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PubMed1999

The effect of pilocarpine and biperiden on salivary secretion during and after radiotherapy in head and neck cancer patients.

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.

Adult↗
PubMed1984

High-performance liquid chromatographic assay for pilocarpine in aqueous humor.

A high-performance liquid chromatographic assay for pilocarpine has been developed for the determination of pilocarpine in aqueous humor. A structurally similar internal standard is used, and pilocarpine is separated from isopilocarpine under the chromatographic conditions used. A 100-microliter sample is mixed with an aliquot of internal standard at pH 8.3 and extracted with methylene chloride. The extract is evaporated to dryness and the alkaloids are quaternized with p-nitrobenzyl bromide. Following the quaternization, the sample is evaporated to dryness, washed and diluted with a mobile phase--triethylamine mixture and analyzed by high-performance liquid chromatography using a reversed-phase octadecylsilane column with detection at a wavelength of 254 nm. This is a highly sensitive, reproducible and selective assay for measuring pilocarpine at physiological levels in individual aqueous humor samples.

Animals↗
PubMed2001

In situ gelling xyloglucan formulations for sustained release ocular delivery of pilocarpine hydrochloride.

Thermoreversible gels formed in situ by aqueous solutions of an enzyme-degraded xyloglucan polysaccharide were evaluated as sustained release vehicles for the ocular delivery of pilocarpine hydrochloride. In vitro release of pilocarpine from gels formed by warming xyloglucan sols (1.0, 1.5 and 2.0% w/w) to 34 degrees C followed root-time kinetics over a period of 6 h. The miotic responses in rabbit following administration of xyloglucan sols were compared with those from in situ gelling Pluronic F127 sols and from an aqueous buffer solution containing the same drug concentration. Sustained release of pilocarpine was observed with all gels, the duration of miotic response increasing with increase of xyloglucan concentration. The degree of enhancement of miotic response following sustained release of pilocarpine from the 1.5% w/w xyloglucan gel was similar to that from a 25% w/w Pluronic F127 gel.

Animals↗
PubMed1999

Miotic effect and irritation potential of pilocarpine prodrug incorporated into a submicron emulsion vehicle.

Pilocarpine prodrug, O,O'-dipivaloyl(1,2-ethylene) bispilocarpic acid diester, was introduced to a submicron emulsion vehicle in a dose equivalent to 0.5% pilocarpine base, and the formulation was studied in albino rabbits using miotic assay. Compared with pilocarpine HCl 0.5% solution delayed and prolonged miosis was observed after application of the prodrug emulsion. AUC(0-6 h) values for the prodrug emulsion and pilocarpine solution were 9252+/-1345 and 6845+/-1967%xmin, respectively. The prodrug was also administered twice daily for 5 days in the form of aqueous solution or submicron emulsion in order to study ocular irritation. Irritation potential of the prodrug was significantly reduced when submicron emulsion was used as a vehicle.

Animals↗
PubMed2000

Temporal profile of neuronal injury following pilocarpine or kainic acid-induced status epilepticus.

Systemic administration of pilocarpine and kainic acid (KA) has been extensively used to model temporal lobe epilepsy in rats. Here the regional distribution of selectively vulnerable neurons and the temporal evolution of such neuronal injury after status epilepticus (SE) are compared in both models. Using the silver staining technique of Gallyas, argyrophilic neurons were measured on a 0-3 (least-most) scale in 53 different brain areas. Few neurons were silver-stained 2.5 h after kainate-induced SE, but many silver-stained cells could be seen in most neocortical, hippocampal, amygdaloid and hypothalamic structures for pilocarpine group. In general, 8 or 24 h intervals between SE onset and perfusion times yielded the most intense neuronal silver-impregnation. Pilocarpine-induced neuronal silver impregnation was more prominent than that induced by kainate treatment for many areas in cortex, hippocampus, endopiriform nucleus, amygdaloid complex and hypothalamus. On the other hand, in the thalamus, some cortical areas, claustrum, lateral septum and caudoputamen, kainate-induced neuronal silver staining was also prominent, but occurred later than in pilocarpine-treated animals. Neuronal injury was found in almost the same brain areas in both models of SE but with different intensity levels and time course profiles. It was suggested that such differences in the temporal profile of cell damage should be taken into account when searching for neuroprotective agents.

Animals↗
PubMed2006

Pilocarpine hydrochloride for the treatment of xerostomia in patients with Sjögren's syndrome in Taiwan--a double-blind, placebo-controlled trial.

