SEARCH · Search PubMed
Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.
Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.
The effects of pilocarpine on the healthy rabbit corneal endothelium were studied by in vitro perfusion, photography, and electron microscopy. The toxicity of endothelial cells to pilocarpine was doserelated. Photography showed shrinkage of cells exposed to pilocarpine. The most striking ultrastructure changes were margination of nuclear heterochromatin and cytoplasmic vacuolation.
A pilocarpine-containing, polymermembrane unit (Ocusert) was evaluated in 29 patients with open-angle glaucoma. Patients placed the system in the cul-desac once a week; they retained it well and tolerated its continuing use without appreciable difficulty. Intraocular pressure was controlled satisfactorily by the use of systems releasing either 20mug/hr or 40mug/hr of pilocarpine; concomitant medications were used where indicated. Side-effects from the ocular therapeutic system were minimal or absent. An attempt to correlate eyedrop strength required for ocular pressure control with the release rate of the Ocusert system required was generally unsuccessful. All the data on pressure response to the system, however, indicate that it provides control comparable to that achieved with the commonly used pilocarpine eyedrop concentrations.
Eighteen glaucoma patients each received four pilocarpine regimens in random sequence: 1% and 4% eyedrops and 20mug/hr and 40mug/hr ocular therapeutic systems. Unimportant changes in refraction, near vision, and distance vision occurred during the use of either ocular therapeutic system. Miosis with ocular therapeutic systems was almost always less intense and variable than with eyedrops. Refractive changes occurred in 12 patients following 1% pilocarpine and in 16 patients following 4% pilocarpine drops; decreased distance vision occurred in nine patients after 1% drops and in 12 patients after 4% drops. Fewer patients showed decreases in near vision. In all cases, visual effects peaked one half hour after eyedrop instillations and returned gradually toward normal in the next two to three hours. Intraocular pressure levels were within comparable ranges during all four treatments, but the ocular therapeutic systems maintained pressure at a more constant level.
The effect of pilocarpine on aqueous humor flow in the human eye was studied using fluorophotometry. Methods of measuring fluorescent intensity and of calculating aqueous humor flow were used that reduced the problem of uneven mixing of fluorescein, which is observed in the presence of miosis. The rate of aqueous humor flow through the anterior chamber of the placebo-treated eyes was 2.2 +/- 0.35 microL/min and of the pilocarpine, treated eyes was 2.5 +/- 0.47 microL/min. This increase in flow (14%) was statistically significant but too small to be clinically important. Pilocarpine was observed to reduce the anterior chamber volume of these subjects from 204 +/- 26 to 188 +/- 32 microL.
Thirty-five patients participated in a clinical trial of pilocarpine hydrochloride gel applied once daily at 10 PM. Patients tolerated the medication well and there were no untoward side effects. Significant lowering of intraocular pressure was found for 24 hours after administration. The effect 12 hours after administration was greater than 24 hours after administration. Therefore, pilocarpine gel can be endorsed as an effective medication for 24 hours in the vast majority of patients. However, it is incumbent on the prescribing ophthalmologist to measure the IOP at 10 PM at least once after prescribing pilocarpine gel to ensure adequate control of IOP at that time.
Ciliary muscle topography and connective tissue distribution were studied by light microscopy in atropinized, pilocarpinized, or untreated eyes from rhesus monkeys of various ages. With age, the connective tissue ground plate between ciliary muscle and ciliary processes thickens, while there is very little increase in connective tissue within the ciliary muscle. With age, the atropinized muscle becomes shorter and smaller in area while it remains unchanged in width and position. In pilocarpinized eyes, the ciliary muscle is shorter, narrower, smaller in longitudinal and total area (ie, more circular and compact), and positioned more anteriorly than in contralateral atropinized eyes. These contractile responses to pilocarpine diminish with age at a rate similar to that for accommodative decline. According to these topographic findings, physicians seeking the pathophysiologic characteristics of presbyopia, which occurs in humans and rhesus monkeys on a comparable relative time scale, should redirect their attention toward the ciliary muscle.
Refractive error and total outflow facility were determined by Hartinger coincidence refractometry and two-level constant-pressure perfusion, respectively, in 17 rhesus monkeys, aged 5 to 29 years. Maximum accommodative response to corneal (iontophoretic) carbachol hydrochloride, baseline outflow facility, and the facility response to strong but submaximal intracameral doses of pilocarpine hydrochloride all declined with age. The correlation between accommodative response to carbachol and facility response to pilocarpine was slightly stronger than that between age and facility response. Since the ciliary muscle plays a major role in controlling both outflow facility and accommodation, and since histologic and videographic techniques demonstrate an age-related decline in rhesus ciliary muscle excursion induced by topical pilocarpine or electrical stimulation of the Edinger-Westphal nucleus, the present data support the hypothesis that an age-related decline in ciliary muscle mobility is associated, perhaps causally, with an age-related decline in facility and facility responsiveness to cholinergic drugs.
