Five-Year Clinical Trial of the Low-Concentration Atropine for Myopia Progression (LAMP) Study: Phase 4 Report.

PURPOSE: To evaluate (1) the long-term efficacy of low-concentration atropine over 5 years, (2) the proportion of children requiring re-treatment and associated factors, and (3) the efficacy of pro re nata (PRN) re-treatment using 0.05% atropine from years 3 to 5. DESIGN: Randomized, double-masked extended trial. PARTICIPANTS: Children 4 to 12 years of age originally from the Low-Concentration Atropine for Myopia Progression (LAMP) study. METHODS: Children 4 to 12 years of age originally from the LAMP study were followed up for 5 years. During the third year, children in each group originally receiving 0.05%, 0.025%, and 0.01% atropine were randomized to continued treatment and treatment cessation. During years 4 and 5, all continued treatment subgroups were switched to 0.05% atropine for continued treatment, whereas all treatment cessation subgroups followed a PRN re-treatment protocol to resume 0.05% atropine for children with myopic progressions of 0.5 diopter (D) or more over 1 year. Generalized estimating equations were used to compare the changes in spherical equivalent (SE) progression and axial length (AL) elongation among groups. MAIN OUTCOMES MEASURES: (1) Changes in SE and AL in different groups over 5 years, (2) the proportion of children who needed re-treatment, and (3) changes in SE and AL in the continued treatment and PRN re-treatment groups from years 3 to 5. RESULTS: Two hundred seventy (82.8%) of 326 children (82.5%) from the third year completed 5 years of follow-up. Over 5 years, the cumulative mean SE progressions were -1.34 ± 1.40 D, -1.97 ± 1.03 D, and -2.34 ± 1.71 D for the continued treatment groups with initial 0.05%, 0.025%, and 0.01% atropine, respectively (P = 0.02). Similar trends were observed in AL elongation (P = 0.01). Among the PRN re-treatment group, 87.9% of children (94/107) needed re-treatment. The proportion of re-treatment across all studied concentrations was similar (P = 0.76). The SE progressions for continued treatment and PRN re-treatment groups from years 3 to 5 were -0.97 ± 0.82 D and -1.00 ± 0.74 D (P = 0.55) and the AL elongations were 0.51 ± 0.34 mm and 0.49 ± 0.32 mm (P = 0.84), respectively. CONCLUSIONS: Over 5 years, the continued 0.05% atropine treatment demonstrated good efficacy for myopia control. Most children needed to restart treatment after atropine cessation at year 3. Restarted treatment with 0.05% atropine achieved similar efficacy as continued treatment. Children should be considered for re-treatment if myopia progresses after treatment cessation. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Efficacy of a combined anti-seizure treatment against cholinergic established status epilepticus following a sarin nerve agent insult in rats.

The development of refractory status epilepticus (SE) following sarin intoxication presents a therapeutic challenge. Here, we evaluated the efficacy of delayed combined double or triple treatment in reducing abnormal epileptiform seizure activity (ESA) and the ensuing long-term neuronal insult. SE was induced in rats by exposure to 1.2 LD50 sarin followed by treatment with atropine and TMB4 (TA) 1 min later. Double treatment with ketamine and midazolam or triple treatment with ketamine, midazolam and levetiracetam was administered 30 min post-exposure, and the results were compared to those of single treatment with midazolam alone or triple treatment with ketamine, midazolam, and valproate, which was previously shown to ameliorate this neurological insult. Toxicity and electrocorticogram activity were monitored during the first week, and behavioral evaluations were performed 2 weeks post-exposure, followed by biochemical and immunohistopathological analyses. Both double and triple treatment reduced mortality and enhanced weight recovery compared to TA-only treatment. Triple treatment and, to a lesser extent, double treatment significantly ameliorated the ESA duration. Compared to the TA-only or the TA+ midazolam treatment, both double and triple treatment reduced the sarin-induced increase in the neuroinflammatory marker PGE2 and the brain damage marker TSPO and decreased gliosis, astrocytosis and neuronal damage. Finally, both double and triple treatment prevented a change in behavior, as measured in the open field test. No significant difference was observed between the efficacies of the two triple treatments, and both triple combinations completely prevented brain injury (no differences from the naïve rats). Delayed double and, to a greater extent, triple treatment may serve as an efficacious delayed therapy, preventing brain insult propagation following sarin-induced refractory SE.

The role of vasoactive intestinal peptide (VIP) in atropine-related inhibition of the progression of myopia.

