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Purpose: The aim of this study was to determine the effects of 2% pilocarpine ophthalmic solution on the depth of field and the pupil size of human eye in the presbyopic population., Settings and Design: Prospective experimental study., Methods: The prospective study included 120 presbyopic people aged between 40 and 55. All willing subjects underwent a comprehensive eye examination that included measuring the visual acuity for distance and near, retinoscopy, refraction, anterior and posterior segment examination, depth of field, and pupil size in room illumination. Following a preliminary examination, 2% pilocarpine ophthalmic solution was instilled in both eyes, and after various intervals of 15, 30, and 45 min, the depth of field and the pupil size were measured., Results: Before instillation of 2% pilocarpine solution, the mean pupil size was 0.34 mm with a standard deviation (SD) of ±0.37. After instillation, the mean pupil size changed to 2.20, 1.91, and 1.57 mm with SD of ±0.43, ±0.27, and ±0.34 mm, respectively, in 15, 30, and 45 min time intervals. Initial mean depth of field also changed from 1.76 D (SD ± 0.20) to 1.72, 1.65, and 1.59 D with SD of ±0.20, ±0.16, and ±0.22 D, respectively, in 15, 30, and 45 min time intervals., Conclusion: The study concludes that pupillary miotics create a pinhole effect after the instillation of 2% pilocarpine ophthalmic drop, extending the depth of field. The effect was highly clinically significant at 45 min with a P value <0.001., (Copyright © 2024 Indian Journal of Ophthalmology.)

Activation of the muscarinic M1 receptor is a promising approach to improve cognitive deficits associated with cholinergic dysfunction in Alzheimer's disease, dementia with Lewy bodies, and schizophrenia. TAK-071 is an M1-selective positive allosteric modulator that improves cognitive deficits induced by scopolamine, a non-selective muscarinic receptor antagonist, with reduced side effects on gastrointestinal function in rats. In this study, we explored changes in quantitative electroencephalography (qEEG) power bands, with or without scopolamine challenge, as a non-invasive translational biomarker for the effect of TAK-071 in cynomolgus monkeys. Scopolamine has been reported to increase theta and delta power bands and decrease alpha power band in healthy volunteers. In line with the clinical observations, scopolamine (25-100 μg/kg, subcutaneous administration [s.c.]) increased theta and delta power bands in cynomolgus monkeys in a dose-dependent manner, whereas it had the opposite effect on alpha power band. The effects of TAK-071 on scopolamine (25 μg/kg, s.c.)-induced qEEG spectral changes were examined using an acetylcholinesterase inhibitor donepezil and a muscarinic M1/M4 receptor agonist xanomeline as comparative cholinomimetics. TAK-071 (0.3-3 mg/kg, oral administration [p.o.]), donepezil (3 mg/kg, p.o.), and xanomeline (1 mg/kg, s.c.) suppressed the scopolamine-induced increases in alpha, theta, and delta power bands. These results suggest that changes in specific qEEG power bands, in particular theta and delta power bands in the context of scopolamine challenge, could be used as translational biomarkers for the evaluation of TAK-071 in clinical studies., Competing Interests: We have the following interests. Emi Kurimoto, Masato Nakashima, Haruhide Kimura and Motohisa Suzuki are employed by Takeda Pharmaceutical Company Limited. TAK-071 is currently being clinically evaluated, and there is a patent: WO/2015/163485A1. This does not alter our adherence to all the PLOS ONE policies on sharing data and materials, as detailed online in the guide for authors.

We optically measured effects of orally available ivacaftor (Kalydeco®) on sweat rates of identified glands in 3 R117H subjects, each having a unique set of additional mutations, and compared them with 5 healthy control subjects tested contemporaneously. We injected β-adrenergic agonists intradermally to stimulate CFTR-dependent 'C-sweat' and methacholine to stimulate 'M-sweat', which persists in CF subjects. We focused on an R117H-7T/F508del subject who produced quantifiable C-sweat off ivacaftor and was available for 1 blinded, 3 off ivacaftor, and 3 on ivacaftor tests, allowing us to estimate in vivo fold-increase in sweat rates produced by ivacaftor's effect on the open probability (PO) of R117H-CFTR. Measured sweat rates must be corrected for sweat losses. With estimated sweat losses of 0.023 to 0.08 nl·gland-1·min-1, ivacaftor increased the average C-sweat rates 3-7 fold, and estimated function as % of WT were 4.1-12% off ivacaftor and 21.9-32% on ivacaftor (larger values reflect increased loss estimates). Based on single tests, an R117H-7T/ R117H-7T subject showed 6-9% WT function off ivacaftor and 28-43% on ivacaftor. Repeat testing of an R117H-5T/F508del subject detected only trace responding to ivacaftor. We conclude that in vivo, R117H PO is strongly increased by ivacaftor, but channel number, mainly determined by variable deletion of exon 10, has a marked influence on outcomes.

