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)

Sequestration of neutrophils (PMNs) in the pulmonary microvasculature and associated neutropenia are characteristic features of experimental models of septic lung injury. The etiology of altered PMN kinetics during septic lung injury is uncertain, but may be partially due to increased adhesiveness of activated PMNs to pulmonary endothelium. This study examines the relationship between the expression of PMN CD18 adhesion receptors, the evolving neutropenia, and plasma tumor necrosis factor (TNF) activity in a porcine model of septic lung injury. Acute lung injury was induced by infusion of live Pseudomonas aeruginosa (5 x 10(8) CFU/ml at 0.3 ml/20 kg/min) for 60 min (Group Ps, n = 6). Control animals (Group C, n = 3) received a 60-min infusion of sterile 0.9% saline. CD18 expression of circulating PMNs was measured by quantitative immunofluorescent flow cytometry. Plasma TNF activity was measured by L929 fibroblast cytolytic assay. Group Ps developed a significant neutropenia by 30 min (14.9 +/- 2.5 vs 23.4 +/- 3.3 x 10(3) cells/microliter at baseline, P less than 0.05, ANOVA) with circulating neutrophils exhibiting significantly increased CD18 expression by 60 min (6.34 +/- 0.72 vs 5.01 +/- 0.52 equivalent soluble fluorescence molecules (ESFM) x 10(3) at baseline, P less than 0.05, ANOVA). Group Ps demonstrated a significant increase in plasma TNF activity by 30 min (2.5 +/- 0.9 vs 0.7 +/- 0.3 U/ml at baseline). There was no significant change in PMN count, PMN CD18 expression, or plasma TNF activity in Group C. In complimentary in vitro studies, porcine PMNs stimulated with recombinant human TNF-alpha (n = 5) demonstrated a time- and dose-dependent increase in CD18 expression.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:CD18 adhesion receptors, tumor necrosis factor, and neutropenia during septic lung injury. 167 83

The efficacy and toxicity of the new anthracycline, 4'-0-tetrahydropyranyl doxorubicin (THP) (50 mg/m2 intravenous [IV] bolus) in association with cisplatin (100 mg/m2 IV as a 4-hour infusion) was assessed in 31 patients with advanced ovarian carcinoma. Twenty-eight patients were assessable for toxicity among whom 25 were assessable for response (International Federation of Gynecology and Obstetrics [FIGO] stage IIIa, four patients; IIIb, 15 patients; IV, six patients). Nine patients had received prior treatment. Patients were randomized to receive schedule (sch) A (THP at 6 hours, then cisplatin from 16 to 20 hours) or sch B (THP at 18 hours, then cisplatin from 4 to 8 hours). Sch A was hypothesized as less toxic since THP was best tolerated in the late rest span and cisplatin near the middle of the activity span in experimental studies. The rate of clinical complete response (CR) was 52%, that of partial response (PR) was 12%, and the overall clinical response rate (CR plus PR) was 64% (sch A, 73%; sch B, 57%). Median progression-free survival and survival times were, respectively, 10 and 19 months. Of 12 patients in clinical CR evaluated at second-look laparotomy, four had a pathological CR (33%), and three had microscopic residual disease (MD). The overall rate of pathological CR was 16%. Sch A was associated with less neutropenia (P = .10), thrombocytopenia (P less than .01), anemia (P less than .01), and renal toxicity (P less than .05) than sch B. Of four patients withdrawn for toxicity, three were on sch B (one death). Mean dose intensities (DIs) of THP and cisplatin, respectively, decreased by 30% and 47% over the five initial courses. Such decrease was significantly more pronounced for sch B than for sch A in previously untreated patients (P from 2-way analysis of variance [ANOVA] less than .01). THP-cisplatin is active against advanced ovarian cancer, and its toxicities can be significantly decreased by dosing THP in the early morning and cisplatin in the late afternoon as compared with THP in the evening and cisplatin the next morning.
 ...
PMID:Chemotherapy of advanced ovarian cancer with 4'-O-tetrahydropyranyl doxorubicin and cisplatin: a randomized phase II trial with an evaluation of circadian timing and dose-intensity. 217 81