BACKGROUND/PURPOSE: Sjögren's syndrome (SS) is characterized by diminished exocrine secretions with the resultant symptoms of dry mouth and dry eye. As genetic predisposition and ethnicity may alter the effectiveness of drug treatment, evaluation of the efficacy and safety of the secretagogue pilocarpine hydrochloride in the treatment of xerostomia in patients with SS in different populations is needed. METHODS: Forty-four patients with SS were enrolled in this double-blind, placebo-controlled trial. Patients were randomized to receive 5 mg pilocarpine (Salagen) or placebo tablet four times daily for 12 weeks. Global evaluation and subjective responses of patients were assessed by questionnaires with visual analog scales and categorical checkboxes. Saliva production was also measured by modified Saxon's test. RESULTS: Pilocarpine treatment significantly improved global assessment of dry mouth, symptoms associated with dry mouth (mouth comfort, ability to sleep and ability to speak), and saliva production compared to placebo. The drug was well tolerated and the most common adverse effect was sweating (5/23, 21.7%) resulting from the muscarinic agonist action of the drug. No serious drug-related adverse effect was found in this study. CONCLUSION: The results of this study suggest that therapy with 5 mg pilocarpine four times daily is effective, safe and well tolerated for the relief of oral symptoms in patients with SS in Taiwan.

Double-Blind Method↗
PubMed2004

Implementing a bioassay to screen molecules for antiepileptogenic activity: chronic pilocarpine versus subdudral haematoma models.

BACKGROUND: There is a need to discover novel chemical compounds that will inhibit the pathological process of epileptogenesis (i.e. agents that will prevent the long-term formation of an active seizure focus following a brain insult). The goal of this paper is to identify a bioassay of value in drug design when screening new chemical entities as putative antiepileptogenic agents. METHODS: We focused on two models: the pilocarpine chronic seizure model of spontaneous recurrent seizures (SRSs) and a chronic subdural haematoma model of SRSs. Both models were evaluated using more than 20 Sprague-Dawley rats for each model. RESULTS: In the pilocarpine-induced model of SRSs, 80% of animals went on to develop SRSs when the dose of pilocarpine was 380 mg/kg i.p. In 50 animals that developed SRSs, the average number of seizures per 15 days of observation was 3.8 seizures with a range of 2-23 seizures per 15-day period. The chronic subdural model was inefficient in producing SRSs. CONCLUSIONS: A pilocarpine-induced SRS model of epilepsy affords a reliable model of epileptogenesis suitable for evaluating new chemical entities as putative antiepileptogenics.

Animals↗
PubMed2003

Pilocarpine-induced seizures in adult rats: monoamine content and muscarinic and dopaminergic receptor changes in the striatum.

High doses of the muscarinic cholinergic agonist pilocarpine are a useful model for investigation of the essential mechanisms for seizure generation and spread in rodents. Pilocarpine (400 mg/kg; subcutaneously) was administered in 2-month-old female rats, and the content of striatum monoamines and (M(1)+M(2)) muscarinic and D(2) dopaminergic receptors was measured in the acute period. All treated animals showed peripheral cholinergic signs, stereotyped and clonic movements, tremors, seizures and the percentage mortality was approximately 63%. High performance liquid chromatography determinations, performed 24 h later, showed a decrease of striatal levels of dopamine, dihydroxyphenylacetic acid, 4-hydroxy-3-methoxy-phenylacetic acid and 5-hydroxytryptamine. Pilocarpine treatment induced downregulation of (M(1)+M(2)) muscarinic receptors and reduced the dissociation constants of (M(1)+M(2)) muscarinic and D(2) dopaminergic receptors, suggesting that these systems exert opposite effects on the regulation of convulsive activity. These and other important neurochemical changes found in the course of establishment of an epileptic focus can be observed after status epilepticus induced by pilocarpine.

Animals↗
PubMed1992

Muscarinic activity of the thiolactone, lactam, lactol, and thiolactol analogues of pilocarpine and a hypothetical model for the binding of agonists to the m1 receptor.

Pilocarpine isosteres have been synthesized and characterized with regard to their in vitro muscarinic properties. The results indicate that the carbonyl oxygen of the lactone function of pilocarpine is of primary importance for agonist activity with the ether oxygen being of lesser or secondary importance. An X-ray structure determination for the hydrogen O,O'-ditoluoyltartrate salt of thiolactone pilocarpine isostere 2a has been performed. This compound has an unusual pharmacological profile exhibiting M1-agonist selectivity as well ass presynaptic antagonism. As a result this compound is also viewed as having therapeutic potential for Alzheimer's disease. A model for the binding of pilocarpine and other muscarinic agonists to the third transmembrane helix of the human m1 muscarinic receptor has been developed.

