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Pilocarpine (P) is of potential utility in the treatment of xerostomia. Because optimal development of P dosage forms for humans requires that its pharmacokinetics and pharmacodynamics be defined, this intravenous study of its disposition and associated salivary responses was performed. In a hospital setting, two healthy female subjects were given a series of graded doses of intravenous P or placebo to stimulate salivary secretion. Plasma levels of P, heart rate, blood pressure, and respiratory rate were simultaneously monitored. Other objective and subjective physiological parameters were assessed. Plasma concentrations of P declined either mono- or bi-exponentially with time, and brisk initial salivation was followed by prolonged salivation at doses > or = 1 mg. At doses between 0.5 and 3.5 mg, dose-independent pharmacokinetic parameters included a small steady-state volume of distribution (2.4 to 3.0 L/kg), a high plasma clearance (0.026 to 0.03 L/kg/min), and a mean residence time of approximately 100 min. The cumulative volume of whole saliva secreted during the first 3 h post-dose was linearly related to the area under the plasma concentration-time curve. Plasma concentrations from 1 to 42 ng/mL were associated with significant levels of salivation. The pharmacokinetic linearity of the system and proportionality between the area under plasma concentration-time curves and overall salivary response have important implications for the design and utilization of pilocarpine dosage forms.

A minimally-invasive method of quantitative electroencephalography (qEEG) that requires no anesthetics and parallels techniques of naturalistic stimulation was developed and validated for regulatory testing of drugs and chemicals in rats. Male and female Fischer 344 rats were utilized in a randomized-block design to measure qEEG target parameters associated with a range of cholinesterase inhibition. For this study, physostigmine was administered ip at doses of 0.05, 0.2 or 1.0 mg/kg, resulting in average cholinesterase inhibition in plasma (28, 38 and 70%), erythrocytes (19, 24 and 36%), and brain (2, 10 and 31%) which correlated well with increased total power and amplitude changes. Additional treatment-related effects consisted of decreased relative alpha and beta, increased relative delta, and a left-shift in the spectral-edge frequency. In a second study, male and female Sprague-Dawley rats were utilized in a treatment-by-subjects design to determine qEEG target parameter changes due to the M2 autoreceptor agonist oxotremorine. Repeated incremental doses (0.05, 0.1, 0.2 mg/kg; ip) of oxotremorine resulted in increased beta contribution, a right-shift in the spectral-edge frequency and decreased alpha contribution. These qEEG results with physostigmine and oxotremorine correlate well with receptor-specific and general muscarinic effects, making it a reliable contribution to analysis of agonist and antagonist effects of cholinergic compounds.

The influence of slaframine (SF), a parasympathomimetic compound isolated from the fungus Rizoctonia leguminicola, on circulating metabolic hormone concentrations was investigated in goats. In Exp. 1, SF was administered i.v. at 0 (CONT), 50 (LSF), 100 (MSF), or 150 (HSF) microgram/kg.75 BW in four mature Spanish-cross does (average BW 36 +/- 7 kg) fitted with indwelling jugular vein catheters in a 4 x 4 Latin square design. Plasma glucose peaked (P < .06) at 120 min with LSF and at 180 min with HSF and was higher (P <.06) than the CONT at these times. Glucose exhibited a quadratic response (P < .03) to SF. Area under the response curve for glucose differed (P < .02) in HSF from CONT and MSF. Insulin peaked (P < .01) at 240 min with MSF and at 180 min with HSF. Plasma triiodothyronine was maintained at a higher level (P < .03) with HSF. Thyroxine peaked (P < .06) at 120 min with MSF and 300 min with HSF. Plasma NEFA and somatotropin concentrations were not affected (P > .10) by SF. In Exp. 2, four mature Spanish-cross wethers (average BW 27 +/- 2 kg) fitted with jugular vein catheters were administered SF (0 and 114 micrograms/kg.75 BW) and 4-diphenylacetoxy-N-methylpiperidine methiodide (4DAMP; 0 and 258 micrograms/kg.75 BW), a M3-muscarinic receptor antagonist, i.v. in a 4 x 4 Latin square design with a 2 x 2 factorial arrangement of treatments. With SF, glucose peaked (P < .06) at 60 min and insulin peaked (P < .05) at 180 min. Plasma triiodothyronine levels were maintained (P < .05) with SF but declined with other treatments. Plasma NEFA and thyroxine concentrations remained unchanged regardless of treatment. Slaframine administration induced hyperglycemia and hyperinsulinemia in goats; however, these changes were blocked by preadministration of isomolar quantities of the M3-muscarinic receptor antagonist, 4DAMP.

