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PubMed1995

Pharmacotherapy of impaired affect in recovering schizophrenic patients.

BACKGROUND: Prominent and persistent anxiety, depression, and/or negative features characterize a substantial minority of recovered or residually psychotic schizophrenic outpatients and contribute to poor outcome. Because extrapyramidal side effects of typical neuroleptic medications often resemble such features, we first systematically studied the contribution of extrapyramidal side effects to these problems and their treatment. For patients who remained distressed, controlled trials of supplemental thymoleptics were undertaken. METHODS: In trial 1, 92 distressed (depressed and/or anxious) patients and 36 patients in a defect state (patients with negative symptoms) participated in a double-blind, intramuscular challenge that compared centrally acting benztropine mesylate with peripherally acting glycopyrrolate. In trial 2, 57 distressed patients and 22 patients in a defect state were randomly assigned to a double-blind, neuroleptic medication dose-reduction group. In trial 3, 57 chronically distressed patients who were maintained on a low dose of fluphenazine decanoate were randomly assigned to a supplemental desipramine hydrochloride, lithium carbonate, or placebo group under double-blind conditions for 12 weeks. RESULTS: For patients who were already maintained on antiparkinsonian medication, impaired affect was not resolved by additional benztropine. Only distressed patients with a family history of severe mental disorder (often affective) showed improvement with neuroleptic medication dose reduction. Patients in the defect-state group reported less dysphoria on a reduced neuroleptic medication dose, but negative symptoms persisted. Desipramine improved diverse aspects of mood and residual psychoticism, possibly as a prophylaxis against minor affective exacerbations. Depression improved in women only. Lithium positively affected multiple indexes of anxiety and anxious depression. CONCLUSION: Most often, persistent affective impairments are neither resistant extrapyramidal side effects nor characterological traits. Thymoleptics improve the nonphasic, chronic types of anxiety and depression in contrast to the acute, episodic forms, for which little support can be found in the literature.

Adolescent↗

PubMed2001

Analyses of quaternary ammonium drugs in horse urine by capillary electrophoresis-mass spectrometry.

A capillary electrophoresis-mass spectrometry (CE-MS) method for the analysis of quaternary ammonium drugs in equine urine was developed. Quaternary ammonium drugs were first extracted from equine urine by ion-pair extraction and then analysed by CE-MS in the positive electrospray ionization (ESI) mode. Within 12 min, eight quaternary ammonium drugs, each at 1 ng/mL in horse urine, could be detected. The confirmation of these drugs in urine samples was achieved by capillary electrophoresis tandem mass spectrometry (CE-MS/MS). A direct comparison of this method was made with existing liquid chromatography/mass spectrometry (LC-MS) methods in the detection and confirmation of glycopyrrolate and ipratropium bromide in horse urine. While the two drugs could be detected within the same CE-MS run at 1 ng/mL in urine, they could only be detected in separate LC-MS runs at 5 ng/mL in urine. In addition, CE-MS consumed a much smaller volume of extract; the analyte peak widths, in some cases, were much narrower; and as the quaternary ammonium ions were well separated electrophoretically from the mainly neutral urine matrix, a much cleaner background in the CE-MS total ion trace was observed.

Animals↗

PubMed2001

Auditory sensory memory and the cholinergic system: implications for Alzheimer's disease.

Auditory sensory memory represents one of the simplest types of short-term memory that can be studied electrophysiologically with mismatch negativity (MMN); a specific auditory event-related potential indexing automatic comparison of incoming stimuli to an existing memory trace. Previous results suggest that auditory sensory memory deteriorates in aging and especially in Alzheimer's disease (AD). It has remained unsettled, however, whether MMN is regulated by the cholinergic system, which is deteriorated in AD contributing to cognitive impairments. We recorded cortical auditory responses with a magnetometer from 13 healthy subjects after intravenous injection of scopolamine, centrally acting cholinergic antagonist, or glycopyrrolate, a drug with a peripheral anticholinergic properties without penetrating the blood-brain barrier, using a double-blind protocol. Scopolamine reduced MMNm amplitude in response to frequency, but not duration, change, increased P50m amplitude, and delayed N100m latency. These findings suggest that the cholinergic system regulates the frequency-specific comparison of incoming stimuli to existing memory trace and modulates the preattentive processing related to stimulus detection. Further, neural mechanisms responsible for cortical frequency- and duration-specific discrimination appear to have different sensitivities to cholinergic modulation. Auditory evoked potentials might be suitable to monitor cholinergic activity in AD.

