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Chembiochem : a European Journal of... Sep 2023Cocaine and hyoscyamine are two tropane alkaloids (TA) from Erythroxylaceae and Solanaceae, respectively. These famous compounds possess anticholinergic properties that... (Review)
Review
Cocaine and hyoscyamine are two tropane alkaloids (TA) from Erythroxylaceae and Solanaceae, respectively. These famous compounds possess anticholinergic properties that can be used to treat neuromuscular disorders. While the hyoscyamine biosynthetic pathway has been fully elucidated allowing its de novo synthesis in yeast, the cocaine pathway remained only partially elucidated. Recently, the Huang research group has completed the cocaine biosynthetic route by characterizing its two missing enzymes. This allowed the whole pathway to be transferring into Nicotiana benthamiana to achieve cocaine production. Here, besides highlighting the impact of this discovery, we discuss how TA biosynthesis evolved via the recruitment of two distinct and convergent pathways in Erythroxylaceae and Solanaceae. Finally, while enriching our knowledge on TA biosynthesis, this diversification of the molecular actors involved in cocaine and hyoscyamine biosynthesis opens perspectives in metabolic engineering by exploring enzyme biochemical plasticity that can ease and shorten TA pathway reconstitution in heterologous organisms.
Topics: Hyoscyamine; Cocaine; Tropanes; Solanaceae; Cholinergic Antagonists
PubMed: 37249120
DOI: 10.1002/cbic.202300234 -
International Journal of Pharmaceutics May 2024Atropine sulfate (ATS) eye drops at low concentrations constitute a limited selection for myopia treatment, with challenges such as low ophthalmic bioavailability and...
Atropine sulfate (ATS) eye drops at low concentrations constitute a limited selection for myopia treatment, with challenges such as low ophthalmic bioavailability and inadequate stability. This study proposes a novel strategy by synthesizing ophthalmic sodium polystyrene sulfonate resin (SPSR) characterized by a spherical shape and uniform size for cationic exchange with ATS. The formulation of ATS@SPSR suspension eye drops incorporates xanthan gum and hydroxypropyl methylcellulose (HPMC) as suspending agents. In vitro studies demonstrated that ATS@SPSR suspension eye drops exhibited sustained release characteristics, and tropic acid, its degradation product, remained undetected for 30 days at 40 °C. The ATS levels in the tear fluids and aqueous humor of New Zealand rabbits indicated a significant increase in mean residence time (MRT) and area under the drug concentration-time curve (AUC) for ATS@SPSR suspension eye drops compared to conventional ATS eye drops. Moreover, safety assessment confirmed the non-irritating nature of ATS@SPSR suspension eye drops in rabbit eyes. In conclusion, the cation-responsive sustained-release ATS@SPSR suspension eye drops enhanced the bioavailability and stability of ATS, offering a promising avenue for myopia treatment.
PubMed: 38823467
DOI: 10.1016/j.ijpharm.2024.124294 -
Cureus Feb 2024Organophosphate poisoning is a significant global health concern with implications for both occupational and environmental settings. This comprehensive review thoroughly... (Review)
Review
Organophosphate poisoning is a significant global health concern with implications for both occupational and environmental settings. This comprehensive review thoroughly explores the biochemical basis, clinical presentation, diagnostic methods, treatment strategies, and long-term effects of organophosphate exposure. The acute phase is characterized by cholinergic crisis, respiratory distress, and neurological manifestations, while delayed complications include the intermediate syndrome and organophosphate-induced delayed neuropathy. Diagnostic approaches involve clinical evaluation, cholinesterase-level assessments, and imaging studies. Treatment strategies encompass decontamination, antidotes such as atropine and pralidoxime, and supportive care. Long-term effects may include cognitive and neurological sequelae, necessitating rehabilitation approaches such as physical and occupational therapy. Prevention strategies include stringent occupational safety guidelines, sustainable agricultural practices, and public awareness initiatives. The implications for clinical practice underscore the importance of a multidisciplinary approach. At the same time, the call to action emphasizes the need for collaborative efforts in prevention and awareness to mitigate the impact of organophosphate poisoning on public health and the environment.
PubMed: 38510851
DOI: 10.7759/cureus.54422 -
Acta Ophthalmologica May 2024The Myopia Outcome Study of Atropine in Children (MOSAIC) is an investigator-led, double-masked, randomized controlled trial investigating the efficacy and safety of... (Randomized Controlled Trial)
Randomized Controlled Trial
PURPOSE
The Myopia Outcome Study of Atropine in Children (MOSAIC) is an investigator-led, double-masked, randomized controlled trial investigating the efficacy and safety of 0.01% atropine eye drops for managing myopia progression in a predominantly White, European population.
METHODS
Children aged 6-16 years with myopia were randomly allocated 2:1 to nightly 0.01% atropine or placebo eye drops in both eyes for 2 years. The primary outcome was cycloplegic spherical equivalent (SE) progression at 24 months. Secondary outcomes included axial length (AL) change, safety and acceptability. Linear mixed models with random intercepts were used for statistical analyses.
RESULTS
Of 250 participants enrolled, 204 (81.6%) completed the 24-month visit (136 (81.4%) treatment, 68 (81.9%) placebo). Baseline characteristics, drop-out and adverse event rates were similar between treatment and control groups. At 24 months, SE change was not significantly different between 0.01% atropine and placebo groups (effect = 0.10 D, p = 0.07), but AL growth was lower in the 0.01% atropine group, compared to the placebo group (-0.07 mm, p = 0.007). Significant treatment effects on SE (0.14 D, p = 0.049) and AL (-0.11 mm, p = 0.002) were observed in children of White, but not non-White (SE = 0.05 D, p = 0.89; AL = 0.008 mm, p = 0.93), ethnicity at 24 months. A larger treatment effect was observed in subjects least affected by COVID-19 restrictions (SE difference = 0.37 D, p = 0.005; AL difference = -0.17 mm, p = 0.001).
