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This study was undertaken to evaluate the safety and efficacy of CSF-1 (0.4% pilocarpine hydrochloride ophthalmic solution) for use in individuals with presbyopia. Two Phase 3 multicenter, randomized, double-masked, vehicle-controlled, parallel-group clinical trials were conducted in 35 private ophthalmology clinics in the United States from October 2020 to February 2022. Key inclusion criteria were the following: (1) age 45–64 years, (2) distance-corrected near visual acuity (DCNVA) at 40 cm ≥0.40 and ≤0.90 logarithm of the minimum angle of resolution (logMAR, approximately 20/50–20/160 Snellen) in at least 1 eye, (3) manifest refraction (MR) between –4.50 and +2.00 diopter (D) sphere in each eye with ≤2.00D difference between eyes, (4) <2.00D of cylinder MR in each eye, (5) ≤0.04 logMAR (20/20–2 or better) corrected distance visual acuity (CDVA) at 4 m in each eye. Key exclusion criteria were the following: (1) >0.14 logMAR (7 letters) improvement in post-vehicle treatment in monocular DCNVA in either eye at visit 1, (2) introcular pressure (IOP) <9 or >22 mm Hg, (3) average dark-adapted pupillometry <3.5 mm in either eye, (4) prior refractive surgery or intraocular lens (IOL) implantation. Participants applied CSF-1 or vehicle twice per day for 2 weeks. Efficacy and safety assessments were performed at several times on days 1, 8, and 15. Response was defined as ≥3-line gain in DCNVA without loss of ≥1-line in CDVA in the study eye under mesopic room lighting conditions. The primary efficacy endpoint was measured 1 hour post-dose 1 on day 8. Key secondary endpoints were 2 hours post-dose 1, and 1 and 2 hours post-dose 2, also on day 8. Safety endpoints were ocular and non-ocular treatment-related adverse events (TRAE), conjunctival redness, drop comfort, slit-lamp biomicroscopy, intraocular pressure, indirect fundoscopy, and CDVA at 4 m. Six hundred thirteen participants were randomized to CSF-1 (n = 309) or vehicle (n = 304). Participants were predominantly White (80.8%) and female (62.0%), with mean age (standard deviation) of 54.7 (4.8). CSF-1 met the primary and key secondary endpoints. At the primary endpoint, 40.1% of the CSF-1 group achieved response versus 19.1% of the vehicle group (P < 0.0001). The percentage of responders was significantly greater in CSF-1 compared with vehicle at all tested times. Changes from baseline in all safety endpoints were comparable between groups. Most adverse events (AEs) were mild and transient. Neither serious nor severe AEs were reported with CSF-1. CSF-1, a low-dose pilocarpine ophthalmic solution, demonstrated superiority to vehicle in improving near vision in individuals with presbyopia without compromising distance vision. CSF-1 demonstrated a favorable safety profile. ClinicalTrials.gov identifier: NCT04599933 (NEAR-1), NCT04599972 (NEAR-2).

The present study was focused on investigating niosomal gels loaded with cholinergic drug; pilocarpine HCl, for prolonged precorneal residence time and improved bioavailability for glaucoma treatment. Pilocarpine HCl niosomes were prepared using various nonionic surfactants (span 20, span 60 and span 80), in the presence of cholesterol in different molar ratios by ether injection method. The selected formulations were incorporated into carbopol 934 and locust bean gum-based gels. TEM analysis confirmed that niosomes formed were spherical in shape and has a definite internal aqueous space with uniform particle size. Formulation F4 composed of span 60 and cholesterol (1:1) gave the highest entrapment (93.26 ± 1.75%) and slower release results after 8 hours (Q8h = 60.35 ± 1.87%) among other formulations. The in-vitro drug permeation studies showed that there was a prolonged release of drug from niosomal gels as compared to niosomes itself. Considering the in-vitro drug release, niosomal gel formulation G2 was the best among the studied formulations. The release data were fitted to an empirical equation, which indicated that the release follows non-Fickian diffusion mechanism. The stability study revealed that incorporation of niosomes in gel increased their stability than the niosome itself. No signs of redness, inflammation, swelling or increased tear production were observed over the study period for tested formulation by Draize's test. The intraocular pressure (IOP) lowering activity of G2 formulation showed relative bioavailability 2.64 times more than bioavailability of marketed Pilopine HS® gel. These results suggest that the niosomal gels containing pilocarpine HCl are promising ocular carriers for glaucoma treatment.

