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D Harmon

Publications and source records attributed to D Harmon.

At least 19 recordsLinked to original sources
PubMed2006

Effect of midazolam on in vitro cerebral endothelial ICAM-1 expression induced by astrocyte-conditioned medium.

BACKGROUND AND OBJECTIVE: Astrocytes exposed to hypoxia produce pro-inflammatory cytokines and upregulate intercellular adhesion molecule-1 on cerebral endothelium. This study investigated the effects of midazolam on this response. METHODS: Mouse astrocytes were exposed to 4 h of hypoxia and 24 h of reoxygenation. Astrocyte-conditioned medium were applied to mouse cerebral endothelial cell cultures for 4 h and 24 h in normoxia. Endothelial cells were pre-incubated for 1 h with midazolam (0, 5, 50 microg L-1). Flow cytometry was used to estimate endothelial ICAM-1 expression. IL-1beta concentrations were measured with ELISA. Repeated comparisons were made using ANOVA and post hoc Tukey Test as appropriate. Data are mean (SD). RESULTS: Mouse cerebral endothelial cell ICAM-1 expression was greater after 24 h exposure to hypoxia-reoxygenation astrocyte-conditioned medium compared to normoxic astrocyte-conditioned medium (mean channel flouresence 112.5 (9.5) vs. 81.5 (7.5), P = 0.01). ICAM-1 expression was decreased by midazolam (5 microg L(-1)) compared to control (mean channel flouresence 81.35 (7.5) vs. 112.5 (9.5), P = 0.01). Supernatant IL-1beta concentrations (pg mL(1)) in astrocytes exposed to hypoxia-reoxygenation were greater than those exposed to normoxia (16.41 (2.35) vs. 10.5 (2.13), P = 0.01). CONCLUSION: We conclude that decreased cerebral endothelial ICAM-1 expression in response to activated glial cell compartment by midazolam may decrease post ischaemic brain inflammation and secondary brain injury.

Anesthetics, Intravenous↗
PubMed2005

Ecteinascidin-743 (ET-743) for chemotherapy-naive patients with advanced soft tissue sarcomas: multicenter phase II and pharmacokinetic study.

PURPOSE: To evaluate the response rate, toxicity profile, and pharmacokinetics of ecteinascidin-743 (ET-743) as first-line therapy in patients with unresectable advanced soft tissue sarcoma (STS). PATIENTS AND METHODS: Thirty-six patients with STS were enrolled onto the study between September 1999 and August 2000. Patients were treated with 1.5 mg/m2 of ET-743 given as a 24-hour continuous intravenous (IV) infusion every 21 days. Pharmacokinetic sampling was performed in 23 patients. RESULTS: One complete and five partial responses were achieved in 35 assessable patients for an overall response rate of 17.1% (95% CI, 6.6% to 33.6%). In addition, one patient had a minor response, leading to an overall clinical benefit of 20%. Neutropenia and transaminitis were the main grade 3 to 4 toxicities, which occurred in 33% and 36% of the patients. The estimated 1-year progression-free and overall survival rates were 21% (95% CI, 11% to 41%) and 72% (95% CI, 59% to 88%), respectively. Total body clearance (L/h) was not significantly correlated with body-surface area (r = -0.28; P = .21). Mild hepatic impairment or the extent of prior cytotoxic therapy does not seem to contribute significantly to the high interpatient variability (49%) in the clearance of this drug. Severity of treatment-related toxicity was not correlated with pharmacokinetic variables. CONCLUSION: ET-743 demonstrates clinical activity as first-line therapy against STS with acceptable toxicity. Additional studies to establish empirical dosing guidelines may be necessary to improve the safety of the drug in patients with varying degrees of hepatic dysfunction and definitively establish the role of ET-743 for patients with these malignancies.

Adult↗
PubMed2005

Plasma concentrations of nitric oxide products and cognitive dysfunction following coronary artery bypass surgery.

