Determination of plasma concentrations of propofol associated with 50% reduction in postoperative nausea

BACKGROUND: Subhypnotic doses of propofol possess direct antiemetic properties. The authors sought to determine the plasma concentration of propofol needed to effectively manage postoperative nausea and vomiting. METHODS: Patients aged 18-70 yr who were classified as American Society of Anesthesiologists physical status 1 or 2 and had surgery during general anesthesia were approached for the study. Only patients who had nausea (verbal rating score > 5 on a 0- to 10-point scale), retching, or vomiting in the postanesthetic care unit participated. Propofol was administered to these patients to achieve target plasma concentrations of 100, 200, 400, and 800 ng/ml using a computer-assisted continuous infusion device. Target concentrations were increased every 15 min until patients described at least a 50% reduction in symptoms on the verbal rating score. An arterial blood sample was obtained at each step. The measured plasma propofol concentrations were used to analyze data. Blood pressure, heart and respiratory rates, arterial blood saturation, sedation score, and overall satisfaction with treatment were recorded. RESULTS: Of the 89 patients who consented to the study, 15 patients met entry criteria and were enrolled. Five of these patients also had retching or vomiting when they entered the study. Fourteen patients responded successfully to treatment. One patient did not achieve the required response at plasma concentrations of 830 ng/ml. Hence the success rate for the treatment of postoperative nausea and vomiting was 93%. Among patients who responded, the median plasma concentration associated with an antiemetic response was 343 ng/ml. There was no difference in sedation scores from baseline and no episodes of desaturation. Hemodynamic parameters were stable during the study. CONCLUSIONS: Propofol is generally efficacious in treating postoperative nausea and vomiting at plasma concentrations that do not produce increased sedation. Simulations indicate that to achieve antiemetic plasma propofol concentrations of 343 ng/ml, a bolus dose of 10 mg followed by an infusion of approximately 10 microg x kg(-1) x min(-1) are necessary.     

A carbocyclic nucleoside analogue is a TNF-alpha inhibitor with immunosuppressive action: role of prostaglandin E2 and protein kinase C and comparison with pentoxifylline

PURPOSE: To compare the activity of topical 0.05% and 0.01% mequitazine versus vehicle in the prevention of allergic conjunctivitis induced by a conjunctival provocation test with allergens. METHODS: Forty subjects with a history of grass pollen allergic conjunctivitis were enrolled in this comparative, randomized, double-masked study. Fifteen minutes before the conjunctival provocation test, subjects received one instillation alone of 0.05% mequitazine eyedrops in one eye and in the fellow eye either one drop of 0.01% dose or vehicle, at the same dosage. Then a specific conjunctival provocation test (CPT) was performed with the allergen threshold concentration previously defined. The therapeutic efficacy was assessed by the decrease in a symptomatic composite score representing the allergic reaction. RESULTS: Topical mequitazine at the dose of 0.05% significantly decreases the intensity of the allergic reaction compared to vehicle. Moreover, the group treated with this dose needed a higher allergen concentration to trigger ocular signs. The 0.01% dose appears efficient only on itching, compared to vehicle. CONCLUSION: The results of this study support the efficacy and the onset of action of 0.05% mequitazine eyedrops versus 0.01% or vehicle in the prevention of allergic conjunctivitis induced by a conjunctival provocation test.     

Exposure to nitrogen dioxide (NO2) and respiratory disease risk

Epidemiological evidence suggests that exposure to nitrogen dioxide (NO2) through the use of unvented gas cookers in homes is associated with respiratory symptoms. Toxicological evidence, mainly in animal models, suggests that NO2 may increase the susceptibility to infection by viruses and bacteria. This review examines the evidence and proposes mechanisms whereby such exposure may occur, in particular how NO2 may aggravate respiratory symptoms in the presence of coexistent infection.     