OBJECTIVE: This study aimed to investigate the potential involvement of vasoactive intestinal polypeptide (VIP) in myopia development and its contribution to the mechanism of action of the anti-myopia drug, atropine. METHODS: Thirty-three-week-old guinea pigs were randomly divided into normal control (NC, n = 10), monocularly form-deprived (FDM, n = 10), and FDM treated with 1% atropine (FDM + AT, n = 10) groups. The diopter and axial length were measured at 0, 2, and 4 weeks. Guinea pig eyeballs were removed at week four, fixed, and stained for morphological changes. Immunohistochemistry (IHC) and in situ hybridization (ISH) were performed to evaluate VIP protein and mRNA levels. RESULTS: The FDM group showed an apparent myopic shift compared to the control group. The results of the H&E staining were as follows: the cells of the inner/outer nuclear layers and retinal ganglion cells were disorganized; the choroidal thickness (ChT), blood vessel lumen, and area were decreased; the sclera was thinner, with disordered fibers and increased interfibrillar space. IHC and ISH revealed that VIP's mRNA and protein expressions were significantly up-regulated in the retina of the FDM group. Atropine treatment attenuated FDM-induced myopic shift and fundus changes, considerably reducing VIP's mRNA and protein expressions. CONCLUSIONS: The findings of elevated VIP mRNA and protein levels observed in the FDM group indicate the potential involvement of VIP in the pathogenesis and progression of myopia. The ability of atropine to reduce this phenomenon suggests that this may be one of the molecular mechanisms for atropine to control myopia.

The effect of glycopyrrolate vs. atropine in combination with neostigmine on cardiovascular system for reversal of residual neuromuscular blockade in the elderly: a randomized controlled trial.

BACKGROUND: Glycopyrrolate-neostigmine (G/N) for reversing neuromuscular blockade (NMB) causes fewer changes in heart rate (HR) than atropine-neostigmine (A/N). This advantage may be especially beneficial for elderly patients. Therefore, this study aimed to compare the cardiovascular effects of G/N and A/N for the reversal of NMB in elderly patients. METHODS: Elderly patients aged 65-80 years who were scheduled for elective non-cardiac surgery under general anesthesia were randomly assigned to the glycopyrrolate group (group G) or the atropine group (group A). Following the last administration of muscle relaxants for more than 30 min, group G received 4 ug/kg glycopyrrolate and 20 ug/kg neostigmine, while group A received 10 ug/kg atropine and 20 ug/kg neostigmine. HR, mean arterial pressure (MAP), and ST segment in lead II (ST-II) were measured 1 min before administration and 1-15 min after administration. RESULTS: HR was significantly lower in group G compared to group A at 2-8 min after administration (P < 0.05). MAP was significantly lower in group G compared to group A at 1-4 min after administration (P < 0.05). ST-II was significantly depressed in group A compared to group G at 2, 3, 4, 5, 6, 7, 8, 9, 11, 13, 14, and 15 min after administration (P < 0.05). CONCLUSIONS: In comparison to A/N, G/N for reversing residual NMB in the elderly has a more stable HR, MAP, and ST-II within 15 min after administration.

Assessing the rebound phenomenon in different myopia control treatments: A systematic review.

PURPOSE: To review the rebound effect after cessation of different myopia control treatments. METHODS: A systematic review that included full-length randomised controlled studies (RCTs), as well as post-hoc analyses of RCTs reporting new findings on myopia control treatments rebound effect in two databases, PubMed and Web of Science, was performed according to the PRISMA statement. The search period was between 15 June 2023 and 30 June 2023. The Cochrane risk of bias tool was used to analyse the quality of the selected studies. RESULTS: A total of 11 studies were included in this systematic review. Unifying the rebound effects of all myopia control treatments, the mean rebound effect for axial length (AL) and spherical equivalent refraction (SER) were 0.10 ± 0.07 mm [-0.02 to 0.22] and -0.27 ± 0.2 D [-0.71 to -0.03] after 10.2 ± 7.4 months of washout, respectively. In addition, spectacles with highly aspherical lenslets or defocus incorporated multiple segments technology, soft multifocal contact lenses and orthokeratology showed lower rebound effects compared with atropine and low-level light therapy, with a mean rebound effect for AL and SER of 0.04 ± 0.04 mm [0 to 0.08] and -0.13 ± 0.07 D [-0.05 to -0.2], respectively. CONCLUSIONS: It appears that the different treatments for myopia control produce a rebound effect after their cessation. Specifically, optical treatments seem to produce less rebound effect than pharmacological or light therapies. However, more studies are required to confirm these results.

