Search

Objectives: To describe the efficacy of atropine in controlling salivary flow in patients with sialorrhea or drooling., Materials and Methods: We included randomized controlled studies, quasi-randomized trials, case reports, clinical trials, systematic reviews, and meta-analyses assessing the use of atropine in patients with sialorrhea or drooling. The endpoints were reduction in salivary flow rate, amount of saliva secreted, reduction in clinical symptoms of sialorrhea, death rattle intensity, or reduction in drooling intensity as measured by an objective scale such as the drooling intensity scale., Results: A total of 56 studies with 2,378 patients were included in the systematic review. The underlying disease states included brain injury, amyotrophic lateral sclerosis, cerebral palsy, clozapine- and perphenazine-induced sialorrhea, Parkinson's disease, and terminal illness. The routes of atropine administration included sublingual, intravenous, subcutaneous, oral tablet or solution, and direct injection of atropine into parotid glands or at the base of the tongue. The generalized estimated equation regression models showed that sublingual administration is superior to oral and subcutaneous routes., Conclusion: Atropine is efficacious in managing sialorrhea in most disease states. Sublingual administration of atropine is superior to other routes of administration in reducing salivary flow in patients with sialorrhea.

Background: Hypersalivation and drooling are commonly reported in clozapine-treated patients. Current management strategies have been evaluated using subjective measures. Many case reports describe the successful use of atropine in the treatment of the condition., Aims: To measure the effect and safety of sublingual atropine on nocturnal unstimulated saliva secretion. Secondary aims were to evaluate the patient's satisfaction with the atropine effect on hypersalivation (or sialorrhea), drooling, and sleep., Method: Twenty-one clozapine-treated patients with hypersalivation, or drooling, were randomised to take a single 600-μg dose of sublingual atropine drops or a matching placebo. The saliva secretion was measured over 5 min at baseline and 2 h after the administration of the study medication., Results: Sublingual atropine reduced the saliva secretion significantly more than the placebo (mean difference = - 57.21%, 95% CI: - 104.30, - 10.11, P = 0.02). A significant decrease in standing pulse rate was recorded in the participants in the atropine group (- 5.8 (- 9.54, - 2.15), P = 0.002). Subjectively, more patients in the atropine group found their pillow to have less saliva the following morning and found their sleep to be better., Conclusions: Sublingual atropine drops significantly reduces nocturnal unstimulated clozapine-induced saliva secretion. More research is required to compare the effect of sublingual atropine with other anticholinergic medications and different dosage forms., Trial Registration: ACTRN12618000051246.

Introduction: Sedation in children can be a challenge for emergency physicians, which demands for selecting an effective medication with few complications and good analgesic effects. This study has been performed to evaluate the adverse effects of ketamine while using either atropine or placebo in emergency departments., Methods: This is a prospective randomized controlled trial involving 200 patients with age ranging between 2 and 15 years, who need a painful procedure. Participants randomly were divided into 2 groups both treated by ketamine (1 mg/kg intravenously administered); group 1 received excessive intravenous atropine (0.01 mg/kg), whereas distilled water was given to group 2 as placebo. Adverse effects and duration of the treatments were recorded., Results: From March to September 2010, 200 of 218 eligible patients were enrolled. The mean (SD) age of patients in the intervention group was 7.0 (3.6) years that showed no statistical difference with the control group (age range, 2-15 years; mean, 7.1 [3.8] years). The mean procedure and sedation time between the intervention and placebo groups were not significantly different (P = 0.919 and 0.783, respectively). Several differences between the intervention and placebo groups were noted including nausea and vomiting, but only the difference in hypersalivation was statistically significant (12% vs 28%). Low oxygen saturation was reported only in 2% of the participants, whereas none of the children experienced apnea or laryngospasm during the sedation process., Conclusions: Atropine added to ketamine significantly reduces hypersalivation without producing any adverse effects on the procedure duration or success rate.

Objectives: Methantheline is a strong muscarinic receptor blocking drug used in the treatment of overactive bladder syndrome, hypersalivation and hyperhidrosis. To provide basic information on the pharmacokinetics, magnitude of pharmacodynamic (PD) effects and their correlations with plasma concentrations, we performed a clinical study in 12 healthy subjects receiving methantheline as immediate-release coated tablets (IR) or in watery solution (SOL) in comparison with atropine and placebo tablets., Methods: The pharmacokinetics and influence of methantheline, atropine and placebo on salivation and accommodation and pupil function (pupillometry: diameter, response to light flash) were studied in a randomized, controlled study after the administration of 100 mg methantheline bromide as IR and in SOL (phase 1) and 1.0 mg atropine sulphate and placebo (phase 2)., Results: Methantheline reached maximum plasma concentrations of approximately 25 ng/ml after 2.5-3 h and was eliminated at an apparent half-life of approximately 2 h. There was no pharmacokinetic (PK) bioequivalence of methantheline IR and SOL. The ratio IR/SOL (90 % confidence interval) were 0.892 (0.532-1.493) for AUC(0-∞) and 0.905 (0.516-1.584) for maximum plasma concentration. The PD effects of both forms were nearly equivalent with a IR/SOL ratio of 1.015 (0.815-1.262) for salivation, which is the most susceptible characteristic. Methantheline reduced salivation at a potency (methantheline concentration at half maximum effects, EC₅₀) of 5.5 ng/ml in accordance with it plasma concentration. The antimuscarinic effects observed after methantheline administration were stronger and persisted longer than those following the administration of atropine., Conclusions: Methantheline is slowly absorbed but rapidly eliminated in humans, and it exerts a strong effect on salivation which is closely associated with its plasma concentrations following a standard sigmoid PD model. Immediate-release tablets and a watery solution of methantheline are equivalent in terms of major PD effects (salivation, pupil function, heart rate) despite its high PK variability.

