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Biomedical subjects

R Love

Publications and source records attributed to R Love.

At least 19 recordsLinked to original sources
PubMed1999

A pilot study of melphalan, tumor necrosis factor-alpha and 41.8 degrees C whole-body hyperthermia.

PURPOSE: To evaluate the feasibilitv of sequencing (based on preclinical modeling) tumor necrosis factor-a (TNF) at two dose levels with melphalan (L-PAM) and 41.8 C whole-body hyperthermia (WBH) for 60 min. PATIENTS AND METHODS: Nine patients with refractory cancer were treated from October 1995 to June 1997. The study encompassed a total of 20 trimodality treatment courses. Three patients were treated at TNF dose level I (50 microg/m2) and six patients were treated at TNF dose level II (100 microg/m2). TNF was delivered as a 24-h intravenous infusion, 48 h prior to the combination of L-PAM and WBH; L-PAM was given over 10 min at target temperature at a dose of 17.5 mg/ m2 based on a previous phase I WBH/L-PAM trial. WBH was administered with an Aquatherm radiant heat device. RESULTS: Myelosuppression was the major toxicity associated with therapy, but there were no instances of bleeding or neutropenic fevers. Grade 3 thrombocytopenia was seen with 15% of treatments. Regarding absolute neutrophil count, 15% of treatments were associated with grade 3 toxicity, and 45% with grade 4 toxicity, and regarding white blood cell count, 50% of treatments were associated with grade 3 toxicity and 10% with grade 4 toxicity. The myelosuppression observed was equivalent to that seen in our earlier phase I study of WBH and L-PAM (without TNF). Only mild toxicities (grade 1 or 2) were associated with TNF; these were seen with <25% of treatments and included nausea, vomiting, diarrhea, fevers, and headache. There were no instances of hypotension. There was no relationship between toxicities observed and the two TNF dose levels. Mild WBH toxicities were seen with less than 15% of treatments; these included nausea, vomiting, and herpes simplex I. Responses included two complete remissions (malignant melanoma, TNF dose level I; breast cancer, TNF dose level II), and two disease stabilizations (both malignant melanoma, TNF dose level I). CONCLUSION: We conclude that the combination of TNF, L-PAM, and WBH is well tolerated at the dose levels studied. The clinical results justify further clinical investigation for this trimodality treatment approach.

Adult↗
PubMed1999

Unopposed neutrophil elastase in bronchoalveolar lavage from transplant recipients with cystic fibrosis.

Large numbers of neutrophils with unopposed neutrophil elastase (NE) proteolytic activity are found in lower respiratory tract secretions from most patients with advanced cystic fibrosis (CF). To determine whether antielastase defenses may be overwhelmed in epithelial lining fluid after lung transplantation, we measured NE activity (cleavage of the specific substrate, MeO-Suc-Ala-Ala-Pro-Val-pNA) in bronchoalveolar lavage fluids (BALF) obtained for surveillance or diagnostic purposes at various intervals (1 mo to 7 yr after transplantation) from 52 recipients who had undergone double or bilateral lung transplantation for end-stage CF. Unopposed NE activity was found in BALF from 14 recipients, most of whom also had >= 10(5) colony forming units (cfu) of Pseudomonas aeruginosa in BALF. Ten of the 14 recipients with unopposed NE in bronchoalveolar lavage (BAL) had developed obliterative bronchiolitis (OB), but only 8 of the 38 subjects without unopposed NE activity had OB (p = 0. 002; Fisher exact test). We conclude that antiprotease defenses in lower respiratory tract secretions of CF patients receiving lung allografts are sufficient in the majority of patients to prevent unopposed NE activity. However, the presence of unopposed NE activity in BAL from lung allografts of patients with CF is associated with progressive, irreversible OB and graft failure.

Adolescent↗
PubMed1999

Rhinovirus replication causes RANTES production in primary bronchial epithelial cells.