Animals↗
PubMed2000

In vivo study of the effect of valpromide and valnoctamide in the pilocarpine rat model of focal epilepsy.

PURPOSE: We evaluated the effectiveness of the commonly used antiepileptic drug sodium valproate (400 mg/kg) and two of its amide derivatives, valpromide and valnoctamide (both 100 mg/kg), in an in vivo rat model of focal epilepsy. Our main interest was to get insight into possible changes in extracellular amino acid neurotransmitter levels following administration of the drugs, both in control and in epileptic conditions. METHODS: Seizures were evoked in freely moving rats by intrahippocampal administration of pilocarpine via a microdialysis probe (10 mM for 40 min at 2 microl/min). Microdialysis was also used as in vivo sampling technique and alterations in extracellular hippocampal glutamate and GABA levels were monitored. Electrophysiological evidence for the presence or absence of seizures was simultaneously recorded with electrocorticography. RESULTS: The focally evoked pilocarpine-induced seizures were completely prevented by acute intraperitoneal pretreatment with each of the three drugs in the respective doses. Effective protection was reflected in the electrocorticographic recordings and in the lack of sustained elevations of the extracellular glutamate levels after pilocarpine perfusion. Little effects were seen on the basal extracellular amino acid levels after systemic administration of each of the compounds, nor after the intrahippocampal administration of sodium valproate. CONCLUSIONS: Valnoctamide and valpromide (100 mg/kg) proved to be at least as effective as their parent compound sodium valproate (400 mg/kg) against pilocarpine-induced seizures. All three compounds however failed to induce significant initial alterations in extracellular hippocampal GABA release. This questions the enhancement of GABA-mediated inhibition as being one of their mechanisms of action.

Amides↗
PubMed1993

Controlled delivery of pilocarpine. 1. In vitro characterization of Gelfoam matrices.

The potential of Gelfoam absorbable gelatin sponge as a carrier for ophthalmic delivery of pilocarpine was examined. Prolonged in vitro release of pilocarpine was achieved through pharmaceutical modification of the device by embedding a retardant in the pores. The device embedded with cetyl ester wax released pilocarpine in a zero-order pattern (release exponent = 0.93 +/- 0.04) for up to 5 hr. This result corresponded well with a linear penetrant uptake by this device. The device impregnated with polyethylene glycol 400 monostearate exhibited anomalous drug transport with a release exponent of 0.63 +/- 0.02. The absorption of water by this retardant and the formation of a gel layer on the surface slowed the penetration of the release medium into the deeper sections of the matrix, as well as the rapid outward diffusion of drug, resulting in a prolonged release of pilocarpine.

Chromatography, High Pressure Liquid↗
PubMed1998

The effect of phenylephrine and pilocarpine on pupil size and aqueous flare intensity in patients with diabetes mellitus.

PURPOSE: The aqueous flare intensity and pupillary size were studied before and after instillation of 10% phenylephrine and 4% pilocarpine in eyes with diabetes mellitus (DM). METHODS: Twenty-three patients with DM type I were compared with 30 age-matched controls, and 25 patients with DM type II were compared with 30 age-matched controls. Patients with DM were divided into two groups: 1) with mild-moderate nonproliferative diabetic retinopathy (NPDR), and 2) with advanced diabetic retinopathy (DR) which includes moderate-severe, severe NPDR and proliferative DR. The aqueous flare intensity and the horizontal diameter of the pupil were measured before and 60 minutes after topical instillation of 10% phenylephrine and 60 min after topical administration of 4% pilocarpine. RESULTS: Degree of induced mydriasis after phenylephrine instillation was not significantly different between diabetic groups and controls. Significantly less pronounced miosis was observed after stimulation of cholinergic receptors by pilocarpine in eyes with mild-moderate NPDR with DM type II and in eyes with advanced DR with DM type I and type II when compared to controls (p<0.05). Phenylephrine decreased flare intensity in all groups without a significant difference between groups. Pilocarpine instillation increased flare intensity in all groups as compared to flare intensity before any treatment. Also, a significantly smaller increase in flare intensity in eyes with advanced retinopathy in both DM type I and type II was found when compared to controls (p<0.05). CONCLUSION: Pharmacological response to cholinergic stimulation on pupil size and flare intensity is weaker in advanced stages of DR.