Here, we describe a human physiology laboratory class measuring changes in autonomic function over time in response to atropine. Students use themselves as subjects, generating ownership and self-interest in the learning as well as directly experiencing the active link between physiology and pharmacology in people. The class is designed to concomitantly convey the importance of bias in experimentation by adopting a double-blind placebo-controlled approach. We have used this class effectively in various forms with ∼600 students receiving atropine over the last 16 yr. This class has received favorable feedback from staff and students of medicine, pharmacy, and neuroscience, and we recommend it for such undergraduates. The learning objectives that students are expected to achieve are to be able to 1) know the ethical, safety, and hygiene requirements for using human volunteers as subjects; 2) implement and explain a double-blind placebo-controlled trial; 3) design, agree, and execute a protocol for making (and accurately recording) precise reproducible measurements of pulse rate, pupil diameter, and salivary flow; 4) evaluate the importance of predose periods and measurement consistency to detect effects (including any reversibility) after an intervention; 5) experience direct cause-and-effect relationships integrating physiology with pharmacology in people; 6) calculate appropriate summary statistics to describe the data and determine the data's statistical significance; 7) recognize normal variability both within and between subjects in baseline physiological parameters and also recognize normal variability in response to pharmacological treatment; 8) infer the distribution and role of muscarinic receptors in the autonomic nervous system with respect to the heart, eye, and mouth; 9) identify and explain the clinical significance of differences in effect due to the route and formulation of atropine; 10) produce and deliver a concise oral presentation of experimental findings; and 11) produce a written report in the form of a short scientific research article. The results of a typical study are presented, which demonstrate that the administration of atropine by a subcutaneous injection elicited a significant increase in pulse rate and pupil diameter and a significant decrease in salivary flow, whereas administration of atropine in an oral liquid elicited significant effects on pulse rate and salivary flow, and an oral solid format elicited a significant alteration in salivary flow alone. More detailed analysis of the salivary flow data demonstrated clear differences between the routes of administration and formulation in the onset and magnitude of action of atropine.

Introduction: The antisialagogue atropine sulphate has been used for many years as an adjunct to orthodontic bonding to reduce moisture contamination. The aims of this study were to investigate the effect of atropine sulphate premedication on orthodontic bond failures and to evaluate the attitudes of patients and parents toward its use in orthodontics., Methods: After ethics committee approval, 51 patients (mean age, 14 years 7 months) were enrolled in this clinical trial. They were randomized to receive 2 interventions, atropine sulphate premedication (600 microg) or no premedication (control) with a Battenburg design (split-mouth). Overall, 852 brackets and 362 molar tubes were bonded. Bond failure data were collected over a 12-month period and analyzed with Kaplan-Meier survival probabilities and the log rank and Wilcoxon tests. Patient-centered outcome measures included a questionnaire relating to treatment with antisialagogues., Results: The results showed no statistically significant difference in the bond survival rates between the 2 interventions--antisialagogue premedication or no premedication (P >.05). From the questionnaire, 94.1% of the subjects said they took the atropine sulphate before the bond appointment. Approximately 76% of them thought that taking medication before placement of orthodontic appliances was an acceptable part of treatment., Conclusions: Although the use of a premedication to induce hypo-salivation before orthodontic bonding appears to be an acceptable procedure to most patients and their parents, we did not find a statistically significant effect on the observed bond failure rates. There is no evidence to support the routine use of atropine sulphate before orthodontic bonding.

Sialorrhea is a relatively common symptom in idiopathic Parkinson's disease and related conditions for which most of the accepted treatments are either highly invasive or may cause substantial systemic side effects. This study describes an open-label pilot study of sublingual atropine drops for the treatment of sialorrhea in 7 patients (6 with Parkinson's disease, 1 with progressive supranuclear palsy). Participants demonstrated statistically significant declines in saliva production, both objectively and subjectively. Self-reported drooling severity showed a significant decline between baseline and 180 minutes, t(6) = 3.240 P < 0.025 (eta(2) = 0.636), and between baseline and 1 week, t(6) = 4.583 P < 0.005 (eta(2) = 0.778). Objectively measured saliva production decreased significantly between baseline and the 1-week follow-up, t(6) = 2.711 P < 0.05 (eta(2) = 0.551). Delirium occurred in 1 patient (concurrent with a urinary tract infection), and 2 patients experienced worsening of hallucinations (active hallucinosis was concealed by both individuals to allow participation in the trial). The remaining trial participants did not experience any anticholinergic side effects. This trial shows that, in selected patient populations, sublingual atropine is a simple and inexpensive treatment for sialorrhea associated with parkinsonism., (Copyright 2002 Movement Disorder Society)

Objective: To investigate systemic antimuscarinic activity after the intravesical administration of 6 mg of atropine sulphate., Subjects and Methods: Ten subjects were recruited to an open study in accordance with strict inclusion and exclusion criteria. Each subject received an instillation of 6 mg atropine sulphate diluted to 20 mL with normal saline. All variables were measured at baseline (before instillation) and the instilled solution retained for at least 2 h. After instillation systemic antimuscarinic activity was monitored every 20 min for 2 h then hourly for the next 4 h. The measurements included blood pressure, sublingual temperature, pulse rate, peak expiratory flow rate, lacrimation and salivation rates; all variables were analysed statistically. Facial skin was also observed for hyperaemia. All subjects were questioned about any known symptoms produced by antimuscarinic agents. The heart rate was recorded continuously before and after instillation using a Holter monitor., Results: None of the variables changed significantly after instillation and the Holter analysis showed no relevant variation in heart rate. All subjects consistently denied any antimuscarinic symptoms. One subject had mild cutaneous hyperaemia, as reportedly occurred consistently when her bladder was distended (> 500 mL). Immediate catheterization drained 600 mL and the hyperaemia resolved., Conclusion: The failure to detect systemic antimuscarinic activity at a dose which has previously been shown to suppress detrusor activity suggests that intravesical atropine therapy is safe for further study by clinical trial, and might provide a treatment for detrusor hyper-reflexia that is free from side-effects.