We attempted to determine the effects of prior antineoplastic chemotherapy and age on gentamicin pharmacokinetics in children (age 1-18 yrs) with cancer and in controls, and to establish a protocol for gentamicin dosing and monitoring to ensure rapid attainment of therapeutic serum concentrations in these patients. In a prospective controlled study, patients with fever who were receiving empiric gentamicin for confirmed or suspected infections were separated into three groups: 29 with cancer who were receiving a continuing chemotherapy protocol with nonnephrotoxic antineoplastic agents; 23 with cancer who were receiving a continuing chemotherapy protocol with nephrotoxic antineoplastic agents; and 25 control patients who did not have cancer. Three blood samples (one predose, two postdose concentrations), collected between the third and sixth gentamicin doses from each patient, were analyzed by the Emit assay. Pharmacokinetic parameters were calculated and gentamicin dosages recommended based on the Sawchuk-Zaske method of serum level interpretation. When normalized by body weight, there was no significant difference in clearance, volume of distribution, and half-life between the control group and either group of patients with cancer. However, when normalized by body surface area, patients receiving prior nephrotoxic chemotherapy appeared to have a lower mean clearance (98.2 ml/min/1.73 m2) than those exposed to nonnephrotoxic chemotherapy (117.4 ml/min/1.73 m2) and controls (113.3 ml/min/1.73 m2; ANCOVA p = 0.033). When kinetic parameters were normalized by body weight, the effect of advancing age yielded a decrease in both clearance (p < 0.001) and volume of distribution (p = 0.02), and an increase in gentamicin half-life (p < 0.001). When normalized by body surface area, age had no significant effect on clearance (p = 0.579). There was no significant difference in gentamicin daily dose requirements (mg/kg) between the chemotherapy groups, which may be due to the lack of significant effects of chemotherapy on gentamicin's volume of distribution and clearance normalized by body weight. The final maintenance doses (mg/kg/day, mean +/- SD) for patients with cancer were 10.8 +/- 1.8 for those age 1-5 years, 8.9 +/- 1.1 for those age 6-12 years, and 7.9 +/- 1.9 for those age 13-18 years. However, when normalized by body surface area, the age-dependent doses became remarkably similar for children in all three age groups (ANOVA p = 0.932), approximately 250 mg/m2/day. We recommend that pediatric patients with cancer who require treatment for fever and neutropenia be given higher than standard gentamicin dosages to achieve therapeutic serum concentrations promptly. In particular, initial empiric doses of 10 mg/kg/day are appropriate for those age 1-5 years.
 ...
PMID:The effects of age and chemotherapy on gentamicin pharmacokinetics and dosing in pediatric oncology patients. 860 84

Neutrophil depletion is commonly used to examine the role of neutrophils in lung injury. However, the effect of neutrophil depletion per se on mechanisms of pulmonary vascular smooth muscle relaxation is unknown. The purpose of this study was to examine the effect of neutropenia on the following mechanisms of cGMP-mediated pulmonary vasorelaxation: (1) receptor-dependent endothelium-dependent relaxation (response to acetylcholine (ACh)), (2) receptor-independent endothelium-dependent relaxation (response to the calcium ionophore A23187), and (3) endothelium-independent relaxation (response to sodium nitroprusside (SNP)). Neutropenia (<75 neutrophils/mu l) was induced with anti-neutrophil antibody serum 24 hr prior to lung harvest in five rats. Saline-injected rats were controls (n = 5). Dose-response curves to ACh, A23187, and SNP were generated in isolated pulmonary artery rings preconstricted with phenylepherine. Statistical comparison was performed using one-way ANOVA with post-hoc Bonferroni-Dunn, and P < 0.05 was accepted as significant. Relaxation to ACh, A23187, and SNP was complete in both control and neutropenic rats. Thus, antibody-mediated depletion does not impair endothelial-dependent or -independent cGMP-mediated pulmonary vasorelaxation.
 ...
PMID:Antibody-mediated neutrophil depletion preserves pulmonary vasomotor function. 860 14