Chemitrodes which permit electrical and chemical stimulation of the same hypothalamic loci were implanted in anterior hypothalamic and preoptic regions. These sites were stimulated electrically using biphasic square wave pulse (1 ms, 60 Hz) at a current strength ranging from 150-800 microA to evoke an aggressive response. At lower current strength of 150-200 micro A, defence response, a sort of non-specific response can be elicited from these regions. Increasing the current strength to 400 microA led to the recruitment of affective and somatic components and changed the response pattern either to affective attack or flight. The loci producing affective attack response were localized more laterally and ventrally while the loci producing flight response were located in the dorsomedial regions of the hypothalamus. In this response the animal made a goal-directed attempt to escape through an escape route. Increasing the current strength to 500 microA in the dorsomedial regions changed the flight response to violent flight, which involved vigorous running with unsheathed claws and attacking objects if obstructed. Similar increase in current strength at loci producing affective attack only led to a decrease in the latency of response and made the attack more vigorous. Microinfusion of carbachol in graded doses of 2-15 microgram at all these loci produced a profound affective display. At lower doses of 2 and 5 microgram, only some components of affective display like alertness, pupillary dilation and ear flatness were exhibited. Increasing the dose to 10 micrograms and 15 micrograms led to the recruitment of other affective components like piloerection, salivation, hissing and baring of teeth. Microinfusion of carbachol at all loci producing affective attack on electrical stimulation produced a prononced affective display while microinfusion of carbachol at loci producing flight response led to the development of defence posture. At six loci a typical flight response was obtained while violent flight was never exhibited at any of these sites. Microinfusion of atropine (10 microgram in 1.0 microliter saline) at these loci completely blocked the carbachol induced response. Both somatomotor and affective components were completely inhibited. However, the responses obtained on electrical stimulation were not totally blocked following atropine infusion and some of the somatomotor and affective components could be elicited with higher current strength. These studies indicate the involvement of cholinoceptive mechanisms in the elicitation of hypothalamically induced aggresive behaviour. Microinfustion of hexamethonium bromide, a nicotinic blocker in 50 micrograms doses did not affect the aggressive response.

Pilocarpine is widely used in the treatment of glaucoma, especially for the acute form of angle-closure glaucoma. Previous studies have shown that pilocarpine decreases central anterior chamber depth. In the present study, a quantitative measurement method, applying Scheimpflug photography, was used to report whether pilocarpine also affected the anterior chamber angles. Twenty-nine normal Chinese subjects, 17 female and 12 male with an age range from 11 to 63 years old, were enrolled. One eye of each subject was treated with one drop of 2% pilocarpine. Photographs of each of four quadrants were taken prior to, and after, pilocarpine treatment in both eyes, using a rotating slit-lamp video camera based on the Scheimpflug principle. The slit beams were set at 0 degrees and 90 degrees. The eyes which did not receive pilocarpine treatment served as control. The angles of the four quadrants were calculated for both eyes both prior to, and after, pilocarpine treatment, and results were compared by Student's paired t-test. The comparison of angles between the eyes prior to, and after, pilocarpine treatment indicated that there is a significant narrowing of angles in all quadrants. The complex factors involved in the change of anterior chamber angle are reviewed in the light of muscarinic action of pilocarpine.

We have previously demonstrated that both pentagastrin and methacholine can stimulate histamine release from the canine stomach during short term administration of the secretagogues into the gastrosplenic artery. In this study we tested the hypothesis that gastric histamine release determines the acid secretory response to acid secretagogues. Increasing doses of pentagastrin (2, 6, and 20 ng/kg/min) and methacholine (0.1, 0.3, and 1 micrograms/min) were infused into the gastrosplenic artery in dogs, while gastric acid output, histamine and N tau-methyl histamine secretory rates were monitored. Histamine and N tau-methyl histamine concentrations in plasma were measured using GC/NICI-MS. Increasing doses of pentagastrin resulted in increasing gastric output. Total histamine secretory rate expressed as the sum of histamine and N tau-methyl histamine secretory rate showed a significant increase above basal with the two highest doses of pentagastrin. Regression analysis correlating the dose of pentagastrin to gastric acid output gave a correlation coefficient of 0.586 which was very significant. Regression analysis correlating the total histamine secretory rate to acid output gave a correlation coefficient of 0.498 which was also very significant. Increasing doses of methacholine also resulted in a dose-dependent increase in acid output. Histamine secretory rates showed a statistically significant increase above basal only at the 1 microgram/min infusion rate, however, the total histamine secretory rates (histamine + N tau-methyl histamine) were no longer significant at any of the doses of methacholine.(ABSTRACT TRUNCATED AT 250 WORDS)