Myopia progression following 0.01% atropine cessation in Australian children: Findings from the Western Australia - Atropine for the Treatment of Myopia (WA-ATOM) study.

BACKGROUND: A rebound in myopia progression following cessation of atropine eyedrops has been reported, yet there is limited data on the effects of stopping 0.01% atropine compared to placebo control. This study tested the hypothesis that there is minimal rebound myopia progression after cessation of 0.01% atropine eyedrops, compared to a placebo. METHODS: Children with myopia (n = 153) were randomised to receive 0.01% atropine eyedrops or a placebo (2:1 ratio) daily at bedtime during the 2-year treatment phase of the study. In the third year (wash-out phase), all participants ceased eyedrop instillation. Participants underwent an eye examination every 6 months, including measurements of spherical equivalent (SphE) after cycloplegia and axial length (AL). Changes in the SphE and AL during the wash-out phase and throughout the 3 years of the study (treatment + wash-out phase) were compared between the treatment and control groups. RESULTS: During the 1-year wash-out phase, SphE and AL progressed by -0.41D (95% CI = -0.33 to -0.22) and +0.20 mm (95% CI = -0.46 to -0.36) in the treatment group compared to -0.28D (95% CI = 0.11 to 0.16) and +0.13 mm (95% CI = 0.18 to 0.21) in the control group. Progression in the treatment group was significantly faster than in the control group (p = 0.016 for SphE and <0.001 for AL). Over the 3-year study period, the cumulative myopia progression was similar between the atropine and the control groups. CONCLUSIONS: These findings showed evidence of rapid myopia progression following cessation of 0.01% atropine. Further investigations are warranted to ascertain the long-term effects of atropine eyedrops.

The efficacy of the use of atropine in children with reflex anoxic syncope during pallid breath-holding spells: can cardiac pacemaker implantation be avoided?

OBJECTIVES: Reflex anoxic syncope is the result of an overreaction of the vagal system, resulting in hypotension and bradycardia or brief cardiac arrest. Because of the benign character and the absence of complications in short or long term, treatment is only necessary in case of frequent or severe clinical presentation. Treatment options are anticholinergic drugs or cardiac pacemaker placement. We investigated atropine treatment and aimed to examine if pacemaker placement can be avoided. METHODS: We retrospectively reviewed patients treated with atropine for severe reflex anoxic syncope in our centre from January 2017 until May 2023, and compared our results to those in the literature. RESULTS: The study population consisted of 10 children, 70% female, with an age ranging from 5 months to 3 years (mean 14.5 months) when atropine treatment was started (dose 17-50 microg/kg/day). All patient's parents reported adequate symptom management during atropine treatment, with complete resolution in 10%. Minor side effects were reported in 60% (dry mucosa in 40%, obstipation in 20%, and nausea or blurry vision in 10%). DISCUSSION: We consider atropine a safe and effective treatment to manage reflex anoxic syncope with similar success rate to pacemaker implantation. However, pacemaker implantation entails substantial risk for complications (up to 25%) such as infection or technical problems and morbidity such as scar formation. This might be considered redundant for a benign and temporary condition, certainly given the possibility of other efficient treatment options. Consequently, we recommend atropine treatment over implantation of a cardiac pacemaker in children with severe reflex anoxic syncope.

Impact of salivary flow inhibition on masticatory behaviours in healthy individuals.

BACKGROUND: It remains unclear how the salivary flow and the fat content of food affect bolus formation during mastication. OBJECTIVES: We aimed to clarify: (1) how hyposalivation affects jaw-closing and hyoid-elevating muscle activities in bolus formation, and (2) if the effect of hyposalivation on muscle activity depends on the fat content of food. METHODS: Eighteen healthy male volunteers were instructed to freely ingest four test foods: Plain, Fat without seasoning, Fat with seasoning, and Soft rice crackers. Masseter and suprahyoid electromyographic activities were recorded before and 30 min after the administration of atropine sulfate, a muscarinic receptor antagonist that induces hyposalivation. RESULTS: Hyposalivation extended the masticatory duration significantly in all the test foods except Fat with seasoning. Masticatory cycle time was significantly longer with vs without hyposalivation for the Soft (p = .011). Suprahyoid activity/cycle was significantly greater with vs without hyposalivation (p = .013). Masticatory cycle time was significantly longer at the late stage with vs without hyposalivation for the Soft (p < .001). Suprahyoid activity/cycle was significantly greater at the middle (p = .045) and late stages (p = .002) with vs without hyposalivation for the Soft and greater at the late stage with vs without hyposalivation for the Plain (p = .043). Changes in masticatory cycle time and suprahyoid activity/cycle for these foods had significantly positive relationship (p < .001). CONCLUSION: Hyposalivation-induced changes in masticatory behaviours resulted from the middle and late stage suprahyoid activity. Fat content and seasoning compensate for salivary flow inhibition.