After reading this article, the reader should be able to describe techniques for the control of saliva during dental procedures; discuss the problems associated with saliva contamination of an operative field; explain the clinical benefits, dosing guidelines, and contraindications for using atropine sulfate to temporarily reduce saliva flow during dental procedures.

In a paediatric population, we compared i.m. v oral atropine premedication to a control group without atropine and determined atropine plasma concentrations (APC). Forty-five children were randomly assigned to one of three groups. Group I received atropine, 20 micrograms.kg-1 i.m., 15 min prior to induction. Group II received atropine, 30 micrograms.kg-1 orally, group III received no atropine. APC (expressed as percent of muscarine-2 receptor subtype occupancy), heart rate, rectal temperature, and salivation were determined before atropine, and 15, 25, 45, 60, 90, 120 (no APC), and 150 min following atropine. Only 10-20% of the M2-cholinoceptors were occupied after oral atropine with a peak at 90 min compared to 60-70% occupancy with a peak 25 min after i.m. atropine. The peak in M2-cholinoceptor occupation in group I was paralleled by a peak percentage change in heart rate of 15% from baseline. The peak in receptor occupation in group II did not correspond to the peak increase in heart rate. The percentage change of heart rate over time was not significantly different from baseline values in any of the groups. Bradycardia or temperature changes did not occur in any of the groups. Antisialogogue effects were observed only in group I. We conclude that atropine; 30 micrograms.kg-1 orally is not an equipotent dosage to atropine, 20 micrograms.kg-1 i.m.

Acute, subchronic and chronic exposures to cholinergic compounds may result in differing effects. The efficacy of pyridostigmine bromide (PY) prophylaxis against organophosphorus poisoning depends on post exposure atropine (AT) administration. AT induces a dose-dependent increase in rate of rise of core temperature in heat exposed humans and rats. To determine whether AT's anticholinergic potency is altered following PY administration, we examined AT's effects following acute or subchronic (2 weeks) PY administration in the sedentary heat-stressed rat. Four groups of rats were acutely (a, i.v.) treated with saline (SAL) or PY (100 ug/kg) followed by SAL or AT (200 ug/kg), and 4 groups were subchronically (c, osmotic pump) treated with SAL or PY (20 ug/hr) followed by SAL or AT (200 ug/kg). Fifteen minutes following the final injection, rats were subjected to an ambient temperature of 41.5 degrees C until a core temperature of 42.6 degrees C was attained. Heat tolerance times were significantly improved for cPY+SAL over aPY+SAL (241 +/- 9 vs 187 +/- 16 min, mean +/- SE) and for cPY+AT over aPY+AT (76 +/- 9 vs 57 +/- 2 min). The improvement in thermoregulation resulted from increased salivary water for evaporative cooling indicated by % weight loss (corrected for fecal loss) during heat stress: cPY+SAL over aPY+SAL (8.4 +/- 0.3 vs 6.6 +/- 0.5%). This increased heat tolerance resulting from subchronic anticholinesterase administration resembles changes seen with heat acclimation.

As glycopyrrolate has been reported superior to atropine with respect to reduction of salivation, stability of cardiac rate and rhythm, and recovery, a comparison of these properties of the two drugs and placebo was made in 45 patients undergoing direct laryngoscopy and 45 patients undergoing bronchoscopy, in most cases followed by mediastinoscopy. When given i.m. 30 min before anesthesia (midazolam, alfentanil, thiopentone, and suxamethonium), the two test drugs were found to be equally potent regarding the antisialogogic effect. The same increase in heart rate after the test drugs was seen before induction, and during anaesthesia heart rate rose to the same level in the placebo group as the test groups. During anaesthesia, blood pressure was lowest in the atropine group. No differences could be demonstrated with respect to cardiac arrhythmias, possibly due to the small size of the material. The present study gives no reason for preferring either drug, and only the efficacy of both test drugs in controlling airway secretions provides an argument for using any anticholinergic drug when laryngoscopy or bronchoscopy is performed under the conditions of the present study.

Should atropine be administered for premedication? This question continues to be controversial; in particular, the combined administration of atropine and succinylcholine has been investigated with conflicting results by numerous researchers. The present study was carried out to assess the effect of premedication with atropine on hemodynamic variables and salivation in patients assigned to ASA class II and III. METHODS. Eighty ASA class II or III patients received pethidine 1.0 mg/kg and promethazine 0.5 mg/kg i.m. 30 min prior to induction of anesthesia and atropine, either 0.01 mg/kg i.v. 10 min or 0.01 mg/kg i.m. 30 min prior to a standardized anesthetic induction with alcuronium (precurarizing dose), thiopental, and succinylcholine. In the control groups (20 patients each), no atropine was given. Systolic, diastolic, and mean arterial pressures (MAP) were measured. The ECG was monitored for arrhythmias. Salivation was assessed semiquantitatively using swabs positioned within the pharyngeal space. RESULTS. Ten minutes after the administration of atropine i.v., a significant increase in heart rate (HR) was observed; this did not occur within 30 min after administration of atropine i.m. At the time of tracheal intubation, HR was significantly increased in both i.v. atropine risk groups. After atropine i.m., an increase in heart rate during intubation was observed in ASA class II patients only. No increase in heart rate occurred in the control groups during tracheal intubation. Neither i.m. nor i.v. atropine had any significant effect on blood pressure. Arrhythmias occurred in a few cases with both routes of administration; several instances of marked tachycardia were recorded.(ABSTRACT TRUNCATED AT 250 WORDS)

