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CNS Drug Reviews 2001Eptastigmine (heptyl-physostigmine tartrate) is a carbamate derivative of physostigmine in which the carbamoylmethyl group in position 5 of the side chain has been... (Review)
Review
Eptastigmine (heptyl-physostigmine tartrate) is a carbamate derivative of physostigmine in which the carbamoylmethyl group in position 5 of the side chain has been substituted with a carbamoylheptyl group. In vitro and ex vivo results suggest that eptastigmine has a long-lasting reversible brain cholinesterase (i.e., acetylcholinesterase and butyryl-cholinesterase) inhibitory effect. When administered in vivo to rodents by various routes, eptastigmine inhibits cerebral acetylcholinesterases (AChE) and increases acetylcholine (Ach) brain levels by 2500-3000%, depending on the dose. This effect leads to an improvement in the cerebral blood flow in the ischemic brain, excitatory and inhibitory effects on the gastrointestinal tract and to a protection from acute soman and diisopropylfluorophosphate intoxication. Eptastigmine, by either acute or chronic administration, has been found to have memory enhancing effects in different species of normal, aged and lesioned animals. It also restored to normal the age-related increase of EEG power without affecting spontaneous motor activity. Clinical investigations on more than 1500 patients with Alzheimer's disease demonstrated that eptastigmine significantly improved cognitive performance (as assessed by the cognitive subscale of the Alzheimer's Disease Assessment Scale) as compared with placebo. This improvement was most evident in patients with more severe cognitive impairment at the baseline. The relationship between patient performance and average steady-state AChE inhibition was described by an inverted U-shaped dose-response curve. Pharmacokinetic studies have revealed that after oral administration eptastigmine is rapidly distributed to the tissues and readily enters the CNS, where it can be expected to inhibit AChE for a prolonged period. Eptastigmine is generally well tolerated and the majority of adverse events (cholinergic) were mild to moderate in intensity. However, the adverse hematologic (granulocytopenia) effects reported in two studies have resulted in the suspension of further clinical trials.
Topics: Acetylcholine; Acetylcholinesterase; Activities of Daily Living; Agranulocytosis; Alzheimer Disease; Animals; Behavior, Animal; Biogenic Monoamines; Brain; Cholinesterase Inhibitors; Cognition Disorders; Erythrocytes; Humans; Learning; Memory; Physostigmine; Randomized Controlled Trials as Topic
PubMed: 11830755
DOI: 10.1111/j.1527-3458.2001.tb00205.x -
The British Journal of Ophthalmology Mar 1972
Topics: Adult; Anterior Chamber; Black People; Cataract; Cataract Extraction; Child; Choroid; Ciliary Body; Cornea; Glaucoma; Hemorrhage; Humans; Iris; Lens, Crystalline; Miotics; Punctures; Sclera; Sutures; Visual Acuity
PubMed: 5032769
DOI: 10.1136/bjo.56.3.299 -
The British Journal of Ophthalmology Oct 1992A single case of bilateral congenital mydriasis is described. A review of the literature is presented and possible modes of inheritance are discussed.
A single case of bilateral congenital mydriasis is described. A review of the literature is presented and possible modes of inheritance are discussed.
Topics: Child, Preschool; Developmental Disabilities; Female; Humans; Mydriasis; Pilocarpine; Pupil
PubMed: 1384690
DOI: 10.1136/bjo.76.10.632 -
British Journal of Clinical Pharmacology Dec 19881. Three experiments were conducted to examine whether mydriatic or miotic drugs instilled into one eye have any effect on the diameter of the pupil of the untreated...
