Physostigmine In Patients Research Articles

Continuous infusion of physostigmine in patients with perioperative septic shock: A pharmacokinetic/pharmacodynamic study with population pharmacokinetic modeling

BackgroundIn the context of the cholinergic anti-inflammatory pathway, the clinical trial Anticholium® per Se (EudraCT Number: 2012-001650-26, ClinicalTrials.gov NCT03013322) addressed the possibility of taking adjunctive physostigmine salicylate treatment in septic shock from bench to bedside. Pharmacokinetics (PK) are likely altered in critically ill patients; data on physostigmine PK and target concentrations are sparse, particularly for continuous infusion. Our objective was to build a population PK (popPK) model for physostigmine, and further evaluate pharmacodynamics (PD) and concentration-response relationship in this setting. MethodsIn the randomized, double-blind, placebo-controlled trial, 20 patients with perioperative septic shock either received an initial dose of 0.04 mg/kg physostigmine salicylate, followed by continuous infusion of 1 mg/h for up to 120 h, or equivalent volumes of 0.9% sodium chloride (placebo group). Physostigmine plasma concentrations and acetylcholinesterase (AChE) activity were measured; concentration-response associations were evaluated, and popPK and PD modeling was performed with NONMEM. ResultsSteady state physostigmine plasma concentrations reached 7.60 ± 2.81 ng/mL (mean ± standard deviation [SD]). PK was best described by a two-compartment model with linear clearance. Significant covariate effects were detected for body weight and age on clearance, as well as a high inter-individual variability of the central volume of distribution. AChE activity was significantly reduced to 30.5%–50.6% of baseline activity during physostigmine salicylate infusion. A sigmoidal direct effect PD model best described enzyme inhibition by physostigmine, with an estimated half maximal effective concentration (EC50) of 5.99 ng/mL. ConclusionsPK of physostigmine in patients with septic shock displayed substantial inter-individual variability with body weight and age influencing the clearance. Physostigmine inhibited AChE activity with a sigmoidal concentration-response effect.

Retracted: Do patients profit from physostigmine in recovery from desflurane anaesthesia?

Physostigmine is the drug of choice in the central anticholinergic syndrome, but has also been used in post-operative mental derangement secondary to sedatives and volatile anaesthetics. The aim of this double-blind, randomized, prospective study was to determine whether physostigmine alters recovery after desflurane anaesthesia. One hundred patients undergoing urologic or surgical procedures were enrolled to receive either NaCl 0.9% (n = 50) or 2 mg of physostigmine (n = 50) at the end of general anaesthesia with propofol, fentanyl, cisatracurium and desflurane. Times to extubation, stating name, birthday and place of residence, and obeying commands such as eye opening and hand squeezing were noted. Haemodynamics, Aldrete and pain scores, the analgesic requirements, and any adverse side-effects were documented until the 1st post-operative day. Demographic, peri-operative data including duration of anaesthesia, surgery and postanaesthetic care unit (PACU) stay, and consumption of anaesthetics were comparable in both groups. No significant difference between the groups was found for extubation time or other emergence parameters. Patients undergoing anaesthesia >150 min showed after receiving physostigmine significantly (P < 0.05) faster spontaneous breathing (2.6 +/- 3.1 vs. placebo 5.0 +/- 4.2 min) and extubation time (6.2 +/- 3.7 vs. placebo 8.8 +/- 5.0 min). Women showed significantly shorter extubation times (5.5 +/- 3.4 min) and eye opening (5.5 +/- 2.6 min) with physostigmine than placebo (7.7 +/- 4.5 and 7.8 +/- 4.0 min). The incidence of post-operative nausea and vomiting (PONV) was significantly higher after physostigmine than placebo, whereas shivering occurred more often after placebo. Physostigmine does not alter desflurane-based anaesthesia compared with placebo. An option is to use physostigmine in patients with a duration of anaesthesia >150 min who profit in earlier return to spontaneous breathing and shorter extubation time.