Adult↗

PubMed1982

Cardiovascular collapse associated with nitrous oxide anaesthetic: a case report.

This is a case report of a one year old infant weighing 6.7 kilograms with a preoperative diagnosis of partial anomalous pulmonary venous drainage whose anaesthetic was complicated by cardiovascular collapse following addition of nitrous oxide to oxygen administered to the patient using a T-piece breathing circuit. The cardiovascular pathopharmacology of all the drugs administered to the patient before the event as well as that of nitrous oxide is discussed in detail. The drugs discussed are atropine 0.1 mg (0.01 mg . kg-1), glycopyrrolate 0.07 mg (0.01 mg . kg-1), morphine 0.9 mg (0.14 mg . kg-1) methylprednisone sodium succinate 165 mg (23.5 mg . kg-1) sodium thiopentone 40 mg (5.7 mg . kg-1), metocurine 3.4 mg (0.4 mg . kg-1).

Anesthesia↗

PubMed1998

Anaesthetic considerations in a patient with lepromatous leprosy.

PURPOSE: To consider the anaesthetic problems in a patient with lepromatous leprosy undergoing general anaesthesia. CLINICAL FEATURES: A 52 yr old man with lepromatous leprosy for five years was booked for elective radical nephrectomy. He received 100 mg dapsone per day po. The patient was asymptomatic for cardiovascular disease but his electrocardiogram showed complete left bundle branch block, inferior wall ischaemia with echocardiogram findings of 58% ejection fraction and left ventricular diastolic dysfunction. Other preoperative investigations (haemogram, serum urea and creatinine, liver function tests and chest X-ray) were normal. After premedication with diazepam, meperidine and promethazine, the patient received glycopyrrolate and anaesthesia was induced with thiopentone. Atracurium was given to facilitate tracheal intubation. Anaesthesia was maintained with intermittent positive pressure ventilation using N2O in oxygen with halothane. Anaesthesia and surgery were uneventful except that the patient had a fixed heart rate that remained unchanged in response to administration of anticholinergic, laryngoscopy, intubation and extubation. CONCLUSION: Patients with lepromatous leprosy may have cardiovascular dysautonomia even when they are asymptomatic for cardiovascular disease.

Adjuvants, Anesthesia↗

PubMed1995

Anaesthetic induction in a child with end-stage cardiomyopathy.

The purpose of this clinical report is to discuss the anaesthetic management of a patient with end-stage cardiomyopathy. An eight-year-old boy sustained electro-mechanical dissociation following a "standard anaesthetic induction" but was subsequently successfully anaesthetized using a combination of etomidate, midazolam, lidocaine, vecuronium and glycopyrrolate. Anaesthetic techniques and their relationship to the specific category of cardiomyopathy (dilated, hypertrophic or restrictive) are discussed. The potential detrimental effects of anaesthetic sympatholysis, myocardial depression and negative chronotropy on cardiac output are explained.

Anesthesia, Intravenous↗

PubMed2006

Alternative to ganglionic blockade with anticholinergic and alpha-2 receptor agents.