The mechanisms by which rhinovirus (RV) infections produce lower airway symptoms in asthmatic individuals are not fully established. To determine effects of RV infection on lung epithelial cells, primary human bronchial epithelial (BE) cells were infected with either RV16 or RV49, and viral replication, cell viability, and cell activation were measured. Both viral serotypes replicated in BE cells at 33 degrees C (DeltaTCID50 / ml = 2 to 2.5 log units) and at 37 degrees C (DeltaTCID50 /ml = 1.6 log units), but only high doses of RV49 (10(6) TCID50 /ml) caused cytopathic effects and reduced cell viability. In addition, regulated on activation, normal T cells expressed and secreted (RANTES) secretion was increased in epithelial cells infected with RV16 or RV49 (243 and 398 pg/ml versus 13 pg/ml uninfected control cells), and a similar pattern was seen for RANTES messenger RNA. RV infection also caused increased secretion of interleukin-8 and granulocyte macrophage colony-stimulating factor, but did not alter expression of either intercellular adhesion molecule-1 or human leukocyte-associated antigen-DR. These observations suggest that RVs can replicate in lower airway cells in vivo, and support epidemiologic studies that link RV with lower respiratory illnesses. Further, RV-induced secretion of RANTES and other cytokines could trigger antiviral immune responses in vivo, but these effects could also contribute to the pathogenesis of respiratory symptoms in subjects with asthma.

Anti-Inflammatory Agents↗
PubMed1998

Olanzapine compared with chlorpromazine in treatment-resistant schizophrenia.

OBJECTIVE: The purpose of this study was to compare the efficacy of olanzapine with that of chlorpromazine plus benztropine in patients with treatment-resistant schizophrenia. METHOD: One hundred three previously treatment-resistant patients with schizophrenia diagnosed according to the DSM-III-R criteria were given a prospective 6-week trial of 10-40 mg/day of haloperidol. Eighty-four of them failed to respond to that trial and agreed to be randomly assigned to an 8-week fixed-dose trial of either 25 mg/day of olanzapine alone or 1200 mg/day of chlorpromazine plus 4 mg/day of benztropine mesylate. RESULTS: Fifty-nine (70%) of the 84 subjects completed the trial. The primary outcome measures were Brief Psychiatric Rating Scale total score and positive symptom score, Scale for the Assessment of Negative Symptoms global score, and Clinical Global Impression score. An analysis of variance for the subjects who completed the study showed no difference in efficacy between the two drugs. Seven percent of the olanzapine-treated patients responded according to a priori criteria; no chlorpromazine-treated patients responded. The olanzapine-treated patients had fewer motor and cardiovascular side effects than the chlorpromazine-treated patients. Extrapyramidal symptoms and akathisia were similar in the two groups, although no antiparkinsonian drugs were used in the olanzapine group. CONCLUSIONS: Olanzapine and chlorpromazine showed similar efficacy, and the total amount of improvement with either drug was modest. Olanzapine-treated patients had fewer side effects than chlorpromazine-treated patients.

Adult↗
PubMed1996

Dopexamine prevents depression of mesenteric blood flow caused by positive end-expiratory pressure in rats.

BACKGROUND: The purpose of this study was to investigate the effects of two vasoactive agents, dopamine and dopexamine, on the depression of mesenteric blood flow caused by positive end-expiratory pressure (PEEP) during mechanical ventilation. METHODS: Sprague-Dawley rats were mechanically ventilated with either no PEEP (control group) or increasing levels of PEEP (PEEP group) up to 20 cm H2O pressure. We evaluated PEEP's effect on blood pressure, cardiac output (CO), and the mesenteric microcirculation with a continuous infusion of 2.5 or 12.5 micrograms/kg/min dopamine or 1, 3, or 5 micrograms/kg/min dopexamine. RESULTS: PEEP caused a 20% to 25% decrease in mean arterial pressure and a 30% decrease in CO at both 15 and 20 cm H2O of PEEP (all p < 0.05 versus baseline). Low dose dopamine partially corrected the decrease in CO to 16% and 21% below baseline at 15 and 20 cm H2O of PEEP, respectively (both p < 0.05 versus PEEP group) and partially ameliorated the depression of mesenteric blood flow associated with the application of PEEP. High dose dopamine did not positively affect either CO or mesenteric blood flow. Dopexamine had little effect on CO compared with dopamine. All three doses of dopexamine blocked the effect of PEEP on mesenteric blood flow (p < 0.05 compared with the PEEP group at all levels of PEEP, p < 0.05 compared with the low dose dopamine group at 15 and 20 cm H2O of PEEP). CONCLUSIONS: Dopexamine is superior to dopamine in protecting mesenteric blood flow in the face of increasing levels of PEEP.

Animals↗
PubMed1996

Pediatric clozapine intoxication.

Clozapine is a tricyclic dibenzodiazepine derivative used as an antipsychotic in adults. Clozapine's safety in children has not been established. This report describes three unintentional clozapine ingestions in pediatric patients. These are the first reported cases of clozapine intoxication in children. All three patients demonstrated dramatic alterations in mental status and tone, and two demonstrated extrapyramidal effects. Serum clozapine levels obtained in two patients were within the average range of steady state plasma concentrations for adults. These cases show the dramatic presentations of pediatric ingestion of clozapine and the differences between adult and pediatric intoxications.

