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)

Retinoids have anti-tumor activity in several malignant and premalignant conditions. Since Kaposi's sarcoma is regulated by steroid hormones both in vivo and in vitro, we hypothesized that retinoids may have anti-tumor effects in AIDS-related Kaposi's sarcoma. Thus, 27 patients with mucocutaneous, non-visceral AIDS-related Kaposi's sarcoma were treated with all-trans retinoic acid (tRA). Poor tolerance was observed at the initial starting dose of 150 mg/m2, and thus subsequent patients were treated using a weekly dose escalation, starting with 45 mg/m2 (given daily, in subdivided doses), to the target dose of 150 mg/m2 (given daily in three subdivided doses). Nearly half (46%) of the patients had extensive mucocutaneous disease with over 25 lesions. No patient had received prior cytotoxic chemotherapy. Ten patients had CD4 lymphocytes of 200/mm3 or greater (strata I); and 17 had under 200/mm3 CD4 lymphocytes (strata II). The median of the average daily tRA dose administered was 150 mg (90 mg/m2; there was no significant difference in the dose tolerance between the two strata). Adverse effects consisted of transient mild to moderate headaches in 65% of patients, mild to moderate skin dryness and cheilitis in 61%, and nausea and vomiting in 31%. Hematologic toxicities included hypertriglyceridemia in 62%, anemia in 23%, and neutropenia in 23%. Partial response to therapy was observed in 4/24 (17%) evaluable patients, occurring after 12, 20, 24, and 28 weeks of therapy, and lasting 4-24 weeks. Three responders had baseline CD4 lymphocyte counts < 200/mm3. Three additional patients experienced reduction in measured indicator lesions of greater than 25% but less than 50%, and seven patients experienced disease stabilization of 16 weeks or greater. In evaluable patients, the median time to disease progression was 22 weeks and the overall median survival in all patients was 27.3 months. No significant changes in CD4 lymphocyte counts, p24 antigen, and beta 2 microglobulin were observed over time. However, a statistically significant increase was observed in soluble IL-2 receptor levels while on tRA (p = 0.037). We conclude that tRA has activity in patients with mucocutaneous AIDS-related Kaposi's sarcoma with acceptable toxicity. tRA has immunological effects without upregulation of HIV parameters. Additional studies in combinations or with more active retinoids are warranted.
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PMID:All-trans retinoic acid for the treatment of AIDS-related Kaposi's sarcoma: results of a pilot phase II study. 780 21

Severe neutropenia and bone marrow (BM) morphologic abnormalities occur during experimentally induced primary infection with feline immunodeficiency virus (FIV), a lentivirus biologically similar to human immunodeficiency virus (HIV). To further characterize the mechanisms involved in this acute infection model of lentivirus-induced BM suppression, peripheral blood counts, histologic BM studies, and BM culture assays were performed on 12 cats that underwent necropsy at regular intervals postinoculation (PI) with FIV Petaluma. Plasma viremia developed at week 3 PI and neutropenia was initially detected at week 6 PI. Low neutrophil counts, but normal hematocrits and platelet counts, persisted through week 12 PI. Infected BM mononuclear cells and megakaryocytes were identified by in situ hybridization assays for FIV nucleic acids in BM sections of cats that underwent necropsy at weeks 4 to 12 PI, correlating with detection of soluble FIV p24 antigen and identification of infected mononuclear and macrophage cells in BM buffy-coat cell cultures from these cats. At weeks 1.5 to 4 PI, the mean frequencies (number per 10(5) BM mononuclear cells) of erythroid progenitors (erythroid colony-forming units [CFU-E] and erythroid burst-forming units [BFU-E] and granulocyte/macrophage progenitors (CFU-granulocyte/macrophage [CFU-GM]) were increased to 508 +/- 74, 143 +/- 24, and 110 +/- 17, respectively (n = 5 cats) as compared with controls (172 +/- 24, 86 +/- 26, and 44 +/- 10; n = 3 cats; P < .02), and the percentages of progenitors in the DNA-synthetic phase of the cell cycle were equivalent to controls. In contrast, the progenitor frequencies at weeks 6 to 12 PI were significantly decreased (72 +/- 16, 43 +/- 6, and 19 +/- 4, respectively; n = 7 cats; P < .01), and these progenitors were more frequently in S-phase. Autologous serum significantly inhibited (P < .05) the growth of CFU-GM in 6 of 9 cats and failed to support the maximal growth of BFU-E in 4 of 9 cats studied at weeks 4 to 12 PI, whereas no such abnormalities were observed in colony assays containing autologous sera from control cats (n = 3) or cats studied at weeks 1.5 or 3 PI (n = 3). In comparison, sera from FIV-infected cats did not inhibit the growth of normal, allogeneic progenitors. However, FIV serum frequently failed to support maximal in vitro growth of normal CFU-GM as compared with uninfected allogeneic sera, further suggesting a lack of progenitor growth-promoting substances in infected cat sera.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Marrow accessory cell infection and alterations in hematopoiesis accompany severe neutropenia during experimental acute infection with feline immunodeficiency virus. 784 16

