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Ophthalmic Surgery, Lasers & Imaging... May 2024We describe an in-office lens repositioning technique for anterior crystalline lens dislocation.
BACKGROUND AND OBJECTIVE
We describe an in-office lens repositioning technique for anterior crystalline lens dislocation.
PATIENTS AND METHODS
We present a case series of four patients with spontaneous or traumatic anterior crystalline lens dislocation.
RESULTS
The technique included supine patient positioning, gentle pressure with a cotton swab on the peripheral cornea to guide the lens into the posterior chamber, and the use of a miotic agent afterward to prevent subsequent subluxation. In the four cases described, the in-office technique successfully restored the lens to the posterior chamber, improved vision, and decreased intraocular pressure in most instances by resolving the angle closure secondary to pupillary block.
CONCLUSIONS
The in-office lens repositioning technique is appropriate as an acute non-surgical intervention or temporizing measure for anterior crystalline lens dislocation. .
Topics: Humans; Lens Subluxation; Male; Lens, Crystalline; Female; Adult; Middle Aged; Visual Acuity; Ambulatory Surgical Procedures; Ophthalmologic Surgical Procedures
PubMed: 38270569
DOI: 10.3928/23258160-20240116-01 -
Journal of Basic and Clinical... Jan 2024How gaseous signalling molecules affect ion transport processes contributing to the physiological functions of the gastrointestinal tract under hypoxic conditions still...
OBJECTIVES
How gaseous signalling molecules affect ion transport processes contributing to the physiological functions of the gastrointestinal tract under hypoxic conditions still needs to be clarified. The objective of the present study was to characterize the impact of gaseous signalling molecules on parameters of colonic ion transport during a hypoxia/reoxygenation cycle and the remaining secretory capacity of the epithelium after such a cycle.
METHODS
Short-circuit current (I) and tissue conductance (G) recordings in Ussing chamber experiments were performed on rat colon samples using CORM-2 (putative CO donor; 35 and 350 µM), sodium nitroprusside (NO donor; 100 µM), NaHS (fast HS donor; 10 - 1,000 µM), GYY 4137 (slow HS donor; 50 µM) and Angeli's salt (HNO donor; 100 µM) as donors for gasotransmitters. Inhibition of endogenous synthesis of HS was operated by inhibitors of cystathionin-γ-lyase, i.e. dl-propargylglycine (1 mM) or β-cyano-l-alanine (5 mM), and the inhibitor of cystathionine-β-synthase, amino-oxyacetate (5 mM).
RESULTS
The fast gasotransmitter donors NaHS, sodium nitroprusside and Angeli's salt, administered 5 min before the onset of hypoxia, induced an increase in I. The response to the subsequently applied hypoxia was characterized by a decrease in I, which tended to be reduced only in the presence of the lowest concentration of NaHS (10 µM) tested. Reoxygenation resulted in a slow increase in I, which was unaffected by all donors or inhibitors tested. The stable acetylcholine derivative carbachol (50 µM) was administered at the end of each hypoxia/reoxygenation cycle to test the secretory capacity of the epithelium. Pretreatment of the tissue with the putative CO donor CORM-2 suppressed the secretory response induced by carbachol. The same was observed when cystathionin-γ-lyase and cystathionin-γ-synthase were inhibited simultaneously. Under both conditions, G drastically increased suggesting an impaired tissue integrity.
CONCLUSIONS
The present results demonstrate that none of the exogenous gasotransmitter releasing drugs significantly ameliorated the changes in epithelial ion transport during the hypoxia/reoxygenation cycle ex vivo. In contrast, the putative CO donor CORM-2 exerted a toxic effect on the epithelium. The endogenous production of HS, however, seems to have a protective effect on the mucosal integrity and the epithelial transport functions, which - when inhibited - leads to a loss of the secretory ability of the mucosa. This observation together with the trend for improvement observed with a low concentration of the HS donor NaHS suggests a moderate protective role of low concentrations of HS under hypoxic conditions.
Topics: Rats; Animals; Gasotransmitters; Hydrogen Sulfide; Nitroprusside; Carbachol; Hypoxia; Ion Transport; Lyases; Nitrites; Organometallic Compounds; Sulfides
PubMed: 38263911
DOI: 10.1515/jbcpp-2023-0034 -
BMC Complementary Medicine and Therapies Jan 2024The continuous evolution of drug-resistant influenza viruses highlights the necessity for repurposing naturally-derived and safe phytochemicals with anti-influenza...
Anti-rheumatic colchicine phytochemical exhibits potent antiviral activities against avian and seasonal Influenza A viruses (IAVs) via targeting different stages of IAV replication cycle.
BACKGROUND
The continuous evolution of drug-resistant influenza viruses highlights the necessity for repurposing naturally-derived and safe phytochemicals with anti-influenza activity as novel broad-spectrum anti-influenza medications.