BACKGROUND AND OBJECTIVE: Prospective longitudinal studies now indicate that cognitive dysfunction following coronary artery bypass surgery (CABG) is both common and persistent. This dysfunction is due in part to the inflammatory response and cerebral ischaemia-reperfusion, with nitric oxide (NO) as an important mediator of both. We hypothesized that a clinically significant association exists between plasma concentrations of nitrate/nitrite (NO3-/NO2-) and cognitive dysfunction after CABG. METHODS: Cognitive assessment was performed on 36 adult patients the day before CABG, on the fourth postoperative day and 3 months postoperatively. Patient spouses (n = 10) were also studied. RESULTS: A new cognitive deficit was present in 22/36 (62%) 4 days postoperatively and in 16/35 (49%) of patients, 3 months postoperatively. Patients who had cognitive dysfunction 3 months postoperatively were more likely to have cognitive dysfunction and increased plasma NO3-/NO2- concentrations compared to the non-deficit group preoperatively (22.6 (9.2) vs. 27.6 (8.4)) (P = 0.002). Plasma NOx (NO3- plus NO2-) concentrations were greater in patients with cognitive dysfunction 3 months postoperatively, 2 h (24.2 (6.3) vs. 19.1 (5.2)) (P = 0.002), and 12 h postoperatively (24.8 (7.6) vs. 18.8 (5.6)) (P = 0.001). There was, however, a time course similarity in NOx elevations for both deficit and non-deficit groups. CONCLUSIONS: Perioperative plasma NOx concentrations do not serve as an effective biomarker of cognitive deficit after CABG.

Adult↗
PubMed2005

Effect of aprotinin on in vitro cerebral endothelial ICAM-1 expression induced by astrocyte-conditioned medium.

BACKGROUND AND OBJECTIVE: Aprotinin administration may decrease the incidence of stroke associated with coronary artery bypass surgery by an unknown mechanism. Astrocytes exposed to hypoxia produce proinflammatory cytokines and upregulate intercellular adhesion molecule (ICAM)-1 on cerebral endothelium. This study investigated the effects of aprotinin on cerebral endothelial activation by hypoxic astrocytes in vitro. METHODS: Mouse astrocytes were exposed to hypoxia in an anaerobic chamber for 4 h followed by reoxygenation for 24 h. Astrocyte-conditioned medium (ACM) collected from mouse astrocytes subjected to hypoxia/reoxygenation (HR) or normoxia were applied to mouse cerebral endothelial cell (MCEC) cultures for 4 and 24 h in normoxia. Endothelial cells were preincubated for 1 h with aprotinin (1600 KIU mL(-1)) prior to exposure to ACM. Flow cytometry was used to estimate endothelial ICAM-1 expression. Interleukin (IL)-1beta space concentrations in ACM were estimated with enzyme-linked immunosorbent assay (ELISA). Repeated comparisons were made using analysis of variance (ANOVA) and post hoc Tukey test as appropriate. P < 0.05 was considered significant. Data is presented as mean (standard deviation, SD). RESULTS: MCEC ICAM-1 expression was greater after 24 h exposure to HR-ACM compared to normoxic-ACM (mean channel flouresence (MCF) 107.5 (4.5) vs. 74.3 (4.5), respectively, P < 0.001). ICAM-1 expression was decreased by aprotinin preincubation compared to control (MCF 91.0 (1.1) vs. 107.5 (2.1), P = 0.006). Supernatant IL-1beta concentrations in astrocytes exposed to HR were greater than those exposed to normoxia (7.1 (0.2) vs. 4.1 (0.2), P = 0.01). CONCLUSIONS: This may be a neuroprotective mechanism associated with aprotinin administration.

Anaerobiosis↗
PubMed2005

A combination of lidocaine and nitrous oxide in oxygen is more effective in preventing pain on propofol injection than either treatment alone.

BACKGROUND AND OBJECTIVE: Propofol is an intravenous (i.v.) anaesthetic agent that possesses many of the qualities of an ideal anaesthetic agent. The most significant side-effect associated with propofol is pain on injection. Despite optimal therapy, the incidence of pain on propofol injection remains a problem. This prospective, randomized, double blinded study evaluated the effect of three different treatment strategies in decreasing pain on propofol injection. METHODS: We studied 102 adult, ASA I-II patients, scheduled for elective surgical procedures. Combination of i.v. lidocaine and nitrous oxide (N2O) in oxygen (O2) inhalation pre-treatment was compared with either treatment alone in the prevention of pain on propofol injection. A standard propofol injection technique and scoring system, to measure the pain on injection was used. RESULTS: Demographic variables were similar between the groups. The incidence of no pain on propofol injection was similar in the lidocaine and N2O groups (63.6% vs. 57.5%) (95% confidence interval (CI): 0.17-0.29, P = 0.61). Combination therapy was associated with a greater incidence of no pain on injection (84% vs. 63.6%) (95% CI: 0.06-0.48, P = 0.04). CONCLUSION: Combination of i.v. lidocaine and N2O in O2 inhalation pre-treatment is more effective than either treatment alone in decreasing pain on propofol injection.