In zootoxinology, drugs such as anesthetics and secretion enhancers are used to increase venom yields, but it is unclear whether this affects the venom composition. After injection of ketamine and pilocarpine into two non-front-fanged snakes, mass spectrometry confirmed the presence of both drugs and their metabolites in the venoms. The quantified high concentrations raise concerns about potential interference in bioassays and pharmacological studies, highlighting the need to consider extraction additives in venom research to ensure unbiased results.

In a recent study, using hydrogen cyanide as paradigm, we have shown that pharmacological knowledge evolves non-linearly ( https://pubmed.ncbi.nlm.nih.gov/38900251/ ). The aim of this study was to investigate the changes in the presentation of the drugs pilocarpine and physostigmine in textbooks from 1878 to 2023. The categories of structure, molecular mechanism of action, pharmacokinetics, effects, indications, adverse drug reactions, interactions, and contraindications were evaluated. The pharmacological knowledge on the molecular mechanism, chemical structure, and pharmacokinetics of pilocarpine and physostigmine changed the most during the period of 150 years. Until 1944, textbooks did not mention a molecular mechanism of action of pilocarpine and from 1951 onwards they described the activation of muscarinic acetylcholine receptors as the molecular basis of pilocarpine’s effect. Until 1944, most textbooks on physostigmine also did not mention the molecular mechanism of action. From 1951 onwards, the reversible inhibition of acetylcholinesterase is mentioned as the mechanism of action of physostigmine. In contrast, in the categories effects , indications , adverse drug reactions , interactions , and contraindications , the detected changes in the pharmacological knowledge presented were comparatively smaller. Older pharmacology textbooks were better than newer ones at discussing changes in knowledge and scientific errors. We noted substantial differences in the presentation of pilocarpine and physostigmine among German and US pharmacology textbooks. We show a decline of the clinical relevance of both drugs and their presentation in pharmacological textbooks with physostigmine being virtually irrelevant. But modern textbooks still discuss physostigmine substantially, fitting to studies on the obsolete drug reserpine ( https://pubmed.ncbi.nlm.nih.gov/38103060/ ). Thus, textbooks often far lag clinical practice. Google Scholar conveys the incorrect impression that physostigmine is clinically more relevant than it is. An exponential decline in prescription numbers is a robust indicator of clinical obsolescence. From our study, we extract nine easily implementable take-home messages for future (pharmacology) textbook authors to ensure that this traditional teaching format will prevail against the competition of allegedly more “modern” teaching media.

Summary Aims The purpose of this study was to assess the safety, tolerability and impact on overactive bladder (OAB) symptoms of a novel combination of tolterodine immediate‐release (IR) 2 mg and delayed‐release pilocarpine 9 mg in patients with OAB. Methods Eligible patients with OAB were randomised to each of three treatments [tolterodine/pilocarpine (2/9 mg), tolterodine IR 2 mg or placebo] twice daily for 4 weeks in a double‐blind, crossover fashion. At the end of the 12‐week, double‐blind treatment period, patients could enter an open‐label extension during which they were re‐randomised to either tolterodine/pilocarpine (3/13.5 mg) twice daily or tolterodine extended‐release 4 mg once daily for 12 weeks. Results A total of 138 patients were randomised to double‐blind medication. Both tolterodine/pilocarpine (2/9) and tolterodine IR 2 mg significantly reduced incontinence episodes and daily micturitions (p < 0.001 vs. placebo), with similar reductions in symptoms observed between active treatment groups. Tolterodine/pilocarpine (2/9) was associated with consistently lower Visual Analogue Scale (VAS) scores for all dry mouth parameters compared with tolterodine alone. Salivary flow over a 3 h period remained fairly constant after tolterodine/pilocarpine (2/9) administration, similar to placebo, but decreased markedly after administration of tolterodine alone. In the extension study, patients receiving tolterodine/pilocarpine (3/13.5) reported comparable dry mouth VAS scores to tolterodine extended‐release alone without additional side effects or loss of efficacy. The combination was well tolerated, and the adverse effects observed were consistent with the known safety profiles of tolterodine and pilocarpine. Conclusions A combination of tolterodine/pilocarpine (2/9) effectively reduced the incidence of dry mouth compared with tolterodine IR alone while maintaining treatment efficacy in OAB.

