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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.

Aim: As only a few basic animal experiments have assessed the usefulness of percutaneous application of oxybutynin, we compared the effects of percutaneous application and intraduodenal injection of oxybutynin on urinary bladder contraction accompanied by micturition in conscious rabbits and salivation in anesthetized rabbits., Methods: Bladder contractions were induced by continuous infusion of saline (2 mL/min) into the bladder. Salivary secretion was induced by pilocarpine (0.1 mg/kg, i.v.). Oxybutynin was administered at 15 mg/animal, and the plasma concentrations of oxybutynin and N-desethyloxybutynin were measured by high-performance liquid chromatography to clarify the effective concentration., Results: The intercontraction interval (ICI) was prolonged from 0.5 h after intraduodenal injection of oxybutynin, and this effect continued for 2 h. The ICI prolongation after percutaneous application of oxybutynin appeared at 2 h and continued throughout the 6-h experimental period. The saliva secretion induced by pilocarpine was inhibited to almost the same level by oxybutynin 3 h after intraduodenal injection and 6 h after percutaneous application. However, the sum of the plasma concentrations of oxybutynin and N-desethyloxybutynin rose steeply to a very high level within 20 min after oral administration instead of intraduodenal injection and decreased within 3 h to about half of the level evident 6 h after percutaneous application., Conclusion: We confirmed that percutaneous application of oxybutynin caused long-lasting ICI prolongation in our rabbit model, as compared with that after intraduodenal injection, and produced weaker inhibitory effects on saliva secretion because it did not cause steep elevation of the plasma concentration.

Background: Muscarinic receptor mediated adverse effects, such as sedation and xerostomia, significantly hinder the therapeutic usefulness of first generation antihistamines. Therefore, second and third generation antihistamines which effectively antagonize the H1 receptor without significant affinity for muscarinic receptors have been developed. However, both in vitro and in vivo experimentation indicates that the third generation antihistamine, desloratadine, antagonizes muscarinic receptors. To fully examine the in vivo antimuscarinic efficacy of desloratadine, two murine and two rat models were utilized. The murine models sought to determine the efficacy of desloratadine to antagonize muscarinic agonist induced salivation, lacrimation, and tremor. Desloratadine's effect on the cardiovascular system was explored in both rodent models., Results: In the pithed rat, both desloratadine (1.0 mg/kg, i.v.) and the muscarinic M2 selective antagonist, methoctramine (0.5 mg/kg, i.v.), inhibited negative inotropic (left ventricular dP/dt) effects caused by oxotremorine, a nonselective muscarinic agonist (p < 0.05). Negative chronotropic effects caused by oxotremorine were inhibited by desloratadine, methoctramine, and the muscarinic M3 selective antagonist, 4-DAMP (1.0 mg/kg, i.v.). A late positive inotropic event observed after the initial decrease was inhibited by all three test compounds with desloratadine and 4-DAMP being the most efficacious. In the conscious animal, inhibition of baroreflex-mediated bradycardia was evaluated. Unlike atropine (0.5 mg/kg, i.v.), desloratadine did not alter this bradycardia. The antimuscarinic action of desloratadine on salivation, lacrimation, and tremor was also explored. In urethane-anesthetized (1.5 g/kg, i.p.) male ICR mice (25-35 g) desloratadine (1.0, 5.0 mg/kg) did not inhibit oxotremorine-induced (0.5 mg/kg, s.c.) salivation, unlike atropine (0.5 mg/kg) and 4-DAMP (1.0 mg/kg). In conscious mice, desloratadine failed to inhibit oxotremorine-induced (0.5 mg/kg, s.c.) salivation, lacrimation, and tremor. However, desloratadine did inhibit oxotremorine-induced tremor in phenylephrine pretreated animals., Conclusion: The presented data demonstrate that the third generation antihistamine, desloratadine, does not significantly antagonize peripheral muscarinic receptors mediating salivation and lacrimation, therefore, xerostomia and dry eyes should not be observed with therapeutic use of desloratadine. Our data also indicate when administered to a patient with a compromised blood-brain barrier, desloratadine may cause sedation. Patients with compromised cardiovascular systems should be closely monitored when administered desloratadine based on our results that desloratadine has the ability to interfere with normal cardiovascular function mediated by muscarinic receptors.