Characterization of Humanized Mouse Model of Organophosphate Poisoning and Detection of Countermeasures via MALDI-MSI.

Organophosphoate (OP) chemicals are known to inhibit the enzyme acetylcholinesterase (AChE). Studying OP poisoning is difficult because common small animal research models have serum carboxylesterase, which contributes to animals' resistance to OP poisoning. Historically, guinea pigs have been used for this research; however, a novel genetically modified mouse strain (KIKO) was developed with nonfunctional serum carboxylase (Es1 KO) and an altered acetylcholinesterase (AChE) gene, which expresses the amino acid sequence of the human form of the same protein (AChE KI). KIKO mice were injected with 1xLD50 of an OP nerve agent or vehicle control with or without atropine. After one to three minutes, animals were injected with 35 mg/kg of the currently fielded Reactivator countermeasure for OP poisoning. Postmortem brains were imaged on a Bruker RapifleX ToF/ToF instrument. Data confirmed the presence of increased acetylcholine in OP-exposed animals, regardless of treatment or atropine status. More interestingly, we detected a small amount of Reactivator within the brain of both exposed and unexposed animals; it is currently debated if reactivators can cross the blood-brain barrier. Further, we were able to simultaneously image acetylcholine, the primary affected neurotransmitter, as well as determine the location of both Reactivator and acetylcholine in the brain. This study, which utilized sensitive MALDI-MSI methods, characterized KIKO mice as a functional model for OP countermeasure development.

Human Plasma Butyrylcholinesterase Hydrolyzes Atropine: Kinetic and Molecular Modeling Studies.

The participation of butyrylcholinesterase (BChE) in the degradation of atropine has been recurrently addressed for more than 70 years. However, no conclusive answer has been provided for the human enzyme so far. In the present work, a steady-state kinetic analysis performed by spectrophotometry showed that highly purified human plasma BChE tetramer slowly hydrolyzes atropine at pH 7.0 and 25 °C. The affinity of atropine for the enzyme is weak, and the observed kinetic rates versus the atropine concentration was of the first order: the maximum atropine concentration in essays was much less than Km. Thus, the bimolecular rate constant was found to be kcat/Km = 7.7 × 104 M-1 min-1. Rough estimates of catalytic parameters provided slow kcat < 40 min-1 and high Km = 0.3-3.3 mM. Then, using a specific organophosphoryl agent, echothiophate, the time-dependent irreversible inhibition profiles of BChE for hydrolysis of atropine and the standard substrate butyrylthiocholine (BTC) were investigated. This established that both substrates are hydrolyzed at the same site, i.e., S198, as for all substrates of this enzyme. Lastly, molecular docking provided evidence that both atropine isomers bind to the active center of BChE. However, free energy perturbations yielded by the Bennett Acceptance Ratio method suggest that the L-atropine isomer is the most reactive enantiomer. In conclusion, the results provided evidence that plasma BChE slowly hydrolyzes atropine but should have no significant role in its metabolism under current conditions of medical use and even under administration of the highest possible doses of this antimuscarinic drug.

Myopia Control in Caucasian Children with 0.01% Atropine Eye Drops: 1-Year Follow-Up Study.

