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)

The increasing doses of 2.4-3.5 g/m2 ifosfamide, i/v, dropwise, were administered for 40 min, on days 1-5 each week, for 3 weeks, in 4 courses. Simultaneously, MESNA was given in a dose two-thirds of that of ifosfamide. The maximum single tolerable dose of ifosfamide was 3.2 g/m2. The dose of 3.5 g/m2 proved neurotoxic causing encephalopathy. The other toxic effects were stage III-IV neutropenia (47%), nausea and vomiting (91%) and weakness (33%). No clinical evidence of renal failure was attributed to the high dosage of the drug in the course of assays of biochemical components of the blood, blood- and urine-beta-2-microglobulins, N-acetyl-D-hexoaminidase (NAG) level in urine, creatinine clearance and complex renoscintigraphy data. On days 3-5, ifosfamide treatment was followed by increase in NAG and beta-2-microglobulin levels in urine which pointed to the toxic effect exerted on the epithelium of renal tubules. The antitumor effect was apparent in 5 (29%) patients for 6 months, which testifies to the high effectiveness of ifosfamide treatment for soft-tissue sarcoma.
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PMID:[High-dose ifosfamide in the treatment of patients with soft tissue sarcoma]. 912 96

Single-agent gemcitabine, when given in doses of > or = 1,250 mg/m2 weekly x 3 with a 1-week break, induces responses in approximately 20% of untreated patients with non-small cell lung cancer. This phase II study was undertaken to determine the efficacy of weekly administration of gemcitabine 1,500 mg/m2 combined with cisplatin 30 mg/m2 x 3 with a rest period of 1 week. Patients younger than 75 years were eligible if they had stage III/IV non-small cell lung cancer, a life expectancy > or = 12 weeks, hemoglobin > or = 10 g/dL, absolute granulocyte count > or = 10(9)/L, platelets > or = 100 x 10(9)/L, hepatic enzymes no more than three times the upper limit of normal, and serum creatinine < or = 130 micromol/L. There were 22 men and 18 women, with a median age of 60 years; 35 had a performance status of 0 or 1. Pathology included adenocarcinoma in 22 patients, squamous cell carcinoma in nine, large cell carcinoma in seven, and mixed non-small cell lung cancer in two. Six patients had stage III and 34 had stage IV tumors. Of the 39 patients eligible for response evaluation, partial remission was seen in 10, for an overall response rate of 26% (95% confidence interval, 12% to 41%). The median duration of response was 19 weeks (range, 7 to 32+ weeks). Grade 3/4 anemia was seen in 11 patients, and 21 patients required red blood cell transfusions. Grade 3/4 neutropenia occurred in 22 patients and grade 3/4 thrombocytopenia in 21 patients. One patient experienced febrile neutropenia Hematologic toxicity, particularly thrombocytopenia, was cumulative over time. Nonhematologic toxicity was modest, but one patient stopped therapy because of a grade 2 skin rash and one stopped because of a grade 4 pulmonary toxicity, both of which were thought to be related to gemcitabine. The modest activity of weekly gemcitabine and weekly cisplatin seen in this trial does not suggest in vivo synergy for these two agents as administered using this schedule and these doses.
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PMID:Phase II trial of gemcitabine and weekly cisplatin for advanced non-small cell lung cancer. 920 13

This study sought to determine the principal toxicities and feasibility of administering paclitaxel as a 3-hour infusion followed by carboplatin without and with granulocyte colony-stimulating factor (G-CSF) in chemotherapy-naive patients with stage IV non-small cell lung carcinoma (NSCLC), and to recommend doses for subsequent clinical trials. Twenty-three patients were treated with paclitaxel at doses ranging from 175 to 225 mg/m2 followed by carboplatin targeting area under the concentration-time curve (AUC) 7 or 9 mg/mL.min every 3 weeks. AUCs were targeted using the Calvert formula with estimated creatinine clearance as a surrogate for the glomerular filtration rate. A high rate of intolerable, mutually exclusive toxicities, consisting primarily of thrombocytopenia, as well as neutropenia, nausea and vomiting, and mucositis, precluded escalation of carboplatin above a targeted AUC of 7 mg/mL.min with paclitaxel 225 mg/m2, which approaches the maximum tolerated dose (MTD) of paclitaxel given as a single agent on a 3-hour schedule. Moderate to severe peripheral neurotoxicity occurred in several patients after multiple courses. Due to the heterogeneous nature of the principal toxicities and the ability to administer clinically-relevant doses of both agents in combination without G-CSF, further dose escalation using G-CSF was not performed. Nine of 23 (39%) total patients and 43% of 21 assessable patients had partial responses (PR). The recommended doses for subsequent clinical trials are paclitaxel 225 mg/m2 as a 3-hour infusion followed by carboplatin at a targeted AUC of 7 mg/mL.min. The ability to administer clinically-relevant single agent doses of paclitaxel and carboplatin in combination, as well as the significant antitumor activity noted in this phase I trial, indicate that further evaluations of this regimen in both advanced and early stage NSCLC are warranted.
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PMID:Phase I study of paclitaxel on a 3-hour schedule followed by carboplatin in untreated patients with stage IV non-small cell lung cancer. 922 Feb 92

