Effects Of Midazolam Research Articles

Effects of Midazolam on Food Intake in Budgerigars (Melopsittacus undulatus).

Currently, drug-induced stimulation of appetite is not commonly performed in hyporexic or anorexic companion psittacine birds. Instead, to prevent a catabolic state and weight loss, supplemental feedings are routinely performed by crop gavage. However, crop gavage is not without complications and is stressful to the patient and labor intensive. The objective of this study was to evaluate the effect of midazolam on food intake in healthy budgerigars. In a randomized, blinded, controlled study, change in food intake after intramuscular administration of midazolam (1 mg/kg) or a placebo-control treatment (0.9% saline) was evaluated in 12 healthy adult budgerigars (Melopsittacus undulatus). Food intake was quantified for 1 hour before and after drug administration. Birds were monitored for feeding behavior as well as signs of sedation. After midazolam administration, a median 6-fold (1.1-28) increase in food intake was recorded. In 3 of 6 (50%) birds, the food intake increase after midazolam administration was >10-fold (median 17-fold [10-28]), whereas in the remaining 3 birds, food intake increased by only 1.7-fold (1.1-1.8). The median amount of food ingested (16.7 g/kg [3.2-43.2 g/kg]) was significantly higher after midazolam administration compared with the control group (1.9 g/kg [0.0-19.7 g/kg], P = .015). The median time birds spent displaying feeding behavior after the midazolam injection was 18% (0-43%), compared with 1% (0-20%) in the control group after saline injection. Five of 6 (83%) birds showed signs consistent with mild sedation after midazolam administration. This study demonstrates that midazolam is an appetite stimulant in budgerigars. Future studies are needed to evaluate whether midazolam's effects on food intake are dose dependent and whether the duration of effect exceeds 1 hour.

Midazolam's Effects on Delayed-Rectifier K+ Current and Intermediate-Conductance Ca2+-Activated K+ Channel in Jurkat T-lymphocytes.

Midazolam (MDZ) could affect lymphocyte immune functions. However, the influence of MDZ on cell’s K+ currents has never been investigated. Thus, in the present study, the effects of MDZ on Jurkat T lymphocytes were studied using the patch-clamp technique. Results showed that MDZ suppressed the amplitude of delayed-rectifier K+ current (IK(DR)) in concentration-, time-, and state-dependent manners. The IC50 for MDZ-mediated reduction of IK(DR) density was 5.87 μM. Increasing MDZ concentration raised the rate of current-density inactivation and its inhibitory action on IK(DR) density was estimated with a dissociation constant of 5.14 μM. In addition, the inactivation curve of IK(DR) associated with MDZ was shifted to a hyperpolarized potential with no change on the slope factor. MDZ-induced inhibition of IK(DR) was not reversed by flumazenil. In addition, the activity of intermediate-conductance Ca2+-activated K+ (IKCa) channels was suppressed by MDZ. Furthermore, inhibition by MDZ on both IK(DR) and IKCa-channel activity appeared to be independent from GABAA receptors and affected immune-regulating cytokine expression in LPS/PMA-treated human T lymphocytes. In conclusion, MDZ suppressed current density of IK(DR) in concentration-, time-, and state-dependent manners in Jurkat T-lymphocytes and affected immune-regulating cytokine expression in LPS/PMA-treated human T lymphocytes.

Midazolam inhibits IgE production in mice via suppression of class switch recombination

Anaphylactic shock is characterized by increased capillary permeability and a decline in blood pressure due to excessive production of IgE. Midazolam (MDZ) is reported to have immunomodulatory properties. However, little is known about the effect of MDZ on the production of IgE antibody. We examined whether MDZ can suppress antigen-specific and total IgE production followed by IgE class switch recombination (CSR). MDZ was administered intraperitoneally to mice prior to ovalbumin (OVA) plus native cholera toxin (nCT) immunization. Serum OVA-specific and total IgE responses, and surface IgE-positive B cells were analyzed by ELISA and flow cytometry. Furthermore, expression levels of CSR-associated molecules such as germ-line transcript ε (εGLT), germ-circle tanscript ε (εCT), AID, and Id2 in the spleen were compared. The levels of interferon-gamma (IFN-γ) and interleukin (IL)-4 mRNA and protein were also examined in the spleen and serum. MDZ significantly suppressed OVA-specific and total IgE levels in plasma and surface IgE-positive B cells in the spleen. Moreover, MDZ-treated mice had significantly reduced levels of εGLT and εCT. Furthermore, although the levels of IFN-γ mRNA and protein were significantly elevated, those of IL-4 were reduced in MDZ-treated mice. Therefore, MDZ may be an important modulator of allergic responses through its ability to downregulate IgE production.