Background and Objectives: Myopia is the most widespread ocular disorder globally and its prevalence has been increasing over the past decades. Atropine eye drops stand out as the only pharmacological intervention used in clinical practice to control myopia progression. The aim of this study was to explore the effect of 0.01% atropine eye drops on myopia progression. Patients and Methods: Healthy children aged 6-12 years with cycloplegic spherical equivalent (SE) from -0.5 D to -5.0 D and astigmatism ≤1.5 D were included. Myopia progression was assessed by changes in SE and axial length (AL) over 1 year and SE changes 1 year before the study enrollment and during the 1-year follow-up. Adverse events were evaluated based on complaints reported by either parents or the children themselves during follow-up visits. Results: The analysis involved 55 patients in the 0.01% atropine eye drops group and 66 in the control group. After the 1-year follow-up, the change in SE was -0.50 (-2.25-0.50) D in the control group compared to -0.50 (-1.50-0.50) D in the 0.01% atropine group (p = 0.935); AL change was 0.31 (0.18) mm in the control group and 0.29 (0.18) mm in the 0.01% atropine group (p = 0.480). The change in SE was -0.68 (-2.0--0.25) D/year before the study and remained similar -0.50 (-2.25-0.25) D over the 1-year follow-up in the control group (p = 0.111); SE change was reduced from -1.01 (-2.0--0.25) D/year before the study to -0.50 (-1.5-0.5) D over the 1-year follow-up in the 0.01% atropine group (p < 0.001). In the 0.01% atropine group, ten (16.4%) children experienced mild adverse events, including blurred near vision, ocular discomfort, photophobia, dry eyes, and anisocoria. Conclusions: Compared to the control group, the administration of 0.01% atropine eye drops demonstrated no significant effect on changes in SE and AL over a 1-year follow-up. However, children in the 0.01% atropine group initially experienced higher myopia progression, which decreased with treatment over the course of 1 year. Future studies should explore the long-term effects, rebound effects, potential genetic associations, and efficacy of higher doses of atropine in managing myopia progression.

Atropine facilitates water-evoked swallows via central muscarinic receptors in anesthetized rats.

Anticholinergic medication causes impaired swallowing with hyposalivation. However, the underlying mechanisms by which these drugs modulate the swallowing reflex remain unclear. This study investigated the effects of the muscarinic acetylcholine receptor (mAChR) nonspecific antagonist atropine on the initiation of swallowing. Experiments were performed on 124 urethane-anesthetized rats. A swallow was evoked by either topical laryngeal application of a small amount of distilled water (DW), saline, citric acid, or capsaicin; upper airway distention with a continuous airflow; electrical stimulation of the superior laryngeal nerve (SLN); or focal microinjection of N-methyl-d-aspartate (NMDA) into the lateral region of the nucleus of the solitary tract (L-nTS). Swallows were identified by electromyographic bursts of the digastric and thyrohyoid muscles. Either atropine, the peripheral mAChR antagonist methylatropine, or antagonists of mAChR subtypes M1-M5 were intravenously delivered. Atropine at a dose of 1 mg/kg increased the number of DW-evoked swallows compared with baseline and did not affect the number of swallows evoked by saline, citric acid, capsaicin, or upper airway distention. Methylatropine and M1-M5 antagonists did not significantly change the number of DW-evoked swallows. Bilateral SLN transection completely abolished DW-evoked swallows, and atropine decreased the swallowing threshold of SLN electrical stimulation. Finally, microinjection of NMDA receptor antagonist AP-5 into the L-nTS inhibited DW-evoked swallows, and atropine facilitated the initiation of swallowing evoked by NMDA microinjection into this region. These results suggest that atropine facilitates DW-evoked swallows via central mAChR actions.NEW & NOTEWORTHY Atropine facilitated the distilled water (DW)-evoked swallows in anesthetized rats. Atropine decreased the swallowing threshold evoked by electrical stimulation of the superior laryngeal nerve, which is a primary sensory nerve for the initiation of DW-evoked swallows. Atropine facilitated the swallows evoked by N-methyl-d-aspartate microinjection into the lateral region of the nucleus of the solitary tract, which is involved in the DW-evoked swallows. We speculate that atropine facilitates the DW-evoked swallows via central muscarinic receptor actions.

An exploration of the binding prediction of anatoxin-a and atropine to acetylcholinesterase enzyme using multi-level computer simulations.

Acetylcholinesterase (AChE) is crucial for the breakdown of acetylcholine to acetate and choline, while the inhibition of AChE by anatoxin-a (ATX-a) results in severe health complications. This study explores the structural characteristics of ATX-a and its interactions with AChE, comparing to the reference molecule atropine for binding mechanisms. Molecular docking simulations reveal strong binding affinity of both ATX-a and atropine to AChE, interacting effectively with specific amino acids in the binding site as potential inhibitors. Quantitative assessment using the MM-PBSA method demonstrates a significantly negative binding free energy of -81.659 kJ mol-1for ATX-a, indicating robust binding, while atropine exhibits a stronger binding affinity with a free energy of -127.565 kJ mol-1. Umbrella sampling calculates the ΔGbindvalues to evaluate binding free energies, showing a favorable ΔGbindof -36.432 kJ mol-1for ATX-a and a slightly lower value of -30.12 kJ mol-1for atropine. This study reveals the dual functionality of ATX-a, acting as both a nicotinic acetylcholine receptor agonist and an AChE inhibitor. Remarkably, stable complexes form between ATX-a and atropine with AChE at its active site, exhibiting remarkable binding free energies. These findings provide valuable insights into the potential use of ATX-a and atropine as promising candidates for modulating AChE activity.