METHODS
In this study, nitrogenous alkaloids were tested for their viral inhibitory activity against influenza A/H1N1 and A/H5N1 viruses. The cytotoxicity of tested alkaloids on MDCK showed a high safety range (CC > 200 µg/ml), permitting the screening for their anti-influenza potential.
RESULTS
Herein, atropine sulphate, pilocarpine hydrochloride and colchicine displayed anti-H5N1 activities with IC values of 2.300, 0.210 and 0.111 µg/ml, respectively. Validation of the IC values was further depicted by testing the three highly effective alkaloids, based on their potent IC values against seasonal influenza A/H1N1 virus, showing comparable IC values of 0.204, 0.637 and 0.326 µg/ml, respectively. Further investigation suggests that colchicine could suppress viral infection by primarily interfering with IAV replication and inhibiting viral adsorption, while atropine sulphate and pilocarpine hydrochloride could directly affect the virus in a cell-free virucidal effect. Interestingly, the in silico molecular docking studies suggest the abilities of atropine, pilocarpine, and colchicine to bind correctly inside the active sites of the neuraminidases of both influenza A/H1N1 and A/H5N1 viruses. The three alkaloids exhibited good binding energies as well as excellent binding modes that were similar to the co-crystallized ligands. On the other hand, consistent with in vitro results, only colchicine could bind correctly against the M2-proton channel of influenza A viruses (IAVs). This might explicate the in vitro antiviral activity of colchicine at the replication stage of the virus replication cycle.
CONCLUSION
This study highlighted the anti-influenza efficacy of biologically active alkaloids including colchicine. Therefore, these alkaloids should be further characterized in vivo (preclinical and clinical studies) to be developed as anti-IAV agents.
Topics: Humans; Colchicine; Influenza A virus; Influenza A Virus, H5N1 Subtype; Pilocarpine; Influenza A Virus, H1N1 Subtype; Influenza, Human; Molecular Docking Simulation; Seasons; Phytochemicals; Atropine; Antiviral Agents
PubMed: 38254071
DOI: 10.1186/s12906-023-04303-2 -
Archives of Disease in Childhood Mar 2024To verify the rate and predictors of 'quantity not sufficient' (QNS) among Brazilian infants younger than 3 months with positive newborn screening (NBS) for cystic...
OBJECTIVE
To verify the rate and predictors of 'quantity not sufficient' (QNS) among Brazilian infants younger than 3 months with positive newborn screening (NBS) for cystic fibrosis (CF).
DESIGN
Prospective, population-based study.
SETTING
Public Statewide Newborn Screening Programme where the incidence rate of CF is ≈1:11 000.
PATIENTS
Subjects with positive two-tiered immunoreactive trypsinogen.
INTERVENTIONS
Sweat induction and collection were performed in the same facility; one sweat sample was obtained per individual.
MAIN OUTCOME MEASURES
The QNS rate and its predictors; analysis corresponded to the day of sweat collection.
RESULTS
Among the 975 participants, QNS rates for 10 and 15 µL were 3.6% (95% CI 2.5% to 4.9%) and 8.3% (95% CI 6.6% to 10.2%). Infants weighing >3056 and >3845 g and with gestational age higher than 37 weeks had a greater likelihood (5.5 and 6.7, and 2.7 and 5.8 times more, respectively) of avoiding QNS than their peers.
CONCLUSION
QNS rates fulfilled the requirements, but predictors differed from those recommended by the Cystic Fibrosis Foundations guidelines.
Topics: Infant, Newborn; Infant; Humans; Pilocarpine; Cystic Fibrosis; Iontophoresis; Sweat; Prospective Studies; Neonatal Screening; Trypsinogen; Cystic Fibrosis Transmembrane Conductance Regulator; Chlorides
PubMed: 38253430
DOI: 10.1136/archdischild-2023-326487 -
Neuroscience Letters Feb 2024Cholinergic innervation of the hippocampus correlates with memory formation. In a well-established animal model of type 1 diabetes mellitus, obtained by injecting young...
Cholinergic innervation of the hippocampus correlates with memory formation. In a well-established animal model of type 1 diabetes mellitus, obtained by injecting young adult rats with streptozotocin (STZ), reductions have been reported in the expression of acetylcholine receptors and choline acetyltransferase. In this study, we showed that long-term synaptic depression (LTD) induced by carbachol (CCh), a nonselective cholinergic receptor agonist, at Schaffer collateral-CA1 synapses in hippocampal slices was significantly weaker in streptozotocin-induced diabetic rats (STZ rats) than in age-matched control rats. No significant change was observed in the paired-pulse ratio between before and 80 min after the application of CCh in control and STZ rats. Moreover, CCh-induced LTD in control and STZ rats was not affected by an NMDA receptor antagonist. Although the application of CCh down-regulated the surface expression of GluA2 in the hippocampus of control rats, but not STZ rats. Therefore, the present results suggest that acetylcholine receptor-mediated LTD in STZ rats requires the internalization of AMPA receptors on the postsynaptic surface and their intracellular effects in the hippocampus.