1. The effects of atropine on gastric emptying, paracetamol absorption, salivary flow and heart rate were examined in young and elderly subjects. 2. Seven healthy young male subjects of age 23 +/- 1.3 years (mean +/- s.e. mean) and seven fit elderly subjects of age 70 +/- 1.6 years received placebo (P), 300 micrograms atropine (A300) or 600 micrograms atropine (A600) in randomized order at weekly intervals. After 10 min they ingested a 500 ml orange drink containing 1 g paracetamol. Gastric emptying was measured by ultrasound, blood samples were taken to measure plasma paracetamol concentration by h.p.l.c., salivary flow was measured by dental cotton wool cylinder technique and pulse rate was recorded. 3. In young subjects, the gastric 5 min volumes were 260.1 +/- 17.9 ml (s.e. mean) with P, 310.6 +/- 10.5 ml with A300 and 317.9 +/- 8.9 ml with A600. In elderly subjects, the gastric 5 min volumes were 166.7 +/- 10.1 ml with P, 252.6 +/- 13.7 ml with A300 and 266.0 +/- 14.8 ml with A600. Thus the early adaptive phase of gastric emptying was more rapid in the elderly than the young with all treatments (P less than 0.05). The gastric emptying half-lives were 18.8 +/- 2.5 min with P, 30.0 +/- 2.7 min with A300 and 34.5 +/- 3.3 min with A600 in young subjects (P less than 0.01). In elderly subjects, the gastric emptying half-lives were 16.1 +/- 2.5 min with P, 23.7 +/- 2.4 min with A300 and 30.0 +/- 2.9 min with A600 (P less than 0.01). Thus atropine intravenously in therapeutic dose (300 and 600 micrograms) delayed gastric emptying in both young and elderly subjects. The inhibitory effect of atropine on the early adaptive phase of gastric emptying appeared to be greater in the elderly. The maximum plasma concentration (Cmax) of paracetamol was greater in the elderly than young with all treatments (P less than 0.05). There was a close relationship between the early adaptive phase of gastric emptying and paracetamol absorption (P less than 0.05). Atropine reduced salivary flow and increased resting heart rate in both young and old subjects. The effect of atropine on salivary flow was greater in the elderly. 4. The dose-response relationship varied in the three systems (stomach, salivary glands and heart rate) studied. Age had an effect on the magnitude of the response, but not on the slope of the dose-response curve for the two doses of atropine studied.(ABSTRACT TRUNCATED AT 400 WORDS)

The potential subchronic (21 days) toxicity of inhaled metered aerosol formulations (solution and suspension) of atropine sulfate was investigated in rats and dogs. The doses administered to rats were 0.78 and 2.5 mg/kg/day (solution) or 1.4 and 3.2 mg/kg/day (suspension). In the dog, the daily doses achieved were 0.5 and 1.3 mg/kg/day, regardless of formulation. In both species, sham control animals inhaled air only and vehicle control animals inhaled either placebo solution or placebo suspension. There was no mortality or other evidence of a toxic effect of atropine sulfate. The expected mydriatic effect of atropine sulfate was seen in both species and, similarly, the pupillary light reflex was impaired in rats and dogs receiving either formulation of atropine sulfate at both dose levels. Reduced salivation was also noted and ophthalmologic examinations in both species were unremarkable. In dogs, atropine sulfate (high-dose) caused tachycardia but there was no evidence of an adverse effect on the electrocardiogram or on systolic blood pressure. In both species, atropine sulfate did not alter body weight, food consumption or clinical pathology parameters. Necropsy observations and histopathological findings revealed no effect of atropine sulfate in either species although, in the rat, adrenal gland hypertrophy in both sexes followed inhalation of the suspension at both dose levels. With this possible exception, nothing but the expected pharmacological effects of atropine sulfate were seen in either rats or dogs.

This study determined the kinetics of the effects of atropine on heart rate and saliva flow in three healthy male volunteers after intravenous administration of 1.35 and 2.15 mg of the drug. The pharmacokinetics of atropine and its primary metabolite, tropine, were determined simultaneously. Both the pharmacokinetic and effect data were fitted to an integrated kinetic-dynamic model. The maximum heart rate and minimum saliva flow occurred with a significant delay of 7-8 min after drug administration. Both effects were nonlinearly related to the amount of drug in the peripheral compartment. Maximum heart rates of 192 and 217% of the control values were observed at the lower and higher dose levels, respectively. Minimum saliva flows of 8 and 3% of the control values were measured after the lower and higher doses of atropine, respectively. The time durations of the positive chronotropic effect of the drug were 170 and 250 min at the lower and higher dose levels, respectively; the corresponding values for the length of the antisialogogue effect of the drug were 230 and 340 min, respectively.

The effects of oral midazolam or intramuscular atropine and pethidine used as premedication in two groups of 35 children over 5 years of age were studied. There was some evidence that the anxiolytic effect of midazolam was rather better than that of atropine plus pethidine, but, in other respects, subjective assessments in the two patient groups were similar. Intramuscular atropine caused tachycardia and subjective side-effects, nevertheless children appear to require anticholinergics during premedication because of excessive salivary secretion, especially during extubation. Oral midazolam is a new anxiolytic drug which can be used as an alternative to existing premedicant drugs, but, in children, it should still be combined with an anticholinergic agent. No correlation between serum levels of midazolam or atropine and their clinical effects was found.

