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PubMed1990

Decomposition of pilocarpine eye drops assessed by a highly efficient high pressure liquid chromatographic method.

A rapid high-resolution high pressure liquid chromatographic method was developed for assaying pilocarpine. Pilocarpine in ophthalmic solutions decomposes fairly rapidly to give isopilocarpine, pilocarpic acid and isopilocarpic acid. The quality of an ophthalmic solution can be assessed by assaying these decomposition products. Existing high pressure liquid chromatographic methods suffer from long analysis times and poor resolution. The new method uses as the mobile phase 6 ml/l of triethylamine in water (pH 2.3, adjusted with 85% phosphoric acid) at a flow of 1.5 ml/min and as the stationary phase a C18-silica 125 x 4.6 mm column. 2-Amino-1-phenyl-1,3-propanediol is used as an internal standard. Complete separation was obtained within 8 min. Pilocarpine eye drops were stored under different conditions and then analysed for decomposition products. During heat treatment, decomposition to isopilocarpine predominated over decomposition to pilocarpic or isopilocarpic acid. However, when stored at room temperature or in a refrigerator, formation of pilocarpic acid clearly prevailed. Thus, from assessment of decomposition products, the cause of decomposition can be established.

Chromatography, High Pressure Liquid↗

PubMed1983

Prolonged pulse-entry of pilocarpine with a soluble drug insert.

Apparent biophase availability of pilocarpine was studied in the eyes of albino rabbits. Pilocarpine doses of 0.85 and 2.30 mg in aqueous solutions, 1.00 mg in oil and 0.85 mg in a solid insert, were applied ocularly. The insert was a water soluble polyvinylpyrrolidone (PVP) matrix, which released 80% of its pilocarpine content in 35 min in vitro. In the inferior fornix of the eye this insert gelled in about 5 min and dissolved in 1 h. Pupillary diameters were measured and converted to values for the response parameter (RP). Time delay and magnitude of peak response, apparent biophasic availability (area under the curve of RP vs time), and a constant for the apparent rate of elimination were calculated from RP values. The time delay for the peak response was 16.l3-24.0 min, and the constant for apparent rate of elimination was 0.69-0.81 h-1. Neither time delay nor this constant was affected by the dose or the dosage form. Magnitude of the peak response and apparent biophasic availability were influenced by the vehicle and the dose: insert (0.85 mg) greater than oily solution (1.00 mg) greater than aqueous solution (2.30 mg) greater than aqueous solution (0.85 mg). The insert and oily solution did not show vehicle-controlled drug absorption and can be regarded as prolonged pulse-entry medication.

Animals↗

PubMed2007

Effects of levetiracetam in lipid peroxidation level, nitrite-nitrate formation and antioxidant enzymatic activity in mice brain after pilocarpine-induced seizures.

: Oxidative stress has been implicated in a large number of human degenerative diseases, including epilepsy. Levetiracetam (LEV) is a new antiepileptic agent with broad-spectrum effects on seizures and animal models of epilepsy. Recently, it was demonstrated that the mechanism of LEV differs from that of conventional antiepileptic drugs. Objectifying to investigate if LEV mechanism of action involves antioxidant properties, lipid peroxidation levels, nitrite-nitrate formation, catalase activity, and glutathione (GSH) content were measured in adult mice brain. The neurochemical analyses were carried out in hippocampus of animals pretreated with LEV (200 mg/kg, i.p.) 60 min before pilocarpine-induced seizures (400 mg/kg, s.c.). The administration of alone pilocarpine, 400 mg/kg, s.c. (P400) produced a significant increase of lipid peroxidation level in hippocampus. LEV pretreatment was able to counteract this increase, preserving the lipid peroxidation level in normal value. P400 administration also produced increase in the nitrite-nitrate formation and catalase activity in hippocampus, beyond a decrease in GSH levels. LEV administration before P400 prevented the P400-induced alteration in nitrite-nitrate levels and preserved normal values of catalase activity in hippocampus. Moreover, LEV administration prevented the P400-induced loss of GSH in this cerebral area. The present data suggest that the protective effects of LEV against pilocarpine-induced seizures can be mediated, at least in part, by reduction of lipid peroxidation and hippocampal oxidative stress.