Topics: Rats; Animals; Streptozocin; Acetylcholine; Diabetes Mellitus, Experimental; Receptors, Cholinergic; Depression; Hippocampus; Synapses; Long-Term Synaptic Depression; Carbachol; Long-Term Potentiation
PubMed: 38253285
DOI: 10.1016/j.neulet.2024.137650 -
International Journal of Medical... 2024Our aim was to evaluate the effect of prophylactic pilocarpine on acute salivary symptoms after radioactive iodine (RAI) therapy in patients with differentiated thyroid...
Our aim was to evaluate the effect of prophylactic pilocarpine on acute salivary symptoms after radioactive iodine (RAI) therapy in patients with differentiated thyroid cancer. We enrolled 88 patients (76 women and 12 men; mean age: 47 years; range: 20-74 years) with differentiated thyroid cancer who received RAI. Patients were divided into pilocarpine (51 patients) and control (37 patients) groups. Pilocarpine was given orally, at a dose of 5 mg three times a day, from 2 days before and 12 days after RAI therapy. Symptoms and signs of acute sialadenitis within 3 months of RAI therapy were recorded. During the 3 months after RAI therapy, 13 of the 88 patients (14.7%) developed acute symptomatic sialadenitis (swelling or pain of salivary glands). Acute salivary symptoms were reported by 4 (7.8%) and 9 (24.3%) patients in the pilocarpine and control groups, respectively. Acute salivary symptoms were less frequent in the pilocarpine than control group ( = 0.04), but did not differ by age, sex, or RAI dose ( = 0.3357, = 0.428, and = 0.2792). Pilocarpine reduced the likelihood of acute sialadenitis after RAI therapy in patients with differentiated thyroid cancer.
Topics: Male; Humans; Female; Middle Aged; Thyroid Neoplasms; Iodine Radioisotopes; Pilocarpine; Sialadenitis; Acute Disease; Adenocarcinoma
PubMed: 38250604
DOI: 10.7150/ijms.84590 -
Acta Physiologica (Oxford, England) Mar 2024Inositol 1,4,5-trisphosphate receptors (IP Rs) are intracellular Ca -release channels with crucial roles in cell function. Current IP R inhibitors suffer from off-target...
AIM
Inositol 1,4,5-trisphosphate receptors (IP Rs) are intracellular Ca -release channels with crucial roles in cell function. Current IP R inhibitors suffer from off-target effects and poor selectivity towards the three distinct IP R subtypes. We developed a novel peptide inhibitor of IP Rs and determined its effect on connexin-43 (Cx43) hemichannels, which are co-activated by IP R stimulation.
METHODS
IP3RPEP6 was developed by in silico molecular docking studies and characterized by on-nucleus patch-clamp experiments of IP R2 channels and carbachol-induced IP -mediated Ca responses in IP R1, 2 or 3 expressing cells, triple IP R KO cells and astrocytes. Cx43 hemichannels were studied by patch-clamp and ATP-release approaches, and by inhibition with Gap19 peptide. IP3RPEP6 interactions with IP Rs were verified by co-immunoprecipitation and affinity pull-down assays.
RESULTS
IP3RPEP6 concentration-dependently reduced the open probability of IP R2 channels and competitively inhibited IP Rs in an IC order of IP R2 (~3.9 μM) < IP R3 (~4.3 μM) < IP R1 (~9.0 μM), without affecting Cx43 hemichannels or ryanodine receptors. IP3RPEP6 co-immunoprecipitated with IP R2 but not with IP R1; interaction with IP R3 varied between cell types. The IC of IP3RPEP6 inhibition of carbachol-induced Ca responses decreased with increasing cellular Cx43 expression. Moreover, Gap19-inhibition of Cx43 hemichannels significantly reduced the amplitude of the IP -Ca responses and strongly increased the EC of these responses. Finally, we identified palmitoyl-8G-IP3RPEP6 as a membrane-permeable IP3RPEP6 version allowing extracellular application of the IP R-inhibiting peptide.
CONCLUSION
IP3RPEP6 inhibits IP R2/R3 at concentrations that have limited effects on IP R1. IP R activation triggers hemichannel opening, which strongly affects the amplitude and concentration-dependence of IP -triggered Ca responses.
Topics: Connexin 43; Molecular Docking Simulation; Carbachol; Peptides; Astrocytes
PubMed: 38240350
DOI: 10.1111/apha.14086 -
Behavioural Brain Research Mar 2024Depression and anxiety are associated with dysfunction of the mesolimbic dopamine system. The rostromedial tegmental nucleus (RMTg) is predominantly composed of...