Combining Physostigmine with Meperidine for Sedation and Analgesia During Colonoscopy

Opiate or benzodiazepine drugs are often used during colonoscopy, but they are associated with respiratory depression and prolonged recovery. Physostigmine, a tertiary anticholinesterase agent, is known to enhance analgesia and to reverse the central nervous system depressant effects of these drugs. This study compared the effect of giving meperidine alone with the effect of giving meperidine in combination with physostigmine in patients who were undergoing complete colonoscopy. A total of 44 outpatients undergoing elective colonoscopy were randomly assigned to receive analgesia with either meperidine 0.5 mg/kg intravenously (group 1, n=24) or physostigmine 10 micrograms/kg intravenously, followed 5 minutes later by meperidine 0.5 mg/kg intravenously (group 2; n=20). The patients were assessed with regard to oxygen saturation, hemodynamic changes, pain perception and sedation scores, readiness to go home, and adverse effects. The group 1 patients' oxygen saturations consistently fell, both during the procedure and in the recovery period; in group 2, oxygen saturations remained stable throughout the procedure and recovery period (95.88%+/-0.99 vs. 98.15+/-0.99, P<0.001). Patients in group 2 reported lower pain perception scores during the procedure (measured using a visual analog scale) than patients in group 1 (1.46+/-0.31 vs. 1.75+/-0.41; F1,42=6.484, P<0.015) and were less sedated during recovery (F1,41=6.56, P<0.015). No significant differences were found between the two groups with regard to heart rate or arterial blood pressure. All patients in group 2 were ready to go home after 25 minutes in the recovery area; three patients in group 1 were not ready to leave at 25 minutes and left the facility after 60 minutes. Four patients suffered from minor side effects of physostigmine (sweating and nausea). Combining physostigmine with meperidine as preparatory treatment for patients undergoing colonoscopy prevents respiratory depression, improves analgesia, and shortens recovery time, with only mild side effects.

A 24-week randomized trial of controlled-release physostigmine in patients with Alzheimer’s disease

To evaluate the safety and efficacy of controlled-release physostigmine, an acetylcholinesterase inhibitor, in patients with probable AD of mild to moderate severity. A prospective, 24-week, randomized, multicenter, double-blind, parallel group study of patients was conducted. The study enrolled 475 patients at 24 sites. Patients met criteria for probable AD and were randomized to one of three arms: placebo, controlled-release (CR) physostigmine 30 mg daily, or CR physostigmine 36 mg daily. Dosage was escalated by a forced upward titration during the first 6 to 9 weeks of the trial, then maintained at a constant dose to 24 weeks. Primary outcome measures were the Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-Cog) and the Clinician's Interview-Based Impression of Change-Plus with caregiver input (CIBIC+). Secondary outcome measures included the Clinical Global Impression of Change (CGIC), the Geriatric Evaluation by Relatives Rating Instrument, and an Instrumental Activities of Daily Living Scale. In an intent-to-treat population, the last observation carried forward analysis revealed a 2.9-point ADAS-Cog (p = 0.002) difference between physostigmine and placebo-treated patients for both dosages, and a 0.26 to 0.31-point difference on the CIBIC+ (p = 0.048). There were no significant differences on the secondary outcome measures except for a difference on the CGIC when analyzed by use of the Cochran-Mantel-Haenszel statistic (p = 0.014). There were significant increases in gastrointestinal side effects including nausea, vomiting, diarrhea, anorexia, dyspepsia, and abdominal pain for patients on either dose of physostigmine, resulting in a high dropout rate. Agitation was decreased significantly. There was no evidence of cardiac rhythm disturbance or liver function abnormalities. CR physostigmine enhanced cognitive and global function. It is relatively safe for the treatment of cognitive dysfunction secondary to AD. However, in light of the gastrointestinal side effects, a lower starting dose and a flexible titration schedule might lead to a more favorable adverse event profile in the clinical arena.

L-Deprenyl and physostigmine for the treatment of Alzheimer's disease

The present study evaluated the safety of and obtained preliminary data on the cognitive effects of l-deprenyl and physostigmine in patients with Alzheimer's Disease. Seventeen outpatients with Alzheimer's Disease participated in a double-blind crossover study in which they received 4 weeks of l-deprenyl at a dose of 10 mg p.o., q.d., and 4 weeks of placebo in random order. During both the l-deprenyl and placebo periods, patients received cognitive assessments during physostigmine (0.5 mg) and placebo infusions separated by 2 days. The cognitive effects of these agents alone and in combination were measured with digit span, verbal fluency, list learning, praxis, delayed recall, and delayed recognition tasks. Fifteen patients completed the study. The two drugs, used alone or in combination, were safe and well tolerated. Analyses of variance demonstrated that neither physostigmine nor l-deprenyl, whether given alone or in combination, significantly improved cognition, when compared with the double placebo condition.