Atropine and glycopyrrolate were compared when given in a mixture with neostigmine for the reversal of non-depolarising neuromuscular block in children. Glycopyrrolate was an effective antimuscarinic agent and could be safely used as an alternative to atropine, although the advantages in this age group were not as marked as have been observed in adults.

Atropine and glycopyrrolate (glycopyrronium bromide), a quaternary ammonium drug, were evaluated in volunteers following intramuscular administration with respect to effects on various end-organs with cholinergic innervation. Glycopyrrolate appears to be five to six times more potent than atropine in its antisialogogue effect and also exhibits a selective, though prolonged, effect on salivary secretion and sweat gland activity. It has minimal cardiovascular, ocular and central nervous system effects.

The effects of equivalent doses of atropine and hyoscine following oral and i.m. administration were assessed on salivary secretion, heart rate, arterial pressure, body temperature, pupillary size, near-point of vision and sweat-gland activity. The ratio of oral to i.m. doses of atropine on heart rate and salivary secretion appears to be 2:1 and that of hyoscine on salivary secretion about 5-6:1. Following oral administration the effects on the eye are minimal even after the highest doses of the two drugs, while the decrease in salivation is adequate.

In our rat model of human heat injury we have administered atropine intravenously (iv); for clinical use in man, administration is by either the intramuscular (im) or iv route. In order to determine potential differences due to route of administration, we compared the dose-response effects of im and iv administration in rats. Adult male rats (500 g) were heat-stressed (41.5 degrees C) while unrestrained which enabled them to thermoregulate by saliva spreading activity. We quantitated the effects of im or iv atropine (10-4000 micrograms.kg-1) on the following variables: heating rate (rate of rise of core temperature), % weight loss (saliva production), and fecal loss (intestinal motility). Further, we examined the effects of atropine on pupil dilation in restrained rats at 26 degrees C. Heating rate was identical for both routes of atropine administration at 200 micrograms.kg-1 (equivalent to the standard 2-mg dosage in man), but the range of doses over which there was a dose-response effect on heating rate with iv administration (10-1000 micrograms.kg-1) was markedly truncated with the im route (10-50 micrograms.kg-1). Both im and iv atropine had similar effects on weight loss rate and mydriasis. The iv route is preferred because that route produced the most consistent results and the most sensitive physiological response (heating rate) is affected over a wider dose range.

The effect of intravenous administration of glycopyrrolate and atropine shortly before induction were compared in a double blind study in children. The study shows that glycopyrrolate, unlike atropine, administered before anaesthesia had little effect on heart rate. The heart rate changes at, and following, tracheal intubation were similar in both groups.

Intravenous atropine sulphate (0.25, 0.40, 0.75 and 1.50 mg), atropine methylnitrate (0.08, 0.13 and 0.25 mg) and saline were given to 72 healthy medical students. The effects on heart rate and rhythm, systolic and diastolic blood pressure and salivary secretion were studied. Salivation was inhibited by all the doses of the two drugs. There was a clear dose-response relationship and methylatropine was about 3 times as potent as atropine. Heart rate was accelerated by 0.75 and 1.50 mg atropine, and 0.25 mg methylatropine, whereas 0.25 mg atropine and 0.08 and 0.13 mg methylatropine induced bradycardia, which was considered to be due to a peripheral action. It is suggested that the drugs act as partial agonists at muscarinic receptors. No clear effect on blood pressure was seen, except for the highest dose of atropine, after which the diastolic pressure was increased. 20 out of 59 subjects who received anticholinergics developed supra-ventricular arrhythmias; with both drugs periods of nodal rhythm were most common. They appeared shortly after the injection and usually lasted for a few minutes.

We have previously reported that administration of atropine (A) to unrestrained, sedentary, heat-stressed rats resulted in a dose-dependent increase in heating rate (rate of rise of core temperature, degree C/min). Additionally, we have demonstrated that the decrements in treadmill endurance and increments in heating rate of physostigmine (PH)-treated running rats can both be restored to control levels by pretreating the animals with A and diazepam (D). Our objective in the present work was to determine if the administration of D + PH to A-treated unrestrained, sedentary, heat-stressed rats (N = 16/group, 510-530 g) could improve their thermal tolerance. The following drugs were administered singly (at 10 min intervals) via lateral tail vein: vehicle-control (C), A (200 micrograms/kg), D (500 micrograms/kg), and PH (200 micrograms/kg). After drug administration, the rats were heat-stressed (Tamb = 41.5 degrees C) until a core temperature of 42.6 degrees C was attained when they were removed to a 26 degrees C chamber. The heating rates (degrees C/min) and tolerance times (min) of the respective groups were: C- 0.02, 235; A- 0.08, 58; A D- 0.06, 94; and A + D + PH- 0.04, 143. Administration of D with A significantly decreased heating rate, and D + PH more than doubled the thermal tolerance of A-treated rats. Thus, the combination of A + D + PH not only restores PH-induced performance and thermoregulatory decrements of rats exercised in a moderate environment, but also reduces A-induced heat intolerance.