The ganglionic blocking agent trimethaphan (TMP) is no longer produced. Therefore, a need exists for alternative pharmacological approaches to investigate baroreflex control of the circulation. The aim of the present study was to examine baroreflex-mediated cardiovascular responses during the administration of a muscarinic receptor antagonist (glycopyrrolate; GLY: ) and a selective alpha-2 receptor agonist (dexmedetomidine; DEX: ) and to compare responses to ganglionic blockade with TMP. We hypothesized that combined GLY-: DEX: would inhibit the baroreflex similar to TMP. Ten volunteers participated in two study days and were instrumented with pulse oximeter, nasal cannula, ECG, continuous blood pressure monitoring (Finapres), and I.V. catheter for drug infusions. Each study day consisted of a control condition followed by either combined GLY: -DEX: or TMP on alternating days. A Valsalva maneuver was performed under each condition with every subject and six subjects received bolus phenylephrine (25 mug) during GLY: -DEX: and TMP. Combined GLY: -DEX: increased (P < 0.05) blood pressure (99 +/- 4 mmHg) and heart rate (99 +/- 3 bpm) relative to control condition (BP: 90 +/- 2 mmHg; HR: 64 +/- 3 bpm) and TMP infusion decreased (P < 0.05) blood pressure (79 +/- 3 mmHg) while increasing heart rate (88 +/- 3 bpm). Valsalva maneuver elicited a persistent drop in arterial pressure (no phase IIb recovery) with the absence of a phase IV overshoot during both GLY: -DEX: and TMP conditions. Phenylephrine increased systolic pressure 34 +/- 4 mmHg under GLY: -DEX: and 23 +/- 3 mmHg with TMP (P < 0.05). Heart rate only decreased 1 +/- 2 bpm during GLY: -DEX: and 1 +/- 1 bpm with TMP. Taken together, our results suggest that GLY: -DEX: is a reasonable alternative to TMP for baroreflex inhibition.

Adrenergic alpha-2 Receptor Agonists↗

PubMed2005

Cholinergic modulation of preattentive auditory processing in aging.

Auditory event-related potential (ERP) components P50 and N100 are thought to index preattentive auditory processing underlying stimulus detection, whereas a subsequent component termed mismatch negativity (MMN) has been proposed to reflect comparison of incoming stimuli to a short-lived sensory memory trace of preceding sounds. Existing evidence suggests impairment of preattentive auditory processing in aging, which appears to be accompanied by decline of cholinergic activity. Previous studies indicate that scopolamine, which is a centrally acting muscarinic receptor antagonist, modulates preattentive auditory processing in young subjects. It has remained elusive, however, to which extent scopolamine affects preattentive auditory processing in aged subjects. We measured auditory responses simultaneously with electroencephalogram (EEG) and magnetoencephalogram (MEG) from nine non-demented elderly subjects after intravenous injection of scopolamine or glycopyrrolate, the latter being a peripherally acting cholinergic antagonist, using a double blind protocol. Scopolamine significantly delayed electric P50, both electric and magnetic N100 responses, whereas subsequent MMN and P200 responses were not altered by scopolamine. Our results indicate that the cholinergic system modulates auditory processing underlying stimulus detection in aging. In addition, auditory evoked responses appear to have different age-related sensitivity to cholinergic modulation. The combined MEG/EEG measurements using particularly auditory N100 response might offer an objective tool to monitor cholinergic activity in aging and Alzheimer's disease (AD).

Aged↗

PubMed1999

Physostigmine challenge before and after chronic cholinergic blockade in elderly volunteers.

BACKGROUND: As a test of possible muscarinic up-regulation, the cortisol response to intravenous (i.v.) physostigmine (an anticholinesterase) was measured in 9 elderly volunteers before and after chronic cholinergic blockade with the muscarinic cholinergic antagonist scopolamine. METHODS: Each of the 9 elderly control subjects was given two physostigmine (0.5 mg i.v.) infusions separated by 21 doses of nightly scopolamine (1.2 mg p.o.). No scopolamine was administered the night before infusions, and glycopyrrolate (0.2 mg i.v.) was administered prior to physostigmine, to block its peripheral effects. Vital signs were monitored and blood samples were collected at six time points surrounding the physostigmine infusion (-10, +10, +20, +30, +50, and +70 min). Behavioral measures and cognitive tests were administered prior to and 30 min after the physostigmine. RESULTS: The cortisol response to physostigmine was greater after the second (post-chronic scopolamine) infusion study compared to the first (p < .05) as measured by an area under the curve analysis of all time points. When individual time points were compared, the mean cortisol response was significantly increased after the second physostigmine infusion at the +50- and +70-min time points (p < .05). There were no significant changes in behavioral rating scales, cognitive tests, or vital signs between the two physostigmine infusion study days. CONCLUSIONS: This study demonstrates increased hypothalamic-pituitary-adrenocortical axis responsivity to a central nervous system cholinergic stimulus after chronic muscarinic blockade in 9 elderly control subjects. It also gives further evidence to support previous suggestions of muscarinic plasticity, specifically postsynaptic up-regulation, in the aging brain following exposure to chronic anticholinergic treatment.

