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)

Patterns of infection were studied in 150 patients with aplastic anemia who were admitted to the Clinical Hematology Branch, National Institutes of Health, between January 1978 and December 1989 for immunosuppressive therapy. Sixty percent of the patients were males, 71% were white, their mean age was 33.6 years (median, 27.5; range, 1-75), and 83% had severe aplastic anemia. One hundred three patients developed 1 or more febrile episodes during the study period. The risk factors for developing a febrile episode included a low Absolute Neutrophil Count (ANC) and Absolute Monocyte Count (AMC) at admission and the presence of an indwelling central venous catheter (Hickman-Broviack or Port-A-Cath). A total of 289 febrile events were studied, including unexplained fever (FUO) in 89 (31%), microbiologically documented infection (MBDI) in 137 (47%), and clinically documented infection (CDI) in 63 patients (22%). Compared to documented infections (MBDI) or CDI), FUO events were associated with a higher frequency of rigors, signs and symptoms of serum sickness, and treatment regimens known to cause fevers. None of the FUO events had a fatal outcome, even if the antibiotic therapy was discontinued before day 7. Among CDI events, bacteria were the most commonly defined etiologic agent (67%), followed by fungi (23%), viruses (7%), and parasites (3%). The patterns of bacterial infections in patients with aplastic anemia were similar to those observed in patients with cancer-related neutropenia. Twenty-one patients (15%) developed invasive fungal infections (aspergillus, 11; candida, 7; and both, 3), which were fatal in 19 (90%). Fungal infections accounted for 30% of the secondary infectious events and for 55% of fatal infectious events. The only identifiable risk factors for developing a fungal infection were the degree of neutropenia and monocytopenia at initial admission or final evaluation. Invasive pulmonary aspergillosis developed despite empirical amphotericin B therapy and was associated with a high incidence of fatal pulmonary hemorrhage (10 of 13 patients [77%]). Infection was responsible for 36 (62%) of the deaths observed during the study period and hemorrhage alone for 4 (7%). However, 20 of the patients who died of infection had concomitant hemorrhage. No significant drop in ANC, AMC, or platelet count could be demonstrated during a fatal infectious event as compared to a nonfatal infectious event. Invasive fungal infections, predominantly with aspergillus and candida, emerged in our study as the major causes of mortality in patients with aplastic anemia. Without bone marrow recovery the prognosis associated with invasive mycoses was grave.
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PMID:Patterns of infection in patients with aplastic anemia and the emergence of Aspergillus as a major cause of death. 154 57

We studied escalating doses of recombinant human interleukin-1 beta (IL-1 beta) alone and after a myelosuppressive dose of 5-fluorouracil (5-FU) in patients with gastrointestinal cancer. Transient neutropenia, monocytopenia, and lymphocytopenia were observed followed by a 1.3- to 6.0-fold (mean, 3.46-fold) dose-dependent neutrophil leukocytosis (P less than .00001) on the days of IL-1 beta administration. Increases in platelet counts were observed at a median of 14 days (range, 6 to 23) after IL-1 beta administration. Transient hypoglycemia, rebound hyperglycemia, elevations in serum cortisol, and C-reactive protein were observed. Side effects included fever, rigors, and headache in the majority of patients. Hypotension was observed in three of five patients at the highest dose level (0.1 micrograms/kg) and was dose-limiting. Fewer days of neutropenia were noted after 5-FU plus IL-1 beta than after 5-FU alone; however, this difference did not reach statistical significance. These data show that IL-1 beta has stimulatory effects in human hematopoiesis.
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PMID:A phase I trial of recombinant human interleukin-1 beta alone and in combination with myelosuppressive doses of 5-fluorouracil in patients with gastrointestinal cancer. 188 14