A randomised, open label phase II study was performed in patients with advanced colorectal cancer to evaluate the safety, toxicity and antineoplastic activity of the topoisomerase I-inhibitor rubitecan. A cross-over design was chosen to determine the intrapatient variation of the bioavailability and pharmacokinetics of the anticancer agent depending on the timing of food intake in relation to the oral drug administration. Patients with previously untreated metastatic disease received two single oral doses of rubitecan 1.5 mg/m2 for assessment of the pharmacokinetics. They were randomised to have the first administration either after an overnight fasting period or immediately after a high calorie breakfast, and crossed over to the alternative schedule after a one-week washout period. After completion of the pharmacokinetic sampling, treatment continued with rubitecan given orally at a dose of 1.5 mg/m2/day, to be increased up to 2.0 mg/m2/day, under fasting conditions for 5 consecutive days per week until disease progression. 19 patients entered the trial after informed consent was obtained. A total number of 35 treatment cycles (median 2, range 1-4) were administered. All patients were evaluable for safety. The toxicity profile of rubitecan was generally mild to moderate, with sporadic cases of grade 4 toxicities (Common Toxicity Criteria (CTC) version 2.0) diarrhoea, leucopenia and neutropenia. None of 15 evaluable patients achieved an objective response. The majority had early disease progression. 14 patients were evaluable for pharmacokinetic analysis. The bioavailability of rubitecan was found to be strongly dependent on the timing of food intake with a fasted-to-fed ratio for C(max) of 1.98 (two-tailed P<0.001; ANOVA), T(max) 0.49 (P<0.001), AUC(0-8 h) 2.52 (P<0.001) and AUC(0-24 h) 1.64 (P=0.003). Rubitecan is well tolerated, but clinically inactive in colorectal cancer at the currently recommended dose and schedule. The bioavailability is strongly dependent on the timing of food intake in relation to the oral administration of the drug. The topoisomerase I-inhibitor should be administered under fasting conditions to achieve adequate drug exposure in future prospective trials in other tumour types.
 ...
PMID:Clinical phase II study and pharmacological evaluation of rubitecan in non-pretreated patients with metastatic colorectal cancer-significant effect of food intake on the bioavailability of the oral camptothecin analogue. 1193 15

The toxicity of irinotecan (CPT-11), a topoisomerase-I inhibitor largely used in cancer patients, was investigated as a function of the circadian time of its administration in mice, with mortality, body weight loss, leukopenia, neutropenia, intestinal lesions, and bone marrow cell cycle phase distribution as end points. Four experiments were performed on a total of 773 male mice standardized with 12h light/12h darkness. Irinotecan was administered daily for 4 or 10 consecutive days (D1-4 and D1-10, respectively, in different experiments) at one of six circadian stages expressed in hours after light onset (HALO). The survival curves differed significantly as a function of the dosage and circadian time of drug administration by the D1-10 schedule, with 70% survival at 7 or 11 HALO and 51% at 19 or 23 HALO (p=0.039 from log rank test). CPT-11 administration at 19 or 23 HALO resulted in (1) greatest mean body weight loss at nadir; (2) most severe colic and bone marrow lesions and/or slowest recovery; and (3) deepest neutropenia nadir and/or slowest hematologic recovery. These circadian treatment time-related differences were statistically validated. The bone marrow cell cycle data revealed a four to eight-fold larger G2-M phase arrest following irinotecan administration at 19 or 23 HALO in comparison to the other times of drug administration, apparently representative of the repair of more extensive DNA damage (p < 0.001 from ANOVA) when the medication was given at these circadian times. Overall, CPT-11 was better tolerated by mice treated during the light (animals' rest) span. The results support the administration of CPT-11 to cancer patients in the second half of the night, during sleep, in order to improve drug tolerability.
 ...
PMID:Circadian rhythm of irinotecan tolerability in mice. 1547 Sep 58