To determine risk factors, frequency, time patterns, and outcome of ganciclovir-related neutropenia in allogeneic marrow transplant recipients, 278 consecutive patients receiving ganciclovir from engraftment until day 100 were studied. In this cohort, 159 patients (57%) had absolute neutrophil counts (ANC) less than 1,500/microL, 112 (41%) had an ANC less than 1,000/microL, 87 (31%) less than 750/microL, and 56 (21%) less than 500/microL for at least 2 consecutive days. Statistically significant risk factors for neutropenia in a Cox model were low marrow cellularity between day 21 and 28 (relative risk [RR] 2.4, P = .0002), hyperbilirubinemia > or =6 mg/dL during the first 20 days (RR 2.5, P = .0001), and elevation of serum creatinine > or =2 mg/dL after day 21 after transplant (RR 2.1, P = .001). Restriction to factors present at engraftment resulted in a similar model with low marrow cellularity, hyperbilirubinemia > or =6 mg/dL, and elevated serum creatinine as significant risk factors. Patients with no risk factor had an incidence of neutropenia of 21%, an incidence of 31% for one risk factor, and of 57% for two or more risk factors (RR 3.8, P = .001). Neutropenia was a negative predictor of overall (RR 2.0, P = .0001) and event-free survival (RR 2.1, P < .0001), and a predictor of relapse (RR 1.7, P = .03) and nonrelapse mortality (RR 2.1, P = .003). Thus, early liver dysfunction, elevated serum creatinine, and low marrow cellularity are risk factors for ganciclovir-related neutropenia. Neutropenia in ganciclovir recipients after marrow transplantation is an independent risk factor for mortality.
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PMID:Neutropenia in allogeneic marrow transplant recipients receiving ganciclovir for prevention of cytomegalovirus disease: risk factors and outcome. 931 May 3

One hundred and thirty-four adults and 204 children were randomized in two prospective, parallel comparative multicentre trials to receive either conventional amphotericin B 1 mg/kg/d (c-AMB), liposomal amphotericin B 1 mg/kg/d(L-AMB1) or liposomal amphotericin B 3 mg/ kg/d (L-AMB3). Patients were entered if they had a pyrexia of unknown origin (PUO) defined as temperature of 38 degrees C or more, not responding to 96 h of systemic broad-spectrum antibiotic treatment, and neutropenia (< 0.5 x 10(9)/l). The safety and toxicity of liposomal amphotericin B was compared with that of conventional amphotericin B. Efficacy of treatment was assessed, with success defined as resolution of fever for 3 consecutive days (< 38 degrees C) without the development of any new fungal infection. Clinical and laboratory parameters were collected for safety analysis. In both the paediatric and adult populations, L-AMB treated patients had a 2-6-fold decrease in the incidence (P < or = 0.01) of test-drug-related side-effects, compared to c-AMB. Severe trial-drug-related side-effects were seen in 1% of L-AMB treated patients, in contrast to 12% of patients on c-AMB (P < 0.01). Nephrotoxicity, in the patient subset not receiving concomitant nephrotoxic agents, defined as a doubling from the patients baseline serum creatinine level, was not observed in the L-AMB1 arm whereas the incidence was 3% in patients on L-AMB3 and 23% in those on c-AMB (P < 0.01). Moreover, time to develop nephrotoxicity was longer in both L-AMB arms than c-AMB (P < 0.01). Severe hypokalaemia was observed less frequently in both L-AMB arms (P < 0.01). Analysis was by intention-to-treat and included all patients randomized. Success was defined by a minimum of 3 consecutive days with fever (< 38 degrees C) continuing to study end indicated by recovery of neutrophils to 0.5 x 10(9)/l. Addition of systemic antifungal therapy or development of systemic fungal infection were failures as was persistent fever to study end. Efficacy assessments indicated success in 49% of the total group treated with c-AMB, 58% of patients responded to L-AMB1 and 64% to L-AMB3. A statistically significant difference was found between c-AMB and L-AMB3 (P = 0.03) but a Kaplan-Meier analysis of time to differvescence of fever showed there was no significant difference between the arms. It was concluded that liposomal amphotericin at either 1 or 3 mg/kg/d was significantly safer than conventional amphotericin B in children and adults. The main aim of this open-label study was to compare safety between the three trial arms. However, we provide evidence for an equivalent or possibly superior efficacy of liposomal amphotericin with regard to resolution of fever of unknown origin. Subsequent trials should compare amphotericin preparations in defined fungal infections.
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PMID:A randomized comparison of liposomal versus conventional amphotericin B for the treatment of pyrexia of unknown origin in neutropenic patients. 933 29