Recombinant alpha-interferon (IFN-R) was given to 17 patients with non-A, non-B chronic hepatitis (NANB-CH) and to 11 patients with B chronic hepatitis (B-CH). Fever (100.4 to 102.2 Fahrenheit) was observed in every patient during the early phase of treatment. Other side-effects included rigors, myalgia, headache and laboratory changes such as leucopenia, neutropenia and, in some cases, thrombocytopenia. However, the tolerance was considered acceptable and treatment had to be interrupted in only one patient presenting generalized mucosal lesions attributed to a hypersensitivity reaction. The response to IFN-R in NANB-CH was considered positive when serum aminotransferase levels became normal or below two times the upper normal limit. Out of eight patients who completed the treatment, four were considered as responders but one of them, treated during five months, showed a relapse after three months. On the other hand, in one patient treated for twelve months, a persistent normalization of serum amino-transferases was observed: a liver biopsy showed a striking decrease of the inflammatory changes. As to the B-CH. 3 out of 8 patients who completed the treatment showed a disappearance of HBeAg and DNA-polymerase and were considered as responders. These preliminary results show that IFN-R is a promising drug but only multicenter controlled trials will establish its value in the treatment of viral chronic hepatitis.
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PMID:[Recombinant alfa interferon in the treatment of chronic B and non-A, non-B hepatitis: preliminary results]. 251 13

The toxicity, pharmacokinetics, and hematologic effects of granulocyte-macrophage colony-stimulating (GM-CSF) were studied in a phase I/II trial of 16 patients with myelodysplastic syndrome (MDS). The GM-CSF was administered subcutaneously (SC) daily so as to achieve prolonged blood levels and to establish an outpatient treatment regimen. Four dose levels were administered for ten days: 0.3 microgram/kg/d (three patients), 1.0 microgram/kg/d (three), 3.0 micrograms/kg/d (four), and 10.0 micrograms/kg/d (six). The most common toxicities were fever and a flu-like syndrome, which were dose-dependent. The maximum-tolerated dose was 10.0 micrograms/kg/d, which induced severe rigors (two patients), fever greater than 40 degrees C (one), severe bronchospasm (one), and WBC 60,000 (one). In one patient, refractory anemia with excess blasts in transformation (RAEB-T) progressed to acute nonlymphocytic leukemia after two doses of GM-CSF, and the patient died of leukemia that did not respond to chemotherapy. After doses of 3.0 and 10.0 micrograms/kg, serum GM-CSF levels peaked at 3.8 to 6.3 hours, and persisted for 14 and 24 hours, respectively. Circulating granulocytes (neutrophils and bands) increased in a dose-dependent manner, as 11 of 13 patients who received greater than or equal to 1.0 microgram/kg/d responded with a two- to 194-fold increase. Although the neutrophils usually returned to pretreatment levels shortly after stopping GM-CSF, two patients continue to exhibit an elevation of neutrophils for 6 months. Dose-related increases in circulating monocytes and eosinophils were also noted. Transient increases in platelet and reticulocyte counts were observed in two and three patients, respectively. Five of the 16 patients later received maintenance GM-CSF at 3 micrograms/kg/d for 2 to 9 weeks. All showed a dramatic increase in neutrophils after 2 weeks. Thereafter, despite continued therapy, the neutrophil count in four patients declined markedly. In conclusion, GM-CSF is well tolerated by the SC route and induces striking, but usually temporary, improvement in the neutropenia of MDS. Larger prospective phase III trials will determine the duration of hematologic responses and the impact on infection, morbidity, and mortality.
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PMID:Subcutaneous granulocyte-macrophage colony-stimulating factor in patients with myelodysplastic syndrome: toxicity, pharmacokinetics, and hematological effects. 265 78

Fifteen patients with metastatic malignant melanoma, including 10 who had not previously received systemic therapy, were treated with recombinant alpha2-interferon (IFN-alpha 2) in a dose of 20 million IU/m2 by 30-min i.v. infusion daily for 5 days each 14 days. Evaluable metastatic sites included lung, subcutaneous tissue, liver, nodes, adrenals, and bone. Subjective toxicity was generally mild to moderate, with fever (38.2-40.2 degrees C), occasional rigors, fatigue, myalgia, headache, and nausea. Objective toxicity included transient neutropenia and elevation of hepatic enzymes, particularly gamma-glutamyl transpeptidase. In 1 of the 10 patients receiving more than one cycle, IFN dosage was reduced because of toxicity, but later reescalated. All patients were evaluated for response. No overall partial or complete responses were observed, but two site responses (lung and subcutaneous tissue) were seen. Median survival from start of IFN treatment was 19 weeks. High doses of IFN were reasonably well tolerated in this study, but the results suggest little activity against malignant melanoma.
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PMID:Phase-II study of recombinant alpha 2-interferon in advanced malignant melanoma. 287 Nov 16