Aged↗

PubMed1982

Upper gastrointestinal lesions after potassium chloride supplements: a controlled clinical trial.

The effects of a new microencapsulated potassium chloride formulation on upper gastrointestinal tract mucosa was compared with that of a popular wax-matrix formulation in 48 healthy volunteers. After a week of KCl, subjects were gastroscoped, the endoscopist being blind to the type of preparation taken. Wax-matrix formulations were associated with a higher incidence of upper gastrointestinal lesions. The lesions were not accompanied by epigastric symptoms. Glycopyrrolate, given to some volunteers to decrease gastric emptying, aggravated the effects of potassium chloride.

Acute Disease↗

PubMed1999

Scopolamine augments transient auditory 40-hz magnetic response in humans.

The influence of neocortical muscarinic transmission on auditory-evoked 40-Hz magnetic response was studied in 13 healthy subjects in a double-blind randomized cross-over design. Either a centrally (scopolamine hydrobromide, 0.3 mg, i.v.) or a peripherally (glycopyrrolate, 0.2 mg, i.v.) acting antagonist of muscarinic transmission was administered during two sessions of magnetoencephalographic recording of 40-Hz response elicited by monaural tones. Scopolamine significantly (P < 0.01) augmented the 40-Hz magnetic response over the hemispheres ipsi- and contralateral to the ear stimulated. This finding suggests muscarinic modulation of the auditory evoked transient 40-Hz response.

Adult↗

PubMed1998

Effects of nicardipine and labetalol on the acute hemodynamic response to electroconvulsive therapy.

STUDY OBJECTIVE: To examine the acute hemodynamic effects of intravenous (i.v.) nicardipine and its ability to attenuate the hyperdynamic response to electroconvulsive therapy (ECT), when used alone or in combination with labetalol. DESIGN: Prospective, randomized, double-blind, positive-control, clinical investigation. SETTING: University hospital. PATIENTS: 36 patients undergoing ECT. INTERVENTIONS: In a series of three studies, the hemodynamic effects of nicardipine were assessed prior to, during, and after ECT. After administration of glycopyrrolate 0.1 mg i.v., placebo (saline) or nicardipine was administered by rapid infusion (1, 2.5, 5, 10, and 15 mg) or bolus injection (1.25, 2.5, and 5 mg), either alone or in combination with labetalol 10 mg i.v. Unconsciousness was induced with methohexital 1 mg/kg i.v.; succinylcholine 1.2 to 1.5 mg/kg i.v. was administered for muscle relaxation. A bilateral electrical stimulus was delivered and the durations of motor and electroencephalographic (EEG) seizures were noted. MEASUREMENTS AND MAIN RESULTS: Mean arterial pressure (MAP) and heart rate (HR) values were recorded at 1- to 5-minute intervals throughout the study period. When administered as a rapid infusion, nicardipine 5 mg i.v. produced a significant decrease in MAP; however, nicardipine dosages of 10 to 15 mg i.v. did not produce a significantly greater decrease in MAP than 5 mg. Bolus administration of nicardipine 1.25 to 5 mg produced a rapid onset of its hemodynamic effects without exacerbating the cardiovascular depressant effects of methohexital. However, the decrease in MAP was accompanied by an increase in HR after administration of the 5 mg i.v. bolus dose. The acute hyperdynamic response to ECT was most effectively controlled by nicardipine 2.5 to 5 mg i.v. bolus, in combination with labetalol 10 mg i.v. Seizure duration was not significantly altered by the use of nicardipine as part of the anesthetic regimen for ECT. CONCLUSION: Nicardipine 2.5 mg i.v. bolus in combination with labetalol 10 mg i.v. was the most effective pretreatment regimen for preventing the acute hyperdynamic response to ECT. However, this combination produced a 20% decrease in MAP immediately prior to ECT and a lower MAP at the time of discharge.