Pirenzepine is used in the treatment of peptic ulcer disease as an inhibitor of gastric acid secretion. Recent studies suggest that the mode of action on the stomach may be selectively anticholinergic. The present study was undertaken to compare the effect of pirenzepine on gastric emptying with the effect of a widely used classical anticholinergic drug and of placebo. In a double-blind double-dummy study nine healthy volunteers received 50 mg pirenzepine twice a day, 0.6 mg L-hyoscyamine twice a day, or two placebo tablets twice a day for 4 days before the gastric emptying test. Gastric emptying of a liquid test meal was measured by the method of George. Maximum salivation capacity was registered by the method of Blum 2 and 4 h after the last dose had been given. Gastric emptying was delayed during L-hyoscyamine, whereas the emptying was slightly accelerated by pirenzepine when compared with placebo. The difference between L-hyoscyamine and pirenzepine was statistically significant for the time in which the volume fell to 75% and 50% (p less than 0.01). The salivation was significantly more inhibited by L-hyoscyamine than by pirenzepine. Pirenzepine in doses inhibiting gastric acid secretion does not delay gastric emptying when compared with an equipotent dose of a classical anticholinergic drug, nor does it inhibit salivary secretion as much as L-hyoscyamine. This study therefore confirms our previous conclusion that pirenzepine may indeed be a 'selective' anticholinergic drug acting on gastric secretion.

The practice of preparing patients about to undergo electroshock treatment with atropine has been re-examined in the light of the great variety of practices which prevail both in terms of dose, route of administration and timing of the drug, as reported in the literature. By using patients as their own controls in the course of a series of treatments, it was determined that there are no appreciable differences between intravenous atropine given in different doses at different times and no atropine at all. Since no evidence was found that atropine contributes to cardiovascular stability or to consistent drying of secretions, and since its omission was not accompanied by untoward effects, it is suggested that the agent is not needed nor even necessarily desirable as a premedicant in electroshock therapy.

Pharmacokinetic and pharmacodynamic parameters of atropine 0.03 mg/kg p.o. or 0.02 mg/kg i.m. were compared in a double-blind study in 20 children with a mean age of 5.1 years undergoing otolaryngological surgery, mostly adenotomy. Outside the study protocol, two small children accidentally received an overdose of atropine 0.3 mg/kg p.o. In addition to atropine, all children received triclofos 70 mg/kg p.o. Following p.o. administration of atropine, the mean maximum serum concentration of 6.7 nmol/l occurred at 2 h. The corresponding result after i.m. administration was 5.7 nmol/l at 0.5 h. Serum concentrations of atropine were 3.5 and 1.3 nmol/l 8 h after p.o. and i.m. administration, respectively. At 70 min the anti-sialogogue effect was clinically satisfactory after both modes of administration. The heart rate increased statistically significantly only after i.m. administration. The mean maximum rise in the rectal temperature before the start of anaesthesia occurred at 1 h and was 0.5 degrees C in the p.o. group and 0.7 degrees C in the i.m. group. The flush phenomenon, mostly on the face and sometimes also on the chest, occurred in both groups, being more intense in the i.m. group than in the p.o. group. The children who developed flush had a statistically significantly higher rise in rectal temperature than the children without flush. There was a positive but weak correlation between the serum concentration of atropine and the heart rate, whereas the correlation between the serum concentration after i.m. atropine and the rectal temperature was weakly negative. On the basis of the present study, there were no decisive differences between the effects and side-effects of the two modes of administration of atropine.(ABSTRACT TRUNCATED AT 250 WORDS)

The neuropharmacological mechanisms involved in the prandial drinking pattern seen in rats with superior salivatory nucleus lesions + parotidectomy were investigated with behavioral methods. Results showed that the administration of low doses (0.1 mg/kg body wt) of atropine in lesioned rats potentiated previously established prandial drinking. Higher doses of atropine (1.0 mg/kg), however, were required to induce a similar degree of prandiality in control rats (parotidectomy alone). These findings suggest that the salivatory nucleus lesions affected a cholinergic brainstem-salivary gland system involved in the neural control of food-associated drinking.

We examined the role of cholinergic mechanisms in causing the increase in histamine bronchial responsiveness that follows allergen exposure. Five stable adult atopic asthmatics received inhalation tests with histamine on 2 days after both placebo and a dose of atropine sulphate (18 mg nebulized during tidal breathing), which reduced saliva output. On a third day, an allergen inhalation test was carried out to stimulate a dual asthmatic response. When the FEV1 had returned to within 10% of baseline, the histamine test was repeated after placebo and atropine. Before allergen inhalation, atropine marginally increased the FEV1 (p = 0.12) and reduced bronchial responsiveness to histamine (p = 0.003). When allergen challenge had induced an increase in histamine responsiveness (p = 0.001), atropine again marginally increased FEV1 (p = 0.063) and reduced the responsiveness (p = 0.004) but did not return the responsiveness to the preallergen level (p = 0.023). There was no evidence that the magnitude of the atropine blockade of histamine responsiveness was different before and after allergen (p = 0.92). We conclude that cholinergic mechanisms are not likely to explain the increase in bronchial responsiveness that follows allergen-induced inflammation.

Hypersalivation and facial skin hyperemia that simultaneously emerge in response to atropinization have been observed in patients who suffered trauma to the skull base combined with damage of the parasympathetic secretory and vasodilatory fibers in the greater and lesser petrosal nerves at the tip of the temporal bone pyramid. The study was facilitated by special vacuum capsules applied to both outlet ducts of the parotid glands. Hyperemia and hyperthermia of the face were evaluated visually, by thermometer readings, and color photography. The events described are distinct from those reported in the literature (i.e., paradoxical disturbances of facial and salivary gland innervation). This study analyzes the mechanism of initiation and the manifestations of this complex syndrome.