Soluble adhesion molecules in CSF are increased in children with severe head injury

Leukocyte-endothelial adhesion molecules, critical to the development of acute inflammation, are expressed in brain as part of the acute inflammatory response to traumatic brain injury (TBI). We measured the concentrations of the adhesion molecules P-selectin, ICAM-1, E-selectin, L-selectin, and VCAM-1 in ventricular cerebrospinal fluid (CSF) from children with severe TBI (Glasgow coma score < 8) and compared these findings with those from children with bacterial meningitis. P-selectin, an adhesion molecule associated with ischemia/reperfusion, was increased in children with TBI versus meningitis and control. Univariate and multivariate regression analyses demonstrated associations between CSF P-selectin and child abuse and age of < 4 years, and a significant, independent association between CSF intercellular adhesion molecule-1 (ICAM-1) and child abuse. These results are consistent with a specific acute inflammatory component to TBI in children. Future studies of secondary injury mechanisms and therapy after TBI should assess on the roles of P-selectin and ICAM-1 in injury and repair processes in brain after TBI.     

Activation of the genetically defined m1 muscarinic receptor potentiates N-methyl-D-aspartate (NMDA) receptor currents in hippocampal pyramidal cells

Evidence suggests that cholinergic input to the hippocampus plays an important role in learning and memory and that degeneration of cholinergic terminals in the hippocampus may contribute to the memory loss associated with Alzheimer's disease. One of the more prominent effects of cholinergic agonists on hippocampal physiology is the potentiation of N-methyl-D-aspartate (NMDA)-receptor currents by muscarinic agonists. Here, we employ traditional pharmacological reagents as well as m1-toxin, an m1 antagonist with unprecedented selectivity, to demonstrate that this potentiation of NMDA-receptor currents in hippocampal CA1 pyramidal cells is mediated by the genetically defined m1 muscarinic receptor. Furthermore, we demonstrate the colocalization of the m1 muscarinic receptor and the NR1a NMDA receptor subunit at the electron microscopic level, indicating a spatial relationship that would allow for physiological interactions between these two receptors. This work demonstrates that the m1-muscarinic receptor gene product modulates excitatory synaptic transmission, and it has important implications in the study of learning and memory as well as the design of drugs to treat neurodegenerative diseases such as Alzheimer's.     

Plasma from women with preeclampsia increases endothelial cell nitric oxide production

In preeclampsia, a factor in the maternal circulation alters endothelial function via a reduction in nitric oxide synthesis. We measured the in vitro effects of 2% plasma from women with preeclampsia, compared with 2% plasma from normotensive pregnant women, on cultured endothelial cell nitrite production and nitric oxide synthase activity. On finding differential effects, we measured the effects on cellular viability (assessed by lactate dehydrogenase levels) and performed a time course study. Endothelial cell nitrite production was found to be higher after exposure to plasma from the preeclamptic group than the normotensive pregnant group. The effects of long-term exposure (120 hours) were similar to those of short-term exposure (24 hours). In addition, nitric oxide synthase activity was significantly greater after exposure to preeclamptic plasma than after exposure to normotensive pregnant plasma. No differential effect on cellular viability was found. Contrary to our hypothesis, exposure of endothelial cells to preeclamptic plasma resulted in increased nitric oxide production and nitric oxide synthase activity.     

Adoptive immunotherapy for leukemia: donor lymphocytes transduced with the herpes simplex thymidine kinase gene for remission induction. HGTRI 0103

This study will evaluate the safety and efficacy of allogenic donor lymphocyte infusions in patients who have relapsed hematologic malignancies after allogeneic bone marrow transplantation (BMT). Donor lymphocyte transfusions have resulted in the cure of some patients with relapsed leukemia or lymphoproliferative disorder after allogeneic BMT, but has been complicated by the development of graft versus host disease (GvHD). We hypothesize that a retroviral vector containing the Herpes simplex thymidine kinase (HStk) gene will allow for retention of the anti-leukemia response of transfused donor lymphocytes while allowing for the adverse effects of GVHD to be mitigated. Patients with relapsed hematologic malignancies after allogeneic BMT will be infused with ex vivo gene modified donor lymphocytes. The Herpes Simplex thymidine kinase (HStk) gene will be transduced into the cells ex vivo using LTKOSN. 1 vector supernate. Insertion of the HStk gene into lymphocytes confers a sensitivity to the anti-herpes drug ganciclovir (GCV). This selective destruction of donor lymphocytes in situ will be used to abrogate the effect of graft versus host disease, if it develops.