Adolescent↗
PubMed2004

Phase II and pharmacokinetic study of ecteinascidin 743 in patients with progressive sarcomas of soft tissues refractory to chemotherapy.

PURPOSE: To assess the efficacy of the marine-derived alkaloid ecteinascidin 743 (ET-743) in patients with soft tissue sarcomas that progressed despite prior conventional chemotherapy and to characterize the pharmacokinetic profiles of ET-743 in this patient population. PATIENTS AND METHODS: Thirty-six previously treated soft tissue sarcoma patients from three institutions received ET-743 as a 24-hour continuous intravenous (IV) infusion at a dose of 1,500 microg/m(2) every 3 weeks. Pharmacokinetic studies were also performed. Patients were restaged every two cycles for response by objective criteria. RESULTS: Objective responses were observed in three patients, with one complete response and two partial responses, for an overall response rate of 8% (95% CI, 2% to 23%). Responses were durable for up to 20 months. Two minor responses (43% and 47% tumor reduction) were observed, for an overall clinical benefit rate of 14%. The predominant toxicities were neutropenia and self-limited transaminitis of grade 3 to 4 severity in 34% and 26% of patients, respectively. The estimated 1-year time to progression and overall survival rates were 9% (95% CI, 3% to 27%) and 53% (95% CI, 39% to 73%), respectively. The maximum observed plasma concentration and total plasma clearance of ET-743 (mean +/- standard deviation), 1.04 +/- 0.48 ng/mL and 35.6 +/- 16.2 L/h/m(2), respectively, were consistent with previously reported values from phase I studies of the drug given as a 24-hour IV infusion. CONCLUSION: ET-743 is a promising new option for the management of several histologic subtypes of sarcoma. Durable objective responses were obtained in a subset of sarcoma patients with disease progression despite prior chemotherapy. Additionally, the relatively high survival rate noted in this series of previously treated patients further justifies development of this agent.

Adult↗
PubMed2004

The effect of lidocaine on in vitro neutrophil and endothelial adhesion molecule expression induced by plasma obtained during tourniquet-induced ischaemia and reperfusion.

BACKGROUND: Changes in neutrophil and endothelial adhesion molecule expression occur during perioperative ischaemia and reperfusion (I/R) injury. We investigated the effects of lidocaine on neutrophil-independent changes in neutrophil and endothelial adhesion molecule expression associated with tourniquet-induced I/R. METHODS: Plasma was obtained from venous blood samples (tourniquet arm) taken before (baseline), during, 15 min, 2 and 24 h following tourniquet release in seven patients undergoing elective upper limb surgery with tourniquet application. Isolated neutrophils from healthy volunteers (n = 7) were pretreated in the presence or absence of lidocaine (0.005, 0.05 and 0.5 mg mL(-1) for 1 h, and then incubated with I/R plasma for 2 h. Human umbilical vein endothelial cells (HUVECs) were pretreated in the presence or absence of lidocaine (0.005, 0.05 and 0.5 mg mL(-1)) for 1 h, and then incubated with the plasma for 4 h. Adhesion molecule expression was estimated using flow cytometry. Data were analysed using ANOVA and post hoc Student-Newman-Keuls tests. RESULTS: I/R plasma (withdrawn 15 min following tourniquet release) increased isolated neutrophil CD11b (P = 0.03), CD18 (P = 0.01) and endothelial intercellular adhesion molecule-1 (ICAM-1) (P = 0.008) expression compared to baseline. CD11b, CD18 and ICAM-1 expression on lidocaine (0.005 mg mL(-1)) treated neutrophils was similar to control. CD11b (P < 0.001), CD18 (P = 0.03) and ICAM-1 (P = 0.002) expression on lidocaine (0.05 mg mL(-1)) treated neutrophils and HUVECs was less than that on controls. CONCLUSION: Increased in vitro neutrophil and endothelial cell adhesion molecule expression on exposure to plasma obtained during the early reperfusion phase is diminished by lidocaine at greater than clinically relevant plasma concentrations.

Adolescent↗
PubMed2004

The effect of lidocaine on neutrophil CD11b/CD18 and endothelial ICAM-1 expression and IL-1beta concentrations induced by hypoxia-reoxygenation.