Animals↗

PubMed1976

Subsensitivity to pilocarpine of the aqueous outflow system in monkey eyes after topical anticholinesterase treatment.

Cynomolgus and vervet monkeys were treated unilaterally with topical echothiophate iodide twice daily for eight to 25 weeks. The effect of intracameral pilocarpine on outflow facility was determined in the ganglionic-blocked animal during and after echothiophate treatment. The echothiophate-treated eyes demonstrated marked subsensitivity to pilocarpine, and required several weeks to months to recover normal pilocarpine sensitivity.

Administration, Topical↗

PubMed1979

Transcorneal flux of topical pilocarpine to the human aqueous.

Aqueous fluid was withdrawn from eyes of patients undergoing cataract extraction at various intervals after administration of two drops of 2% pilocarpine HCl in a standard manner. Determination of aqueous pilocarpine concentration was made both by spectroscopy of a ferric hydroxylamine complex and by gas-liquid chromatography. Results of both methods were consistent in indicating that concentration does not rise at any time following such topical instillation beyond 5 microgram/ml, with an average of 1.67 microgram/ml, representing a flux efficiency of 0.03%. These findings correlate well with previous investigations of transcorneal flux of pilocarpine for the rabbit in a transport chamber system, in which comparable low flux efficiency was found after simulated drop administration. This serves in some measure to validate an extrapolation of other findings in chamber experiments to the living human eye.

Administration, Topical↗

PubMed1993

The cholinergic REM sleep induction test with pilocarpine in mildly depressed patients and normal controls.

Previous studies suggested that depressed patients enter rapid-eye movement (REM) sleep more quickly than normal controls following the administration of muscarinic agonists such as arecoline or RS 86. We recently reported that pilocarpine, an orally active muscarinic agonist, induced REM sleep and reduced Stage 3 & 4 (Delta) sleep in young normal volunteers. In this study we present preliminary evidence that pilocarpine had similar effects on REM latency, REM percentage, and Delta (Stages 3 & 4) sleep percentage in depressed patients and controls. Pilocarpine, however, decreased stage-4 sleep in controls more than in depressed patients. Because this group of patients were only mildly depressed at the time of the study, had a high frequency of comorbid substance abuse diagnoses, and had normal electroencephalogram (EEG) sleep patterns under placebo conditions, further studies are necessary to test the hypothesis that depressed patients show hypersensitive cholinergic REM sleep induction.

Adult↗

PubMed1993

Effects of chronic nicotine and pilocarpine administration on neocortical neuronal density and [3H]GABA uptake in nucleus basalis lesioned rats.

We investigated the possible long-term neuroprotective roles of (-)nicotine and muscarinic agonist, pilocarpine, in the neocortices of rats receiving bilateral nucleus basalis lesions. Ibotenic acid-lesioned animals eventually displayed a 15-20% reduction in the density of neocortical Nissl staining neurons in layers II, III and VI, as well as a 27% loss in high-affinity GABA uptake 8 months post-lesioning. Deficits were not observed at earlier intervals. (-)Nicotine (0.2 mg/kg, i.p.) or (-)nicotine plus pilocarpine (1 mg/kg, i.p.) attenuated these losses when administered once daily to rats from 5-8 months post-lesioning. Pilocarpine alone had no protective effect on neuronal density or GABA uptake. These results suggest that nicotine receptor activation may counteract neocortical neuronal loss/atrophy following loss of ascending basal forebrain neurons.

Animals↗

PubMed1976

The influence of delta9-tetrahydrocannabinol on pilocarpine-induced parotid secretions of the rat.