Purpose: The influence of parasympathicomimetic pilocarpine and anticholinergic biperiden on salivation in patients irradiated for malignant tumors of the head and neck region was assessed in a prospectively designed clinical study., Methods and Materials: Sixty-nine patients, irradiated for head and neck cancer with salivary glands included in the irradiation fields, were randomly assigned into three groups (A, B, and C). Group A consisted of patients receiving pilocarpine, group B of those who were receiving biperiden during radiotherapy and pilocarpine for 6 weeks after its completion, while group C comprised patients not receiving any xerostomy prevention therapy during or after radiotherapy. The quantity of secreted unstimulated saliva was measured before the beginning of radiotherapy, after 30 Gy of irradiation, on completed irradiation, and 3, 6, and 12 months after completion of radiotherapy., Results: Saliva secretion has been found to be the least affected by irradiation treatment in the group of patients receiving biperiden throughout the course of radiotherapy. Six months after completed irradiation, the differences in the quantity of secreted saliva between groups C and B as well as between groups A and B were statistically significant (P = 0.002 and 0.05 respectively). In patients receiving pilocarpine during radiotherapy, and those in the control group, further decrease in saliva secretion was observed. One year after completed therapy, the quantity of secreted saliva could only be measured in the patients receiving biperiden during radiotherapy: it amounted to 16% of the average quantity of saliva secreted before the beginning of irradiation., Conclusion: It seems that the inhibition of saliva production during irradiation treatment and the stimulation after completed radiotherapy may contribute to the preservation of salivary gland function after therapy.

Background: Describing a therapeutic index for a drug is important for evaluating safe and effective dosage regimens. Therapeutic index can be evaluated as the relative position of the dose-efficacy and the dose-side effect curves. Oxybutynin XL (Ditropan XL), a once-daily oral controlled-release formulation for oxybutynin chloride, is being developed. Oxybutynin XL efficacy and side-effect data obtained from two parallel-group, randomized, controlled clinical trials were modeled to evaluate the therapeutic index., Methods: A nonlinear mixed-effects model was used to characterize the oxybutynin dose-efficacy and dose-dry mouth relationship. Weekly urge urinary incontinence episodes, the primary efficacy variable, is a discrete variable (counts) with only non-negative integer values and was therefore modeled as a Poisson variable. The probability of dry mouth severity (the most frequently reported side effect), assessed on a categorical four-point scale, was modeled with a proportional odds model. In the modeling process, it was assumed that the time effect was the same for the active and placebo treatments and that the drug effect was additive., Results and Conclusions: The urge urinary incontinence episodes declined log-linearly, and no significant difference was observed between the two formulations. However, there was a trend toward higher efficacy with oxybutynin XL than with immediate-release oxybutynin at the same dose in one study. Dose-dry mouth analysis showed that the probability of dry mouth with an increasing dose was significantly lower with oxybutynin XL than with immediate-release oxybutynin in the second study, and a similar trend was observed in the first study. By combining the dose-urge urinary incontinence and dose-dry mouth relationship, a wider therapeutic index was predicted for oxybutynin XL than for immediate-release oxybutynin.

Propiverine is a drug for the treatment of incontinence and pollakiuria. Such micturitional disorders are principally caused by a hyperactive bladder. The effects of propiverine, its active metabolite, 1-methyl-4-piperidyl benzilate N-oxide (DPr-P-4 (N-->O)), oxybutynin and terodiline on muscarinic receptors in guinea pig urinary bladder, salivary glands, cerebral cortex, ileal longitudinal muscle and heart were compared. Both propiverine and DPr-P-4 (N-->O) competitively inhibited specific binding of 3H-quinuclidinyl benzilate (3H-QNB) to membrane fractions of these tissues. Oxybutynin, terodiline, pirenzepine and atropine also competitively inhibited the binding of 3H-QNB. The order of these drugs in terms of their affinity for muscarinic receptors was as follows: atropine > oxybutynin > pirenzepine, DPr-P-4 (N-->O), terodiline > propiverine. Propiverine and DPr-P-4 (N-->O) had no selectivity for muscarinic receptors in these tissues, the same as atropine. In contrast, pirenzepine, a M1-selective drug, had 10.1 times greater affinity for muscarinic receptors in the cerebral cortex than in urinary bladder, and the affinity of oxybutynin for muscarinic receptors in salivary glands and in cerebral cortex was 10.9 times and 13.9 times higher, respectively, than in urinary bladder. The affinity of terodiline for muscarinic receptors in the cerebral cortex was 4.4 times higher than in urinary bladder. In this study, the effect of propiverine and oxybutynin on pilocarpine (1 mg/kg, s.c.)-induced salivation in conscious dogs was also compared. Propiverine (5 mg/kg, i.v.) had no effect on pilocarpine-induced salivation, whereas oxybutynin (0.1 mg-0.5 mg/kg, i.v.) inhibited it significantly and dose-dependently. The ID50 values (95% confidence limits) for propiverine and oxybutynin during the 20 min after intravenous administration were 6.88 mg/kg (4.71-15.67) and 0.154 mg/kg (0.115-0.205), respectively. These findings suggest that although propiverine, its active metabolite DPr-P-4 (N-->O), oxybutynin and terodiline competitively inhibit the binding of 3H-QNB to muscarinic receptors, the affinity of these drugs for the muscarinic receptors of these tissues is very different and that propiverine has less effect on salivation than oxybutynin.