BACKGROUND: Lidocaine has actions potentially of benefit during ischaemia-reperfusion. Neutrophils and endothelial cells have an important role in ischaemia-reperfusion injury. METHODS: Isolated human neutrophil CD11b and CD18, and human umbilical vein endothelial cell (HUVEC) ICAM-1 expression and supernatant IL-1beta concentrations in response to hypoxia-reoxygenation were studied in the presence or absence of different concentrations of lidocaine (0.005, 0.05 and 0.5 mg mL(-1)). Adhesion molecule expression was quantified by flow cytometry and IL- 1beta concentrations by ELISA. Differences were assessed with analysis of variance and Student-Newman-Keuls as appropriate. Data are presented as mean+/-SD. RESULTS: Exposure to hypoxia-reoxygenation increased neutrophil CD11b (94.33+/-40.65 vs. 34.32+/-6.83 mean channel fluorescence (MCF), P = 0.02), CD18 (109.84+/-35.44 vs. 59.05+/-6.71 MCF, P = 0.03) and endothelial ICAM-1 (146.62+/-16.78 vs. 47.29+/-9.85 MCF, P < 0.001) expression compared to normoxia. Neutrophil CD18 expression on exposure to hypoxia-reoxygenation was less in lidocaine (0.005 mg mL(-1)) treated cells compared to control (71.07+/-10.14 vs. 109.84+/-35.44 MCF, P = 0.03). Endothelial ICAM-1 expression on exposure to hypoxia-reoxygenation was less in lidocaine (0.005 mg mL(-1)) treated cells compared to control (133.25+/-16.05 vs. 146.62+/-16.78 MCF, P = 0.03). Hypoxia-reoxygenation increased HUVEC supernatant IL-1beta concentrations compared to normoxia (3.41+/-0.36 vs. 2.65+/-0.21 pg mL(-1), P = 0.02). Endothelial supernatant IL-1beta concentrations in lidocaine-treated HUVECs were similar to controls. CONCLUSIONS: Lidocaine at clinically relevant concentrations decreased neutrophil CD18 and endothelial ICAM-1 expression but not endothelial IL-1beta concentrations.

Analysis of Variance↗
PubMed2004

The effect of aprotinin on hypoxia-reoxygenation-induced changes in neutrophil and endothelial function.

BACKGROUND AND OBJECTIVE: An acute inflammatory response associated with cerebral ischaemia-reperfusion contributes to the development of brain injury. Aprotinin has potential, though unexplained, neuroprotective effects in patients undergoing cardiac surgery. METHODS: Human neutrophil CD11 b/CD18, endothelial cell intercellular adhesion molecule-1 (ICAM-1) expression and endothelial interleukin (IL)-1beta supernatant concentrations in response to in vitro hypoxia-reoxygenation was studied in the presence or absence of aprotinin (1600 KIU mL(-1)). Adhesion molecule expression was quantified using flow cytometry and IL-1beta concentrations by enzyme-linked immunosorbent assay. Data were analysed using ANOVA and post hoc Student-Newman-Keuls test as appropriate. RESULTS: Exposure to 60-min hypoxia increased neutrophil CD11b expression compared to normoxia (170+/-46% vs. 91+/-27%, P = 0.001) (percent intensity of fluorescence compared to time 0) (n = 8). Hypoxia (60 min) produced greater upregulation of CD11b expression in controls compared to aprotinin-treated neutrophils [(170+/-46% vs. 129+/-40%) (P = 0.04)] (n = 8). Hypoxia-reoxygenation increased endothelial cell ICAM-1 expression (155+/-3.7 vs. 43+/-21 mean channel fluorescence, P = 0.0003) and IL-1beta supernatant concentrations compared to normoxia (3.4+/-0.4 vs. 2.6+/-0.2, P = 0.02) (n = 3). Hypoxia-reoxygenation produced greater upregulation of ICAM- 1 expression [(155+/-3.3 vs. 116+/-0.7) (P = 0.001)] and IL-1beta supernatant concentrations [(3.4+/-0.3 vs. 2.6+/-0.1) (P = 0.01)] in controls compared to aprotinin-treated endothelial cell preparation (n = 3). CONCLUSIONS: Hypoxia-reoxygenation-induced upregulation of neutrophil CD11b, endothelial cell ICAM-1 expression and IL-1beta concentrations is decreased by aprotinin at clinically relevant concentrations.

Analysis of Variance↗
PubMed2003

Nitrous oxide/oxygen mixture and the prevention of pain during injection of propofol.