Oral physostigmine in alzheimer's disease: Effects on norepinephrine and vasopressin in cerebrospinal fluid and plasma

Physostigmine is a cholinesterase inhibitor which enhances central and peripheral cholinergic activity. In this study, we explored in persons with Alzheimer's disease (AD) the effects of an acute dose of physostigmine in patients receiving chronic physostigmine treatment on the activity of the cholinergically regulated noradrenergic and arginine vasopressin (AVP) systems. Specifically, we estimated the effects of sustained release oral physostigmine on central and peripheral noradrenergic and AVP systems by measuring norepinephrine (NE) and AVP in cerebrospinal fluid (CSF) and plasma. Lumbar punctures were performed in both physostigmine and no drug treatment conditions. In some subjects the effects of physostigmine on the plasma AVP response to the osmolar stimulus of a hypertonic saline infusion also were measured. NE concentrations in both CSF and plasma were significantly lower in the physostigmine than in the no drug condition. AVP concentrations did not differ between conditions in either compartment, nor did physostigmine affect the AVP response to hypertonic saline. Physostigmine appears to decrease both central and peripheral noradrenergic activity in AD.

Clinical pharmacokinetics of physostigmine in patients with Alzheimer's disease*

To study the pharmacokinetic and pharmacodynamic properties of physostigmine in subjects with Alzheimer's disease. Plasma physostigmine concentration and butyrylcholinesterase inhibition were measured in blood samples collected during and after a single high-dose (1 to 1.5 mg for 45 to 60 minutes) and a sustained low-dose steady-state intravenous infusion in nine subjects with Alzheimer's disease. Escalating doses (0.5 to 25 mg/day) were administered during a 2-week period. A dose (2 to 12 mg/day) that optimized cognition in each subject was identified and then administered in a randomized, double-blind, placebo-controlled crossover design for 1 week. The elimination half-life of physostigmine was 16.4 +/- 3.2 (SE) minutes. Clearance and volume of distribution were 7.7 +/- 0.9 (SE) L/min and 2.4 +/- 0.6 (SE) L/kg, respectively. Butyrylcholinesterase inhibition half-life was 83.7 +/- 5.2 (SE) minutes. During sustained steady-state infusion, plasma physostigmine concentration (r = 0.95) and butyrylcholinesterase inhibition (r = 0.99) were linearly correlated with the dose. In five cognitive responders, the memory enhancement was significantly correlated (r = 0.86; p < 0.05) with butyrylcholinesterase inhibition. These results showed that, in cognitive responders, memory enhancement by physostigmine in Alzheimer's disease is correlated directly to the magnitude of plasma cholinesterase inhibition. Furthermore, during single-dose conditions, the dynamic half-life is five-fold longer than the kinetic half-life.

Inhibition of the startle reaction by physostigmine in patients with early brain damage.

The influence of physostigmine and atropine on the startle reaction and EEG epileptic paroxysmal activity was examined in 24 severely impaired children with early brain damage. The startle motor reaction could be regularly evoked by tapping on the sternum in 12 of the patients. Physostigmine inhibited this reaction significantly, while atropine was without effect. In 12 patients without a previous startle reaction, atropine had a possible activating effect, however, the result was not significant. Physostigmine had no effect. The EEG paroxysmal activity was inhibited by physostigmine and activated by atropine in both groups of patients. A cholinergic system disturbance was suggested in the pathophysiology of the paroxysmal activity. The disturbance which is probably present in early brain damage, is presumed to be also involved in the genesis of the startle reaction.

Cerebral blood flow is increased by physostigmine in patients with Alzheimer's disease ???

Cerebral blood flow is increased by physostigmine in patients with Alzheimer's disease ???

Hemodynamic Responses to Physostigmine in Patients with a Drug Overdose

Hemodynamic responses to physostigmine were evaluated in eight patients with coma due to overdose with mainly anticholinergic drugs (AC) and in five patients with coma due to overdose with nonanticholinergic drugs (NAC). After correction of hypovolemia, but before administration of physostigmine, AC patients had significantly lower systemic vascular resistances, slightly higher cardiac outputs, and lower mean arterial pressures than NAC patients. Physostigmine produced negligible hemodynamic and, as expected, negligible neurological changes in NAC patients. In AC patients physostigmine produced, also as expected, improved consciousness and in addition significantly increased mean arterial pressure, cardiac output, and cardiac work without significantly affecting systemic vascular resistance.

Hemodynamic Responses to Physostigmine in Patients with a Drug Overdose

Hemodynamic Responses to Physostigmine in Patients with a Drug Overdose