrome (AIDS) or AIDS-related complex (ARC) who were intolerant to zidovudine because of neutropenia, we performed a randomized, open-label study in which patients were assigned to one of two groups. Zidovudine was discontinued in group A patients before instituting GM-CSF treatment and was restarted in a graduated fashion over 4 weeks. Group B patients continued on full-dose (1,200 mg/d) zidovudine therapy while beginning GM-CSF therapy. A total of 17 patients were entered, eight in group A and nine in group B. Five of eight patients in group A and seven of nine in group B had a history of Pneumocystis carinii pneumonia (PCP). All were homosexual males, except one female in group A who was the sex partner of a bisexual male with AIDS. All patients had neutropenia (absolute neutrophil count [ANC] less than 1,000/microL) while taking full-dose zidovudine. The mean CD4 (+/- SD) lymphocyte level was 37 (+/- 29)/microL and 39 (+/- 44)/microL in groups A and B, respectively. After randomization, patients were begun on subcutaneous GM-CSF at a dose of 1.0 microgram/kg/d. Patients in group A received 2 weeks of daily GM-CSF, at which time zidovudine was restarted if the ANC was greater than 1,000/microL; if the ANC was less than 1,000/microL, the dose of GM-CSF was increased to 3.0 micrograms/kg, and at 2-week intervals either zidovudine was restarted or the dose of GM-CSF was increased to 5 micrograms/kg and then 10 micrograms/kg, to maintain the ANC greater than 1,000/microL. Group B patients received full-dose zidovudine concurrently with GM-CSF administration. The dose of GM-CSF was increased every 2 weeks if necessary to keep the ANC greater than 1,000/microL while maintaining full-dose zidovudine therapy. Patients in each group showed an increase in total white blood cell (WBC) count. Neutrophils and eosinophils were responsible for the majority of this increase. Patients in group A had a more rapid increase in WBC than those in group B; however, by week 8, the WBC in each group was essentially equal. Viral replication as measured by human immunodeficiency virus (HIV) p24 antigen (Ag) was decreased in four patients in each group, increased in one patient in each group, and remained unchanged in the remainder. The ability to culture virus from peripheral blood mononuclear cells was not changed by the regimen. The major toxicities of the regimen were fever and malaise.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Recombinant human granulocyte-macrophage colony-stimulating factor ameliorates zidovudine-induced neutropenia in patients with acquired immunodeficiency syndrome (AIDS)/AIDS-related complex. 174 82

Zidovudine (AZT) is a potent inhibitor of the replication of the human immunodeficiency virus (HIV), and it has been shown to improve survival in advanced HIV disease. We conducted a randomized, double-blind trial in adults with asymptomatic HIV infection who had CD4+ cell counts of fewer than 500 per cubic millimeter on entry into the study. The subjects (92 percent male) were randomly assigned to one of three treatment groups: placebo (428 subjects); zidovudine, 500 mg per day (453); or zidovudine, 1500 mg per day (457). After a mean follow-up of 55 weeks (range, 19 to 107), 33 of the subjects assigned to placebo had the acquired immunodeficiency syndrome (AIDS), as compared with 11 of those assigned to receive 500 mg of zidovudine (P = 0.002; relative risk, 2.8; 95 percent confidence interval, 1.4 to 5.6) and 14 of those assigned to receive 1500 mg of zidovudine (P = 0.05; relative risk, 1.9; 95 percent confidence interval, 1.0 to 3.5). In the three treatment groups, the rates of progression (per 100 person-years) to either AIDS or advanced AIDS-related complex were 7.6, 3.6, and 4.3, respectively. As compared with those assigned to placebo, the subjects in the zidovudine groups had significant increases in the number of CD4+ cells and significant declines in p24 antigen levels. In the 1500-mg zidovudine group, severe hematologic toxicity (anemia or neutropenia) was more frequent than in the other groups (P less than 0.0001). In the 500-mg zidovudine group, nausea was the only toxicity that was significantly more frequent (in 3.3 percent) than in the placebo group (P = 0.001). We conclude that zidovudine is safe and effective in persons with asymptomatic HIV infection and fewer than 500 CD4+ cells per cubic millimeter. Additional study will be required to determine whether such treatment will ultimately improve survival for persons infected with HIV.
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PMID:Zidovudine in asymptomatic human immunodeficiency virus infection. A controlled trial in persons with fewer than 500 CD4-positive cells per cubic millimeter. The AIDS Clinical Trials Group of the National Institute of Allergy and Infectious Diseases. 238 74

A number of studies have illustrated the effectiveness of hematopoietic growth factors in managing treatment-related cytopenias in patients with human immunodeficiency virus (HIV) infection. One of these factors, granulocyte-macrophage colony-stimulating factor, has been shown to restore absolute neutrophil counts in patients with acquired immunodeficiency syndrome (AIDS) and Kaposi's sarcoma receiving a combination of zidovudine (AZT) and interferon alfa. A combination of granulocyte colony-stimulating factor and erythropoietin has also been demonstrated to alleviate both neutropenia and anemia in patients with advanced AIDS or AIDS-related complex receiving zidovudine. Hematopoietic growth factors, in combination with each other and with antiretroviral agents, thus have an important supportive role to play in the treatment of patients with HIV disease.
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PMID:Antiretroviral therapy and immunomodulators in patients with AIDS. 201 46

Studies with fluconazole in oropharyngeal candidiasis have focused primarily on three groups of infections: chronic atrophic candidiasis, oropharyngeal infections associated with either neutropenia or AIDS, and chronic mucocutaneous candidiasis. In two studies of chronic atrophic candidiasis associated with dentures, 82 patients received 7 or 14 days of therapy with fluconazole (50 mg daily). Clinical and mycologic cure rates ranged from 69% to 100%, with the best results occurring with 14 days of therapy in combination with the cleansing of dentures. Thirteen patients with oroesophageal candidiasis associated with chronic mucocutaneous candidiasis were treated with 50 or 200 mg of fluconazole daily, and clinical and mycologic remissions were achieved in a mean period of 10 days. So far 95 patients have been treated with fluconazole for oropharyngeal candidiasis associated with malignancy, therapeutic immunosuppression, AIDS, or AIDS-related complex. Infection was cured by clinical criteria in 84% of those studied. While the majority of patients with clinical cure had significant reductions in the number of yeast colonies, only 48% had negative oral cultures at the end of therapy with courses of 50 mg of fluconazole daily for 5 days to 8 weeks.
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PMID:Overview of studies of fluconazole in oropharyngeal candidiasis. 218 11


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