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)

RMP-7, a nine amino acid peptide bradykinin agonist, increases the delivery of hydrophilic compounds across the blood-tumour barrier. In this dose ranging study, 14 patients with progressing malignant glioma (9 glioblastoma multiforme, 4 anaplastic astrocytoma, 1 anaplastic oligodendroglioma; age range 31-68 years, baseline Karnofsky range 60-90%, 5 having had prior chemotherapy) were treated with intravenous RMP-7 and carboplatin to assess the safety, tolerability, and side-effect profile of increasing doses of this combination. Carboplatin dosing was by target area under the curve (AUC) according to the Calvert protocol. Patients were allocated to one of five treatment regimes: cohort A (n = 2) received 50 ng/kg RMP-7 and target AUC 5 mg/ml/min carboplatin; cohort B (n = 3) 100 ng/kg RMP-7 + AUC 5; cohort C (n = 2) 100 ng/kg RMP-7 + AUC 7; cohort D (n = 2) 200 ng/kg RMP-7 + AUC 7; cohort E (n = 5) 300 ng/kg RMP-7 + AUC 7. Treatment was given once every 4 weeks with magnetic resonance imaging scans every 2 months. Patients received 37 cycles in total (median 2, range 1-7). The drug combination, as a cancer treatment, was tolerated in all groups. Effects possibly related to RMP-7 included flushing, nausea, headache and mild increase in heart rate, all transient. 3 patients in cohort E experienced grade 3/4 neutropenia and thrombocytopenia. These toxicities are consistent with known effects of carboplatin at this dose range. In cohort E (n = 5) 1 patient improved and another remained stable for > or = 6 months. In summary, the dose was escalated to the maximum dose of RMP-7 given to volunteers without additional related side-effects. The side-effects of the combination were consistent with giving the two drugs alone and would merit further study for efficacy.
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PMID:A phase I study of intravenous RMP-7 with carboplatin in patients with progression of malignant glioma. 989 73

Intravascular chemotactic factor activation of neutrophils (polymorphonuclear leukocytes; PMNLs), associated with actin polymerization resulting in PMNL stiffening, induces rapid and transient sequestration in the pulmonary vasculature and lung dysfunction. Recent studies have proposed that this sequestration is mediated by physical lodging of PMNLs because of loss of deformability. To examine the contribution of cell adhesion molecules in this process, we used blocking monoclonal antibodies (mAbs) to rat selectins and integrins in a model of PMNL margination (reflected by acute blood neutropenia) induced by N-formyl-met-leu-phe (FMLP) chemotactic factor infusion in normal or lipopolysaccharide (LPS)-primed rats. Blood PMNL levels dropped by 70% within 1 minute and for the duration of FMLP infusion (20 minutes) in normal or by 90% in LPS-primed rats. Pretreatment with mAbs to beta2(WT.3), VLA-4(TA-2 F(ab)(2)), and VLA-5 (HMalpha5 F(ab)(2)) in combination inhibited the decrease by 50% and to a greater degree than beta2 blockade alone (35% inhibition). F(ab)(2) mAbs to L-(HRL-3), P-(RMP-1), plus E-(RME-1) selectins had no effect but they potentiated inhibition by anti-beta2 + anti-VLA-4 + anti-VLA5 mAb treatment (69% inhibition, P < 0.05). Similar results were observed in the first 6 minutes in LPS-primed rats with complete inhibition of sequestration thereafter by combined selectin and integrin blockade. These results indicate that besides PMNL stiffening because of actin polymerization, both selectins and integrins substantially contribute to activated PMNL sequestration in the lung.
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PMID:The beta2, alpha4, alpha5 integrins and selectins mediate chemotactic factor and endotoxin-enhanced neutrophil sequestration in the lung. 1133 79