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

The number of recognized fungal pathogens and the alternatives for treatment of infections due to these organisms have increased dramatically in the 1980s. Use of the traditional agent, amphotericin B, has been hampered by severe dose-limiting toxicity and variable efficacy, and flucytosine is characterized by a narrow spectrum, rapid emergence of resistance, and significant dose-limiting toxicities. In recent years, the appearance of a variety of azole antifungal drugs has permitted exploration of the use of different agents in a wide range of dosages for treatment of a variety of fungal infections. Even so, the azoles are often ineffective or cannot be used, and major therapeutic gaps still remain, particularly for patients with AIDS and those with severe neutropenia. For those with acute, life-threatening disease, the use of amphotericin B-lipid complex or ampholiposomes offers the potential of delivering much higher doses of amphotericin B safely. However, the efficacy of these formulations compared with that of amphotericin B is as yet uncertain. In addition to treatment of established disease, there has been interest in using antifungal azoles for prophylaxis for mucocutaneous candidiasis and systemic mycoses in patients who are predisposed to these conditions. Recently completed large-scale studies suggest that antifungal prophylaxis can be accomplished with use of azoles; however, the cost versus benefits of the prophylactic use of these agents is not yet defined. The 1990s will see consolidation of the uses of antifungals presently available, exploration of the use of much higher doses of amphotericin B (perhaps other polyenes as well in liposomal form), and perhaps the use of azoles in combination as well as alone or sequentially in the form of polyene/azole antifungal therapy. New entries may include beta-1,3-glucan inhibitors in the mid-1990s and other classes of drugs toward the end of the decade.
 ...
PMID:Future directions of antifungal chemotherapy. 132 40

We evaluated the clinical utility of a new endotoxin-specific chromogenic limulus test in febrile patients with haematological malignancies. The specificity is assured by the removal of factor G, which is sensitive to (1-->3)-beta-D-glucan, from horseshoe crab amoebocyte lysate. The sensitivity and specificity of the test to systemic gram-negative bacterial infections were 69.7 and 96.3%, respectively. Meanwhile, gram-negative bacteria grew in only 39.7% of endotoxaemic samples. Thus, it seems appropriate to consider gram-negative bacteraemia and endotoxaemia as different entities. Endotoxaemia was significantly associated with septic shock and infectious death, especially in patients with neutropenia. The new test, the results of which are available within 3 h, should help physicians to recognise this ominous sign early and to initiate a prompt countermeasure to endotoxaemia.
 ...
PMID:Diagnostic and prognostic significance of plasma endotoxin determination in febrile patients with haematological malignancies. 815 85

Recent advances in the diagnosis and therapy of infections in patients with hematological diseases are reviewed. In general, 40-60% of febrile episodes lack clinical or microbiological evidence of infection and are thus treated empirically. Among the cases of microbiologically documented bacteremia treated in our department, the incidence of Gram-negative bacteria was high (47.1%) and the incidence of Gram-positive bacteremia is increasing. To improve the diagnostic rate of Gram-negative sepsis, the measurement of plasma endotoxin was performed. Of 147 febrile neutropenic episodes, endotoxemia was observed in 58 (39.5%) and the causative microorganisms of these infections were deemed Gram-negative bacteria. The measurement of plasma (1-->3)-beta-D-glucan, a ubiquitous component of fungi, was also performed for making early diagnosis of deep mycosis; the sensitivity of this assay was 90% and the specificity was 100%. The detection of (1-->3)-beta-D-glucan appears to be useful as a screening test of deep mycosis. The effects of the concomitant use of granulocyte-colony stimulating factor (G-CSF) and empiric antibiotic therapy for febrile neutropenia were studied in a randomized fashion. G-CSF did not affect the rate of the response to the empiric antibiotic therapy, although a significant effect of G-CSF on neutrophil recovery was observed. Guidelines for empiric antibiotic and antifungal therapy combined with serological diagnosis are proposed.
 ...
PMID:Infections in patients with hematological diseases: recent advances in serological diagnosis and empiric therapy. 940 Dec 73