1. Three experiments were conducted to examine whether mydriatic or miotic drugs instilled into one eye have any effect on the diameter of the pupil of the untreated fellow eye, in healthy volunteers. 2. In Experiment 1, the effects of four subjects, using photography in an illuminated room to assess pupil diameter. The drug evoked a dose-dependent mydriasis in the index eye which was accompanied by a simultaneous dose-dependent miosis in the fellow eye. 3. In Experiment 2, the same method was used to assess pupil diameter as in Experiment 1. The effects of mydriatic (methoxamine and tyramine) and of miotic (pilocarpine) drugs instilled into the fellow eye, were studied on the sizes of pupillary responses to the same drugs instilled into the index eye. The presence of a mydriatic drug in the fellow eye resulted in a decrease in the size of the mydriatic responses in the index eye. 4. In Experiment 3, the effects of three concentrations of phenylephrine hydrochloride (0.15-0.60 M) and of three concentrations of pilocarpine hydrochloride (0.002-0.008 M), were studied in darkness using an infra-red binocular television pupillometer, in seven subjects. Phenylephrine evoked dose-dependent mydriasis and pilocarpine evoked dose-dependent miosis. The pupillary responses of the index eye were not accompanied by any changes in the diameter of the pupil of the fellow eye. 5. It is concluded that drug-induced mydriasis in the index eye is accompanied by a consensual miosis in the fellow eye.(ABSTRACT TRUNCATED AT 250 WORDS)
Topics: Adolescent; Adult; Dose-Response Relationship, Drug; Female; Humans; Male; Methoxamine; Mitosis; Mydriatics; Phenylephrine; Pilocarpine; Pupil; Time Factors; Tyramine
PubMed: 3242574
DOI: 10.1111/j.1365-2125.1988.tb05307.x -
PloS One 2013Neuronal dysfunction and demise together with a reduction in neurogenesis are cardinal features of Alzheimer's disease (AD) induced by a combination of oxidative stress,...
Neuronal dysfunction and demise together with a reduction in neurogenesis are cardinal features of Alzheimer's disease (AD) induced by a combination of oxidative stress, toxic amyloid-β peptide (Aβ) and a loss of trophic factor support. Amelioration of these was assessed with the Aβ lowering AD experimental drugs (+)-phenserine and (-)-phenserine in neuronal cultures, and actions in mice were evaluated with (+)-phenserine. Both experimental drugs together with the metabolite N1-norphenserine induced neurotrophic actions in human SH-SY5Y cells that were mediated by the protein kinase C (PKC) and extracellular signal-regulated kinases (ERK) pathways, were evident in cells expressing amyloid precursor protein Swedish mutation (APP(SWE)), and retained in the presence of Aβ and oxidative stress challenge. (+)-Phenserine, together with its (-) enantiomer as well as its N1- and N8-norphenserine and N1,N8-bisnorphenserine metabolites, likewise provided neuroprotective activity against oxidative stress and glutamate toxicity via the PKC and ERK pathways. These neurotrophic and neuroprotective actions were evident in primary cultures of subventricular zone (SVZ) neural progenitor cells, whose neurosphere size and survival were augmented by (+)-phenserine. Translation of these effects in vivo was assessed in wild type and AD APPswe transgenic (Tg2576) mice by doublecortin (DCX) immunohistochemical analysis of neurogenesis in the SVZ, which was significantly elevated by 16 day systemic (+)-phenserine treatment, in the presence of a (+)-phenserine-induced elevation in brain- derived neurotrophic factor (BDNF).
Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Animals; Cell Line, Tumor; Cell Proliferation; Dose-Response Relationship, Drug; Doublecortin Protein; Drug Discovery; Gene Expression Regulation; Humans; Mice; Mice, Transgenic; Mutation; Neural Stem Cells; Neurons; Neuroprotective Agents; Oxidative Stress; Peptide Fragments; Physostigmine; Stereoisomerism
PubMed: 23382994
DOI: 10.1371/journal.pone.0054887 -
Investigative Ophthalmology & Visual... Jun 2021Patients that medicate with antidepressants commonly report dryness of eyes. The cause is often attributed to the anticholinergic properties of the drugs. However,...
PURPOSE
Patients that medicate with antidepressants commonly report dryness of eyes. The cause is often attributed to the anticholinergic properties of the drugs. However, regulation of tear production includes a substantial reflex-evoked component and is regulated via distinct centers in the brain. Further, the anticholinergic component varies greatly among antidepressants with different mechanisms of action. In the current study it was wondered if acute administration of antidepressants can disturb production of tears by affecting the afferent and/or central pathway.