The pilocarpine iontophoresis test (P-test) is used as a predictor of the capacity to produce sweat. Therefore, we studied the reproducibility of this test in 12 normal subjects on 10 consecutive days. Furthermore, we determined whether the P-test reflects whole-body and regional sweat secretion during exercise in the heat. Finally, we determined whether the P-test stimulates the eccrine sweat glands to maximal sweat secretion. Six growth hormone-deficient (GHD) patients who are known to have decreased sweating, and 11 healthy control subjects were studied. To induce maximal sweat secretion, the patients exercised on a bicycle ergometer at a workload corresponding to 40% of their maximal aerobic power (VO2max). The 11 healthy subjects exercised at a workload of 150 W. All subjects exercised for 60 min in ambient air at 35 degrees C, with 50% relative humidity. The P-test showed a mean day-to-day variation of 20.8% between individual subjects. There was a significant positive correlation between the P-test and regional sweat secretion (r2 = 0.74). The correlation coefficient (r2) was 0.50 for the correlation between the P-test and whole-body sweat secretion, and 0.52 for the correlation between regional sweat secretion and whole-body sweat secretion. We conclude that the pilocarpine iontophoresis test reflects heat- and exercise-induced sweating capacity. However, this test does not induce maximal sweating, and it cannot be used as a single reliable predictor of whole-body sweating, due to considerable day-to-day variation.

1. The aim of this study was to find a drug that induces an almost complete degranulation of secretory cells in rat parotid and submandibular glands. 2. Phenylephrine (alpha-adrenergic), isoproterenol (beta-adrenergic) and mecholine (muscarinic cholinergic) were tested. Time and degree of maximal depletion of acinar and granular convoluted tubule cells were determined morphologically. 3. Following phenylephrine-injection (5 mg/kg or 10.2 mg/kg, i.p.), no effect on the acinar granulation level was observed in either of the glands, while about 50-60% granular convoluted tubules were degranulated for at least 120-180 min post-injection. 4. With isoproterenol (5, 10, 40, 70 or 100 mg/kg, i.p.), degranulation of 100% of the acinar cells in the parotid and 80% of the acinar cells in the submandibular gland was observed 90 min post-injection. Granular convoluted tubule cells did not respond to this beta-adrenergic drug. 5. Mecholine (3.75 or 7.5 mg/kg, i.p.) induced mainly degranulation of granular convoluted tubule cells (about 50% after 120 min). Numbers of granulated acinar cells decreased only slightly in both glands (about 10%, 90-120 min). 6. From this study it appears that with a relatively low dosage (5 mg/kg, i.p.) of isoproterenol, a high level of degranulation can be induced in acinar cells of rat parotid and submandibular glands without toxic side effects. Concerning granular convoluted tubules, only moderate degranulation was observed with phenylephrine and mecholine, respectively.

1. The characteristics of muscarinic receptors mediating relaxation and/or contraction in the rat iris dilator muscle were examined. 2. Relaxation was induced in a dilator muscle by application of acetylcholine (ACh) at low doses (3 microM or less) and contraction was induced by high doses. Methacholine and carbachol also showed biphasic effects similar to those of ACh; in contrast, bethanechol, arecoline, pilocarpine and McN-A-343 induced mainly relaxation but no substantial contraction. 3. After parasympathetic denervation by ciliary ganglionectomy, the relaxant response to muscarinic agonists disappeared upon nerve stimulation. Application of McN-A-343 and pilocarpine induced only small contractions in denervated dilator muscles, indicating that these are partial agonists for contraction. 4. pA2 values of pirenzepine, methoctramine, AF-DX 116, himbacine, and 4-DAMP for antagonism to pilocarpine-induced relaxation in normal dilator muscles and those for antagonism to ACh-induced contraction in denervated dilator muscles were determined. The pA2 values for antagonism to relaxation of all these antagonists were most similar to those for M3-type muscarinic receptors. 5. Although pA2 values for contraction of these antagonists, except for methoctramine, were very close to those for relaxation, contraction was not significantly antagonized by methoctramine. Contraction might be mediated by M3-like receptors which have a very low affinity for methoctramine. 6. In conclusion, ACh-induced biphasic responses in rat iris dilator muscles were clearly distinguished from each other by specific muscarinic agonists and parasympathetic denervation, whereas muscarinic receptors could not be subclassified according to the pA2 values of 5 specific antagonists only.