Neonatal, young adult, and aged specific pathogen-free cats were experimentally infected with cat-passaged Petaluma strain of feline immunodeficiency virus. The primary stage of illness occurred 6-8 weeks following infection in cats of all ages, but it differed in severity and clinical signs. Generalized lymphadenopathy persisted for the entire 42-week study period in neonatally infected cats, was transient in young adults, but inapparent in aged cats. Only two aged cats became chronically and severely ill during the study. One aged cat died with severe necrotizing transmural enteritis, while a second developed chronic generalized staphylococcal pyoderma that was partially controlled with antibiotics. Neutropenia appeared 6-8 weeks following infection in cats of all ages, but was more severe in newborn and aged cats than in young adults. A persistent decrease in CD4+/CD8+ T lymphocyte ratios, due to both increased CD8+ and decreased CD4+ T lymphocytes, occurred in the neonatal and aged cats. Decreased CD4+/CD8+ T lymphocyte ratios in the young adult cats was due solely to decreased CD4+ T lymphocytes. Antibody response to FIV virus, as measured by ELISA to recombinant FIV p24 antigen, was lower in aged cats than the other age groups during the first 6 weeks after infection. Antibody levels were not significantly different among the three age groups thereafter. Although there are some differences between FIV infection of cats and HIV infection of human beings, age at infection influences the severity of disease in both species.
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PMID:The effect of age on the course of experimental feline immunodeficiency virus infection in cats. 825 37

Neutropenia complicates HIV disease or its treatment in a large proportion of patients. Hematopoietic growth factor support has been tested in a number of clinical settings in HIV disease and has been demonstrated to be of benefit for specific parameters. One consideration regarding the use of hematopoietic growth factors in HIV disease is their potential effect on HIV viral burden, since alterations in HIV expression have been documented with certain cytokines in vitro. It has also been reported that some cytokines, notably GM-CSF, potentiate the antiviral properties of thymidine analogs such as zidovudine (AZT) in vitro. We tested these observations in vivo. Twelve HIV-positive patients with a CD4 cell count < or = 200/mm3 or HIV plasma viremia who were receiving a stable dose of zidovudine were enrolled into three dose cohorts of yeast-derived GM-CSF at 50, 125, or 250 micrograms/m2 daily by subcutaneous self-injection for 28 days. Measurements of HIV activity included serum acid-dissociated HIV p24 antigen levels, plasma and peripheral blood mononuclear cell (PBMC) limiting dilution HIV culture, and plasma HIV quantitative competitive polymerase chain reaction (PCR). Serum and intracellular zidovudine levels were measured as well as hematologic, immunologic, and toxicity parameters. Virologic measures showed neither significant upregulation nor downregulation of serum acid-dissociated HIV p24 antigen, plasma and PBMC HIV culture, or PCR in association with GM-CSF administration. A trend toward increased intracellular AZT levels was noted, but this did not achieve statistical significance (p = 0.073). CD4 and CD8 lymphocytes were essentially unaffected while absolute neutrophil counts increased with GM-CSF administration as expected. These data suggest that administration of GM-CSF does not perturb HIV activity or immunologic parameters in patients receiving AZT for advanced HIV disease. No potentiation of AZT antiviral effect was demonstrated.
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PMID:Lack of in vivo effect of granulocyte-macrophage colony-stimulating factor on human immunodeficiency virus type 1. 884 19