Adult↗

PubMed2003

Effects of scopolamine on MEG spectral power and coherence in elderly subjects.

OBJECTIVE: Scopolamine, a muscarinic receptor antagonist, can produce temporary cognitive impairments as well as electroencephalographic changes that partially resemble those observed in Alzheimer's disease. In order to test the sensitivity of spectral power and hemispheric coherence to changes in cholinergic transmission, we evaluated quantitative magnetoencephalogram (MEG) after intravenous injection of scopolamine. METHODS: MEG of 8 elderly healthy subjects (59-80 years) were measured with a whole-head magnetometer after intravenous injection of scopolamine. An injection of glycopyrrolate, a peripheral muscarinic antagonist, was used as the placebo in a double-blind, randomized, cross-over design. Spectral power and coherence were computed over 7 brain regions in 3 frequency bands. RESULTS: Scopolamine administration increased theta activity (4-8 Hz) and resulted in the abnormal pattern of MEG desynchronization in eyes-open vs. eyes-closed conditions in the alpha band (8-13 Hz). These effects were most prominent over the posterior regions. Interhemispheric and left intrahemispheric coherence was significantly decreased in the theta band (4-8 Hz). CONCLUSIONS: Spontaneous cortical activity at the theta and alpha range and functional coupling in the theta band are modulated by the cholinergic system. MEG may provide a tool for monitoring brain dynamics in neurological disorders associated with cholinergic abnormalities.

Aged↗

PubMed2001

Mucus altering agents as adjuncts for nonviral gene transfer to airway epithelium.

Nonviral vectors have been shown to be a safe and valid alternative to recombinant viruses for gene therapy of cystic fibrosis (CF). Nevertheless, gene transfer efficiency needs to be increased before clinical efficacy is likely in man. One barrier to increased efficacy is normal airway mucus. Using an ex vivo model of sheep tracheal epithelium, we show that this barrier can, in part, be overcome by treatment with the mucolytic agents, Nacystelyn or N-acetylcysteine using either a cationic lipid or a cationic polymer as the gene transfer agent. Further, in vivo application of either Nacystelyn or the anticholinergic glycopyrrolate, both clinically used agents, resulted in increased reporter gene expression in the mouse lung, but no significant correction of the bioelectric defect in CF null mice. These results, whilst unlikely to be sufficient in themselves to achieve clinically relevant gene therapy, may be a further useful step in the attainment of this goal.

Acetylcysteine↗

PubMed1998

Effect of potassium-magnesium citrate on upper gastrointestinal mucosa.

BACKGROUND: Potassium supplements may cause mucosal damage of the gastrointestinal tract. AIM: To evaluate the effect of a new potassium supplement, potassium-magnesium citrate (K-Mag), on upper gastrointestinal mucosa and to compare it with an older potassium supplement, potassium citrate (Urocit-K). METHODS: A randomized and double-blind study was conducted utilizing 36 healthy adults. Subjects were randomized into three groups: K-Mag (70 mmol/day K, 35 mmol/day citrate and 17.6 mmol/day Mg); Urocit-K (70 mmol/day K and 23.4 mmol/day citrate), and placebo. All subjects took 5 tablets b.d. of the allocated drug and 2 mg t.d.s. of glycopyrrolate for 7 days. On day 8, stool was examined for occult blood, a symptom score was calculated and an oesophagogastroduo-denoscopy was performed. Mucosal lesions were scored at five anatomic sites. RESULTS: Demographic characteristics and symptom score were similar in the three groups (< 10% with more than mild symptoms). There were no significant differences in the endoscopic scores at any site examined nor in the total scores among the three groups. Erosion or ulcers were found in 18% of K-Mag, 23% of Urocit-K and 17% of the placebo group. CONCLUSION: Short-term use of K-Mag does not appear to induce lesions in the upper gastrointestinal mucosa and its oral tolerance is similar to Urocit-K or placebo.