Administration, Topical↗
PubMed1976

Interactions of amygdala lesions with effects of pilocarpine and d-amphetamine on mouse killing, feeding, and drinking in rats.

Repeated injections of 7.5 mg/kg pilocarpine induced mouse killing in both amygdala-lesioned and sham-operated rats, but more injections were required in the lesioned animals. Killing was evoked least readily in rats that showed substantial weight loss after surgery and that had damage to more medial regions of the amygdala. d-Amphetamine (.75, 1.50, or 3.00 mg/kg), administered either before or after a killing test, inhibited pilocarpine-induced killing in both surgical groups. Amygdala lesions attenuated pilocarpine-facilitated drinking in sated animals but did not alter the inhibitory effects of either pilocarpine or d-amphetamine on feeding or drinking.

Aggression↗
PubMed1993

Pilocarpine drops do not reduce intraocular pressure sufficiently in pseudoexfoliation glaucoma.

The reason for the poorer prognosis of pseudoexfoliation syndrome glaucomas (PXSG) compared with primary open angle glaucomas (POAG) is not fully understood. An open, comparative, cross-over study was performed in 15 patients (= eyes) with POAG and 15 patients (= eyes) with PXSG. Two different pharmacokinetic principles of drug administration were applied to uncover possible differences in short-term (hours) response to topical antiglaucomatous treatment. Intermittent pilocarpine drop medication (2%) and continuous low-dose pilocarpine delivery by a membrane-controlled Ocusert unit (P40) were used. The 'carry-over' pressure reduction of an ordinary four times a day drop medication was significantly less effective in controlling the morning intraocular pressure (9 a.m.) in PXSG than in POAG. The duration of action of pilocarpine drops was reduced in PXSG. Defining 'normotensive' pressure as < or = 20 mmHg, only 1 of the 15 PXSG eyes (6.7%) reached a normotensive level in the morning, compared with 8 of the 15 POAG eyes (53.3%). Using a continuous supply of pilocarpine (Ocusert), no differences between POAG and PXSG eyes were found. The study demonstrates the insufficient control of intraocular pressure in PXSG, compared with POAG, by identical antiglaucomatous drop medications. This may suggest an insufficient depot function of topical drugs in PXSG. In consequence, pseudoexfoliation material (PXM) must be sought in eyes with glaucoma, as PXM eyes will probably benefit from a more intense medical treatment compared with eyes without PXM.

Adult↗
PubMed2005

Randomized controlled trial of pilocarpine hydrochloride for the moderation of oral mucositis during autologous blood stem cell transplantation.

Pilocarpine hydrochloride has been reported to increase salivation and decrease oral mucositis in patients receiving head and neck radiotherapy, but there is only one report of its use in a cancer chemotherapy patient population. This prospective, double-blinded, randomized, placebo-controlled trial was undertaken to determine the efficacy of pilocarpine for the moderation of oral mucositis during autologous blood stem cell transplantation. Subjects were randomized to receive a 5 mg tablet of pilocarpine, or a placebo, during and following chemotherapy. Subjects were seen every other day and evaluated for gingival, oral, and oropharyngeal mucositis; nutrition; oral hygiene; eating; speaking; sleeping; pain at rest and/or with swallowing; and mouth dryness. We recorded the mean and highest scores and duration of problems, along with white blood cell counts and differentials, and the use of systemic narcotics for oral mucosal pain. We enrolled and randomized 36 subjects, and there were no statistically or clinically significant differences for the primary outcome of severity of mucositis and no clinically significant differences in any of the other outcome measures. Pilocarpine has no benefit for the moderation of the incidence, severity, or duration of mucositis in patients receiving autologous blood stem cell transplantation.

Adult↗
PubMed2002

The role of muscarinic acetylcholine receptor-mediated activation of extracellular signal-regulated kinase 1/2 in pilocarpine-induced seizures.