Splenic volume and Helicobacter pylori (H. pylori) infection were evaluated in 67 patients with chronic idiopathic neutropenia (CIN) and 39 healthy individuals. Using ultrasound, splenomegaly was found in 61.7% of H. pylori-infected subjects compared to only 8.7% noted in the group of H. pylori-non-infected individuals (P < 0.0001). Splenomegaly was also found in 47.8% of CIN patients compared to 12.8% in the group of non-CIN subjects (P = 0.0003). However, applying the two-way ANOVA test, a statistically significant effect on splenic volume was documented for "factor H. pylori " (F1(102) = 16.800, P < 0.0001) but not for "factor CIN" (F1(102) = 3.213, P = 0.0760), suggesting that CIN-associated splenomegaly is probably due to H. pylori infection.
 ...
PMID:Helicobacter pylori infection is probably the cause of chronic idiopathic neutropenia (CIN)-associated splenomegaly. 1643 51

Previously studied candidate genes have failed to account for inter-individual variability of docetaxel and doxorubicin disposition and effects. We genotyped the transcriptional regulators of CYP3A and ABCB1 in 101 breast cancer patients from 3 Asian ethnic groups, that is, Chinese, Malays and Indians, in correlation with the pharmacokinetics and pharmacodynamics of docetaxel and doxorubicin. While there was no ethnic difference in docetaxel and doxorubicin pharmacokinetics, ethnic difference in docetaxel- (ANOVA, P=0.001) and doxorubicin-induced (ANOVA, P=0.003) leukocyte suppression was observed, with Chinese and Indians experiencing greater degree of docetaxel-induced myelosuppression than Malays (Bonferroni, P=0.002, P=0.042), and Chinese experiencing greater degree of doxorubicin-induced myelosuppression than Malays and Indians (post hoc Bonferroni, P=0.024 and 0.025). Genotyping revealed both PXR and CAR to be well conserved; only a PXR 5'-untranslated region polymorphism (-24381A>C) and a silent CAR variant (Pro180Pro) were found at allele frequencies of 26 and 53%, respectively. Two non-synonymous variants were identified in HNF4alpha (Met49Val and Thr130Ile) at allele frequencies of 55 and 1%, respectively, with the Met49Val variant associated with slower neutrophil recovery in docetaxel-treated patients (ANOVA, P=0.046). Interactions were observed between HNF4alpha Met49Val and CAR Pro180Pro, with patients who were wild type for both variants experiencing least docetaxel-induced neutropenia (ANOVA, P=0.030). No other significant genotypic associations with pharmacokinetics or pharmacodynamics of either drug were found. The PXR-24381A>C variants were significantly more common in Indians compared to Chinese or Malays (32/18/21%, P=0.035) Inter-individual and inter-ethnic variations of docetaxel and doxorubicin pharmacokinetics or pharmacodynamics exist, but genotypic variability of the transcriptional regulators PAR, CAR and HNF4alpha cannot account for this variability.
 ...
PMID:PXR, CAR and HNF4alpha genotypes and their association with pharmacokinetics and pharmacodynamics of docetaxel and doxorubicin in Asian patients. 1787 42