Central anticholinergic syndrome secondary to atropine eye drops: A case study.

Atropine eye drops are frequently used in the treatment of keratitis and during ophthalmic surgery. We described a rare complication of central anticholinergic syndrome secondary to atropine eye drops.

Gastroparesis Worsens Indomethacin-Induced Gastric Antral Ulcers by Bile Reflux via Activation of 5-HT3 and Dopamine D2 Receptors in Mice.

BACKGROUND/AIMS: We examined the contributions of gastric emptying and duodenogastric bile reflux in the formation of gastric antral ulcers induced by NSAIDs in mice. METHODS: We used the murine re-fed indomethacin (IND) experimental ulcer model. Outcome measures included the appearance of gastric lesions 24 h after IND treatment and the assessment of gastric contents and the concentration of bile acids 1.5 h after re-feeding. The effects of atropine, dopamine, SR57227 (5-HT3 receptor agonist), apomorphine, ondansetron, haloperidol, and dietary taurocholate and cholestyramine were also examined. RESULTS: IND (10 mg/kg, s.c.) induced severe lesions only in the gastric antrum in the re-fed model. The antral lesion index and the amount of food intake during the 2-h refeeding period were positively correlated. Atropine and dopamine delayed gastric emptying, increased bile reflux, and worsened IND-induced antral lesions. SR57227 and apomorphine worsened antral lesions with increased bile reflux. These effects were prevented by the anti-emetic drugs ondansetron and haloperidol, respectively. The anti-emetic drugs markedly decreased the severity of antral lesions and the increase of bile reflux induced by atropine or dopamine without affecting delayed gastric emptying. Antral lesions induced by IND were increased by dietary taurocholate but decreased by the addition of the bile acid sequestrant cholestyramine. CONCLUSIONS: These results suggest that gastroparesis induced by atropine or dopamine worsens NSAID-induced gastric antral ulcers by increasing duodenogastric bile reflux via activation of 5-HT3 and dopamine D2 receptors.

Prevention of myopia shift and myopia onset using 0.01% atropine in premyopic children - a prospective, randomized, double-masked, and crossover trial.

This study aims to evaluate the efficacy of 0.01% atropine eye drops in preventing myopia shift and myopia onset in premyopic children. A prospective, randomized, double-masked, placebo-controlled, and crossover trial was conducted over 13 months. Sixty premyopic children aged 6-12 years with cycloplegic spherical equivalent refraction (SER) > - 0.75 D and ≤ + 0.50 D in both eyes were assigned in a 1:1 ratio to receive one drop of 0.01% atropine or placebo once nightly for 6 months (period 1), followed by a 1-month recovery period. Then, the 0.01% atropine group was crossed over to the placebo group, and the latter was crossed over to the 0.01% atropine group for another 6 months (period 2). The primary outcomes were changes in SER and axial length (AL), and the secondary outcomes were the proportion of myopia onset (SER ≤ - 0.75D) and fast myopic shift (change in SER ≤ - 0.25D) in the two periods. Generalized estimating equation (GEE) model performed a statistically significant treatment effect of 0.01% atropine compared with placebo (pSER = 0.02, pAL < 0.001), with a mean SER and AL difference of 0.20D (- 0.15 ± 0.26D vs. - 0.34 ± 0.34D) and 0.11 mm (0.17 ± 0.11 mm vs. 0.28 ± 0.14 mm) in period 1, and 0.17D (- 0.18 ± 0.24D vs. - 0.34 ± 0.31D) and 0.10 mm (0.15 ± 0.15 mm vs. 0.24 ± 0.11 mm) in period 2. The GEE model showed that the proportion of myopia onset (p = 0.004) and fast myopic shift (p = 0.009) was significantly lower in the 0.01% atropine group than that in the placebo group. The period effect was not statistically significant (all p > 0.05). A total of 0.01% atropine significantly prevented myopic shift, axial elongation, and myopia onset in premyopic schoolchildren in central Mainland China. CONCLUSION: Within the limits of only two consecutive 6-month observation period, 0.01% atropine eye drops effectively prevented myopic shift, axial elongation, and myopia onset in premyopic children. TRIAL REGISTRATION: This trial was registered in the Chinese Clinical Trial Registry (Registration number: ChiCTR2000034760). Registered 18 July 2020. WHAT IS KNOWN: • Minimal studies on interventions for pre-myopia, despite the International Myopia Institute stating that preventing myopia is an "even more valuable target" for science and practice than reducing progression after onset. WHAT IS NEW: • A total of 0.01% atropine eye drops may safely and effectively reduce the proportion of myopia onset and fast myopic shift in premyopic schoolchildren.