METHODS
Tear production was examined in vivo in anesthetized rats in the presence or absence of the tricyclic antidepressant (TCA) clomipramine or the selective serotonin reuptake inhibitor (SSRI) escitalopram. The reflex-evoked production of tears was measured by challenging the surface of the eye with menthol (0.1 mM) and cholinergic regulation was examined by intravenous injection with the nonselective muscarinic agonist methacholine (1-5 µg/kg).
RESULTS
Acute administration of clomipramine significantly attenuated both reflex-evoked and methacholine-induced tear production. However, escitalopram only attenuated reflex-evoked tear production, while methacholine-induced production of tears remained unaffected.
CONCLUSIONS
This study shows that antidepressants with different mechanisms of action can impair tear production by attenuating reflex-evoked signaling. Further, antimuscarinic actions are verified as a likely cause of lacrimal gland hyposecretion in regard to clomipramine but not escitalopram. Future studies on antidepressants with different selectivity profiles and mechanisms of action are required to further elucidate the mechanisms by which antidepressants affect tear production.
Topics: Animals; Antidepressive Agents; Cholinergic Antagonists; Citalopram; Clomipramine; Dry Eye Syndromes; Evoked Potentials, Visual; Lacrimal Apparatus; Methacholine Chloride; Miotics; Rats; Tears
PubMed: 34096973
DOI: 10.1167/iovs.62.7.8 -
Transactions of the American... 1966
Comparative Study
Topics: Adult; Aged; Carbachol; Cataract; Cholinesterase Inhibitors; Echothiophate Iodide; Female; Glaucoma; Humans; Isoflurophate; Male; Middle Aged; Parasympathomimetics; Pilocarpine; Quaternary Ammonium Compounds; Retrospective Studies
PubMed: 6007355
DOI: No ID Found -
American Journal of Physiology. Lung... Oct 2019The transient receptor potential polycystin-2 (TRPP2) is encoded by the gene, and mutation of this gene can cause autosomal dominant polycystic kidney disease (ADPKD)....
The transient receptor potential polycystin-2 (TRPP2) is encoded by the gene, and mutation of this gene can cause autosomal dominant polycystic kidney disease (ADPKD). Some patients with ADPKD experience extrarenal manifestations, including radiologic and clinical bronchiectasis. We hypothesized that TRPP2 may regulate airway smooth muscle (ASM) tension. Thus, we used smooth muscle- conditional knockout () mice to investigate whether TRPP2 regulated ASM tension and whether TRPP2 deficiency contributed to bronchiectasis associated with ADPKD. Compared with wild-type mice, mice breathed more shallowly and faster, and their cross-sectional area ratio of bronchi to accompanying pulmonary arteries was higher, suggesting that TRPP2 may regulate ASM tension and contribute to the occurrence of bronchiectasis in ADPKD. In a bioassay examining isolated tracheal ring tension, no significant difference was found for high-potassium-induced depolarization of the ASM between the two groups, indicating that TRPP2 does not regulate depolarization-induced ASM contraction. By contrast, carbachol-induced contraction of the ASM derived from mice was significantly reduced compared with that in wild-type mice. In addition, relaxation of the carbachol-precontracted ASM by isoprenaline, a β-adrenergic receptor agonist that acts through the cAMP/adenylyl cyclase pathway, was also significantly attenuated in mice compared with that in wild-type mice. Thus, TRPP2 deficiency suppressed both contraction and relaxation of the ASM. These results provide a potential target for regulating ASM tension and for developing therapeutic alternatives for some ADPKD complications of the respiratory system or for independent respiratory disease, especially bronchiectasis.
Topics: Animals; Bronchi; Bronchiectasis; Bronchodilator Agents; Calcium; Carbachol; Disease Models, Animal; Gene Expression Regulation; Isometric Contraction; Isoproterenol; Male; Mice; Mice, Knockout; Miotics; Muscle Tonus; Muscle, Smooth; Polycystic Kidney, Autosomal Dominant; Pulmonary Artery; Respiration; Signal Transduction; TRPP Cation Channels; Trachea
PubMed: 31411061
DOI: 10.1152/ajplung.00513.2018 -
Transactions of the American... 1975Patients with nanophthalmos are prone to develop a chronic painless type of glaucoma in middle age, probably due to the natural increase in the size of the lens which is...