Status epilepticus (SE) triggers many not yet fully understood pathological changes in the nervous system that can lead to the development of epilepsy. In this work, we studied the effects of SE on the properties of excitatory glutamatergic transmission in the hippocampus in the lithium-pilocarpine model of temporal lobe epilepsy in rats. The studies were performed 1 day (acute phase), 3 and 7 days (latent phase), and 30 to 80 days (chronic phase) after SE. According to RT-qPCR data, expression of the genes coding for the AMPA receptor subunits GluA1 and GluA2 was downregulated in the latent phase, which may lead to the increased proportion of calcium-permeable AMPA receptors that play an essential role in the pathogenesis of many CNS diseases. The efficiency of excitatory synaptic neurotransmission in acute brain slices was decreased in all phases of the model, as determined by recording field responses in the CA1 region of the hippocampus in response to the stimulation of Schaffer collaterals by electric current of different strengths. However, the frequency of spontaneous excitatory postsynaptic potentials increased in the chronic phase, indicating an increased background activity of the glutamatergic system in epilepsy. This was also evidenced by a decrease in the threshold current causing hindlimb extension in the maximal electroshock seizure threshold test in rats with temporal lobe epilepsy compared to the control animals. The results suggest a series of functional changes in the properties of glutamatergic system associated with the epilepsy development and can be used to develop the antiepileptogenic therapy.

Bruch´s membrane (BM) is firmly connected posteriorly to the optic nerve head through the peripapillary choroidal border tissue, and anteriorly through the longitudinal ciliary muscle to the scleral spur. We assessed, whether a difference in the contractile state of the ciliary muscle influences the position of the posterior BM by lifting the posterior BM pole, i.e., induces changes in the subfoveal choroidal thickness (SFCT). Healthy young adult individuals received one drop of cyclopentolate 1% into their right eyes and one drop of pilocarpine 1% into their left eyes. Using optical coherence tomography (OCT), three examiners measured independently SFCT and choroidal thickness in the fundus midperiphery at baseline and 30 min after eye drop instillation. The study included 21 healthy individuals (age:21.9 ± 2.6 years; range:15.7–25.8 years; axial length:24.4 ± 1.2 mm). In the right eyes, SFCT changed by 8.7 ± 34.9 μm (examiner 1), -2.9 ± 18.6 μm (examiner 2), and 10.5 ± 21.8 μm (examiner 3), respectively, and the midperipheral choroidal thickness changed by -10.6 ± 25.9 μm (examiner 1), 0.9 ± 17.5 μm (examiner 2), and 4.2 ± 24.7 μm (examiner 3), respectively, without significant differences between the measurements taken before and after eye drop application (all P  > 0.05). In the left eyes, SFCT changed by 5.8 ± 22.2 μm (examiner 1), 5.5 ± 36.5 μm (examiner 2), and 3.9 ± 29.5 μm (examiner 3), respectively, and the midperipheral choroidal thickness changed by -6.9 ± 47.9 μm (examiner 1), -3.5 ± 28.7 μm (examiner 2), and 16.0 ± 28.2 μm (examiner3), respectively, without significant differences between baseline and study end (all P  > 0.05). Application of cyclopentolate 1% and of pilocarpine 1% did not result in a statistically significant change in choroidal thickness in young healthy adults.