Pilocarpine and placebo tablets were administered for 90 day periods in a double-blind, sequential crossover trial to 12 patients with postradiation xerostomia. Salivary flow was measured by two techniques, symptomatic change and adverse side effects were also recorded. Nine of the 12 patients showed marked improvement by two or more criteria while taking pilocarpine. None of the 12 patients showed meaningful improvement while on placebo. Side effects were minimal and easily controlled. These results show that pilocarpine is effective in relieving the signs and symptoms of postradiation xerostomia.
Fetuses were obtained on the 28th gestational day from pregnant New Zealand white rabbits treated daily, on the 24th through the 27th gestational day, with pilocarpine HCl, 5 mg/kg in saline, or saline alone. Lung fragments from these fetuses were incubated for two hours in medium containing 3H-thymidine. Scintillation autoradiography of 1-micrometer-thick sections of these fetal lungs revealed that the lung tissue from pilocarpine-treated fetuses had significantly lower labelled cell indices for both alveolar epithelial cells and interstitial cells. These results indicate that pilocarpine treatment promotes differentiation of immature cells in the fetal lung at the expense of cell proliferation.
Reorganization of excitatory and inhibitory circuits in the hippocampal formation following seizure-induced neuronal loss has been proposed to underlie the development of chronic seizures in temporal lobe epilepsy (TLE). Here, we investigated whether specific morphological alterations of the GABAergic system can be related to the onset of spontaneous recurrent seizures (SRS) in the rat lithium-pilocarpine model of TLE. Immunohistochemical staining for markers of interneurons and their projections, including parvalbumin (PV), calretinin (CR), calbindin (CB), glutamic acid decarboxylase (GAD), and type 1 GABA transporter (GAT1), was performed in brain sections of rats treated with lithium-pilocarpine and sacrificed after 24 h, during the silent phase (6 and 12 days), or after the onset of SRS (10-18 days after treatment). Semiquantitative analysis revealed a selective loss of interneurons in the stratum oriens of CA1, associated with a reduction of GAT1 staining in the stratum radiatum and stratum oriens. In contrast, interneurons in CA3 were largely preserved, although GAT1 staining was also reduced. These changes occurred within 6 days after treatment and were therefore insufficient to cause SRS. In the dentate gyrus, extensive cell loss occurred in the hilus. The pericellular innervation of granule cells by PV-positive axons was markedly reduced, although the loss of PV-interneurons was only partial. Most strikingly, the density of GABAergic axons, positive for both GAD and GAT1, was dramatically increased in the inner molecular layer. This change emerged during the silent period, but was most marked in animals with SRS. Finally, supernumerary CB-positive neurons were detected in the hilus, selectively in rats with SRS. These findings suggest that alterations of GABAergic circuits occur early after lithium-pilocarpine-induced status epilepticus and contribute to epileptogenesis. In particular, the reorganization of GABAergic axons in the dentate gyrus might contribute to synchronize hyperexcitability induced by the interneuron loss during the silent period, leading to the onset of chronic seizures.
Previous studies demonstrated that the spiny rat Proechimys guyannensis exhibits resistance to experimental epilepsy. Neural activation was studied in the Proechimys hippocampus, using Fos induction, within 24 h after pilocarpine-induced seizures; neurodegenerative events were investigated in parallel, using FluoroJade B histochemistry. These parameters were selected since pilocarpine-induced limbic epilepsy is known to elicit immediate early gene expression and cell loss in the hippocampus of seizure-prone laboratory rodents. At variance with matched experiments in Wistar rats, pilocarpine injection resulted in Proechimys in seizure episodes that, as previously reported, did not develop into status epilepticus. At 3 h and 8 h after seizure onset, Fos immunoreactivity filled the dentate gyrus of both rat species, and was quite marked in pyramidal cells of the Proechimys Ammon's horn. At 24 h, Fos immunoreactivity dropped in the Wistar hippocampus and persisted in Proechimys. At 8 h and 24 h, FluoroJade-stained neurons were very few in the Proechimys hippocampus, whereas they were abundant in that of Wistar rats. Double immunohistochemistry for Fos and parvalbumin, the protein expressed by fast-spiking hippocampal interneurons, indicated that Fos was induced up to 24 h in the vast majority of parvalbumin-containing cells of the Proechimys hippocampus, and in a minority of these cells in the Wistar hippocampus. The findings demonstrate that early postepileptic neurodegeneration is very limited in the Proechimys hippocampus, in which sustained Fos induction persists for several hours. The findings also indicate that Fos induction and persistence may not correlate with seizure intensity and may not be associated with neuronal death. Finally, the data implicate differential mechanisms of interneuron activity in anti-convulsant and pro-convulsant phenomena.