Effect of low-dose atropine eyedrops on pupil metrics: results after half a year of treatment and cessation.

PURPOSE: To evaluate the effect of low-dose atropine eyedrops on pupil metrics. METHODS: This study was based on a randomized, double-masked, placebo-controlled, and cross-over trial in mainland China. In phase 1, subjects received 0.01% atropine or placebo once nightly. After 1 year, the atropine group switched to placebo (atropine-placebo group), and the placebo group switched to atropine (placebo-atropine group). Ocular parameters were measured at the crossover time point (at the 12th month) and the 18th month. RESULTS: Of 105 subjects who completed the study, 48 and 57 children were allocated into the atropine-placebo and placebo-atropine groups, respectively. After cessation, the photopic pupil diameter (PD) and mesopic PD both decreased (- 0.46 ± 0.47 mm, P < 0.001; - 0.30 ± 0.74 mm, P = 0.008), and the constriction ratio (CR, %) increased (4.39 ± 7.54, P < 0.001) compared with values at the crossover time point of the atropine-placebo group; pupil metrics of the atropine-placebo group had no difference from the values at the crossover time point of the placebo-atropine group. After 6 months of treatment, the photopic PD and the mesopic PD increased (0.54 ± 0.67 mm, P < 0.001; 0.53 ± 0.89 mm, P < 0.001), the CR (%) decreased (- 2.53 ± 8.64, P < 0.001) compared with values at the crossover time point of the placebo-atropine group. There was no significant relationship between pupil metrics and myopia progression during 0.01% atropine treatment. CONCLUSION: Pupil metrics and the CR could return to pre-atropine levels after cessation. Pupil metrics had no significant effect on myopia progression during treatment.

Studies on the interactions of retinal dopamine with choroidal thickness in the chicken.

PURPOSE: Recently, an increasing number of studies relied on the assumption that visually induced changes in choroidal thickness can serve as a proxy to predict future axial eye growth. The retinal signals controlling choroidal thickness are, however, not well defined. We have studied the potential roles of dopamine, released from the retina, in the choroidal response in the chicken. METHODS: Changes in retinal dopamine release and choroidal thickness changes were induced by intravitreal injections of either atropine (250 µg or 360 nMol), atropine combined with a dopamine antagonist, spiperone (500 µMol), or spiperone alone and were tracked by optical coherence tomography (OCT). To visually stimulate dopamine release, other chicks were exposed to flicker light of 1, 10, or 400 Hz (duty cycle 0.2) and choroidal thickness was tracked. In all experiments, dopamine and 3,4-Dihydroxyphenylacetic acid (DOPAC) were measured in vitreous, retina, and choroid by high-performance liquid chromatography with electrochemical detection (HLPC-ED). The distribution of the rate-limiting enzyme of dopamine synthesis, tyrosine hydroxylase (TH), neuronal nitric oxide synthase (nNOS), vascular endothelial growth factor (VEGF), and alpha2A adrenoreceptors (alpha2A-ADR) was studied in the choroid by immunofluorescence. RESULTS: The choroid thickened strongly in atropine-injected eyes, less so in atropine + spiperone-injected eyes and became thinner over the day in spiperone alone-, vehicle-, or non-injected eyes. Flickering light at 20 lx, both 1 and 10 Hz, prevented diurnal choroidal thinning, compared to 400 Hz, and stimulated retinal dopamine release. Correlation analysis showed that the higher retinal dopamine levels or release, the thicker became the choroid. TH-, nNOS-, VEGF-, and alpha2A adrenoreceptor-positive nerve fibers were localized in the choroid around lacunae and in the walls of blood vessels with colocalization of TH and nNOS, and TH and VEGF. CONCLUSIONS: Retinal DOPAC and dopamine levels were positively correlated with choroidal thickness. TH-positive nerve fibers in the choroid were closely associated with peptides known to play a role in myopia development. Findings are in line with the hypothesis that dopamine is related to retinal signals controlling choroidal thickness.