1. The effects of stimulating the postganglionic parasympathetic nerve to the parotid gland, the auriculo-temporal nerve, continuously at 40 Hz for 80 min have been assessed on the flow of saliva and its amylase content during each 10 min period and on the glandular morphology at the end of the stimulation, in female Sprague-Dawley rats under chloralose anaesthesia. Adrenergic responses were blocked by prior administration of dihydroergotamine (1 mg/kg I.P.) and propranolol (1 mg/kg I.P.). The contralateral unstimulated parotid gland from each animal was used for morphological control purposes. 2. In normal animals there was a copious flow of saliva reaching 3 ml or more in 80 min. It was well maintained after a gradual small decline and the flow in the last 10 min period was still 60% of that in the initial period. Amylase output was relatively high in the initial period but then declined more rapidly than the flow. The acini were densely packed with granules on the control side and showed a moderate amount of degranulation on the parasympathetically stimulated side. 3. After atropine (2 mg/kg I.V.), normal animals initially showed a moderate flow of saliva, being 41% of the non-atropinized animals, but there was a rapid decline and the total flow over 80 min was only 15% of that in the non-atropinized animals. The amylase secreted was also high initially and showed a rapid decline; the total amount secreted was similar to that in non-atropinized animals. The morphology was similar to that in non-atropinized animals and showed a similar loss of acinar granules on the stimulated side. 4. Chronic bilateral postganglionic sympathectomy (4-6 weeks duration) caused a drastic reduction in the capacity of the gland to secrete saliva in response to parasympathetic stimulation, reaching only one-third of that from normal animals. The initial output of amylase was greater than in normal animals but the total output was similar. The control unstimulated sympathectomized glands appeared similar morphologically to normal resting glands. However, on the parasympathetically stimulated side, besides the usual amount of acinar degranulation, there was also a conspicuous development of acinar vacuolation, not seen in the other groups of animals.(ABSTRACT TRUNCATED AT 400 WORDS)

A double blind study of 98 patients was undertaken to compare the clinical usefulness of atropine and glycopyrrolate for pre-anaesthetic medication and their relative effectiveness in antagonizing the muscarinic effects of neostigmine methylsulphate given to reverse neuromuscular blockade. Intramuscular administration of atropine 0.4 mg or of glycopyrrolate 0.2 mg produced the same degree of dryness of the pharynx. However, glycopyrrolate was found to be a more potent antagonizer of the increased salivation induced by neostigmine. By intramuscular administration, both drugs produced the same degree of tachycardia, although atropine tended to cause no change in the pulse rate or even to produce bradycardia in a greater number of patients. Administered intravenously, atropine produced a more significant tachycardia in a large number of patients prior to neostigmine administration, although the protection against a decreased pulse rate from neostigmine is greater in those patients who received glycopyrrolate. It would appear, therefore, that glycopyrrolate is more effective in antagonizing the muscarinic effects of neostigmine methylsulphate.

In a prospective study a total of 51 patients were given either a premedication with atropine (10 micrograms/kg) (n = 17), with glyopyrrolate (5 micrograms/kg) (n = 15) or no anticholinergic premedication (n = 19). In the group of patients premedicated with glycopyrrolate the pH levels of the gastric juice were more often above 2.50 than in the group without anticholinergic premedication (p less than 0.05). During the microlaryngoscopic interventions there was a trend to fewer A-node rhythms or bradycardias in the group premedicated with glycopyrrolate than in the other groups. Reduction of salivary gland secretion by anticholinergics made intervention easier. Glycopyrrolate has advantages over atropine as far as the induction of anaesthesia for microlaryngoscopic interventions is concerned.

To determine the efficacy of atropine as an endoscopic premedication, we prospectively evaluated in double-blind fashion 196 elective endoscopies performed on 189 consecutive consenting patients. Group 1 (95 endoscopies) received meperidine, 1.5 mg/kg, intramuscularly 30 min prior to endoscopy. Group 2 (101 endoscopies) additionally received atropine, 0.6 mg, in the same injection. Endoscopy was performed by one of two investigators using a 13-mm fiberoptic instrument. Endoscopists and patients filled out postendoscopy questionnaires. Both endoscopists (p less than 0.01) and patients (p less than 0.05) noted less oral secretions after atropine. Endoscopists noted less gastric motility after atropine (p less than 0.05) and guessed correctly whether or not atropine had been given in two thirds of cases. They noted no overall difference, however, in the ease of the endoscopy (p greater than 0.05). Moreover, there were no differences in the patients' assessments of the acceptability of the procedure between the two groups (p greater than 0.05). We concluded that although atropine does not improve patients' tolerance for the examination or the endoscopists' ability to do an adequate examination, it does objectively decrease the amount of gastric motility and oral secretions. This latter effect could potentially decrease the hazard of aspiration, but such a benefit could not be demonstrated in our series.

The absorption of a quartenary (propantheline, 30 mg) and a tetiary (1-hyoscyamine, 0.8 mg) anticholinergic compound was studied in 8 healthy volunteers by measuring the effects on salivation. Both compounds were administered as rapidly disintegrating tablets, 1-hyoscyamine also in a slow-release formulation (Egazil Durules). The three preparations and placebo were administered under fasting conditions and with a standardized light meal using a randomized cross-over design. Salivation measurement were performed with a citric acid stimulation method every hour for 10 hours. In the fasting patient, all three anticholinergic test preparations decreased the salivation significantly. When taken with food, the effect of propantheline was almost abolished, while the effects of the 1-hyoscyamine preparations were uninfluenced. It was concluded that the clinical effects of proprantheline might be extremely varying depending how the drug is taken in relation to meals. In contrast the clinical effects of 1-hyoscyamine seem to be independent of food intake.