A series of phenylacetyl derivatives containing the 5,10-dihydro-11H-dibenzo[b,e,][1,4]diazepin-11-one or 5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one skeleton was prepared and evaluated for their binding affinities to muscarinic receptors in vitro and for antagonism of bradycardia, salivation and tremor in vivo. Among them, compounds 56 and 66 had high affinity for M2 muscarinic receptors in the heart (pKi = 8.7 and 8.9, respectively) with low affinity for M3 muscarinic receptors in the submandibular gland. A structure-activity relationship (SAR) study suggested that the high M2 selectivity over the M3 muscarinic receptors of 56 may be attributed to the direction of the carboxamide carbonyl group. In in vivo studies, 56 and 66 antagonized oxotremorine-induced bradycardia in rats on both intravenous and oral administration, and their heart rate increasing effect in dogs with nocturnal bradycardia was about 3-fold greater than that of AF-DX 116. Furthermore, they had almost no influence on oxotremorine-induced tremor in mice, presenting no evidence of central transfer.

1. The inhibitory action of vamicamide (FK176, (+/-)-(2R*,4R*)-4-dimethylamino-2-phenyl-2-(2-pyridyl)valeramide, CAS 132373-81-0) on the responses of various tissues to the cholinergic agonists, carbachol and McN-A-343 (4-[m-chlorophenylcarbamoyloxy]-2-butynyl-trimethylammonium chloride, CAS 55-45-8), was investigated in isolated tissue preparations. Vamicamide showed competitive antagonistic actions against all the preparations tested and its pA2 value for the urinary bladder was 6.82, which was higher than that for the atria (5.94) and almost the same as that for the vas deferens (6.90) and for the stomach (6.81). The pA2 values of oxybutynin hydrochloride (oxybutynin) and atropine sulfate monohydrate (atropine) were nearly the same in all the tissues tested. 2. Oral administration of vamicamide 0.1-1.0 mg/kg inhibited dose-dependently spontaneous bladder contractions caused by raising the intravesical volume in conscious rats. Inhibitory actions were also obtained with 0.32-3.2 mg/kg of oxybutynin or 0.0032-0.032 mg/kg of atropine, but the duration of action of oxybutynin was shorter than that of vamicamide or atropine. Vamicamide further inhibited bladder contractions in rats following intravesical administration of 0.05-0.5 mg/ml solution. 3. Vamicamide had no effect or only slightly inhibited spontaneous motility of the stomach and distal colon in conscious rats, as well as heart rate and salivary secretion in conscious dogs, after oral dosing with 3.2 mg/kg of the compound. Similar results were obtained with oxybutynin, excepting the occurrence of tachycardia.(ABSTRACT TRUNCATED AT 250 WORDS)

The safety and tolerance of increasing single oral doses of 20, 40, 80, 120, 180, 240 and 360 mg trospium chloride (Spasmo-lyt, CAS 10405-0204) were investigated in 29 healthy male volunteers in a double-blind placebo-controlled study. Blood pressure, heart rate, ECG, pupillary diameter, salivary secretion, and subjective reports of tolerance revealed no essential differences between placebo and trospium chloride in doses up to 120 mg. Starting with single doses of 180 mg, anticholinergic effects were observed with increasing intensity, i.e., dilatation of the pupils, reduction of salivary flow, and increase of heart rate. While the highest administered dose of 360 mg trospium chloride did not cause any relevant changes of vital parameters (blood pressure, pulse, ECG), it was subjectively rated as quite unpleasant. The data show that trospium chloride is well tolerated in single oral doses well above the current therapeutic daily dose of up to 40 mg.

A new class of substituted 1-phenyl-3-piperazinyl-2-propanones with antimuscarinic activity is reported. As part of a structure-activity relationship study of this class, various structural modifications, particularly ones involving substitution of position 1 and the terminal piperazine nitrogen, were investigated. The objective of this study was to derive new antimuscarinic agents with potential utility in treating urinary incontinence associated with bladder muscle instability. These compounds were examined for M1, M2, and M3 muscarinic receptor selectivity in isolated tissue assays and for in vivo effects on urinary bladder contraction, mydriasis, and salivation in guinea pigs. Potency and selectivity in these assays were influenced most notably by the nature of the substituent group on the terminal nitrogen of the piperazine moiety. Benzyl substitution was particularly advantageous in producing compounds with functional M3 receptor (smooth muscle) and bladder selectivity; it provided several candidates for clinical study. In vivo, 3-(4-benzyl-piperazinyl)-1-cyclobutyl-1-hydroxy-1-phenyl-2-propanone (24) demonstrated 11- and 37-fold separations in its effect on bladder function versus mydriatic and salivation responses, respectively. The corresponding 2-chlorobenzyl derivative 25 was more than 178-fold selective for M3 versus M1 and M2 muscarinic receptors. 3-(4-Benzylpiperazinyl)-1,1-diphenyl-1-hydroxy-2-propanone (51) was 18-fold selective for M3 versus M1 and 242-fold selective for M3 versus M2 receptors. It was also selective in guinea pigs, where it displayed 20- and 41-fold separations between bladder function and effect on mydriasis and salivation, respectively. In general, the results of this study are consistent with the proposition that the described piperazinylpropanones interact with muscarcinic receptors in a hydrogen-bonded form that presents a conformation similar to that apparently adopted by classical antimuscarinic agents.