Unlabelled: Peripheral muscarinic acetylcholine receptors regulate insulin and glucagon release in rodents but their importance for similar roles in humans is unclear. Bethanechol, an acetylcholine analogue that does not cross the blood-brain barrier, was used to examine the role of peripheral muscarinic signaling on glucose homeostasis in humans with normal glucose tolerance (NGT; n = 10), impaired glucose tolerance (IGT; n = 11), and type 2 diabetes mellitus (T2DM; n = 9). Subjects received four liquid meal tolerance tests, each with a different dose of oral bethanechol (0, 50, 100, or 150 mg) given 60 min before a meal containing acetaminophen. Plasma pancreatic polypeptide (PP), glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide-1 (GLP-1), glucose, glucagon, C-peptide, and acetaminophen concentrations were measured. Insulin secretion rates (ISRs) were calculated from C-peptide levels. Acetaminophen and PP concentrations were surrogate markers for gastric emptying and cholinergic input to islets. The 150 mg dose of bethanechol increased the PP response 2-fold only in the IGT group, amplified GLP-1 release in the IGT and T2DM groups, and augmented the GIP response only in the NGT group. However, bethanechol did not alter ISRs or plasma glucose, glucagon, or acetaminophen concentrations in any group. Prior studies showed infusion of xenin-25, an intestinal peptide, delays gastric emptying and reduces GLP-1 release but not ISRs when normalized to plasma glucose levels. Analysis of archived plasma samples from this study showed xenin-25 amplified postprandial PP responses ~4-fold in subjects with NGT, IGT, and T2DM. Thus, increasing postprandial cholinergic input to islets augments insulin secretion in mice but not humans., Trial Registration: ClinicalTrials.gov NCT01434901.

Introduction: Chronic Obstructive Pulmonary Disease (COPD) is one of the top leading causes of death and disability, and its management is focused on reducing risk factors, relieving symptoms, and preventing exacerbations. The study aim was to describe COPD prescribing patterns in Greece by using existing health administrative data for outpatients., Methods: This is a retrospective cross-sectional study based on prescriptions collected by the largest social insurance fund, during the first and last trimester of 2012. Selection criteria were the prescription of specific active substances and a COPD diagnosis. Extracted information included active substance, strength, pharmaceutical form and number of packages prescribed, diagnosis, time of dispensing, as well as insurees' age, gender, percentage of co-payment and social security unique number. Statistical analysis included descriptive statistics and logistic regression., Results: 174,357 patients received medicines for COPD during the study period. Patients were almost equally distributed between male and female, and age above 55 years was strongly correlated with COPD. Most patients received a long-acting beta agonist plus inhaled corticosteroid combination (LABA +ICS), followed by long-acting muscarinic agonist (LAMA). 63% patients belonging in the 35-54 age received LABA+ICS. LAMA was prescribed more frequently among males and was strongly correlated with COPD., Conclusion: The study provides big data analysis of Greek COPD prescribing patterns. It highlights the need for appropriate COPD classification in primary care illustrating the role of electronic prescribing in ensuring appropriate prescribing. Moreover, it indicates possible gender differences in treatment response or disease severity, and the impact of statutory co-payments on prescribing.

As pharmacological data sets become increasingly large and complex, new visual analysis and filtering programs are needed to aid their appreciation. One of the most commonly used methods for visualizing biological data is the Venn diagram. Currently used Venn analysis software often presents multiple problems to biological scientists, in that only a limited number of simultaneous data sets can be analyzed. An improved appreciation of the connectivity between multiple, highly-complex datasets is crucial for the next generation of data analysis of genomic and proteomic data streams. We describe the development of VENNTURE, a program that facilitates visualization of up to six datasets in a user-friendly manner. This program includes versatile output features, where grouped data points can be easily exported into a spreadsheet. To demonstrate its unique experimental utility we applied VENNTURE to a highly complex parallel paradigm, i.e. comparison of multiple G protein-coupled receptor drug dose phosphoproteomic data, in multiple cellular physiological contexts. VENNTURE was able to reliably and simply dissect six complex data sets into easily identifiable groups for straightforward analysis and data output. Applied to complex pharmacological datasets, VENNTURE's improved features and ease of analysis are much improved over currently available Venn diagram programs. VENNTURE enabled the delineation of highly complex patterns of dose-dependent G protein-coupled receptor activity and its dependence on physiological cellular contexts. This study highlights the potential for such a program in fields such as pharmacology, genomics, and bioinformatics.