Pilocarpine-induced seizures are mediated by the M(1) subtype of muscarinic acetylcholine receptor (mAChR), but little is known about the signaling mechanisms linking the receptor to seizures. The extracellular signal-regulated kinase (ERK) signaling cascade is activated by M(1) mAChR and is elevated during status epilepticus. Yet, the role of ERK activation prior to seizure has not been evaluated. Here, we examine the role of pilocarpine-induced ERK activation in the induction of seizures in mice by pharmacological and behavioral approaches. We show that pilocarpine induces ERK activation prior to the induction of seizures by both western blot and immunocytochemistry with an antibody to phosphorylated ERK. In addition, we show that the ERK pathway inhibitor SL327 effectively blocks the pilocarpine-induced ERK activation. However, SL327 pretreatment has no effect on the initiation of seizures. In fact, animals treated with SL327 had higher seizure-related mortality than vehicle-treated animals, suggesting activated ERK may serve a protective role during seizures. In addition, ERK inhibition had no effect on the development of the long-term sequelae of status epilepticus (SE), including mossy fiber sprouting, neuronal death and spontaneous recurrent seizures.

Aminoacetonitrile↗
PubMed2002

Effectiveness of muscimol-containing microparticles against pilocarpine-induced focal seizures.

PURPOSE: To investigate the efficacy of in situ lipid-protein-sugar particles (LPSPs) in mitigating the epileptogenic and histologic effects of intrahippocampal pilocarpine in rats. METHODS: LPSPs with and without muscimol were produced by spray-drying, sized by Coulter counter, and muscimol content determined by high-pressure liquid chromatography (HLPC). Particles, free muscimol or saline, were injected into the hippocampi of Sprague-Dawley rats before 40 mM pilocarpine, and seizure activity was scored. The trajectories of behavioral scores between groups were compared with two-way repeated measures analysis of variance. Animals were killed after 2 weeks. Brain sections were stained (Timm and thionin) and scored. RESULTS: LPSPs were 4 to 5 microm in diameter, and contained 0 or 2% (wt/wt) muscimol. In vitro, muscimol was released over a 5-day period. Intrahippocampal injections of normal saline and blank LPSPs did not deter seizure activity from pilocarpine. The rise of the trajectory in behavior scores in animals given LPSPs containing 5 microg muscimol was significantly slower than in those receiving saline, blank particles, or 5 microg of unencapsulated muscimol. There was less apparent neuronal injury and CA3 and supragranular mossy fiber sprouting in hippocampi of animals receiving muscimol-containing particles than in animals that did not receive muscimol. Hippocampi of animals that received 5 microg of encapsulated muscimol showed less supragranular sprouting than did those receiving 5 microg of unencapsulated muscimol, but showed no difference in cell loss or CA3 sprouting. CONCLUSIONS: Focally delivered biodegradable microparticles loaded with muscimol are effective in reducing seizure activity from pilocarpine in animals and mitigate the histologic effects.

Animals↗
PubMed2003

Long-term pregabalin treatment protects basal cortices and delays the occurrence of spontaneous seizures in the lithium-pilocarpine model in the rat.

PURPOSE: To determine whether a pharmacologic treatment could delay or prevent the epileptogenesis induced by status epilepticus (SE) through the protection of some brain areas, we studied the effects of the long-term exposure to pregabalin (PGB) on neuronal damage and epileptogenesis induced by lithium-pilocarpine SE. METHODS: SE was induced in adult and 21-day-old (P21) rats. At 20 min after pilocarpine, rats received 50 mg/kg PGB (pilo-preg) or saline (pilo-saline). PGB treatment was given daily at the dose of 50 mg/kg for 7 days after SE and at 10 mg/kg from day 8 until killing. Neuronal damage was assessed in hippocampus and piriform and entorhinal cortices in brain sections stained with thionine and obtained from adult and P21 animals killed 6 days after SE. The number of glial fibrillary acidic protein (GFAP)-reactive astrocytes was tested by immunohistochemistry in sections adjacent to those used for cell counting. The latency to spontaneous seizures was controlled by visual observation and EEG recording. RESULTS: PGB induced neuroprotection in layer II of piriform cortex and layers III-IV of ventral entorhinal cortex of adult rats, whereas no hippocampal region was protected. In P21 rats, damage was limited to the hilus and similar in pilo-preg and pilo-saline animals. The number of GFAP-positive astrocytes was higher in pilocarpine- than in saline-treated rats. It was decreased in pilo-preg compared with pilo-saline rats in layer II of the piriform cortex. Adult pilo-preg rats became epileptic after a longer latency (39 days) than did pilo-saline rats (22 days). CONCLUSIONS: These data underline the antiepileptogenic consequences of long-term PGB treatment, possibly mediated by the protection of piriform and entorhinal cortices in the lithium-pilocarpine model of epilepsy.

Animals↗