The effects of delta9-THC and its ethanol vehicle on pilocarpine-induced parotid gland secretions were investigated in rats. Single doses of delta9-THC (1, 2.5, 5 and 10 mg/kg) or 95% ethanol were administered i.v. prior to pilocarpine stimulation of saliva. Total flow, alpha-amylase and cation content of the induced saliva were determined at the end of the collection period; while heart rate and blood pressure were monitored throughout each experiment. The ethanol vehicle did not alter any of the parameters when compared to the pilocarpine controls. delta9-THC produced a bradycardia and hypotension which was not dose related in spontaneously breathing rats. Furthermore delta9-THC caused an increase in alpha-amylase concentration without a reduction in salivary flow. The results suggest that delta9-THC exerts a profound influence on the protein composition of parotid secretion which is independent of its cardiovascular effects and its ethanol vehicle.

Amylases↗

PubMed1976

Tolerance to hexobarbital and supersensitivity to pilocarpine after chronic barbital treatments in the rat.

Tolerance and physical dependence induced by chronic treatments with depressant drugs has been proposed as being due to denervation or disuse supersensitivity in the central nervous system. To illustrate this hypothesis, tolerance to barbiturates and the sensitivity to central cholinergic stimulation were recorded in the same male rats. Tolerance to barbiturates was recorded with a hexobarbital threshold. The dose needed to obtain an EEG criterion was measured. Sensitivity in central cholinergic structures was recorded by a temperature threshold method. A subthreshold dose of pilocarpine (3.5 mg/kg) was given s.c. together with 1.0 mg/kg methylscopolamine i.p. An increase in sensitivity to pilocarpine was recorded as a decrease in body temperature. In the abstinence period after 42 weeks of oral treatment with barbital, tolerance was recorded with the hexobarbital threshold method. The tolerance had two peaks, one after the end of the treatment and one approximately 3 weeks later. An increased sensitivity to pilocarpine was also recorded in the abstinence period. It had the same biphasic time pattern as the tolerance. Cholinergic neurones are thus probably involved in the changes induced by chronic barbital treatment. The denervation supersensitivity hypothesis of tolerance was not refuted by the present experiments.

Animals↗

PubMed1987

Pilocarpine-induced purposeless chewing behaviour in rats is dependent on intact central stores of 5-HT.

Pilocarpine-induced purposeless chewing behaviour in rats was partially antagonised by pretreatment with reserpine, tetrabenazine or p-chlorophenylalanine (PCPA). In contrast, pretreatment with alpha-methyl-p-tyrosine (AMPT) had no effect on pilocarpine-induced chewing. These data suggest that enhancement of purposeless chewing by pilocarpine is dependent, in part, on intact central stores of 5-HT.

Animals↗

PubMed1996

Regional changes in brain dopamine utilization during status epilepticus in the rat induced by systemic pilocarpine and intrahippocampal carbachol.

Systemic administration of pilocarpine (400 mg/kg i.p.) or intrahippocampal injection of carbachol (100 micrograms/1 microliters) induced limbic motor seizures in rats, characterized by head weaving and paw treading, rearing and falling, and forepaw myoclonus, developing into status epilepticus. After being in status for 30 min, rats were killed and levels of dopamine, dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) were determined in eight brain regions by high performance liquid chromatography. Pilocarpine-induced seizures significantly elevated dopamine in the striatum, and in both dorsal and ventral aspects of the hippocampus, but did not affect dopamine in substantia nigra, nucleus accumbens, olfactory tubercle, cingulate cortex or amygdala. Metabolite levels were increased in striatum, substantia, nigra, nucleus accumbens and cingulate cortex, and fell in the hippocampus, but remained unchanged in the olfactory tubercle and amygdala. Intrahippocampal carbachol significantly raised the dopamine contents of striatum and nigra, and in both ventral and dorsal aspects of the hippocampus, but not elsewhere. DOPAC and/or HVA were elevated in all brain regions tested, save for amygdala and dorsal hippocampus. These changes translated into seizure-induced increases in dopamine utilization in the nucleus accumbens, olfactory tubercle and cingulate cortex, and to a fall in dopamine utilisation in the hippocampus, with no net change in amygdala. In addition pilocarpine (but not carbachol) increased dopamine utilization in the nigrostriatal axis, possibly through a seizure-unrelated mechanism. The relevance of these findings to seizure development are discussed.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1988

Characteristics of limbic seizures evoked by peripheral injections of lithium and pilocarpine.

