Short-acting Benzodiazepine Midazolam Research Articles

Baseline Functional Connectivity Predicts Connectivity Changes Due to a Small Dose of Midazolam in Older Adults.

In the perioperative context, benzodiazepines are widely used as anxiolytics. They affect cognition in general, but it is unclear whether the effects of a small dose of the short-acting benzodiazepine midazolam can be assessed objectively. To address this scientific question, we conducted a prospective observational study in adults 55-73 years of age. Using both validated psychometric and functional imaging techniques, we determined whether a 2-mg intravenous (IV) dose of midazolam affects cognitive function. We measured the effect of 2 mg IV of midazolam with both the well-established Repeatable Battery for the Assessment of Neuropsychological Status test and resting-state functional magnetic imaging (rs-fMRI) in older adults. Midazolam reduces immediate and delayed memory and has a profound and robust effect on rs-fMRI. Baseline resting-state connectivity predicts memory decline after midazolam administration. Observed effects of midazolam on brain networks were statistically significant even in a small group of volunteers. If validated by other investigators, resting-state brain connectivity may have utility as a measure to predict sensitivity to midazolam in older adults.

Оптимизация премедикации больных артериальной гипертензией и нарушениями ритма сердца с амиодарон-ассоциированным тиреотоксикозом I типа

The aim of the work was to reduce the risk of unstable hemodynamic reactions in patients with arterial hypertension and heart rhythm disorders against amiodarone-inducible thyroid dysfunction after neurosurgical operations due to pharmacological optimization of premedication. The study was conducted on 51 patients with arterial hypertension and amiodarone-associated thyrotoxicosis type I, which were divided into two groups. 1 group (n = 30) - at the stage of preoperative preparation, patients received prolonged premedication (for three days before the operation) with long-acting benzodiazepines (diazepam) and magnesium preparations. 2 group (n = 21) - benzodiazepines of short action (midazolam) were used for premedication before the operation. As a result of the study, it was established that in patients with arterial hypertension with cardiac arrhythmias and type I amiodarone-associated thyrotoxicosis, the use of long-acting benzodiazepine with diazepam in prolonged mode in combination with magnesium sulfate compared with short-acting benzodiazepine midazolam provides a more effective reduction intravitual, short-term and medium-term variability of blood pressure, increasing the variability of the duration of the cardiac cycle, which a more stable and predictable hemodynamics reaction.

Memory and hippocampal architecture following short-term midazolam in western diet-treated rats

The impact of short-term benzodiazepine exposure on cognition in middle-aged or older patients is a highly debated topic among anesthesiologists, critical care physicians and public media. “Western diet” (WD) consumption is linked to impaired cognition as well. The combination of benzodiazepines with substantial exposure to WD might set the stage for increased hippocampal vulnerability for benzodiazepines leading to exaggerated cognitive impairment in the postoperative period. In this study, Fischer 344 rats were fed either WD or standard rodent diet from 5 to 10.5 months of age. Rats were exposed to midazolam or placebo two days prior to an MRI scan using Diffusional Kurtosis Imaging (DKI) to assess brain microstructural integrity, followed by behavioral testing using a water radial arm maze. Hippocampal tissue was collected to assess alterations in protein biochemistry in brain regions associated with learning and memory. Our results showed that rats exposed to the combination of midazolam and WD had significantly delayed time of learning and exhibited spatial memory impairment. Further, we observed an overall increase of kurtosis metrics in the hippocampus and increased expression of the mitochondrial protein VDAC2 in midazolam-treated rats. Our data suggest that both the short-acting benzodiazepine midazolam and WD contribute to negatively affect the brain in middle-aged rats. This study is the first application of DKI on the effects of midazolam and WD exposure, and the findings demonstrate that diffusion metrics are sensitive indicators of changes in the complexity of neurite architecture.

Does Oral Midazolam Reduce Anxiety and Pain with First-Trimester Surgical Abortion?

Most first-trimester surgical abortions involve suction curettage under local anesthesia, and many women are anxious about the potential for pain. In a double-blind study of the potent, rapid-onset, short-acting benzodiazepine midazolam, investigators randomized 124 women (mean age, 25; 70% white; 57% nulliparous) presenting for first-trimester abortion (mean gestational age, 8 weeks) to 10 mg of oral midazolam or placebo 30 to 60 minutes before suction curettage. All participants …

Charakteristika und Auswahl der Substanzen

Prior to an operation, patients experience a high degree of stress and internal tension. Preoperative drug administration (premedication) is intended to reduce these stresses through anxiolytic and sedative effects. On account of their good anxiolytic actions, there excellent tolerability and only few side effects benzodiazepines are most frequently used for this purpose. To support the induction and continuation of sleep, premedication is usually initiated in the evening before operation with the administration of a benzodiazepine with middle- or long-term activity. The standard drug for the day of operation is the short-acting benzodiazepine midazolam, under the action of which the patient may be transferred to the operation room in a drowsy and calm state. The onset of action of drugs applied as preoperative medication is delayed. Thus, it is of major importance that the premedication be administered at the appropriate time point so that the patient really is shielded fro preoperative stress at the time of the drug's optimal effect. Although midazolam is not the ideal substance for all situations where an anxiolytic premedication is needed, with the exception of a few special indications, no decisive advantages over other drugs have been demonstrated in comparative trials.