Effects of atropine and tropicamide on ocular biological parameters in children: a prospective observational study.

BACKGROUND: The effectiveness of cycloplegia in delaying the progression of myopia and its application in refractive examination in children have been extensively studied, but there are still few studies on the effects of atropine/tropicamide on ocular biological parameters. Therefore, the purpose of this study was to explore the effects of atropine/tropicamide on children's ocular biological parameters in different age groups and the differences between them. METHODS: This was a prospective observational study in which all school children were examined for dioptres and ocular biological parameters in the outpatient clinic, and 1% atropine or tropicamide was used for treatment. After examination, we enrolled the patients grouped by age (age from 2 to 12 years treated by atropine, 55 cases; age from 2 to 10 years treated by tropicamide, 70 cases; age from 14 to 17 years treated by tropicamide, 70 cases). The ocular biological parameters of each patient before and after cycloplegia were measured, and the difference and its absolute value were calculated for statistical analysis using an independent-samples t test. RESULTS: We compared the value and the absolute value of the differences in ocular biological parameters before and after cycloplegia in the same age group, and we found that the differences were not statistically significant (P > 0.05). There were significant differences in the corresponding values of AL, K1 and ACD among the different age groups (P < 0.05). Before cycloplegia, there were significant differences in AL, K, K1, K2 and ACD in different age groups (P < 0.05). However, the differences in AL, K, K1, K2 and ACD among different age groups disappeared after cycloplegia (P > 0.05). CONCLUSIONS: This study demonstrated that atropine/tropicamide have different effects on cycloplegia in children of different ages. The effects of atropine/tropicamide on ocular biological parameters should be fully considered when evaluating the refractive state before refractive surgery or mydriasis optometry for children of different ages.

Safety and efficacy of 0.01% and 0.1% low-dose atropine eye drop regimens for reduction of myopia progression in Danish children: a randomized clinical trial examining one-year effect and safety.

BACKGROUND: To investigate the efficacy and safety of 0.1% and 0.01% low-dose atropine eye drops in reducing myopia progression in Danish children. METHODS: Investigator-initiated, placebo-controlled, double-masked, randomized clinical trial. Ninety-seven six- to twelve-year old myopic participants were randomized to 0.1% loading dose for six months followed by 0.01% for six months (loading dose group, Number (N) = 33), 0.01% for twelve months (0.01% group, N = 32) or vehicle for twelve months (placebo, N = 32). Primary outcomes were axial length and spherical equivalent refraction. Secondary outcomes included adverse events and reactions, choroidal thickness and ocular biometry. Outcomes were measured at baseline and three-month intervals. Data was analyzed with linear-mixed model analysis according to intention-to-treat. RESULTS: Mean axial elongation was 0.10 mm less (95% confidence interval (CI): 0.17; 0.02, adjusted-p = 0.06) in the 0.1% loading dose and 0.07 mm less (95% CI: 0.15; 0.00, adjusted-p = 0.16) in the 0.01% group at twelve months compared to placebo. Mean spherical equivalent refraction progression was 0.24 D (95% CI: 0.05; 0.42) less in the loading dose and 0.19 D (95% CI: 0.00; 0.38) less in the 0.01% groups at twelve months, compared to placebo (adjusted-p = 0.06 and 0.14, respectively). A total of 108 adverse events were reported during the initial six-month loading dose period, primarily in the loading dose group, and 14 were reported in the six months following dose switching, all deemed mild except two serious adverse events, unrelated to the intervention. CONCLUSIONS: Low-dose atropine eye drops are safe over twelve months in otherwise healthy children. There may be a modest but clinically relevant reduction in myopia progression in Danish children after twelve months treatment, but the effect was statistically non-significant after multiple comparisons adjustment. After dose-switching at six months the loading dose group approached the 0.01% group, potentially indicating an early "rebound-effect". TRIAL REGISTRATION: this study was registered in the European Clinical Trials Database (EudraCT, number: 2018-001286-16) 05/11/2018 and first posted at www. CLINICALTRIALS: gov (NCT03911271) 11/04/2019, prior to initiation.