Atropine and other anticholinergic drugs are widely used in common medications and in the treatment of organophosphate poisoning. Man dissipates heat by the evaporation of sweat. Analogously, rats spread saliva over their bodies for evaporative cooling. Atropine inhibits both sweating and salivation. Therefore, we sought to quantitate the effects of atropine in our rat heatstroke model. While heat-stressing adult male rats of 500 or 250 g at 41.5 degrees C, we measured the effects of i.v. atropine (10-4000 micrograms X kg-1) on the following: heating rate (HR), % wt loss (saliva production), and fecal loss (intestinal motility). HR (degree C X min-1) was the most sensitive index of drug activity with a 200 micrograms X kg-1 dose (equivalent to 2 mg in man for organophosphate poisoning) eliciting an increased HR from 0.022 degrees C (saline) to 0.087 degrees C X min-1 (atropine). Atropine (200 micrograms X kg-1) increased HR even if administered 3 h prior to heat exposure. Large (500 g) rats showed an increase in HR with 25 micrograms X kg-1 of atropine, but 250 g rats required 50 micrograms X kg-1. This model could be used to assess the relative effects of other anticholinergic drugs and as a non-dehydrated heatstroke model.

Compared with manual intramuscular injection, automatic injector delivery substantially enhances drug absorption rate. We examined the effect of two types of automatic injector delivery of two drugs which are components of the standard antidote to anticholinesterase poisoning and which have been previously shown to have a reduced absorption rate when mixed together in a manual injection. In crossover experiments one week apart, 20 nonsmoking healthy young male humans (ages 20-30) were studied after citrated atropine (6.9 mumol/0.7 mL) and pralidoxime chloride (3.5 mmol/2.0 mL; PAMCL) were injected sequentially into a single intramuscular site by either a multichambered autoinjector or a device which delivers the drugs into two separate intramuscular sites (MARK I). Atropine absorption was assessed by the appearance of atropine in the serum and by changes in heart rate, salivary secretion, pupil diameters, and near vision accommodation. Atropine absorption was significantly greater in the first 30 min following injection with the MARK I. The results of this study suggest that: (1) the MARK I device produces a faster absorption of atropine, probably through some combination of its broader dispersal of atropine in the muscle site and its separation of atropine from the PAMCL; (2) salivary secretion may be the most convenient and sensitive marker of atropine action; and (3) the 6.9- mumol (2-mg) dose of atropine delivered by either autoinjector gives near maximal antisialogogue activity in normal male humans.

The effects were studied of various drug combinations, recommended for use in reversal of neuromuscular blockade, on heart rate and salivary secretions in 80 healthy patients anaesthetized with nitrous oxide-oxygen-halothane and relaxed with d-tubocurarine. The drug combinations were mixtures of atropine 1 mg--neostigmine 2.5 mg, atropine 1 mg--pyridostigmine 15 mg, glycopyrron 0.5 mg--neostigmine 2.5 mg, and glycopyrron 0.5 mg--pyridostigmine 15 mg, respectively. It was found that administration of the atropine-containing mixtures induced more pronounced initial increases and delayed decreases in heart rate than the mixtures containing glycopyrron. Pyridostigmine-containing mixtures elicited a somewhat more pronounced initial increase in heart rate than neostigmine-containing mixtures, but a less pronounced and delayed decrease in heart rate. Supraventricular arrhythmias occurred less frequently in the pyridostigmine groups than in the neostigmine groups. No such difference was found between the atropine and glycopyrron groups. Glycopyrron caused a more intense dryness of the mouth than atropine. A differential attitude towards the use of drugs for reversal of neuromuscular blockade, based on the cardiovascular state of the particular patient, might be recommendable.

In unpremedicated patients presenting for general anaesthesia for electroconvulsive therapy (ECT), the use of atropine combined with methohexitone as an intravenous induction agent was found to produce a significantly greater increase in heart rate than glycopyrrolate in similar combination. There was no difference in the antisialogogue effect of the two drugs at the doses used, and both drugs provided similar protection against the effects of suxamethonium and ECT on heart rate.

1 The anticholinergic effects of atropine and two antihistamines (terfenadine and mequitazine) were investigated vs placebo in a double-blind study. 2 Salivary secretion, basal pupil diameter, pilocarpine (0.25%) induced miosis and heart rate were determined in eight healthy volunteers, seven male and one female, aged between 23 and 35 years. Each volunteer received all four separate courses of treatment: i.e. terfenadine 60 mg or mequitazine 5 mg twice daily for 3 days, and one single dose on the day of the trial; for the placebo or atropine courses they received the placebo twice daily during 3 days and, on the morning of test day, either the placebo again or atropine 1 mg. Pupillary diameter was measured under standardized conditions using a pupil gauge (Smith and Nephew Pharmaceuticals Ltd). 3 Atropine significantly reduced salivary output (-2.25 +/- 0.36 ml from control values of 4.17 +/- 0.42 ml, P less than 0.001) and heart rate (-9.7 +/- 3.7 beats min-1 from 77.5 +/- 2.7, P less than 0.05). These maximal effects were observed 3 h after atropine dosing for salivary secretion and 1 h for heart rate. Atropine did not affect basal pupil diameter or pilocarpine-induced miosis. 4 Mequitazine and terfenadine did not affect salivary flow, heart rate or pilocarpine-induced miosis. 5 Terfenadine and mequitazine had no anticholinergic effect in these tests involving a limited number of subjects.

The possibility of inducing a special status of the salivary gland function has been demonstrated in 20 subjects with its denervation. This status is characterized by an immediate transformation of the cholinolytic response to atropine administration to the cholinomimetic one, extremely intense and durable, as a result of minimal reflex stimulation playing a role of the inducing agent.