Intrathecal midazolam regulates spinal AMPA receptor expression and function after nerve injury in rats

Spinal γ-aminobutyric acid (GABA) and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors have been implicated in the mechanisms of neuropathic pain after nerve injury; however, how these two receptors interact at the spinal level remains unclear. Here we show that intrathecal midazolam through activation of spinal GABAA receptors attenuated the expression and function of spinal AMPA receptors in rats following peripheral nerve injury. Thermal hyperalgesia and mechanical allodynia induced by chronic constriction nerve injury (CCI) in rats were attenuated by the short-acting benzodiazepine midazolam (20 = 10 > 5 μg > vehicle) administered intrathecally once daily for 7 postoperative days. CCI-induced upregulation of AMPA receptors within the spinal cord dorsal horn was also significantly reduced by the intrathecal midazolam (10, 20 μg) treatment. The inhibitory effects of midazolam (10, 20 μg) on neuropathic pain behaviors and AMPA receptor expression were prevented by co-administration of midazolam with the GABAA receptor antagonist bicuculline (3 μg), whereas intrathecal treatment with bicuculline (1 or 3 μg) alone in naive rats induced the upregulation of spinal AMPA receptor expression and nociceptive responses, indicating a tonic regulatory effect from endogenous GABAergic activity on the AMPA receptor expression and spinal nociceptive processing. These results indicate that modulation of spinal AMPA receptor expression and function by the GABAergic activity may serve as a mechanism contributory to the spinal nociceptive processing.

Flumazenil Failed to Rapidly Terminate Midazolam Anesthesia in an Opiate Addict

AbstractDuring the course of a rapid opiate detoxification procedure, withdrawal symptoms in opiate addicts caused by the application of naloxone were suppressed by an anesthesia induced by the short-acting benzodiazepine midazolam. This anesthesia usually can be easily and rapidly terminated by the administration of the benzodiazepine receptor antagonist flumazenil. In the presented case, relatively high doses of midazolam had to be administered in order to suppress agitation of the patient during anesthesia. Low doses of flumazenil failed to immediately terminate midazolam anesthesia. However, the patient awoke 45 minutes later after he had received a total of 10 mg flumazenil. Possible explanations for this failure of flumazenil to immediately antagonize midazolam anesthesia are discussed.

Further characterization of intravenous self-administration of midazolam in the rat.

The present experiments further characterized intravenous self-administration of the short-acting benzodiazepine midazolam in rats under conditions of unlimited access to the drug. The results of the first experiment demonstrated that rats responded at higher rates on a lever that produced an infusion of 0.05mg midazolam than on a lever that did not result in reinforcement, and that they transferred responding to the other lever when the reinforcement contingencies were reversed. These results provide further evidence of the reinforcing effects of midazolam. In the second experiment, rats responding at stable rates for 0.05mg midazolam per infusion exhibited increased responding when transferred to a lower dose (0.0125mg/infusion) and decreased responding when transferred to a higher dose (0.20mg/infusion) of the drug. However, the inverse relationship between responding and drug dose was apparent only during the first transfer session, after which no consistent relationship was observed. In support of previous observations, all rats exhibited a temporal pattern of responding for midazolam over the 24h sessions, with maximal responding occurring during the dark phase of the 12h light/dark cycle. However, the present results also provide preliminary evidence that rats given prolonged access to midazolam (more than 49 days) develop a more constant within session pattern of responding for midazolam. This may be related to the development of physical dependence and reflect an attempt to avoid withdrawal effects by maintaining a stable intake of midazolam within a session.

Intravenous self-administration of the short-acting benzodiazepine midazolam in the rat

Intravenous self-administration of the short-acting benzodiazepine midazolam was assessed in rats under conditions of unlimited access to the drug (24 hr day ). Evaluation of the temporal pattern of responding within a session revealed that maximal responding occurred during the dark phase of the 12 hr light dark cycle. Upon attaining stable rates of responding for midazolam, the rats were tested under extinction conditions (saline). Responding progressively decreased with repeated extinction sessions. Over the course of subsequent reacquisition sessions responding increased, such that asymptotic levels of responding were similar to, or greater than, the rates obtained during the initial acquisition phase. In addition, the total number of sessions required to approach asymptote were fewer than during the initial acquisition phase. Thus, rats given continuous access to midazolam exhibited reliable and stable rates of intravenous self-administration of this short-acting benzodiazepine.