Both classical (atropine, scopolamine) and nontraditional (pirenzepine, telenzepine) cholinolytic agents themselves cause no salivation in human subjects. Ordinarily, they block salivation caused by pilocarpine. Conversely, they all stimulate intense salivatory response in the chronically denervated human parotid gland. The author presents critical comments on the concept that cholinolytic agents cause salivation by suppression of the mechanism of presynaptic autoinhibition. An alternative explanation of the initial cholinomimetic effect of cholinolytic agents is suggested.

The purpose of this work was to study the effect of graded mechanical and gustatory stimulation on the secretion of the acinar products fluid and amylase and the ductal product kallikrein from the human parotid gland (n = 9). The involvement of parasympathetic and sympathetic nerves in the salivary reflexes was subsequently examined using receptor blocking agents (n = 4). Chewing elevated the secretion of all products as compared to rest (P less than 0.013). When increasing the length of the chewing object, secretion of fluid (P less than 0.013), but not enzymes, further increased. The shift from mechanical to gustatory stimulation with 0.5% citric acid enhanced significantly the secretion of amylase and kallikrein (P less than 0.009), while application of 5.0% citric acid increased the secretion of both acinar products (P less than 0.009) more than kallikrein. A differentiated reflex control of salivation both with regard to input and output was thereby indicated. The muscarinic-cholinergic antagonist oxyphencyclimin reduced median fluid secretion between 54 and 76% depending on the stimuli. During citric acid stimulation, but not during chewing, fluid secretion was reduced about 40% by the beta 1-adrenergic antagonist metoprolol, and about 20% by the alpha 1-adrenergic antagonist prazosin. Median amylase secretion was reduced 30% during chewing and 75% during gustatory stimulation by metoprolol. It was concluded that the masticatory-salivary reflex mainly activated parasympathetic pathways producing saliva of low protein content.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of AF-DX 116, a cardioselective antagonist, on M cholinergic receptors (M-ChR) were studied in healthy volunteers. Occupancy of M-ChR subtypes by drug present in plasma samples (radioreceptor assay) was compared with these effects. After an intravenous dose of AF-DX 116 saturating greater than 90% of cardiac M2-ChR, an increase in heart rate by 25 beats/min was observed. This cardiac receptor occupancy and effect wore off with a parallel time course within 10 hours. No inhibition of salivary flow was observed, coinciding with a lack of M3-ChR blockade in the radioreceptor assay. Beta-adrenergic receptor blockade by propranolol did not affect either of the effects. No indication for active metabolites or stereoselective drug metabolism was found comparing HPLC and receptor assay for drug concentrations in plasma. We conclude that AF-DX 116 may be a useful drug for the treatment of bradycardia. Its lack of troublesome side effects is the result of its selectivity for cardiac M-ChR.

The affinity and selectivity of racemic terodiline (N-tert-butyl-1-methyl-3,3-diphenylpropylamine HCl) for muscarinic receptor subtypes was determined from functional responses of rabbit vas deferens (M1), guinea pig atria (M2) and bladder detrusor muscle (M3). (+/-)-Terodiline was found to be about as potent as pirenzepine in the rabbit vas deferens (Kb = 15 and 31 nM, respectively) and at least as selective for M1 relative to M2 (11-fold) and M3 (19-fold) receptors. Like pirenzepine, (+/-)-terodiline does not distinguish between M2 and M3 receptors in vitro. The peripheral actions of (+/-)-terodiline were evaluated in vivo in terms of its ability to induce mydriasis, and to inhibit salivary secretion and urinary bladder contraction. (+/-)-Terodiline given s.c. was equipotent in inhibiting intravesical bladder pressure and carbachol-induced salivary secretion (ID50 = 24 and 35 mg/kg, respectively), and in increasing pupil diameter (ED50 = 59 mg/kg). These results suggest that the in vivo actions of racemic terodiline at (M3) receptors mediating bladder contraction may not be separable from its actions at receptors mediating mydriasis and salivation. Moreover, its effects on the pupil and salivary glands are apparently not mediated through M1 receptors. Together, these findings help clarify the action of (+/-)-terodiline in the treatment of neurogenic bladder.