The mediodorsal nucleus of the thalamus (MD) is a rich source of afferents to the medial prefrontal cortex (mPFC). Dysfunctions in the thalamo-prefrontal connections can impair networks implicated in working memory, some of which are affected in Alzheimer disease and schizophrenia. Considering the importance of the cholinergic system to cortical functioning, our study aimed to investigate the effects of global cholinergic activation of the brain on MD-mPFC synaptic plasticity by measuring the dynamics of long-term potentiation (LTP) and depression (LTD) in vivo. Therefore, rats received intraventricular injections either of the muscarinic agonist pilocarpine (PILO; 40 nmol/µL), the nicotinic agonist nicotine (NIC; 320 nmol/µL), or vehicle. The injections were administered prior to either thalamic high-frequency (HFS) or low-frequency stimulation (LFS). Test pulses were applied to MD for 30 min during baseline and 240 min after HFS or LFS, while field postsynaptic potentials were recorded in the mPFC. The transient oscillatory effects of PILO and NIC were monitored through recording of thalamic and cortical local field potentials. Our results show that HFS did not affect mPFC responses in vehicle-injected rats, but induced a delayed-onset LTP with distinct effects when applied following PILO or NIC. Conversely, LFS induced a stable LTD in control subjects, but was unable to induce LTD when applied after PILO or NIC. Taken together, our findings show distinct modulatory effects of each cholinergic brain activation on MD-mPFC plasticity following HFS and LFS. The LTP-inducing action and long-lasting suppression of cortical LTD induced by PILO and NIC might implicate differential modulation of thalamo-prefrontal functions under low and high input drive.

We investigated the effect of Ninjin-yoei-to (Ren-Shen-Yang-Rong-Tang), a Japanese herbal medicine, and found that 1000 mg/kg p.o. improved the scopolamine-induced impairment of passive avoidance response in mice. Further, the same dose of Ninjin-yoei-to enhanced oxotremorine-induced tremors in mice. The water extract of Polygalae radix, one of the constituent herbs of Ninjin-yoei-to, at a dose of 100 mg/kg significantly improved the scopolamine-induced impairment of passive avoidance response and enhanced oxotremorine-induced tremors in mice. Moreover, the enhancement of oxotremorine-induced tremors by Ninjin-yoei-to (1000 mg/kg) and Polygalae radix (100 mg/kg) was completely antagonized by pretreatment of scopolamine hydrobromide (0.5 mg/kg). These results suggest that Ninjin-yoei-to may improve the scopolamine-induced impairment of passive avoidance response by enhancing the cholinergic system and that Polygalae radix may be involved in the action of Ninjin-yoei-to.

This work investigates pilocarpine trapped in a matrix diffusion-controlled drug delivery system using hydrophilic inserts of Poly(2-hydroxyethyl methacrylate) (pHEMA) to ensure an increased bioavailability of pilocarpine and prolong the length of time in which the medication remains in the eyes of the test subjects. The physical and chemical properties of pilocarpine were investigated to elucidate the mechanism of drug-polymer interaction and the effect on drug release behavior of controlled release polymeric devices. In vitro release studies indicated that pilocarpine continued to be released from the inserts for a 24 h period. The results of intraocular pressure tests performed on albino rabbits were consistent with the observed in vitro behavior. The pressure decrease was significant for a period longer than 48 h. It confirms that the inserts, as sustainable releasing devices, are promising carriers for ophthalmic drug delivery systems.

All the presently available antiglaucoma medications have either local or systemic adverse effects. Combinations of drugs are being used not only to increase the effectivity and compliance but also to decrease the incidence and magnitude of side effects. The single dose response of open angle glaucoma eyes to pilocarpine 1%, clonidine 0.125%, a combination of pilocarpine 1% and clonidine 0.125%, and timolol 0.5% was studied in a double blind, masked, cross over study. Over a period of twelve hours the effectivity of the combination of pilocarpine 1% and clonidine 0.125% was significantly more than that of either drug alone and was found to be similar to that of timolol 0.5%. No local or systemic adverse effects were seen.

Corneal opacities and urinary tract sepsis were previously observed by the authors in rats given muscarinic agonists mixed in the diet or by gavage. To explain the differential toxicity generated by each means of administration, toxicokinetics of the muscarinic agonist CI-979 were investigated. In addition, the muscarinic antagonist scopolamine was co-administered with CI-979 to evaluate the relationship of these effects to pharmacological mechanism of action of CI-979. Female rats were given CI-979 daily by gavage at 0, 1, 10 and 30 mg/kg body weight or in the diet at 0, 1, 10 and 50 mg/kg body weight for up to 14 days. Dose-related clinical signs of muscarinic stimulation, such as sialorrhoea and dacryorrhoea, were observed predominantly in rats given 10 and 30 mg/kg body weight CI-979 by gavage, and corresponded with the high plasma drug concentrations. In contrast, hydronephrosis, pyelonephritis, and inflammation and necrosis of the kidney, urinary bladder, urethra and urinary papilla were linked to sustained, albeit lower plasma drug concentrations attained by dietary administration of CI-979 at 10 and 50 mg/kg body weight. Comparable incidences of corneal opacities were induced by both means of administration, but lesions appeared more rapidly and were generally of greater severity when CI-979 was given in the diet. The induction of corneal lesions, as well as urinary sepsis, may not relate simply to maximum plasma concentrations or to areas under the curve per se, but rather may arise when plasma drug concentrations are sustained. Corneal opacification and development of urinary tract pathology were inhibited by scopolamine, suggesting that these effects were related to the muscarinic mechanism of action of CI-979.