Prevention of cysteamine-induced myoclonus blocks the long-term inhibition of kindled seizures

In kindled rats, the administration of cysteamine (CSH, 200 mg/kg, i.p.) 4 h prior to a kindled seizure leads to long-term (up to 10 days) inhibition of kindled seizures. CSH (200 mg/kg, i.p.) also induces myoclonic seizures in kindled rats. We suggest that the long-term inhibition of kindled seizures might be the result of the myoclonus, not the somatostatin depletion as previously suggested. Prior administration of the short-acting benzodiazepine midazolam (5 mg/kg, i.p.) eliminated the CSH-induced myoclonus and prevented the long-term inhibition of kindled seizures. These results suggest that the CSH-induced the long-term inhibition of kindled seizures is the result of an interaction between the myoclonic seizure and a subsequent kindled seizure.

Analysis of the role of behavioural factors in the development of tolerance to the benzodiazepine midazolam

Two experiments were conducted on the acute and chronic effects of the short-acting benzodiazepine midazolam on fixed ratio schedule-maintained operant responding in rats. Acute administration of midazolam produced suppression of responding in large doses but elevation of responding in small doses. Following intermittent (every third day) chronic treatment tolerance developed rapidly to the rate-suppressant effects of large doses of midazolam but did not develop to the rate-elevating effects of small doses, even after chronic treatment with large doses of the drug. Thus, when tolerance was measured in terms of shifts in dose-effect curves, it was manifested as a non-parallel shift in the curve after chronic treatment. Since tolerance developed to the effects of large but not small doses, the observed tolerance could not be attributed to changes in disposition of the drug. The development of tolerance did not depend on whether the drug was given before or after behavioural testing. These findings contrast with data reported in behavioural studies with other sedative-hypnotics (ethanol, barbiturates). Animals tolerant to midazolam showed no cross-tolerance to ethanol, a drug for which there is reliable evidence indicating that behavioural factors play a role in acquisition of tolerance. Tolerance to midazolam cannot therefore be explained in terms of learned strategies acquired as a result of drug-induced loss of rewarding stimuli. This conclusion contrasts with recent suggestions (File, 1985; File and Pellow, 1985) that tolerance to benzodiazepines may be mediated by instrumental conditioning processes.

Analysis of the role of drug-predictive environmental stimuli in tolerance to the hypothermic effects of the benzodiazepine midazolam.

The role of classical conditioning processes in the development of tolerance to the hypothermic effects of the short-acting benzodiazepine midazolam was studied in three experiments in rats. The experiments were all designed so that one set of environmental stimuli reliably predicted drug treatments whilst another set of stimuli predicted control (vehicle) treatment. According to the classical conditioning account of tolerance, the degree of tolerance observed should be greater in the presence of drug-predictive stimuli than in their absence, i.e. tolerance should show environmental (context) specificity. A preliminary study was conducted to determine the dose- and time-effect curves for midazolam-induced hypothermia. The results of this study provided essential background data for the design of all the subsequent tolerance studies. In the first tolerance study, it was found that virtually complete tolerance developed to the hypothermic effects of 4 mg/kg (IP) midazolam given on alternate days. However, the observed tolerance was clearly not environmentally specific. Since there is evidence that conditioned tolerance to some drug effects develops most readily if drugs are given at low doses with long inter-injection intervals, a second study was conducted with a lower (1.6 mg/kg IP) dose of midazolam, which was given every 5th day. Despite these procedural changes, the second study indicated that the observed tolerance again did not show context specificity, even though tolerance developed rapidly with the lower dose of a short acting drug which was given infrequently.(ABSTRACT TRUNCATED AT 250 WORDS)

Midazolam oral self-administration.

The technique of chronic schedule-induced drug solution intake was used to determine the possible addiction liability of the short-acting benzodiazepine midazolam. Schedule-induction produces polydipsia over a wide range of fluids as a function of the imposed schedule of food availability. The inducing schedule used presented food pellets automatically once per minute, fixed time (FT) 1-min, for 3 h daily. Two groups of rats, drinking either water or 0.05 mg/ml midazolam solution, were exposed to schedule-induction sessions for approx. 2 months. Then, other FT-values (0, 0.5, 3 and 5 min) were instituted on occasion for single sessions. Each of these 'probe' session determinations was done twice. Although midazolam concentration had been adjusted so that the mean group intakes were equal at FT 1-min, probe values greater than 1 min revealed a greater acceptance of midazolam compared to water. This technique produced session midazolam intakes as great as 25 mg/kg. In the next phase, the entire experiment was repeated except both groups were offered a choice between water and midazolam solution during sessions. Only at FT 0 and FT 5-min was there an indication that midazolam was preferred over water. Two additional groups of animals were exposed to the same schedule-induced polydipsia regimen, drinking water and midazolam solution, respectively. Pre-session administration of doses of Ro 15-1788, CGS 8216 (benzodiazepine antagonists) or midazolam had no effects on either water or midazolam intakes, although the higher dose of midazolam (2 mg/kg, s.c) had a moderately suppressive effect on the non-tolerant water-polydipsic group. All groups were tested on occasion for physical dependence on midazolam with an auditory stimulus as the precipitator and midazolam polydipsic groups were found to have a mild to moderate dependence (clonic seizures, running fits).