The electrocardiographic and anticholinergic effects of trazodone (150 mg) and imipramine (75 mg) were investigated in 8 healthy volunteers. Both agents increased the QTc interval and decreased T wave height, but the effects occurred earlier with trazodone (from 30 min onwards) than with imipramine (150 and 180 min after dosing). Both drugs decreased heart rate, imipramine at 30 and 60 min and trazodone at 90 min. After 120 min, heart rate began to increase with imipramine an effect which was not seen with trazodone. Salivary volume was significantly decreased by imipramine at 120 and 180 min whereas trazodone did not influence salivary volume. Plasma levels of trazodone and imipramine were significantly related to the decrease in T wave amplitude. The increase in QTc interval correlated significantly with the plasma level of imipramine. These results suggest that trazodone, like the tricyclic antidepressants prolongs ventricular repolarization; but, in contrast to imipramine, it does not have anticholinergic activity.

N, N-Diethylaminoethyl ester and 3-quinuclidinyl ester of 2, 2-diphenylpropanoic acid (compound 1 and 2, respectively) were prepared and pharmacologically evaluated in vitro and in the intact animal. Both compounds attenuated the effects of increasing doses of ACh in the isolated rat ileum (pA2 = 8.40 and 8.55, respectively). These effects were comparable to that of atropine (pA2 = 8.73). The duration of methacholine-induced salivation in male Swiss-Webster mice was significantly decreased by compound 2 but not by compound 1. Cardiorespiratory studies in adult male Sprague-Dawley rats revealed that both compounds shifted the dose-response curves to methacholine in terms of arterial blood pressure, heart rate and respiration upwards; indicative of cholinergic blockade. The observed pharmacological differences between the two compounds may be attributed to apparent in vivo hydrolysis of compound 1 by esterases.

In anesthetized cats antidepolarising curare-like drugs anatruxonium, cyclobutonium, diadonium and decadonium in doses lower than myoparalytic ones, completely blocked acetylcholine-induced bradycardia, only slightly changing the hypotensive action. In a myoparalytic dose anatruxonium and cyclobutonium decreased acetylcholine bronchospasm approximately by 50 %, diadonium altered this response in various directions, while decadonium essentially increased the bronchoconstricting action of acetylcholine. Anatuxonium and cyclobutonium failed to affect significantly the ileum, urinary bladder or salivary glands responses to acetylcholine; diadonium increased or did not change these reactions, while decadonium significantly enhanced them. Anatruxonium like atropine antagonized carbachol effects on isolated ileum and spontaneously beating atria of the rat, causing parallel shifts of the concentration-response curves for the agonist with no depression of maximum responses. Still, unlike atropine the affinity (pA2) of anatruxonium for muscarine-sensitive acetylcholine receptors of the atria was higher than that for the receptors of the ileum. The data obtained testify to the heterogenity of muscarine-sensitive acetylcholine receptors of different localisation.

Cetiedil, a new vasodilating drug with anticholinergic properties, was shown to be metabolised very rapidly in man after intravenous and oral administration of the 14C-compound. Higher concentrations of labelled compound after oral than after intravenous administration at the same sampling time, and proportional differences in urinary excretion, suggest that metabolic handling of the drug differs depending on the route of administration. Experiments in which inhibition of saliva secretion was measured indicated that (an) active metabolite(s) probably was (were) responsible for the action of the drug. As an anticholinergic drug, cetiedil is at least 400 times weaker than atropine.

Desmethylimipramine (DMI) and atropine were compared in a variety of organ system tests in rats and mice involving muscarinic receptor function in order to assess the anticholinergic-like activity of this tricyclic antidepressant drug. DMI was similar to atropine in maximally inhibiting basal gastric acid secretion and markedly protecting against restraint-induced stomach ulceration. It did not, however, substantially increase pupil size, reduce fecal pellet output, inhibit cholinergically induced salivation or specifically antagonize the CNS effects of carbachol and oxotremorine as did atropine. From these data and previous work indicating that DMI acts at a site in the central nervous system to inhibit gastric acid secretion, it is concluded that the biological effects of this drug are not mediated through an atropine-like mechanism.

1 C 49802 B-Ba and CGP 12103/A are the racemate and the R (-)-enantiomer respectively of the hydroxylated derivative of the tetracyclic antidepressant maprotiline, which differed in their ability to block noradrenaline-uptake and in their anticholinergic activity in animal models. 2 The sympathomimetic and anticholinergic activities of both substances were evaluated in eight healthy subjects and compared with the treatment with placebo and amitriptyline. 3 Heart rate, pupillary diameter, stimulated salivary flow rate and blood pressure were measured over a 15 h period keeping a very strict protocol. Plasma catecholamine levels were determined. 4 Saliva production was diminished following the administration of C 49802 B-Ba, CGP 12103/A and amitriptyline. 5 A moderate, but significant increase in heart rate and mean arterial blood pressure in the recumbent position was observed when C 49802 B-Ba was given. 6 The results in man are in agreement with the different activities found in animal experiments. 7 It can be concluded that the S (+)-enantiomer which the racemate contains is more active than the R (-)-enantiomer as to the anticholinergic and the sympathomimetic property.