Herpes infections continue to be prevalent, especially in immunocompromised patients. Some of these patients will develop resistant HSV infections. Therefore, it is important to explore new treatment options. Animal studies have shown cidofovir to be effective in the treatment and prevention of HSV infections. Human data are limited, with only one randomized, double-blind, placebo-controlled trial performed to date. The results from this study look promising; however, due to the small sample size, a larger clinical trial is warranted. The human data available as case reports are suboptimal in the quality of reporting time frames for resolution of lesions/symptoms and outcomes of therapy. Another problem with the case report data is that the TK status of the herpes simplex isolates was not reported. This would have helped substantiate the acyclovir resistance seen in these patients. It was evident in these case reports that acyclovir resistance can be overcome, as acyclovir-resistant strains became sensitive following cidofovir therapy. This may be because TK(+) viruses have been shown to establish latency more readily than do TK(-) viruses. This pattern suggests that alternating between acyclovir and cidofovir therapies may provide a strategy to manage the emergence of alternatively acyclovir-sensitive and -resistant infections. At present, only the intravenous formulation of cidofovir is commercially available. Advantages of the intravenous formulation include weekly dosing and efficacy. Disadvantages are the complexity of administration and the adverse effect profile. The most common adverse effects with this formulation include nephrotoxicity manifested as proteinuria (12%), and increased creatinine (5%) and neutropenia (15%). Administration of probenecid and NaCl 0.9% hydration are used to reduce the incidence and severity of nephrotoxicity in patients who are receiving cidofovir. Probenecid also has toxicities, including nausea, vomiting, headache, fever, and flushing. The topical formulation of cidofovir looks promising for mucocutaneous HSV infection because it is usually undetectable in the blood following topical administration. Therefore, systemic adverse effects should be minimized. A cidofovir gel product (Forvade, Gilead Sciences) is currently being reviewed by the Food and Drug Administration for the treatment of refractory HSV. Ultimately, more controlled clinical studies are necessary to determine whether routine cidofovir use can be justified in patients with acyclovir-resistant HSV infection.
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PMID:Cidofovir use in acyclovir-resistant herpes infection. 941 91

The safety, tolerance, and pharmacokinetics of a small unilamellar liposomal formulation of amphotericin B (AmBisome) administered for empirical antifungal therapy were evaluated for 36 persistently febrile neutropenic adults receiving cancer chemotherapy and bone marrow transplantation. The protocol was an open-label, sequential-dose-escalation, multidose pharmacokinetic study which enrolled a total of 8 to 12 patients in each of the four dosage cohorts. Each cohort received daily doses of either 1.0, 2.5, 5.0, or 7.5 mg of amphotericin B in the form of AmBisome/kg of body weight. The study population consisted of patients between the ages of 13 and 80 years with neutropenia (absolute neutrophil count, <500/mm3) who were eligible to receive empirical antifungal therapy. Patients were monitored for safety and tolerance by frequent laboratory examinations and the monitoring of infusion-related reactions. Efficacy was assessed by monitoring for the development of invasive fungal infection. The pharmacokinetic parameters of AmBisome were measured as those of amphotericin B by high-performance liquid chromatography. Noncompartmental methods were used to calculate pharmacokinetic parameters. AmBisome administered as a 1-h infusion in this population was well tolerated and was seldom associated with infusion-related toxicity. Infusion-related side effects occurred in 15 (5%) of all 331 infusions, and only two patients (5%) required premedication. Serum creatinine, potassium, and magnesium levels were not significantly changed from baseline in any of the dosage cohorts, and there was no net increase in serum transaminase levels. AmBisome followed a nonlinear dosage relationship that was consistent with reticuloendothelial uptake and redistribution. There were no breakthrough fungal infections during empirical therapy with AmBisome. AmBisome administered to febrile neutropenic patients in this study was well tolerated, was seldom associated with infusion-related toxicity, was characterized by nonlinear saturation kinetics, and was effective in preventing breakthrough fungal infections.
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PMID:Safety, tolerance, and pharmacokinetics of a small unilamellar liposomal formulation of amphotericin B (AmBisome) in neutropenic patients. 973 69