In the study of temporal lobe epilepsy (TLE) the characterization of genes expressed in the hippocampus is of central importance for understanding their roles in epileptogenic mechanisms. Although several large-scale studies on TLE gene expression have been reported, precise assignment of individual genes associated with this syndrome is still debatable. Here we investigated differentially expressed genes by comparison of mRNAs from normal and epileptic rat hippocampus in the pilocarpine model of epilepsy. For this we used a powerful EST sequencing methodology, ORESTES (Open Reading frame Expressed Sequence Tags), which generates sequence datasets enriched for mRNAs open reading frames (ORFs) rather than simple 5' and 3' ends of mRNAs. Analysis of our sequences shows that ORESTES readily enables the identification of epilepsy associated ORFs. PFAM analysis of protein motifs present in our ORESTES epilepsy database revealed diverse important protein family domains, such as cytoskeletal, cell signaling and protein kinase domains, which could be involved in processes underlying epileptogenesis. More importantly, we show that the expression of homer 1a, known to be coupled to mGluR and NMDA synaptic transmission, is associated with pilocarpine induced status epilepticus (SE). The combined use of the pilocarpine model of epilepsy with the ORESTES technique can significantly contribute to the identification of specific genes and proteins related to TLE. This is the first study applying a large-scale method for rapid shotgun sequencing directed to ORFs in epilepsy research.
The mechanism of corneal pilocarpine penetration was studied in the albino rabbit using radiochemical techniques. The apparent rate and extent of pilocarpine accumulation in the aqueous humor and the various cell layers of the cornea were determined for both intact and abraded eyes. For the first time, drug levels were monitored in the epithelium and stroma-endothelium of the intact cornea using a tissue-scraping technique. In addition, a new postinstillation rinsing method was devised to evaluate the rate of corneal uptake. The results demonstrate a dual role for the corneal epithelium, both as a barrier to drug penetration and as a reservoir for drug in the intact cornea. The transcorneal pilocarpine flux is slower than the data appear to indicate, and previous overestimates of the apparent absorption rate constant are due to parallel elimination processes occurring at the absorption site. Pharmacokinetic parameters were determined for each tissue to generate an overall mechanism for corneal permeation.
We recently reported that systemic administration of the anticholinesterase, soman, caused rapid depletion of forebrain norepinephrine (NE) in convulsive but not in nonconvulsive rats. As neurons in nucleus locus coeruleus (LC) provide the bulk of NE innervation to most of the forebrain and the sole source of NE input to the cortex and the olfactory bulb, soman-induced NE depletion was hypothesized to result from activation of LC neurons. This activation was thought to be due to inhibition of acetylcholinesterase by soman, leading to rapid, sustained accumulation of acetylcholine in LC, causing these cells to fire at a high sustained rate. Support for this hypothesis was provided by neurophysiological findings showing that: (i) Systemic administration of soman in anesthetized rats caused a sustained, fivefold increase in the mean firing rate of LC neurons and (ii) microinjections of soman directly into LC caused a similar increase in the firing rate of LC neurons. Soman-induced activation of LC occurred prior to and even in the absence of seizures. As systemic administration of the muscarinic receptor antagonist, scopolamine, rapidly and completely reversed soman-induced activation of LC, it was further hypothesized that activation of LC neurons following soman administration is due to muscarinic receptor stimulation. The rapid release of NE by cholinolytic agents, thus, may play an important role in the initiation and/or maintenance of convulsions. To further test the hypothesis that NE release in soman-intoxicated rats is due to muscarinic activation of LC, we have investigated the effects of the muscarinic receptor agonist, pilocarpine, on NE release and LC discharge. In one set of experiments, rats were injected with a periconvulsive dose of pilocarpine (300 mg/kg, ip); both convulsive and nonconvulsive rats were sacrificed between 1 and 96 h and monoamine levels in the rostral forebrain and olfactory bulb were determined by HPLC with electrochemical detection. NE levels declined substantially only in convulsive rats; forebrain NE levels in convulsive rats rapidly decreased to 50% of control levels at 1 h and to 37% of controls level between 2 and 4 h. The time course and magnitude of these changes were similar to those observed following soman administration in our previous study. Recovery of forebrain NE began at 8 h and was complete by 96 h following pilocarpine administration. Neither dopamine (DA) nor serotonin (5-HT) levels were changed in the forebrain and olfactory bulb of either convulsive or nonconvulsive rats.(ABSTRACT TRUNCATED AT 400 WORDS)