Background Pilocarpus microphyllus , widely known as jaborandi, faces a decline in its natural population due to unsustainable harvesting for pilocarpine extraction, an imidazole alkaloid with significant pharmacological properties. This study presents the first comparative transcriptomic analysis in jaborandi by investigating gene expression across four different tissues (leaflets, rachis, root, and stem) and exploring potential pathways and functions involved in pilocarpine biosynthesis. Results The comparisons involving the root had the highest number of DEGs, including root vs. leaflets, rachis vs. root, and stem vs. root. In contrast, no DEGs were identified in the comparison between stem and leaflets. We observed that the root exhibited the most diverse functional profile, including an abundance of TFs involved in alkaloid biosynthesis. Functional enrichment analysis of root-overexpressed genes revealed associations with cell transport, regulatory processes, and defense responses. In contrast, aerial tissues exhibited enrichment for photosynthesis and oxidative stress response pathways, with antioxidant enzymes highly expressed in the leaflets—the primary site of pilocarpine accumulation in its final form—suggesting a potential link between pilocarpine production and the plant’s antioxidative response. Conclusions The presence of enzymes potentially involved in pilocarpine biosynthesis in both aerial and root tissues supports the idea that its biosynthesis is a multi-tissue process. This study provides important insights into the metabolic pathways for advancing conservation strategies and promoting sustainable management of this species.

Acute seizures after a severe brain insult can often lead to epilepsy and cognitive impairment. Aberrant hippocampal neurogenesis follows the insult but the role of adult-generated neurons in the development of chronic seizures or associated cognitive deficits remains to be determined. Here we show that the ablation of adult neurogenesis before pilocarpine-induced acute seizures in mice leads to a reduction in chronic seizure frequency. We also show that ablation of neurogenesis normalizes epilepsy-associated cognitive deficits. Remarkably, the effect of ablating adult neurogenesis before acute seizures is long lasting as it suppresses chronic seizure frequency for nearly 1 year. These findings establish a key role of neurogenesis in chronic seizure development and associated memory impairment and suggest that targeting aberrant hippocampal neurogenesis may reduce recurrent seizures and restore cognitive function following a pro-epileptic brain insult. Aberrant hippocampal neurogenesis often occurs after acute seizures that produce epilepsy and cognitive impairment but the role of neurogenesis in the development of epilepsy is unclear. Here the authors suppress adult neurogenesis in mice preceding seizures and show that it reduces subsequent chronic seizure frequency and epilepsy-associated cognitive decline.

Purpose To evaluate dynamic changes in ciliary parameters and Implantable Collamer Lens V4C (ICL) (STAAR Surgical) haptic position using mydriatic and miotic agents and their effects on the central and peripheral vault. Methods This study involved 80 eyes from 40 consecutive patients (mean age: 28.05 years; range: 19 to 42 years) examined 3 months after ICL implantation. Patients were randomly assigned to either a mydriasis group or a miosis group. Ultrasound biomicroscopy was used to measure the following parameters at baseline and after pharmacological induction with tropicamide or pilocarpine: ciliary process length (CPL), iris ciliary angle (ICA), final tip point of the ICL haptic (ftICL haptic), central vault (c-vault), mid-peripheral vault (m-vault), and peripheral vault (p-vault). Results In the mydriatic group, the proportion of eyes with all ICL haptics in the ciliary sulcus increased from 70.0% to 77.5% after tropicamide administration, whereas in the miotic group, this proportion decreased from 67.5% to 57.5% after pilocarpine administration. The CPL and ftICL haptic increased significantly in the mydriatic group (all P < .01) but decreased in the miotic group (all P < 0.01). Conversely, the ICA decreased significantly in the mydriatic group and increased in the miotic group (all P < .01). The correlation analysis showed no significant relationship between changes in c-vault, m-vault, and p-vault with alterations in CPL, ICA, and ftICL haptic in both groups. Conclusions Haptic position contributes to the movement of the ICL optical zone during accommodation, but changes in haptic position were not significantly correlated with changes in the vault. [J Refract Surg. 2025;41(1):e22–e28.]