Antidepressive Agents, Tricyclic↗
PubMed1996

Neither dopamine nor dobutamine reverses the depression in mesenteric blood flow caused by positive end-expiratory pressure.

UNLABELLED: Positive end-expiratory pressure (PEEP) has been shown to cause a depression of mesenteric blood flow (MBF) and redistribution of blood flow away from the mesenteric vascular bed. OBJECTIVE: We sought to determine whether two commonly used vasoactive agents, dopamine, a known mesenteric vasodilator and inotrope, and dobutamine, with its inotropic properties, would correct the MBF depression caused by PEEP. DESIGN, MATERIAL, AND METHODS: Sprague-Dawley rats, 180 to 250 g, were treated with mechanical ventilation and either no PEEP (control group) or increasing levels (0, 10, 15, and 20 cm of H2O pressure) of PEEP (PEEP group). Also, we evaluated PEEP's effect on MBF and cardiac output (CO) under the influence of a continuous infusion of 2.5 or 12.5 microgram/kg/min of dopamine or 2.5 or 12.5 microgram/kg/min of dobutamine. Cardiac output and, using in vivo videomicroscopy, mesenteric A1, A2, and A3 arteriolar intraluminal radii and A1 arteriolar optical Doppler velocities were measured. After 20 cm of H2O pressure PEEP was attained, two boluses of 2 mL of 0.9 normal saline were given. The MBF was calculated from vessel radius and red blood cell velocity. MEASUREMENTS AND MAIN RESULTS: There were no significant changes from baseline in mean arterial pressure or A2 or A3 diameters in any of the groups. Both MBF and CO were unchanged over time in the control group. The MBF was reduced 78% (p < 0.05) and the CO was reduced 31% (p < 0.05) from baseline at 20 cm of H2O pressure PEEP. After 4 mL of normal saline, the MBF was still 53% below baseline (p < 0.05), while the CO had returned to baseline in the PEEP group. Low-dose dopamine partially ameliorated both the decrease in CO and MBF caused by PEEP, but 4 mL of normal saline was required in addition to the low-dose dopamine to return MBF to baseline levels while on 20 cm of H2O pressure PEEP. High-dose dopamine with the addition of 4 mL of normal saline returned CO to baseline on 20 cm of H2O pressure PEEP, but MBF remained approximately 46% below baseline despite fluid boluses. Neither low-dose nor high-dose dobutamine, with or without fluid boluses, had an appreciable positive effect on CO or MBF. CONCLUSIONS: It is clear that inotropes are not a replacement for adequate fluid loading to correct the depression in cardiac output and mesenteric blood flow associated with the use of mechanical ventilation and PEEP. Low-dose dopamine may serve as an adjunct to adequate fluid resuscitation to improve MBF.

Analysis of Variance↗
PubMed1995

Genetic instability associated with adenoma to carcinoma progression in hereditary nonpolyposis colon cancer.

BACKGROUND & AIMS: Genetic instability related to defective DNA mismatch repair genes may be involved in the pathogenesis of carcinoma in hereditary nonpolyposis colon cancer (HNPCC). However, nonneoplastic tissues from patients inheriting defects in human MSH2 or human MLH1 do not show significant genetic instability. The aim of this study was to determine whether acquisition of genetic instability at the adenoma stage promotes malignant transformation by studying adenoma-carcinoma progression in HNPCC. METHODS: Dinucleotide repeat loci were analyzed by polymerase chain reaction from microdissected adenoma and/or carcinoma stages from formalin-fixed paraffin-embedded HNPCC tumors. RESULTS: Although genetic instability was observed at some loci in almost all cases, the proportion of microsatellite loci altered was significantly less (P < 0.01) in completely benign adenomas (24%) than in benign areas of adenomas with malignancy (54%). Molecular fingerprints indicated intratumor heterogeneity, with evolution of related subclones of neoplastic cells. However, in all cases of tumor progression, at least one subclone from the adenoma stage was closely related to the carcinoma. CONCLUSIONS: Some genetic instability develops at the benign adenoma stage in most HNPCC tumors. Adenomas with a greater rate of genetic instability are more likely to progress to carcinoma. Topographic genotyping data provides evidence supporting the hypothesis of adenoma-carcinoma progression in HNPCC.

Adenoma↗