Depression and anxiety are associated with dysfunction of the mesolimbic dopamine system. The rostromedial tegmental nucleus (RMTg) is predominantly composed of GABAergic neurons that exhibit dense projections and strongly inhibit mesolimbic dopaminergic neurons, proposed as a major "brake" for the system. Consequently, the RMTg may be a crucial brain region for regulating these emotions. The central cholinergic system, particularly the muscarinic receptors, plays an important regulatory role in depression and anxiety. M muscarinic receptors are distributed on GABAergic neurons in the RMTg, but their involvement in the regulation of depression and anxiety remains uncertain. This study aimed to examine the effects of RMTg M muscarinic receptors on regulating depression- and anxiety-like behaviors in adult male Wistar rats, as assessed through the forced swim, tail suspension, and elevated plus maze tests. The results showed that intra-RMTg injections of the M/M muscarinic receptors agonist, pilocarpine (3, 10, and 30 μg/side), or the M muscarinic receptors antagonist, 4-DAMP (0.5, 1, and 2 μg/side), did not alter the immobility time in the forced swim and tail suspension tests. Additionally, pilocarpine (30 μg/side) decreased time spent in open arms and increased time in closed arms in the elevated plus maze; while 4-DAMP (1 and 2 μg/side) played the opposite role by increasing time spent in open arms and decreasing time in closed arms. These findings suggest that RMTg M muscarinic receptors have differential effects on regulating depression- and anxiety-like behaviors. Enhancing or inhibiting these receptors can produce anxiogenic or anxiolytic effects, but have no impact on depression-like behavior. Therefore, RMTg M muscarinic receptors are involved in regulating anxiety and may be a potential therapeutic target for anxiolytic drugs.
Topics: Rats; Animals; Male; Ventral Tegmental Area; Pilocarpine; Depression; Rats, Wistar; Receptors, Muscarinic; Anxiety; Piperidines
PubMed: 38220059
DOI: 10.1016/j.bbr.2023.114833 -
Epilepsy Research Feb 2024Mutations within the Kv7.2 and Kv7.3 genes are well described causes for genetic childhood epilepsies. Knowledge on these channels in acquired focal epilepsy, especially...
Mutations within the Kv7.2 and Kv7.3 genes are well described causes for genetic childhood epilepsies. Knowledge on these channels in acquired focal epilepsy, especially in mesial temporal lobe epilepsy (mTLE), however, is scarce. Here, we used the rat pilocarpine model of drug-resistant mTLE to elucidate both expression and function by quantitative polymerase-chain reaction, immunohistochemistry, and electrophysiology, respectively. We found transcriptional downregulation of Kv7.2 and Kv7.3 as well as reduced Kv7.2 expression in epileptic CA1. Consequences were altered synaptic transmission, hyperexcitability which consisted of epileptiform afterpotentials, and increased susceptibility to acute GABAergic disinhibition. Importantly, blocking Kv7 channels with XE991 increased hyperexcitability in control tissue, but not in chronically epileptic tissue suggesting that the Kv7 deficit had precluded XE991 effects in this tissue. Conversely, XE991 resulted in comparable reduction of the paired-pulse ratio in both experimental groups implying preserved presynaptic Kv7.2 function of Schaffer collateral terminals. Consistent with Kv7.2/7.3 downregulation, the Kv7.3 channel opener β-hydroxybutyrate failed to mitigate hyperexcitability. Our findings demonstrate that compromised Kv7 function is not only relevant in genetic epilepsy, but also in acquired focal epilepsy. Moreover, they help explain reduced anti-seizure efficacy of Kv7 channel openers in drug-resistant epilepsy.
Topics: Animals; Child; Humans; Rats; Down-Regulation; Epilepsy, Temporal Lobe; Membrane Potentials; Pilocarpine; KCNQ2 Potassium Channel; KCNQ3 Potassium Channel
PubMed: 38219422
DOI: 10.1016/j.eplepsyres.2024.107296 -
Clinical Therapeutics Feb 2024This study was undertaken to evaluate the safety and efficacy of CSF-1 (0.4% pilocarpine hydrochloride ophthalmic solution) for use in individuals with presbyopia. (Randomized Controlled Trial)
Randomized Controlled Trial
PURPOSE
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.
METHODS
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.
FINDINGS
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.
IMPLICATIONS
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).
Topics: Female; Humans; Middle Aged; Lens Implantation, Intraocular; Lenses, Intraocular; Macrophage Colony-Stimulating Factor; Ophthalmic Solutions; Pilocarpine; Presbyopia
PubMed: 38216351
DOI: 10.1016/j.clinthera.2023.12.005