It has been suggested that a better outcome of neutropenia-associated invasive fungal infections can be achieved when high doses of lipid formulations of amphotericin B are used. We now report a randomized multicentre study comparing liposomal amphotericin B (AmBisome, 5 mg/kg/d) to amphotericin B deoxycholate (AmB, 1 mg/kg/d) in the treatment of these infections. Of 106 possible patients, 66 were enrolled and analysed for efficacy: nine had documented fungaemia, 17 had other invasive mould infections and 40 had suspected pulmonary aspergillosis. After completion of the course medication, in the AmBisome group (n = 32) 14 patients had achieved complete response, seven a partial response and 11 were failures as compared to 6, 13 and 15 patients (n = 34) treated with AmB (P=0.09); P=0.03 for complete responders. A favourable trend for AmBisome was found at day 14, in patients with documented infections and in patients with pulmonary aspergillosis (P=0.05 and P=0.096 respectively). Mortality rates were lower in patients treated with AmBisome (adjusted for malignancy status, P=0.03). More patients on AmB had a >100% increase of their baseline serum creatinine (P<0.001). The results indicate that, in neutropenic patients with documented or suspected invasive fungal infections AmBisome 5 mg/kg/d was superior to AmB 1 mg/kg/d with respect to efficacy and safety.
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PMID:Liposomal amphotericin B compared with amphotericin B deoxycholate in the treatment of documented and suspected neutropenia-associated invasive fungal infections. 1005 Jul 32

The purpose of this study was to evaluate the efficacy and toxicity of paclitaxel and cisplatin combination chemotherapy as salvage treatment in patients with non-seminomatous germ cell tumour. Sixteen patients with histologically proven germ cell tumour, measurable disease and/or elevated serum tumour markers were eligible for the protocol. All patients had previously not achieved a complete remission (CR) to platinum-based induction chemotherapy and cytoreductive surgery. The treatment consisted of paclitaxel 175-225 mg/m2 as a 3-hour infusion, followed by cisplatin 100 mg/m2, repeated every 3 weeks for up to four cycles. Seven patients achieved a marker-positive partial remission (PR) by the end of the cisplatin-based induction chemotherapy; the remainder had disease progression at the start of the paclitaxel plus cisplatin treatment. One (6%) CR and 3 (19%) PRs were achieved, with an overall response rate of 25% (90% confidence interval 7-43). The duration of the CR is currently 9+ months; two PRs lasted 2 months. One patient with a PR has been lost to follow-up. During a median follow-up of 8 months (range 1-11), 12 patients died from the disease progression. The median survival for the whole group was 7 months. Toxicity was moderate, with neutropenia grade 3 occurring in 29% of patients, thrombocytopenia grade 1-3 in 29%, creatinine > 130 mmol/l in 36%, peripheral neuropathy grade 1-2 in 50%, and nausea and vomiting in 43%. Paclitaxel plus cisplatin showed modest activity, with an overall response rate of 31% in patients with poor prognosis who had not achieved a CR on induction chemotherapy.
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PMID:Paclitaxel and cisplatin as salvage treatment in patients with non-seminomatous germ cell tumour who failed to achieve a complete remission on induction chemotherapy. 984 29

The aim of this study was to evaluate the efficacy and safety of gemcitabine, a pyrimidine antimetabolite, in the treatment of advanced transitional cell carcinoma of the urinary tract. 35 patients with unresectable or metastatic transitional cell carcinoma of the urinary tract previously treated with a platinum-based regimen were studied. Gemcitabine was administered at a dosage of 1200 mg/m2 as a 30-min intravenous infusion on days 1, 8 and 15, repeated every 28 days. 31 patients were evaluable for efficacy. 4 patients achieved a complete response (12.9%), 3 a partial response (9.6%) and 13 (42%) were stable for at least 4 weeks (overall response 22.5%; 95% confidence interval 8-37%). The median response duration was 11.8 months (range 3.6-17.7 + months) and median survival for all patients entered was 5 months (range 2-21 + months). 2 patients with complete response are still alive with no evidence of disease after 14 and 21 months. Gemcitabine also provided subjective symptomatic relief from pain, cystitis, dysuria, haematuria and peripheral oedema. Patients experienced little WHO grade 3-4 toxicity, with anaemia in 8 patients (23%), thrombocytopenia in 5 (14.2%), leucopenia in 4 (11.4%) and neutropenia in 7 (20%). WHO grade 3-4 hepatic toxicity occurred in 4 patients (11.4%) and transient elevations of transaminase was noted in 3 (8.6%). No patient had WHO grade 3-4 elevation of serum creatinine level. There was no WHO grade 4 symptomatic toxicity and no alopecia was noted. Transient influenza symptoms with gemcitabine occurred in 18 patients (51.4%) with 13 patients (37.1%) experiencing fever (2.9% WHO grade 3). In conclusion, gemcitabine is an new active agent for the treatment of transitional cell carcinoma of the urinary bladder with a mild toxicity profile; it warrants further investigation in combination with cisplatin in chemotherapy naive patients.
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PMID:A phase II study of gemcitabine in patients with transitional cell carcinoma of the urinary tract previously treated with platinum. Italian Co-operative Group on Bladder Cancer. 984 81


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