BACKGROUND AND OBJECTIVE: The incidence of pain associated with the injection of propofol still remains a problem. This study sought to examine the analgesic effects of inhaled nitrous oxide in oxygen on the prevention of propofol injection pain. METHODS: Nitrous oxide in oxygen was compared with a lidocaine (20 mg)-propofol mixture and with propofol alone (control) in a prospective, randomized, observer-blinded study. ASA I and II patients (n = 135) scheduled for elective surgical procedures were studied. A standard propofol injection technique and scoring system to measure the pain on injection was used. RESULTS: Demographic variables were similar between the study groups. Without analgesia (control) 26 of 45 patients (58%) reported pain on injection compared with 11 of 45 patients (24%) in both the nitrous oxide (95% CI: 14-52%, P = 0.001) and lidocaine groups (95% CI: 14-52%, P = 0.001). CONCLUSIONS: The inhalation of a nitrous oxide/oxygen mixture significantly reduces the incidence of pain during propofol injection. This therapeutic stratagem was as effective as a lidocaine-propofol mixture.

Adolescent↗
PubMed2003

The effect of clomethiazole on plasma concentrations of interleukin-6, -8, -1beta, tumor necrosis factor-alpha, and neutrophil adhesion molecule expression during experimental extracorporeal circulation.

UNLABELLED: Clomethiazole (CMZ), a neuroprotective drug, has antiinflammatory actions. We investigated the effects of CMZ administration on plasma concentrations of interleukin (IL)-6, IL-8, IL-1beta, tumor necrosis factor-alpha, and neutrophil adhesion molecule expression during experimental extracorporeal circulation. Five healthy volunteers each donated 500 mL of blood, which was subsequently divided into equal portions. Identical extracorporeal circuits were simultaneously primed with donated blood (250 mL) and circulated for 2 h at 37 degrees C. CMZ was added to 1 of the circuits of each pair to achieve a total plasma concentration of 40 micro mol/L. Blood samples were withdrawn at (i) donation, (ii) immediately after addition of CMZ, and at (iii) 30, 60, 90, and 120 min after commencing circulation. Plasma concentrations of IL-6, IL-8, and tumor necrosis factor-alpha were less in the CMZ group compared with control after 60 min of circulation (2.2 [0.3] versus 3.2 [0.4], 14.9 [4.8] versus 21.9 [18.4], 63.3 [43.5] versus 132.2 [118.9] pg/mL, respectively, P < 0.05). After 120 min of circulation, neutrophils from CMZ-treated circuits showed significantly less CD18 expression compared with control (237.5 [97.4] versus 280.5 [111.5], P = 0.03). The addition of CMZ to experimental extracorporeal circuits decreases the inflammatory response. This effect may be of clinical benefit by decreasing inflammatory-mediated neurological injury during cardiopulmonary bypass. IMPLICATIONS: Enhancement of gamma-aminobutyric acid(A)-mediated effects by clomethiazole (CMZ) and associated neuroprotection has been established in animal models of cerebral ischemia. In an ex vivo study, we demonstrated antiinflammatory activity of CMZ in experimental extracorporeal circulation. This represents a potential neuroprotective mechanism of CMZ in patients undergoing coronary artery bypass surgery.

Acid-Base Equilibrium↗
PubMed2001

A dose-finding and safety study of novel erythropoiesis stimulating protein (NESP) for the treatment of anaemia in patients receiving multicycle chemotherapy.

Darbepoetin alfa is a novel erythropoiesis stimulating protein (NESP), which stimulates erythropoiesis by the same mechanism as recombinant human erythropoietin (rHuEPO). NESP has been shown to be safe and efficacious in patients with chronic renal failure. NESP is biochemically distinct from rHuEPO, due to its increased sialic acid content. NESP has an approximately 3-fold greater half-life. rHuEPO has been shown to be safe and effective for the treatment of chemotherapy-induced anaemia. This study assessed the safety and efficacy of NESP administered once per week, under the supervision of a physician, to patients with solid tumours who were receiving multicycle chemotherapy for up to 12 weeks. Three dose cohorts are presented in this sequential, unblinded and dose-escalating study. Thirteen to 59 patients received NESP (0.5, 1.5 or 2.25 mcg kg(-1)wk(-1)) in each cohort. Patients were monitored for adverse events, including antibody formation to NESP and for effects on haemoglobin. NESP appeared to be well tolerated. Adverse events were similar across all cohorts and were consistent with the population being studied. No antibody formation was detected over the 16-week study period and follow-up. A dose-response relationship was evident for NESP and multiple measures of efficacy, including proportion of patients responding to NESP and the mean change in haemoglobin by week 4 and end of treatment for NESP 0.5, 1.5 and 2.25 mcg kg(-1)wk(-1)cohorts (mean change in haemoglobin at end of treatment was 1.24, 1.73 and 2.15 g dl(-1)respectively). Controlled studies of this agent at higher doses and less frequent schedules of administration are ongoing.

Adult↗