The purpose of this study was to compare the toxicity profiles of docetaxel administered on a weekly schedule and the standard three-week schedule in the treatment of advanced primary ovarian carcinoma. Eligible patients were treated with intravenous docetaxel (30 mg/m2) on days 1, 8 and 15, and carboplatin (AUC 5) on day 1 or with docetaxel (75 mg/m2) and carboplatin (AUC 5) on day 1; Q21 days for 6 cycles. This study was a pooled study of two primary phase II studies. A total of 108 patients received the weekly schedule and 59 patients received the three-week schedule. All patients were evaluated for toxicity. The overall response rate was 79% and the biochemical response 93% for the weekly schedule. The median overall survival rate was 35.3 months. Neutropenia was significantly more common (ANOVA; p<0.0001) in the three-week group than in the weekly group during all six courses of chemotherapy. Fever and infections were also more common in this group. Thrombocytopenia and anemia were slightly more common in the weekly group. Fatigue, epiphora, nail changes and taste disturbances were specific side-effects following weekly docetaxel. Peripheral sensory neuropathy (grade 1-2) increased with every cycle of treatment, but in a similar manner in the two groups. Grade 3-4 neuropathy was not recorded. Oral mucositis and myalgia were two side-effects associated with the three-week schedule. Nausea and vomiting, diarrhea and dyspnea were a limited problem in both groups. Cardiac toxicity was rare and did not differ between the two docetaxel schedules. The weekly administration was favored due to the lower rates of neutropenia, fever, infections, oral mucositis and myalgia. However, epiphora and nail changes were specific side-effects of the weekly treatment. Both regimens appeared to be rather well tolerated with similar compliance (66 and 70%) with regard to completion of the planned six courses of chemotherapy.
 ...
PMID:A study of docetaxel weekly or every three weeks in combination with carboplatin as first line chemotherapy in epithelial ovarian cancer: Hematological and non-hematological toxicity profiles. 2359 53

Excess dietary nitrogen (EDN) is commonly expected in dairy herds, but no data are available regarding its consequences on cattle immunity. In this study neutrophil functions were assessed during EDN in steers. In experiment 1, 4 one-month periods, 4 diets [16% crude protein (CP; DM basis), 20% CP based on soybean meal, 20% CP based on urea, and 24% CP based on urea and soybean meal], and 4 steers were included in a crossover design to determine the effects of a chronic excess. In experiment 2, the repercussions of an acute excess were assessed with 2 periods of 10 d, the same 4 steers, and 2 diets containing 14 and 20% CP. Sampling was done during the fourth week of each period in experiment 1, and on d 0, 1, 2, 3, 7, and 9 of each period in experiment 2. Individual blood biochemistry parameters were measured and neutrophil factors, such as counts, recovery after isolation, surface expression of CD11b and CD62L, phagocytosis, diapedesis, reactive oxygen species (ROS) production, and bacteria killing, were determined. Data were analyzed by general linear models of R, with period, diet or biochemical component, and animal as explanatory variables. The outcome variables were biochemical or immune variables. The variables diet, period, and animal were forced as fixed effects. Data collected over the entire period of experiment 2 were pooled. Several multiples linear regressions or ANOVA were performed and a Bonferroni correction was applied. In experiment 2 (acute EDN), neutrophil counts were negatively associated with nitrogen intake, conversely to CD62L expression. The observed relative neutropenia may be due to neutrophil margination because CD62L-expressing neutrophils are more likely to stick to endothelium. Interestingly, ROS production was changed by EDN: chronic EDN (experiment 1) was negatively associated with opsonized zymozan (OZ)-induced ROS production and acute EDN (experiment 2) with spontaneous ROS production. For chronic EDN, ROS production upon phorbol 12-myristate 13-acetate was not modified, in contrast to OZ stimulation. Decreased ROS production during chronic EDN probably involves the early events leading to ROS production, as OZ acts through membrane receptors and phorbol 12-myristate 13-acetate directly activates protein kinase C. This is the first study to provide evidence that the modifications of neutrophil functions produced by excess nitrogen depend on the intensity and duration of the excess. Further studies, including epidemiological studies during risk periods, are needed to resolve the issues linked to EDN.
...
PMID:Effect of acute and chronic excesses of dietary nitrogen on blood neutrophil functions in cattle. 2530 72


1 2 Next >>