Purpose: The aim of the study was to compare 2 combinations of eye drops containing 2% carteolol and 2% pilocarpine: LCM 1010: ready to use eye drops CBS 341A: eye drops to be reconstituted (freeze-dried powder + solvent)., Methods: Ninety-seven patients with primary open angle glaucoma or simple ocular hypertension were included in a randomized, double-blind multicentric study comparing 2 parallel groups of treatment. Intra-ocular pressure was greater than 21 mmHg with beta-blocker alone. One instillation of 2% carteolol-2% pilocarpine combination was given twice a day for one month. Before and after this treatment, intra-ocular pressure was measured at 9 am (12 hours after evening instillation) and at 11 am (2 hours after morning instillation)., Results: Both treatments reduced intra-ocular pressure by a comparable amount and there was no significant difference between groups at either measure: at 9 am: 2.11 +/- 2.39 mmHg (mean +/- SD) for LCM 1010 1.79 +/- 1.73 mmHg for CBS 341 A p = 0.25 at 11 am: 3.75 +/- 3.83 mmHg for LCM 1010 3.40 +/- 1.69 mmHg for CBS 341 A p = 0.42. Both eye drops were generally well tolerated., Conclusion: Efficacy and safety of ready to use eye drops 2% carteolol-2% pilocarpine combination proved to be comparable to that of eye drops to be reconstituted in the treatment of ocular hypertension poorly controlled by beta-blocker eye drops alone.

Reabsorption of peritoneal dialysis fluid during the prolonged dwell time of continuous ambulatory peritoneal dialysis (CAPD) reduces the efficiency of ultrafiltration and sacrifices effective dialysis adequacy. Studies by Nolph indicate a predominant role of lymphatics in this fluid loss. Khanna has reported that lymphatic flow may be influenced by acetylcholine. This study was designed to determine if bethanechol chloride (BC) would increase the availability of drained volume during CAPD. Nine patients were studied, including 7 patients who exhibited inadequate ultrafiltration. During a 5-day control period, total dialysate drained volume was collected and a standard peritoneal equilibration test (PET) performed. This was followed by a corresponding 5-day test period in which BC (mean dose 0.27 +/- 0.13 mg/kg/day) was administered orally. Drained volume during the control standard 4-hr PET was 1996.68 +/- 279.87 mL. The result for the test period was 2363.33 +/- 321.13 mL (p < 0.05), indicating an 18.4% increase using BC. The PET indicated no change in transport of urea, creatinine, and glucose. In conclusion, the total drained volume can be effectively increased with a subsequent increase in metabolite clearance using BC. Patients exhibiting inadequate ultrafiltration were able to be maintained on CAPD using this cholinergic drug.

We have reported that arecoline, a muscarinic receptor agonist replicably enhanced verbal memory in five of nine subjects with Alzheimer's disease (AD). To investigate the mechanism of cognitive improvement, circulating hormone measurements were made during high-dose acute and low-dose chronic intravenous (i.v.) arecoline administration to AD patients. Acute hormone responses were measured during, and for 6 h after, infusion of arecoline 5 mg i.v. over 30 min. Chronic responses were measured in cognitive responders during continuous i.v. infusion of arecoline escalating over 2 weeks (0.5-40 mg/day) and then during a 1 week infusion of the dose optimizing cognition (4-16 mg/day). Acute arecoline administered to 14 subjects produced unpleasant side-effects (e.g. nausea, vomiting), mean adrenocorticotrophic hormone (p = .0006), cortisol (p = .0001) and beta-endorphin (p = .0001) levels were elevated. During chronic arecoline treatment, no side-effects occurred and plasma cortisol, adrenocorticotrophic hormone and beta-endorphin levels were unchanged in nine subjects overall and in five cognitive responders. Thus, high-dose arecoline activates the hypothalamic-pituitary-adrenal (HPA) axis and may increase other anterior pituitary hormone levels, likely representing a 'stress response', but cognition-enhancing, low doses of arecoline do not produce a glucocorticoid response. Hence, arecoline-induced memory improvement is not due to the induction of 'stress' nor to the elevation of peripheral corticosteroid levels.

Topical echothiophate administration to the cynomolgus monkey eye for 5-6.5 months produced marked subsensitivity of the accommodative response to pilocarpine and a 65% decrease in specific high affinity 3H-QNB binding sites (ostensibly indicating muscarinic receptors) in the ciliary muscle. The decrease in 3H-QNB binding sites was quantitatively similar in surgically untouched, totally iridectomized, and ciliary muscle disinserted eyes. Following a 5-month off treatment recovery period, 3H-QNB binding sites increased to more than twice the number in untreated control eyes. In echothiophate-treated eyes whose contralateral eyes had previously received atropine+echothiophate, 3H-QNB binding sites were three to six times more numerous than in other long-term echothiophate-treated eyes, and one to two times more numerous than in untreated controls. Topical pilocarpine administration for 1 day to 7 months reduced ciliary muscle 3H-QNB binding sites by approximately 25%. Alterations in muscarinic receptors during and following cholinergic drug therapy may in part explain the observed subsensitization and recovery of ciliary muscle physiological responses.