Betafectin PGG-glucan is a novel beta-(1,3)glucan that has broad-spectrum anti-infective activities without cytokine induction. Here we report that PGG-glucan also has both in vitro and in vivo hematopoietic activities. In vitro studies with bone marrow target cells from the C3H/HeN mouse revealed that although PGG-glucan alone had no direct effect on hematopoietic colony-forming cell (CFC) growth, when combined with granulocyte colony-stimulating factor (CSF) or granulocyte-macrophage CSF, it increased CFC numbers 1.5- to 2.0-fold over those obtained with CSFs alone. Bone marrow cells cultured for high-proliferative-potential CFCs in the presence of interleukin (IL)-1, IL-3, macrophage CSF, and stem cell factor (SCF), or cultured for erythroid burst-forming units in the presence of IL-3, SCF, and erythropoietin, also exhibited enhanced growth in the presence of PGG-glucan. The synergistic effect of PGG-glucan was specific and could be abrogated by anti-PGG-glucan antibody. The ability of PGG-glucan to modulate hematopoiesis in vivo was evaluated in myelosuppressed rodents and primates. C3H/HeN female mice were intravenously administered saline solution or PGG-glucan (0.5 mg/kg) 24 hours before the intraperitoneal administration of cyclophosphamide (200 mg/kg), and the recovery of bone marrow cellularity and granulocyte-macrophage progenitor cells was evaluated on days 4 and 8 after cyclophosphamide treatment. At both time points, enhanced hematopoietic recovery was observed in PGG-glucan-treated mice compared with saline-treated control mice. In a final series of in vivo experiments, we evaluated the ability of therapeutically administered PGG-glucan to enhance hematopoietic recovery in cyclophosphamide-treated cynomolgus monkeys. Monkeys received intravenous infusions of cyclophosphamide (55 mg/kg) on days 1 and 2, followed on days 3 and 10 by intravenous infusion of PGG-glucan (0.5, 1.0, or 2.0 mg/kg). Compared with those in saline-treated monkeys, accelerated white blood cell recovery and a reduction in the median duration of neutropenia were observed in PGG-glucan-treated monkeys. These studies illustrate that PGG-glucan has both in vitro and in vivo hematopoietic activities and that this agent may be useful in the prevention and/or treatment of chemotherapy-associated myelosuppression.
 ...
PMID:In vitro and in vivo hematopoietic activities of Betafectin PGG-glucan. 984 81

Non-culture methods being developed and evaluated for mycotic infections include polymerase chain reaction (PCR), galactomannan (GM) antigenemia, Western blot (WB) to detect antibodies, and detection of the fungal metabolites D-arabinitol and (1,3)-beta-D-glucan. Sample preparation for PCR from blood specimens depends on fractionation of peripheral blood, its pre-incubation in blood culture broth, or a total DNA method, which does not rely on fractionation, or pre-incubation. Targets for PCR of fungi in the 18S or ITS2 subunits of the ribosomal RNA genes facilitated the design of Aspergillus and Candida genus and species probes. Amplicons were identified using PCR-enzyme linked immunosorbent assay (ELISA) or reverse line-blot formats. A pilot study indicated that PCR tests on blood specimens were positive at least once in patients with confirmed invasive aspergillosis (IA). When serum-PCR and serum-GM tests were compared in IA patients, antigenemia was more often positive. PCR detected Aspergillus DNA in bronchoalveolar lavage specimens from patients at risk even when cultures were negative. D-Arabinitol can be detected as a marker of candidiasis with gas chromatography-mass spectrometry or enzyme dependent-fluorometry. Each method can differentiate the microbial D- and host L-enantiomers. (1,3)-beta-D-Glucan is produced by most genera of pathogenic fungi and can be detected in plasma by the 'G-test'. In patients with febrile neutropenia the efficacy of azole therapy correlated with plasma (1,3)-beta-D-glucan concentrations of > or = 10 pg ml(-1). The diagnosis of early acute pulmonary histoplasmosis can be improved by a WB test utilizing deglycosylated M antigen, a 94-kDa glycoprotein. The identity of M antigen as a catalase was deduced from the sequence of the cloned gene. PCR identification of Histoplasma capsulatum cultures was accomplished with primer pairs selected from H and M antigen gene sequences.
 ...
PMID:Non-culture based diagnostic tests for mycotic infections. 1120 40

Blood and radiological tests are used to diagnose invasive aspergillosis (IA), but it remains unknown which is more useful. We recently made a prospective study to compare the usefulness of chest CT scan, latex agglutination test (LA) and determination of plasma (1-3)-beta-D-glucan (BDG) levels for IA diagnosis. Of 215 patients, 16 were diagnosed as definite IA. While sensitivities of LA and BDG were 44% and 63%, respectively, all the patients showed some abnormal signs on chest CT scans. On average, CT scans preceded LA by 7.1 days and BDG by 11.5 days. Interestingly, false-positive rate of the blood tests increased during neutropenia. Because lung is the usual portal of Aspergillus, chest CT scan may be more beneficial than the blood tests for early diagnosis of IA. Care is necessary in interpreting the results of these tests, especially when patients are neutropenic. Blood tests must be sensitive and their results must be interpreted quantitatively. We recently developed a new quantitative diagnostic system for IA using real-time PCR. In vitro examination using 10(2) copies of Aspergillus DNA showed that linearity was obtained when there were more than 20 copies. We examined 323 samples taken from 122 patients with hematological malignancies. Blood samples were subjected to real-time PCR, enzyme-linked immunosorbent assay (EIA) and BDG. Sensitivity of real-time PCR, EIA and BDG was 79, 58 and 67%, respectively. Specificity of each assay was 92, 97 and 84%, respectively. Real-time PCR was highly sensitive for IA diagnosis, and quantification was accurate.
 ...
PMID:[Current approaches to diagnose invasive aspergillosis: application of real-time automated polymerase chain reaction]. 1170 42