The effect of midazolam on mouse Leydig cell steroidogenesis and apoptosis

The peripheral-type benzodiazepine receptor (PBR), a putative receptor in Leydig cells, modulates steroidogenesis. Since benzodiazepines are commonly used in regional anesthesia, their peripheral effects need to be defined. Therefore, this study set out to investigate in vitro effects of the benzodiazepine midazolam (MDZ) on Leydig cell steroidogenesis, and the possible underlying mechanisms. The effects of MDZ on steroidogenesis in primary mouse Leydig cells and MA-10 Leydig tumor cells were determined by radioimmunoassay. PBR, P450scc, 3β-HSD and StAR protein expression induced by MDZ was determined by Western blotting. Inhibitors of the signal transduction pathway and a MDZ antagonist were used to investigate the intracellular cascades activated by MDZ. In both cell types, MDZ-stimulated steroidogenesis in dose- and time-dependent manners, and induced the expression of PBR and StAR proteins, but had no effect on P450scc and 3β-HSD expressions. Moreover, H89 (PKA inhibitor) and GF109203X (PKC inhibitor) attenuated MDZ-stimulated steroid production. Interestingly, the MDZ antagonist (flumazenil) did not decrease MDZ-induced steroid production in both cell types. These results highly indicated that MDZ-induced steroidogenesis in mouse Leydig cells via PKA and PKC pathways, along with the expression of PBR and StAR proteins. In addition, MDZ at high dosages induced rounding-up, membrane blebbing, and then death in MA-10 cells. In conclusion, midazolam could induce Leydig tumor cell steroidogenesis, and high dose of midazolam could induce apoptosis in Leydig tumor cells.

Midazolam's effects on myocardial load and coronary perfusion: Reduced regional O 2 consumption and lactate production during ischemia in dogs

It is hypothesized that because of its potential to increase coronary flow and simultaneously decrease myocardial performance and O 2 consumption, midazolam would minimize regional metabolic impairment during myocardial ischemia. Therefore, the hemodynamic and regional metabolic effects of systemic midazolam administration were compared during moderate and severe constrictions of the left anterior descending artery (LADa) to nontreated but ischemic animals in a canine model of acute coronary occlusion. In 16 anesthetized, ventilated, surgically prepared, and catheterized dogs, resting flow in the LADa was decreased by 50% and 75% for 15 minutes with 1 hour of normal flow in between. By arbitrary assignment, 7 dogs received midazolam (0.3 mg/kg and then 0.05 mg/kg/min) before thoracotomy. In all dogs, heart rate, electrocardiogram, LADa flow, left ventricular (LV) first time-derivative, and aortic, pulmonary artery, LADa, and LV pressures were measured continuously. Before and during constrictions, cardiac output by thermodilution and regional myocardial blood flow by microspheres were measured and blood was sampled for analysis. Data (mean ± SEMI were compared within and between groups using ANOVA. Before placement of the LADa ligature, mid-azolam decreased heart rate and mean aortic pressure. Before ischemia, heart rate and LADa pressure were lower with midazolam than without it, but baseline metabolic variables were similar between the two groups (except for O 2 consumption in the ischemic zone, which was lower with midazolam than without it). During 75% constriction with midazolam, LV end-diastolic pressure, coronary resistance, and ischemic zone O 2 consumption were lower than without midazolam. Ischemic zone O 2 delivery/consumption ratio was higher. Also, ischemic zone lactate consumption, consumption rate (flux consumption/heart rate), and extraction values were less negative compared with those values without midazolam. Based on these hemodynamic and metabolic changes, it is concluded that midazolam improved the relationship of supply to demand and decreased ischemic lactate production before and after ischemia was induced. This should be further explored clinically for potential use in patients with ischemic heart disease, in whom midazolam is used as an adjuvant or as a main anesthetic.

The Effects of Large-Dose Flumazenil on Midazolam-Induced Ventilatory Depression

Flumazenil, a benzodiazepine antagonist, clearly reverses midazolam-induced sedation; reversal of ventilatory depression has not been as well demonstrated. Thirty-two subjects completed this randomized, double-blind, placebo-controlled study investigating the dose-response relationship and duration of flumazenil's effects on ventilatory depression and hypnosis induced by a continuous midazolam infusion. A computer-controlled infusion of midazolam was used to titrate the predicted midazolam plasma concentration to a level at which subjects were unresponsive to verbal commands and then to maintain that concentration. Measurements of ventilation and hypnosis were repeated at predetermined intervals: before midazolam administration, before test drug (flumazenil [1, 3, or 10 mg] or placebo), and 5, 30, 60, 120, and 180 min after test drug administration. Ventilation and tidal volume were measured during an isocapnic hyperoxia clamp at a PETCO2 of 46 mm Hg (VE46 and VT46, respectively). A pseudo-rebreathing technique was used to measure the hypercapnic ventilatory response (HCVR) slope and ventilation intercept at a PETCO2 of 58 mm Hg (VE58). Midazolam reduced VE46, VT46, and VE58, as well as hypnosis scores, in all test drug groups. The reduction in HCVR slope, however, was significant only when all 32 subjects were considered in aggregate. All three doses of flumazenil reversed hypnosis and also reversed the reduction in VE46 and VT46 within 5 min. The reduction in VE58, however, was reversed less consistently. Flumazenil's effect on VE46 and VT46 lasted at least 30 min after 1 mg and at least 60 min after 3 mg, paralleling the effect of these doses on hypnosis.(ABSTRACT TRUNCATED AT 250 WORDS)