Anticholinergic effects of the tricyclic antidepressant desipramine were studied in 12 outpatients. Objective measurements of salivation and pulse rate and subjective ratings of mouth dryness and palpitations were made before and during treatment with desipramine at a final daily dosage of 150 mg. There were significant changes after 3 wk of treatment in all parameters except ratings of palpitation. Subjects with moderate or high plasma desipramine levels had more suppression of salivation than those with low levels. Changes in salivation and pulse did not correlate, nor did they correlate with subjective reports.

Anticholinergic drugs inhibit a variety of intrapulmonary events related to airflow obstruction. When administered as an inhaled aerosol, approximately 90 percent of ipratropium bromide (as with beta-adrenergic aerosols) can be assumed to be swallowed. Peak pharmacologic effects occur prior to any detectable plasma drug concentrations. Ipratropium does not exhibit the well-known toxic effects of atropine, and doses many times those required for maximum therapeutic benefit do not produce any effects on the eye, urinary bladder, heart rate, or mucociliary function. Ipratropium seems to act primarily on large- and intermediate-size airways; beta-adrenergic agents, on the other hand, appear to act primarily on the smaller airways. The drug is a promising addition to the therapeutic armamentarium, and may be especially useful in certain groups of patients whose condition is less responsive to other agents.

Rolipram, in contrast to the tricyclic antidepressants amitriptyline and imipramine or the acetylcholine receptor antagonist atropine, failed to antagonize the salivation, hypothermia, or tremor caused in mice by the muscarinic receptor agonists pilocarpine or oxotremorine. The absence of anticholinergic activity, the extremely low therapeutic dose, and the novel mechanism of antidepressant action suggest that rolipram may also be a well tolerable antidepressant suitable for the treatment of problematic subpopulations of depressives such as elderly patients.

The effects of three single oral doses (25 mg, 50 mg and 100 mg) of amitriptyline and desipramine, and of placebo, were compared on a range of cholinergic functions (resting pupil diameter, pilocarpine-evoked miosis, baseline-sweating, carbachol-evoked sweating, salivation, heart rate) in eight healthy volunteers. Three measures (pilocarpine-evoked miosis, carbachol-evoked sweating and salivation) reflected the antimuscarinic property of the antidepressants; in two tests (pilocarpine-evoked miosis and salivation) amitriptyline appeared to be more potent than desipramine. Resting pupil diameter was not affected by amitriptyline, whereas desipramine caused mydriasis, indicating that pupil size is not a reliable measure of anticholinergic activity in the case of drugs which also affect adrenergic mechanisms. Baseline-sweating and heart rate were not affected by the antidepressants.

Using a double-blind crossover Latin square design, the authors evaluated the peripheral anticholinergic and central nervous system effects of three dose levels of two tricyclic antidepressants in female volunteers. Results showed that 5 hours after drug administration, desipramine (50 and 100 mg) caused significantly less reduction in salivation than did amitriptyline. Amitriptyline produced more sedation (Clyde Mood Scale) and a greater number of subjective complaints than did desipramine. These results are consistent with anticholinergic profiles from animal experiments and suggest that clinically meaningful differences may exist among tricyclic antidepressants.

Telenzepine is an analogue of pirenzepine with a higher potency and similar selectivity for M1-receptors in animals. In this placebo controlled, double blind, randomised study mean peptone stimulated gastric acid secretion (mean +/- SEM) of 10 male healthy subjects (58 +/- 6 mmol H+/3 h for placebo) was significantly and dose dependently inhibited by oral telenzepine (2 mg: 31 +/- 5, 3 mg: 23 +/- 5, 5 mg: 21 +/- 4 mmol H+/3 h). Telenzepine 3 and 5 mg were significantly stronger than pirenzepine 50 mg orally (37 +/- 8 mmol H+/3 h). Mean percentage acid inhibition was 37% for pirenzepine, and 48, 61, and 64% for 2, 3, and 5 mg telenzepine, respectively. Basal and peptone stimulated gastrin release was unaffected. Mean salivary output per three hours declined moderately from 156 +/- 45 g (placebo) to 136 +/- 45 g with pirenzepine and significantly to 88 +/- 28 g, 95 +/- 39 g and 39 +/- 13 g with telenzepine 2, 3, and 5 mg, respectively. There was a parallel effect on Na+, K+, Ca++ and amylase output in saliva. Near point vision was not altered by either drug. Pulse rates were lowered by both substances. Complaints of dry mouth were more frequent with telenzepine 5 mg. On a molar basis telenzepine proved to be a 25 and 50 times more potent inhibitor of gastric and salivary secretion, respectively.