In untreated, fasting animals the cells of the serous demilunes of the sublingual gland incorporate [3H]-leucine at a higher rate than any other of the 5 main cell types of the 3 major salivary glands. The acinar cells of the submandibular and the mucous cells of the sublingual gland show intermediate values, while the cells of the granular ducts of the submandibular and the acini of the parotid gland have a low rate of incorporation. In fasting animals extrusion of newly synthesized protein starts early in the cells of the serous demilunes. It starts between 4 and 7 hrs after [3H]-leucine injection in the acinar cells of the submandibular gland, while the other cell types did not lose substantial amounts of labelled (glyco)protein within 7 hrs. The secretion of protein is stimulated by the cholinergic drug pilocarpine in all but one of the 5 types of salivary gland cells studied. The acinar cells of the submandibular gland react strongly, the granular duct cells less strongly. Still less are the reactions of the acinar cells of the parotid and of the nucous cells of the sublingual gland. The cells of the serous demilunes of the latter appear to be insensible to pilocarpine. The effect of food uptake on secretion does not differ from pilocarpine stimulation, with one exception: the acinar cells of the parotid gland react more strongly on food uptake than on cholenergic stimulation.
The messenger RNAs (mRNAs) for the neurotrophins, brain-derived neurotrophic factor (BDNF), and nerve growth factor (NGF), are upregulated during epileptic seizure activity, as visualized by in situ hybridization techniques. Neurotrophins might be protective against excitotoxic cell stress, and the upregulation during seizures might provide such cell protection. In this study, a high dose of pilocarpine (300 mg/kg) was used to induce long-lasting, limbic motor status epilepticus and a selective pattern of brain damage. The regulation of BDNF, trkB, and NGF mRNA was studied by in situ hybridization at 1, 3, 6, and 24 h after induction of limbic motor status epilepticus. BDNF immunoreactivity was examined with an anti-peptide antibody and the neuropathological process studied in parallel. BDNF mRNA increased in hippocampus, neocortex, piriform cortex, striatum, and thalamus with a maximum at 3-6 h. Hybridization levels increased earlier in the resistant granule and CA1 cells as compared to the vulnerable CA3 neurons. BDNF immunoreactivity was elevated in dentate gyrus at 3-6 h. trkB mRNA increased in the entire hippocampus. NGF mRNA in hippocampus appeared in dentate gyrus at 3-6 h and declined in hilar neurons at 6-24 h. Cell damage was found in the CA3 area, entire basal cortex, and layers II/III of neocortex. Endogenous neurotrophins are upregulated during status epilepticus caused by pilocarpine, which is related to the coupling between neuronal excitation and trophic factor expression. This upregulation of neurotrophic factors may serve endogenous protective effects; however, the excessive levels of neuronal hyperexcitation resulting from pilocarpine seizures lead to cell damage which cannot be prevented by endogenous neurotrophins.
Chronic administration of delta9-tetrahydrocannabinol (THC) for 5--8 weeks at 4 dose levels (2, 10, 20, 50mg/kg/day) or of pilocarpine (12.5, 25 mg/kg/day) for 3 weeks induced mouse-killing in 25--70% of previously "non-killer" rats of the Sprague-Dawley strain. The maximum percent of drug-induced mouse-killing depended on the daily dose and housing conditions, 20mg/kg/day THC and 25 mg/kg/day pilocarpine in single-housed rats being the most effective treatments. Drug-induced mouse-killing appeared to be a form of behavioral pathology, differing from the species-specific predatory response, when it first appeared. Concurrent assessment of locomotor and rearing activities showed dose-dependent depressant effects of THC and pilocarpine without evidence for tolerance. Different dose-dependencies and time courses suggest that changes in motor activities are not directly linked to the appearance of the killing behavior.
Stimulation by pilocarpine led to a marked increase in amylase activity in the submandibular and sublingual glands and serum, and resulted in a considerable depletion of the enzyme in the parotid gland and pancreas of rats. Parotidectomy reduced these pilocarpine effects. It is concluded that amylase released by pilocarpine from the parotid gland but not from the pancreas elevated the enzyme activity in the submandibular and sublingual glands.