A healthy 19-year-old woman had vaginal intercourse on a single occasion with an HIV-1 positive male from Gambia. Two days later she developed an acute HIV infection presenting as a fulminant multisystem disease that lasted for 35 hospital days and included: immediate immunosuppression with extreme CD4+ lymphocytopenia and combined with CD8+ lymphocytosis, neutropenia and hypogammaglobulinemia; intermittent spiking fever; pneumonitis; hepatitis; changing skin rashes; peripheral neuropathy with myopathy, and panencephalitis. P24 antigen was detected by Western blot on day 23 and seroconversion was detected by ELISA on day 25. Cultured lymphocytes from peripheral blood and cerebrospinal fluid grew HIV-1.
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PMID:Immediate immunosuppression caused by acute HIV-1 infection: a fulminant multisystemic disease 2 days post infection. 887 88

Kaposi's sarcoma (KS), the most common malignancy associated with HIV infection, is caused by the Kaposi sarcoma herpesvirus (KSHV). Exacerbations of KSHV are associated with increased human interleukin-6 (HuIL-6), and elevated IL-6 could be related to the development of KS. IL-4, a cytokine with pleiotropic effects, suppresses IL-6 in vivo and modestly inhibits AIDS-KS-derived cells in vitro. Suppression of IL-6 by exogenous IL-4 could result in antitumor activity. We report the results of a clinical trial to test this hypothesis. A phase I/II dose escalation safety, tolerance, and efficacy trial was conducted in patients with biopsy-proven AIDS-related KS, at two university medical centers. Patients were scheduled to receive IL-4 (0.5, 1.5, 3.0, or 4.0 microg/kg/day) administered subcutaneously (s.c.) in sequential cohorts. Patients were continued on study as long as the drug was tolerated or the disease progressed. Patients were followed for antitumor activity, effects on viral replication, immune status, and clinical and laboratory toxicity. Seventeen patients were enrolled at two sites over a 21-month period. There were 15 males and 2 females, and 1 patient was Hispanic. All patients had a Karnofsky score >70. Patients enrolled only into the two lower dose cohorts (0.5 and 1.5 microg/kg/day). Both groups had similar baseline characteristics. The median time on treatment was only 7.4 and 8.4 weeks for the 0.5 and 1.5 microg/kg/day dose levels, respectively. There was significant neutropenia, with 6 patients having grade 3 or greater toxicity requiring granulocyte colony-stimulating factor (G-CSF). Three patients on a dose of 1.5 microg/kg/day stopped treatment due to protocol-defined toxicity. There were no appreciable effects on CD4/CD8 counts. HIV viral RNA did not significantly change over time. However, in several people, it appeared to decline with treatment and rebound with discontinuation of treatment. Corresponding changes were noted in the HIV immunocomplex dissociated (ICD) p24 antigen. One patient had a partial response, 11 patients had stable disease, and 5 patients had disease progression during the short period of treatment. The maximum tolerated dose for IL-4 in patients with advanced AIDS-related KS is 1.5 microg/kg/day. At this dose level, IL-4 is poorly tolerated and is not an effective KS treatment. Treatment of the majority of patients is discontinued because of drug-related toxicity or because of disease progression. Future studies of IL-4 should be confined to studies of cytokine manipulation of the underlying HIV infection, as there appears to be little antitumor activity.
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PMID:Lack of antitumor activity and intolerance of interleukin-4 in patients with advanced HIV disease and Kaposi's sarcoma. 1251 14


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