Midazolam suppresses maturation of murine dendritic cells and priming of lipopolysaccharide-induced t helper 1-type immune response.

BACKGROUND: Dendritic cells (DCs), as antigen-presenting cells, play a key role in the induction and regulation of adaptive immune response. Midazolam is reported to have immunomodulatory properties that affect immune cells. However, the effect of midazolam on DCs has not been characterized. We examined the immunomodulatory properties of midazolam on DC-mediated immune response. METHODS: After allowing murine bone marrow-derived DCs induced by granulocyte macrophage colony stimulating factor to mature, we analyzed their expression of costimulatory molecules (CD80 and CD86), major histocompatibility complex class II molecules, and the secretion of interleukin-12 p40. In vitro, we evaluated the effect of midazolam on maturing DCs in mixed cell cultures containing DCs and T cells. In vivo, we investigated the contact-hypersensitivity response. RESULTS: Midazolam suppressed the expression of CD80, CD86, and major histocompatibility complex class II molecules from murine DCs. Treated with midazolam, DCs also secreted less interleukin-12 p40. In mixed cell cultures with CD3-positive T cells, midazolam-treated DCs showed less propensity to stimulate the proliferation of CD3-positive T cells and the secretion of interferon-γ from CD4-positive T cells. Midazolam-treated DCs impaired the induction of contact-hypersensitivity response. Treatment with ligands for peripheral benzodiazepine receptor inhibited the up-regulation of CD80 during DC maturation. CONCLUSION: Midazolam inhibits the functional maturation of murine DCs and interferes with DC induction of T helper 1 immunity in the whole mouse. In addition, it appears that the immunomodulatory effect of midazolam is mediated via the action of midazolam on the peripheral benzodiazepine receptor.

Effects of midazolam on equine innate immune response: a flow cytometric study.

Benzodiazepines (BDZ) are among the most frequently used class of psychotropic drugs employed in veterinary medicine in Brazil and worldwide due to their anxiolytic, muscle relaxant and anticonvulsant effects [J. Clin. Pharmacol. 33 (1993) 124]. Peripheral benzodiazepine receptor (PBR) sites were described in peripheral organs, endocrine steroidogenic tissues and immune organs and cells. Midazolam is a mixed-type agonist of PBRs. The present study is focused on the effects of midazolam on equine peripheral blood neutrophils, peritoneal macrophages and cortisol levels in plasma. Adult horses were treated with a single dose of midazolam (0.06 or 0.1 mg/kg) or with 0.9% NaCl. Immune cells were collected 24 h after treatment for flow cytometry analysis of Staphylococcus aureus-induced phagocytosis and oxidative burst. Plasma cortisol concentration was measured 30, 90, 180 and 360 min after midazolam treatment. Midazolam induced a dose-dependent reduction on: (1) peripheral blood neutrophil and peritoneal macrophage oxidative burst; (2) the capacity of both peripheral blood neutrophils and peritoneal macrophages to phagocyte S. aureus. Increments on plasma cortisol concentration were not found after 0.06 and 0.1 mg/kg of midazolam. The effects on oxidative burst of neutrophils and macrophages from horses treated with midazolam were interpreted as a consequence of an impairment of S. aureus-induced phagocytosis. The present data suggest that midazolam, most probably acting on PBRs present on equine macrophage and neutrophil membranes, might have changed some mechanisms related to both phagocytosis and oxidative burst. These results support the use of flow cytometry to identify functional properties and dysfunction of equine immune cells. They also confirm the notion that changes in the functional capacity of the immune system may represent an important hazard of exposure to drugs or chemicals.

Incidence of histamine release after the administration of midazolam-ketamine in allergic patients.

OBJECTIVE: We examined the effects of midazolam-ketamine which was used during the induction of anesthesia against histamine release, skin reactions and hemodynamic changes in patients with a history of allergy. SUBJECTS: Forty allergic patients and 40 non-allergic patients undergoing oral surgery were examined. METHODS: Midazolam ketamine was used for the induction of anesthesia in 40 patients with a history of allergy (M-K group) and thiamylal was used for the induction of anesthesia in 40 patients without any history of allergy (BARB group). Venous blood samples were obtained before induction as a control and 0.5, 1, 3, 5 minutes after the administration of each drug in order to measure the plasma histamine level. In addition, any observed hemodynamic changes were simultaneously recorded. The plasma histamine level was measured using the HPLC (high performance liquid chromatography) post-label system. RESULTS: The incidence of histamine release, skin reactions and hemodynamic changes were 37.5%, 10.0% and 7.5%, in the M-K group, and 40.0%, 12.5% and 12.5%, in the BARB group, respectively. Although the mean basal plasma histamine level in the M-K group (0.46 +/- 0.23 ng/ml) who had a history of allergy was much higher than that in the BARB group (0.28 +/- 0.17 ng/ml) (p < 0.001), the incidence of histamine release and clinical symptoms were similar between the two groups. CONCLUSIONS: The induction of anesthesia with midazolam-ketamine was thus found to be a valuable method for allergic patients, because the incidence of histamine release, skin reactions and hemodynamic changes in allergic patients were similar to those in non-allergic patients induced by thiamylal and no significant changes were observed in the plasma histamine level after the administration of midazolam-ketamine in spite of the high level of basal plasma histamine.