Based upon in vitro and in vivo synergistic activity of Type I and Type II interferons (IFNs) in preclinical in vitro and in vivo studies, we initiated a phase I trial evaluating the doses, safety, and pharmacokinetics of combinations of recombinant DNA-produced human IFN-beta ser and IFN-gamma in 27 patients with cancer. Twenty-four patients were treated with a 2-hour infusion of IFN-gamma, followed by a 10-minute iv injection of IFN-beta ser, three times a week. Patients were entered on fixed dose levels of 1 X 10(6), 3 X 10(6), 10 X 10(6), 30 X 10(6), and 100 X 10(6) units of each IFN. In addition, three patients were treated at the highest dose level with a 10-minute iv infusion of IFN-gamma and a 10-minute iv infusion of IFN-beta ser. The maximally tolerated dose when administered by this schedule for greater than or equal to 4 weeks was 30 X 10(6) units of each IFN. Dose-limiting side effects at doses of 100 X 10(6) units of each IFN consisted of fatigue, nausea, vomiting, anorexia, paralytic ileus, and neutropenia. The most common side effects at the three highest dose levels were fever, rigors often requiring parenteral meperidine, and constitutional symptoms. Reversible elevations in SGOT and LDH were also noted. Serum IFN levels were dose related, with peak titers occurring immediately after IFN administration. One patient with a nodular mixed lymphoma had a partial response which has been sustained for over 1 year. We conclude that combinations of IFN-beta ser and IFN-gamma can be safely administered on a chronic basis without enhanced or cumulative toxic effects.
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PMID:Phase I trial of combinations of recombinant interferons beta(ser) and gamma in patients with advanced malignancy. 311 70

Thirteen patients with relapsed or refractory Non-Hodgkin's Lymphoma were treated with 131I-Lym-1 during the course of a dose escalation trial. Principal aims were to establish the maximum tolerated single dose (MTD), as well as to assess clinical and dosimetric effects of the MTD. Patients were eligible if > 25% of tumor cells bound Lym-1 on immunohistochemistry, stain intensity was +2/4 or greater and human anti-mouse antibody (HAMA) assay was negative. Radioimmunotherapy was performed with escalating doses at levels of 50 mCi, 65 mCi/m2 and 80 mCi/m2 (50-139 mCi total). Patients were eligible for retreatment after 6-10 weeks if there was no severe toxicity, their disease was at least stable and HAMA remained negative. Three were retreated. Four have achieved partial responses which lasted 11, 11, 18 and 22 weeks. Acute toxicities included rigors (69%), fever (62%), nausea (46%), vomiting (46%), pruritus (23%), urticaria (23%), chest pain (23%) and bronchospasm (15%). HAMA developed in 3 patients. Myelosuppression, manifested as thrombocytopenia and neutropenia, was dose-limiting and defined the single dose MTD at 65 mCi/m2. Plasma radioactivity clearance was biphasic, with a 0.9 hr alpha-T1/2 and a 19.8 hr beta-T1/2. At completion of Lym-1 infusion, a mean of 45% of the injected dose was recoverable in the circulation. Images obtained within the first 2 hours indicated mean hepatic and splenic uptake was 29% and 11%, respectively. Radiation absorbed doses to tumor ranged from 18-61 rads; mean doses to whole body ranged from 17 to 71 rads.
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PMID:A phase I escalating-dose safety, dosimetry and efficacy study of radiolabeled monoclonal antibody LYM-1. 781 46