TAK-457 is an injectable prodrug of TAK-456, which is a novel oral triazole compound with potent antifungal activity. The in vivo efficacy of TAK-457 was evaluated in two models of invasive pulmonary aspergillosis with CDF(1) mice and CBA/J mice with transient neutropenia induced by cyclophosphamide. Against the infection in CDF(1) mice, treatment with 10 mg of TAK-457 and 1 mg of amphotericin B/kg reduced the fungal burden in lungs and rescued all mice. In the infection model with CBA/J mice, TAK-457 at a dose of 10 mg/kg significantly prolonged the survival time of mice, showing significant reduction of lung chitin levels and the plasma beta-D-glucan levels. On the other hand, amphotericin B at 1 mg/kg which was a maximum tolerable dose showed slight but not significant prolongation of survival time of mice, although it also reduced the lung chitin levels and the plasma beta-D-glucan levels to a lower extent but still significantly. These results suggest that TAK-457 is a promising candidate for development for the treatment of invasive aspergillosis in humans.
 ...
PMID:Efficacy of TAK-457, a novel intravenous triazole, against invasive pulmonary Aspergillosis in neutropenic mice. 1179 31

There is an increased awareness of the morbidity and mortality associated with fungal infections caused by resistant fungi in various groups of patients. Epidemiological studies have identified risk factors associated with antifungal drug resistance. Selection pressure due to the continuous exposure to azoles seems to have an essential role in developing resistance to fluconazole in Candida species. Haematological malignancies, especially acute leukaemia with severe and prolonged neutropenia, seem to be the main risk factors for acquiring deep-seated mycosis caused by resistant filamentous fungi, such us Fusarium species, Scedosporium prolificans, and Aspergillus terreus. The still unacceptably high mortality rate associated with some resistant mycosis indicates that alternatives to existing therapeutic options are needed. Potential measures to overcome antifungal resistance ranges from the development of new drugs with better antifungal activity to improving current therapeutic strategies with the present antifungal agents. Among the new antifungal drugs, inhibitors of beta glucan synthesis and second-generation azole and triazole derivatives have characteristics that render them potentially suitable agents against some resistant fungi. Other strategies including the use of high doses of lipid formulations of amphotericin B, combination therapy, and adjunctive immune therapy with cytokines are under investigation. In addition, antifungal control programmes to prevent extensive and inappropriate use of antifungals may be needed.
 ...
PMID:Antifungal drug resistance to azoles and polyenes. 1220 71

We treated a 52-year-old woman with acute lymphoblastic leukemia (ALL) who developed invasive pulmonary aspergillosis (IPA) as a result of neutropenia following remission-induction chemotherapy. Although serological test results, such as those for platelia and pastrex, were all negative and the serum level of beta-D-glucan was low, Aspergillus DNA was detected in blood by the polymerase chain reaction method. A clinically documented diagnosis of IPA was made on the basis of chest x-rays, computed tomography scan findings, and the detection of Aspergillus DNA. Micafungin (FK463), a candin class antifungal agent, was administered at a dose of 75 to 150 mg/day, because other antifungal agents were not effective. The increase in serum concentration of micafungin was dose-dependent and was accompanied by improvement of symptoms and objective findings. Micafungin was effective for the treatment of IPA in this patient with ALL.
 ...
PMID:Successful micafungin (FK463) treatment of invasive pulmonary aspergillosis in a patient with acute lymphoblastic leukemia in a phase II study. 1521 72

Caspofungin is a parenteral antifungal that inhibits beta-1,3-D-glucan synthesis. Although licensed for adult use, the appropriate caspofungin dosing regimen in pediatric patients is not yet known. We therefore investigated the pharmacokinetics and safety of caspofungin in pediatric patients. Thirty-nine children (ages 2 to 11 years) and adolescents (ages 12 to 17 years) with neutropenia were administered caspofungin using either a weight-based regimen (1 mg/kg of body weight/day) or a body surface area regimen (50 mg/m2/day or 70 mg/m2/day). Plasma samples for caspofungin profiles were collected on days 1 and 4. These results were compared to those from adults treated with either 50 or 70 mg/day for mucosal candidiasis. In children receiving 1 mg/kg/day (maximum, 50 mg/day), the area under the concentration-time curve over 24 h (AUC(0-24)) was significantly smaller (46% after multiple doses) than that observed in adults receiving 50 mg/day (P < 0.001). In children and adolescents receiving 50 mg/m2/day (maximum, 70 mg/day), the AUC(0-24) following multiple doses was similar to that for the exposure in adults receiving 50 mg/day. The AUC(0-24) and concentration trough (at 24 h) in pediatric patients receiving the 50-mg/m2 daily regimen were consistent across the range of ages. Caspofungin was generally well tolerated in this study. None of the patients developed a serious drug-related adverse event or were discontinued for toxicity. These results demonstrate that caspofungin at 1 mg/kg/day in pediatric patients is suboptimal. Caspofungin administration at 50 mg/m2/day provides a comparable exposure to that of adult patients treated with 50 mg/day.
 ...
PMID:Pharmacokinetics, safety, and tolerability of caspofungin in children and adolescents. 1625 Dec 93


1 2 3 4 5 6 Next >>