Adult↗

PubMed2001

Development of a Visual Analogue Scale questionnaire for subjective assessment of salivary dysfunction.

OBJECTIVE: This study's objective was to develop a Visual Analogue Scale (VAS) xerostomia questionnaire and to evaluate the validity and reliability for the clinical diagnosis of salivary gland dysfunction. STUDY DESIGN: Thirty-six healthy adults participated in this double-blind, crossover study. Each subject received an antisialagogue (glycopyrrolate) or placebo. Unstimulated and stimulated parotid and submandibular saliva samples were collected 16 times over a period of 6 hours. An 8-item VAS xerostomia questionnaire was administered after each saliva collection. RESULTS: The results demonstrated significant reliability for 7 of the 8 VAS items, whereas validity was significant for unstimulated submandibular saliva. Moving averages were calculated for VAS and salivary flow rate values, and significant correlations were observed between these factors, indicating that changes in VAS responses were predictive of changes in salivary flow. CONCLUSIONS: These findings suggest that this VAS xerostomia questionnaire may be helpful in the diagnosis of salivary dysfunction and for detecting changes in salivary flow rate values over time.

Adult↗

PubMed1987

The cardioacceleratory response to arecoline infusion during sleep in narcoleptic subjects and controls.

Nine narcoleptic and nine control subjects underwent 4 nights of sleep recordings. On nights 3 and 4, they received continuous intravenous infusions of saline. Additionally, on both nights they received 0.2 mg glycopyrrolate at the end of the first REM period (REM1) and 0.5 mg arecoline or placebo in random order 20 min after the end of REM1. Heart rates were counted for a 40-min period following the end of REM1. There was a significant and similar cardioacceleratory effect after arecoline in both narcoleptic and normal subjects, beginning at 5 min from the start of the infusion and peaking at 9 min. Placebo had no effect. Narcoleptic subjects had consistently higher baseline heart rates than controls on infusion and noninfusion nights, most likely owing to age differences between the two groups. The results suggest that narcoleptic persons do not have increased cholinergic sensitivity, or that the canine model of narcolepsy differs from the human model, or that the muscarinic receptors that play a role in the pathophysiology of narcolepsy differ in sensitivity from those that regulate heart rate.

Adult↗

PubMed1996

Intrathecal clonidine and tizanidine in conscious dogs: comparison of analgesic and hemodynamic effects.

Intrathecal delivery of alpha(2)-adrenergic agonists produces an analgesic effect. However, hemodynamic side effects limit their clinical usage. To more fully characterize the effects on heart rate and arterial blood pressure of alpha(2)-adrenergic agonists, clonidine and tizanidine were injected intrathecally in conscious dogs. Both compounds produced a potent inhibition of thermal foot-withdrawal latencies at 1000 micrograms, which was blocked by the alpha(2)-adrenergic antagonist yohimbine. Tizanidine (250-500 micrograms) did not change heart rate. Clonidine (500 -2000 micrograms) and tizanidine (1000-2000 micrograms) decreased heart rate. The tizanidine effect was inhibited by yohimbine and the alpha(2)/imidazoline antagonist idazoxan, as well as the parasympathetic blocker glycopyrrolate. No drug completely inhibited the clonidine-induced bradycardia. Clonidine had a biphasic effect on arterial blood pressure, a decrease at 500 micrograms and an increase at 2000 micrograms. Tizanidine decreased arterial blood pressure at all doses. The results indicate that, while the analgesic effects of both drugs are similar, the hemodynamic responses differ. While the decrease in heart rate with tizanidine is consistent with alpha(2)-adrenergic binding and vagal action, the bradycardia induced by clonidine is more complex. In addition, the increased arterial blood pressure with high doses of clonidine, which is suggestive of a peripheral vasoconstrictive effect, does not occur with tizanidine.

Adrenergic alpha-Agonists↗