The characteristics and consequences of limbic seizures evoked by single peripheral injections of lithium (3 mEq/kg) and pilocarpine (30 mg/kg) were investigated over a three-year period. The seizures occurred when 3 mEq/kg of lithium was followed 4 to 28 hours later by 30 mg/kg of pilocarpine. The seizures did not occur if the intervals were shorter or longer or if the pilocarpine preceded the lithium. The acute mortality or persistent aphagia and adipsia could be compensated by postseizure injections of acepromazine and a special milk-bread diet. Gender, age and preinjection environmental effects, but not hybrid genetics, influenced the seizure onset latency. Fifty to 100 days after the seizures massive lesions were found in the entorhinal-pyriform cortices, amygdala and selected thalamic groups.

Animals↗

PubMed1976

Drinking induced by parenteral injections of pilocarpine.

Parenteral (IP) injections of pilocarpine, in doses from 3.75 - 30 mg/kg, reliably produced drinking in water-satiated rats. This effect was not diminished by pretreatment with either centrally active (scopolaime, atropine) or peripherally active (methyl scopolamine, methyl atropine) cholinergic blocking agents, suggesting that pilocarpine does not induce drinking via a cholingergic meachnism. Repated injections of low doses, but not high doses, of pilocarpine augments drinking over trials.

Animals↗

PubMed1994

The new competitive NMDA receptor antagonist CGP 40116 inhibits pilocarpine-induced limbic motor seizures and unconditioned motor behaviour in the mouse.

The biologically active enantiomer (CGP 40116) of the new competitive N-methyl-D-aspartate (NMDA) receptor antagonist CGP 37849 was investigated for its effects on pilocarpine-induced limbic motor seizures and unconditioned motor behaviour in the mouse. CGP 40116 (1-8 mg/kg IP) reduced the incidence and severity of pilocarpine-induced motor seizures, although the overall effect was weak. In contrast to the noncompetitive NMDA antagonist MK 801, there were no signs of CGP 40116 producing a proconvulsant response in this model. In the nonhabituated mouse, MK 801 promoted hyperlocomotion at low doses and hypolocomotion and ataxia at high doses, while CGP 40116 dose-dependently suppressed motor behaviour. Because CGP 40116 and MK 801 exert opposite effects on the seizure threshold to pilocarpine and differentially alter species-typical behaviours in the mouse, it is suggested that different populations of NMDA receptors may mediate their effects. The indivisibility of seizure suppression and motor impairment noted previously with noncompetitive NMDA antagonists such as MK 801 appears also to apply to the new generation competitive NMDA antagonist CGP 40116.

2-Amino-5-phosphonovalerate↗

PubMed1995

Atropine increases pilocarpine-induced yawning behavior in paradoxical sleep deprived rats.

Paradoxical sleep (PS) deprivation has been suggested to induce supersensitivity of postsynaptic dopamine (DA) receptors and subsensitivity of acetylcholine (ACh) receptors. Yawning behavior is reduced after PS deprivation and is believed to result from an interaction between ACh and DA systems. Concomitant treatment of PS deprived animals with DA agonists reverses PS deprivation effects on stereotypy and aggressiveness. To examine this possibility on yawning behavior, rats were treated, during the deprivation period, with atropine, methamphetamine, haloperidol or distilled water. Following PS deprivation, rats were injected with apomorphine or pilocarpine and number of yawns was recorded. Atropine increased yawning of PS deprived rats induced by pilocarpine, but not by apomorphine. Treatment with methamphetamine and haloperidol did not change PS deprivation effect on pilocarpine- and apomorphine-induced yawning. The data suggest that reversal of PS deprivation-induced yawning inhibition is mediated distinctly by both acetylcholine and dopamine systems.

Animals↗

PubMed1983

Limbic seizures produced by pilocarpine in rats: behavioural, electroencephalographic and neuropathological study.