Patients with nanophthalmos are prone to develop a chronic painless type of glaucoma in middle age, probably due to the natural increase in the size of the lens which is already relatively too large for the small eye. Although the underlying mechanism is obscure, a slowly progressive "creeping" chronic angle-closure is postulated, but gonioscopic evaluation is difficult due to the shallow anterior chamber, with grade I and slit angles. Response to medical treatment is poor and miotics may even make the condition worse by producing relative pupillary block and by relaxing the lens zonule. Ordinary glaucoma surgery is to be avoided in nanophthalmos because of the fear of postoperative ciliary-block malignant glaucoma. Periopheral iridectomy performed in five eyes at an advanced stage of the chronic angle-closure did not facilitate glaucoma control in three eyes, and in two eyes in which the operation was combined with posterior sclerotomy, the eyes became blind from vitreous hemorrhage. Lenx extraction in five eyes controlled the glaucoma but was followed by choroidal effusion and nonrhegmatogenous retinal detachements in two eyes and blindness in another eye when combined with a posterior sclerotomy. No firm therapeutic recommendations can be made on the basis of the author's experience in the six reported cases. Conventional medical therapy seems ineffectual even when begun early in the glaucoma. Conventional glaucoma surgery must be performed early, before permanent damage to the outflow mechanism occurs but removal of the lens must be anticipated. The surgeon must also remain aware of the high incidence of serious posterior-segment complications which inexplicably follow glaucoma or lens surgery in nanophthalmos, as described by Brockhurst.
Topics: Adult; Choroid; Eye Diseases; Female; Glaucoma; Hemorrhage; Humans; Intraocular Pressure; Iris; Lens, Crystalline; Male; Microphthalmos; Middle Aged; Pigmentation; Pilocarpine; Postoperative Complications; Retinal Detachment; Vision, Ocular; Vitreous Body
PubMed: 1246819
DOI: No ID Found -
Drug Delivery Dec 2019The objective of this work was to investigate phytantriol-based liquid crystal (LC) gels including cubic (Q) and hexagonal (H) phase for ocular delivery of pilocarpine...
The objective of this work was to investigate phytantriol-based liquid crystal (LC) gels including cubic (Q) and hexagonal (H) phase for ocular delivery of pilocarpine nitrate (PN) to treat glaucoma. The gels were produced by a vortex method and confirmed by crossed polarized light microscopy, small-angle X-ray scattering, and rheological measurements. Moreover, the release behaviors and permeation results of PN from the gels were estimated using studies. Finally, the anti-glaucoma effect of LC gels was evaluated by animal experiments. The inner structure of the gels was Pn3m-type Q and H phase, and both of them showed pseudoplastic fluid properties based on characterization techniques. release profiles suggested that PN could be sustainably released from LC gels within 48 h. Compared with eye drops, Q and H gel produces a 5.25-fold and 6.23-fold increase in the value ( < .05), respectively, leading to a significant enhancement of corneal penetration. Furthermore, a good biocompatibility and longer residence time on precorneal for LC gels confirmed by animal experiment. Pharmacokinetic studies showed that LC gels could maintain PN concentration in aqueous humor for at least 12 h after administration and remarkably improve the bioavailability of drug. Additionally, pharmacodynamics studies indicated that LC gels had a more significant intraocular pressure-lowering and miotic effect compared to eye drops. These research findings hinted that LC gels would be a promising pharmaceutical strategy for ocular application to enhance the efficacy of anti-glaucoma.
Topics: Administration, Ophthalmic; Animals; Aqueous Humor; Biological Availability; Cornea; Drug Delivery Systems; Gels; Glaucoma; Intraocular Pressure; Liquid Crystals; Male; Nanoparticles; Ophthalmic Solutions; Particle Size; Permeability; Pilocarpine; Rabbits
PubMed: 31544551
DOI: 10.1080/10717544.2019.1667451