Clostridium tertium bacteremia is unusual, seen most often with gastrointestinal disease and/or neutropenia. Two cases are described. The first was a 19-yr-old female with acute leukemia, who developed gastrointestinal symptoms and C. tertium bacteremia while neutropenic. The second was a 57-yr-old female with quiescent ulcerative colitis, who presented with fever, rigors and epigastric pain. Four organisms including C. tertium were isolated from blood cultures. This patient responded to broad spectrum antimicrobial therapy, whereas the first patient required the addition of specific agents to recover. C. tertium is aerotolerant and thus can be misidentified as a Bacillus or Corynebacterium spp. Our isolates had a distinctive Gram stain morphology, were catalase negative and failed to sporulate aerobically--this aided in the recognition of this significant Gram-positive bacillus.
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PMID:Clostridium tertium bacteremia: 2 cases and review. 871 77

A considerable effort has been spent in the past three decades to investigate various aspects of liposomes as novel drug delivery systems. In 1990, the first amphotericin B (AmB) liposomal preparation (L-AmB) under the brand name AmBisome was introduced into the market by Vestar. The successful marketing of the product moved liposomes out of the stage of experimental obscurity to the realistic stage of clinical utility. The launch of AmBisome sparked off the introduction of other lipid-based AmB products marketed by Liposome Technology (Amphocil) and The Liposome Co. (Abelcet). The drive behind the development of a modified formulation of AmB was to improve the therapeutic index of this drug with respect to its major drawback associated with both acute and chronic toxic effects. In a 30-year-long experience with AmB, several reports were recorded in the literature of acute adverse effects, such as fever, rigors, vomiting, cardiotoxicity and hypotension occurring during infusion; while long-term therapy was reported to be associated with hypokalemia, renal dysfunction and hematological abnormalities. Another serious problem encountered with the drug had been the poor response obtained in immunocompromised patients like those with AIDS, neutropenia and cancer patients on chemotherapy. The encapsulation of amphotericin B in liposomal vesicles was hence targeted not only to obtain an improvement in the therapeutic index but also to see if it was useful in eradicating deep-seated fungal infections in immunocompromised patients. The liposomal AmB was found to have a better therapeutic index and lower toxicity than the commercial AmB preparations. The LD50 of AmBisome in mouse was 175 mg/kg compared with 3.7 mg/kg for Fungizone, the commercial preparation of AmB. Additionally, L-AmB has prolonged circulation time, and extravasates into the site of infection and delivers the drug directly to the site, with no nephrotoxicity and neurotoxicity as experienced with AmB. This review traces the course of development of L-AmB and discusses the rationale behind the development of its liposomal preparation. The results in in vitro, in vivo and clinical studies, mechanism of action, biodistribution, and formulation considerations of L-AmB are described. The clinical experience with the marketed preparation is reviewed.
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PMID:Development of liposomal amphotericin B formulation. 953 20

Improved understanding of the pharmacodynamics and toxicity of aminoglycoside antibiotics has resulted in the study of once-daily dosing regimens. Although studies have suggested a therapeutic advantage and possibly a decrease in toxicity with once-daily administration, these effects have been modest. The cost savings associated with once-daily aminoglycoside administration, however, makes this approach appealing. Although a syndrome of fever, tachycardia, hypotension, and rigors has been associated with once-daily dosing of gentamicin, this appears to have been the result of impurities in the antibiotic from a single offshore supplier. This syndrome has not been associated with other aminoglycoside antibiotics, and the FDA has now withdrawn its recommendation that once-daily aminoglycoside use be avoided. As with any medical regimen, the decision to use once-daily dosing of aminoglycoside agents must take into account special patient characteristics and the disease state being treated. Although once-daily dosing appears effective in limited studies in children, in individuals with neutropenia, and in individuals with cystic fibrosis, its role in gram-positive coccal endocarditis and in individuals with altered volumes of distribution remains uncertain. Further data are needed to clarify the role of once-daily dosing in these situations.
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PMID:Once-daily dosing of aminoglycoside antibiotics. 1082 67


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