Behavioural, electroencephalographic and neuropathological responses to increasing doses of pilocarpine (100-400 mg/kg) administered intraperitoneally to rats were studied. At the dose of 400 mg/kg pilocarpine produced a sequence of behavioural alterations including staring spells, olfactory and gustatory automatisms and motor limbic seizures that developed over 1-2 h and built up progressively into limbic status epilepticus. Smaller doses showed different threshold for these behavioural phenomena but a similar time course of development. The earliest electrographic alterations occurred in the hippocampus and then epileptiform activity propagated to amygdala and cortex. Subsequently electrographic seizures appeared in both limbic and cortical leads. The ictal periods recurred each 5-15 min and were followed by variable periods of depression of the electrographic activity. The sequence of electrographic changes correlated well with the development of behavioural phenomena. Histological examination of frontal forebrain sections revealed disseminated, apparently seizure-mediated pattern of brain damage. Neuropathological alterations were observed in the olfactory cortex, amygdaloid complex, thalamus, neocortex, hippocampal formation and substantia nigra. Pretreatment of animals with scopolamine (20 mg/kg) and diazepam (10 mg/kg) prevented the development of convulsive activity and brain damage. These results show that systemic pilocarpine in rats selectively elaborates epileptiform activity in the limbic structures accompanied by motor limbic seizures, limbic status epilepticus and widespread brain damage. It is suggested that a causative relationship between excessive stimulation of cholinergic receptors in the brain and epileptic brain damage may exist.

Animals↗

PubMed1989

The role of the central serotonergic system in pilocarpine-induced seizures: receptor mechanisms.

Modification of central serotonergic transmission resulted in alterations of pilocarpine convulsive activity in male Wistar rats. Seizure activity was increased after pizotifen injection and the latency period to onset of convulsions was shortened in animals pretreated with mianserine and quipazine. Stimulation of 5-HT1A receptors with 8-hydroxy-di-N,N-propylaminotetralin (8-OH-DPAT) and blockade of 5-HT1B receptors with cyanopindolol resulted in seizure protection. Intracerebroventricular injections of 5,6-dihydroxytryptamine (5,6-DHT) did not change the protective effect of cyanopindolol. Other agents specifically affecting serotonergic receptors, the agonists 1-(3-chlorophenyl)piperazine (mCPP) and 5-methoxytryptamine (5-MT) and the antagonists spiperone, metergoline, methysergide, cyproheptadine and metoclopramide, did not influence pilocarpine-induced seizures. In conclusion, the present study suggests that the inhibition of pilocarpine-induced seizures may be mediated by stimulation of 5-HT1A and by blockade of 5-HT1B receptors, located probably on the cholinergic terminals.

8-Hydroxy-2-(di-n-propylamino)tetralin↗

PubMedDate not supplied

Na+K+ ATPase activity in the rat hippocampus: a study in the pilocarpine model of epilepsy.

Biochemical abnormalities have been implicated in possible mechanisms underlying the epileptic phenomena. Some of these alterations include changes in the activity of several enzymes present in epileptic tissues. Systemic administration of pilocarpine in rats induces electrographic and behavioral limbic seizures and status epilepticus, that is followed by a transient seizure-free period (silent period). Finally a chronic phase ensues, characterized by spontaneous and recurrent seizures (chronic period), that last for the rest of the animal's life. The present work aimed to study the activity of the enzyme Na+K+ ATPase, in rat hippocampus, during the three phases of this epilepsy model. The enzyme activity was determined at different time points from pilocarpine administration (1 and 24 h of status epilepticus, during the silent and chronic period) using a spectrophotometric assay previously described by Mishra and Delivoria-Papadopoulos [Neurochem. Res. (1988) 13, 765-770]. The results showed decreased enzyme activities during the acute and silent periods and increased Na+K+ ATPase activity during the chronic phase. These data show that changes in Na+K+ ATPase activity could be involved in the appearance of spontaneous and recurrent seizures following brain damage induced by pilocarpine injection.

Animals↗