The effects on memory and psychomotor functions of four antidepressants which differ in sedative and anticholinergic properties were assessed. Amitriptyline (37.5, 70 mg), trazodone (100, 200 mg) viloxazine (100, 200 mg), protriptyline (10, 20 mg) or placebo were administered in a double blind, independent groups design in which 90 subjects participated. Subjects completed a battery of tests before and 2 and 4 h after drug administration. The different antidepressants produced different patterns of effects across tasks. The relatively non-sedating compounds viloxazine and protriptyline produced very similar profiles and did not impair psychomotor or memory functions. In contrast, the two more sedative antidepressants produced global impairments on test of attention, manual motor speed, recording skills and primary memory. Although both amitriptyline and trazodone impaired performance on episodic memory tasks, the effect of amitriptyline was significantly greater and this may reflect specific anticholinergic action over and above global sedative effects.

Anticholinergic properties of oxitropium bromide (Ba 253) were compared with those of atropine and ipratropium bromide (Sch 1000). The metabolites of Ba 253 (Ba 941, BEA 1125), the decomposition product (Ba 250), and the impurity (Ad 187) were also studied. In rat salivary activity, gastric secretion and rabbit gastric-motility, the anticholinergic activities of parenterally administered Ba 253 were 2.3 to 11.8 times and 1 to 2 times stronger than that of atropine and Sch 1000, respectively. The mydriatic and antisecretory actions of Ba 253 (p.o. or i.d.) were 1/7 and 1/47 those of atropine, respectively. In isolated rat stomach, guinea pig gallbladder and ileum, the anticholinergic activity of Ba 253 is similar to that of atropine. Inhalation of Ba 253 aerosol prevented ACh- and histamine-induced cough in guinea pigs, and its potency was 1/5 that of atropine or as the same as that of Sch 1000. In the isolated guinea pig trachea and ileum, the potencies of the anticholinergic activities of Ba 250 and Ad 187 were the same as that of Ba 253, but those of the other metabolites were very weak. These results suggest that the anticholinergic activity of Ba 253 is stronger than that of atropine when parenterally administered, and it cannot distinguish between the subtypes of muscarinic receptors.

The effects of premedication with the anticholinergic drugs atropine, hyoscine and glycopyrronium when administered by oral and i.m. routes have been evaluated in patients undergoing minor surgery and compared with a placebo using a double-dummy double-blind technique. Although the mouths of those patients who received adequate doses of anticholinergic drugs were dry, subjectively and observed, as compared with those who received a placebo, the overall course of anaesthesia did not appear to be different. Of the three drugs atropine seemed to be absorbed best following oral administration. Equally effective oral and i.m. doses of atropine were considered to be 2.0 and 1.0 mg respectively; of hyoscine 1.0 and 0.25--0.5 mg. The appropriate dose of glycopyrronium was 0.2 mg i.m. The routine use of anticholinergic drugs in preanaesthetic medication in minor surgery appears to be unnecessary.

The parotid salivary response to citric acid and cholinergic agonist and antagonist was assessed in normal volunteers. Gustatory stimulation by circulation of citric acid in the mouth evoked reproducible parotid salivary burst. The salivary response to citric acid was minimally affected by anticholinergic drugs. Analysis of citric acid-evoked parotid saliva revealed a linear relationship between saliva and serum lithium concentrations in affectively ill patients treated with lithium only, or with lithium in combination with anticholinergic drugs. We suggest that parotid saliva lithium levels can be used to guide lithium therapy in patients for whom phlebotomy is not practical.

Peripheral anticholinergic activity of single acute doses of three tricyclic antidepressants (amitriptyline 50 mg, desipramine 50 mg, doxepin 100 mg) and placebo was assessed by several physiologic measures in normal male volunteers. Amitriptyline and doxepin produced similar significant depressions in salivary flow and finger sweating compared to placebo, while desipramine produced no change. Supine and standing blood pressures and standing pulse yielded significant differences among the drugs. Measures in at least three areas (salivation, perspiration, and pulse-blood pressure) offer a simple and reliable battery of tests for the peripheral autonomic effects of tricyclic antidepressants.

Six healthy male subjects were randomly given nortriptyline (NT) (25 and 50 mg) and placebo in a double-blind, crossover study. An NT dose of 50 mg (but not 25 mg) clearly reduced saliva flow (P less than 0.05) and was therefore used for comparison with the major and active metabolite of NT, E-10-hydroxynortriptyline (E-10-OH-NT). Equimolar doses of both compounds (and placebo) were randomly given to eight healthy male subjects in another double-blind, crossover study aimed to assess the reduction of saliva flow. NT significantly depressed saliva flow compared with both placebo (P less than 0.01) and E-10-OH-NT (P less than 0.05). By contrast, there was no difference between E-10-OH-NT and placebo. This study confirms previous indications that the anticholinergic effect of E-10-OH-NT is considerably less than that of the parent drug NT.

1. Chlorosyle, a modified asymmetric and somewhat heavier cholinolytic, produces a lower, by its level, paradoxical salivary effect in the human denervated parotid gland than atropine and metacine. 2. When chlorosyle acts in combination with atropine and metacine, the former inhibits the effect of the latter two and only the chlorosyle effect dominates. 3. Using atropine and metacine, which are complete agonists, chlorosyle, in this situation, plays the role of a partial agonist.

Both classical (atropine) and non-traditional (pirenzepine, metacine) antagonists of the muscarinic cholinoreceptors induce, rather than block, an intense and prolonged salivary response in chronically denervated human parotid glands and thus are capable of discriminating between neuronal and aneuronal receptors. Hexamethonium (benzohexonium) a ganglion-blocking agent (0.4 mL, 2.5%) completely inhibits this paradoxical salivation to atropine, benzilylcholine (metacine) and pirenzepine in the chronic preganglionically denervated human parotid gland. The authors discuss the essence of the revealed paradoxical phenomena.

Dualism in the effects of atropine, and metixene upon the denervated human parotid salivary gland is demonstrated by the fact that they suppress pilocarpine secretion while themselves causing an extremely intense and prolonged salivation. A still stronger cholinolytic, chlorosyle, although causing salivation, blocks paradoxical salivation initiated by atropine and metacine. With respect to the latter ligands, chlorosyle acts as a partial agonist. Dualism in the cholinolytics' effect is conditioned by generation, following chronic enervation of the gland, of cholinoreceptor subpopulations of different functional significance and evolutional maturity. Depending on the length of the cholinoreceptor reactive zone, cholinolytics initiate blockade of some receptors and excitement of others.

Rolipram is an antidepressant with a novel mechanism of action: enhanced noradrenaline (first messenger) synthesis and release, and inhibition of cAMP (second messenger) breakdown. This study was aimed at objectively assessing potential anticholinergic effects of rolipram in healthy elderly volunteers by measurement of saliva production and pupil size. Eight male volunteers between 67 and 77 years of age first received in a randomized manner either a single dose of 50 mg amitriptyline or a placebo control. After a minimum washout period of seven days, they then received a multiple dosing regimen of a) 0.75 mg and b) 1.5 mg rolipram given every eight hours over a 5-day period with a two day washout between a) and b). Whereas no changes at all in pupil size could be observed, amitripyline significantly reduced salivary flow. Rolipram however had no effect on saliva production after either single or repeated administration of 0.75 or 1.5 mg. The results are discussed in connection with pharmacokinetic parameters obtained in the study.

Pharmacological experiments with the spasmolytic 4,4-diphenyl-N-isopropyl-cyclohexylamine hydrochloride (pramiverine, Sistalgin) are reported. The anticholinergic and spasmolytic action was tested in vitro on segments of abdominal organs in comparison with atropin, hyoscin-N-butylbromide and Eupaverin. Acetylcholine, arecoline, carbachol and pilocarpine were used as cholinergic agonists. Besides, neostigmine was applied. Pramiverine is distinguished by a strong anticholinergic and a papaverine-like spasmolytic component. In vitro the anticholinergic action of pramiverine on the small intestine (guinea pig, rabbit), gall bladder (guinea pig) and uterus (guinea pig, rat) was equally strong as the effect of atropine, but on the urinary bladder (guinea pig) the effect was 5 times weaker. The anticholinergic effect was also demonstrated in other models: intestinal spasms after neostigmine injection in the guinea pig; hypotensive effect after acetylcholine administration in rabbits, cats and dogs; salivation after pilocarpine administration in rabbits; tremorine test in rats. The gastric secretion in the Shay rat and the gastrointestinal passage were reduced or inhibited by pramiverine. The test substance was also active on oral application.

The effect of graded doses of the new antimuscarinic agent telenzepine on human gastric secretion has been studied in a double-blind placebo-controlled trial in nine healthy volunteers. Over a period of 60 minutes basal acid output as well as acid response to sham feeding was examined. Telenzepine reduced dose-dependently basal acid secretion: This parameter was inhibited with 1 mg by 2%, with 2 mg by 37%, with 3 mg by 53% and with 5 mg by 76%, respectively. The corresponding values for stimulated acid secretion were 16%, 34%, 40% and 57%, respectively. The reduction of basal and stimulated acid secretion was statistically significant (p less than 0.05) following the two larger telenzepine doses. Production of saliva was inhibited by 9%, 21%, 28% and 48%, respectively. The latter reaching statistical significance (p less than 0.05).

Meperidine (20 and 40 mg/kg, IP) did not block the cholinergic effects (tremor, salivation, and tearing) produced by oxotremorine (0.4 mg/kg, SC) in rats, whereas atropine blocked these three effects (10 mg/kg, 2.5 mg/kg and 0.08 mg/kg, respectively.

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.