CONCLUSIONS
Atropine 0.01% was safe, well-tolerated and effective in slowing axial elongation in this European population. Treatment efficacy varied by ethnicity and eye colour, and potentially by degree of COVID-19 public health restriction exposure during trial participation.
Topics: Child; Humans; Atropine; Axial Length, Eye; COVID-19; Disease Progression; Myopia; Ophthalmic Solutions; Refraction, Ocular; Treatment Outcome; Adolescent
PubMed: 37694816
DOI: 10.1111/aos.15761 -
Journal of the American College of... Sep 2023Factors determining hemodynamic stability during human ventricular tachycardia (VT) are incompletely understood.
BACKGROUND
Factors determining hemodynamic stability during human ventricular tachycardia (VT) are incompletely understood.
OBJECTIVES
The purposes of this study were to characterize sinus rate (SR) responses during monomorphic VT in association with hemodynamic stability and to prospectively assess the effects of vagolytic therapy on VT tolerance.
METHODS
This is a retrospective analysis of patients undergoing scar-related VT ablation. Vasovagal responses were evaluated by analyzing sinus cycle length before VT induction and during VT. SR responses were classified into 3 groups: increasing (≥5 beats/min, sympathetic), decreasing (≥5 beats/min, vagal), and unchanged, with the latter 2 categorized as inappropriate SR. In a prospective cohort (n = 30) that exhibited a failure to increase SR, atropine was administered to improve hemodynamic tolerance to VT.
RESULTS
In 150 patients, 261 VT episodes were analyzed (29% untolerated, 71% tolerated) with median VT duration 1.6 minutes. A total of 52% of VT episodes were associated with a sympathetic response, 31% had unchanged SR, and 17% of VTs exhibited a vagal response. A significantly higher prevalence of inappropriate SR responses was observed during untolerated VT (sustained VT requiring cardioversion within 150 seconds) compared with tolerated VT (84% vs 34%; P < 0.001). Untolerated VT was significantly different between groups: 9% (sympathetic), 82% (vagal), and 32% (unchanged) (P < 0.001). Atropine administration improved hemodynamic tolerance to VT in 70%.
CONCLUSIONS
Nearly one-half of VT episodes are associated with failure to augment SR, indicative of an under-recognized pathophysiological vasovagal response to VT. Inappropriate SR responses were more predictive of hemodynamic instability than VT rate and ejection fraction. Vagolytic therapy may be a novel method to augment blood pressure during VT.
Topics: Humans; Prospective Studies; Retrospective Studies; Tachycardia, Ventricular; Hemodynamics; Atropine; Ubiquitin-Protein Ligases
PubMed: 37673510
DOI: 10.1016/j.jacc.2023.06.033 -
Journal of Visualized Experiments : JoVE Nov 2023The protocol here provides a simple, highly replicable methodology to induce in situ acute regional myocardial ischemia in the rabbit for non-survival and survival...
The protocol here provides a simple, highly replicable methodology to induce in situ acute regional myocardial ischemia in the rabbit for non-survival and survival experiments. New Zealand White adult rabbit is sedated with atropine, acepromazine, butorphanol, and isoflurane. The animal is intubated and placed on mechanical ventilation. An intravenous catheter is inserted into the marginal ear vein for the infusion of medications. The animal is pre-medicated with heparin, lidocaine, and lactated Ringer's solution. A carotid cut-down is performed to obtain arterial line access for blood pressure monitoring. Select physiologic and mechanical parameters are monitored and recorded by continuous real-time analysis. With the animal sedated and fully anesthetized, either a fourth intercostal space small left thoracotomy (survival) or midline sternotomy (non-survival) is performed. The pericardium is opened, and the left anterior descending (LAD) artery is located. A polypropylene suture is passed around the second or third diagonal branch of the LAD artery, and the polypropylene filament is threaded through a small vinyl tube, forming a snare. The animal is subjected to 30 min of regional ischemia, achieved by occluding the LAD by tightening the snare. Myocardial ischemia is confirmed visually by regional cyanosis of the epicardium. Following regional ischemia, the ligature is loosened, and the heart is allowed to re-perfuse. For both survival and non-survival experiments, the myocardial function can be assessed via an echocardiography (ECHO) measurement of the fractional shortening. For non-survival studies, data from sonomicrometry collected using three digital piezoelectric ultrasonic probes implanted within the ischemic area and the left ventricle developed pressure (LVDP) using an apically inserted left ventricle (LV) catheter can be continuously acquired for evaluating the regional and global myocardial function, respectively. For survival studies, the incision is closed, a left needle thoracentesis is performed for pleural air evacuation, and postoperative pain control is achieved.
Topics: Rabbits; Animals; Polypropylenes; Ischemia; Reperfusion Injury; Myocardial Ischemia; Heart
PubMed: 37982519
DOI: 10.3791/64752 -
Optometry and Vision Science : Official... Jan 2024Popularity of publicly searched myopia terminologies is reported, for example, myopia control over myopia management and myopia over nearsighted or shortsighted....
SIGNIFICANCE
Popularity of publicly searched myopia terminologies is reported, for example, myopia control over myopia management and myopia over nearsighted or shortsighted. Insights are also provided for searches on specific myopia control interventions. The findings offer an evidence-based starting point for public messaging and communications by clinicians, policymakers, and other industry leaders.
PURPOSE
Public understanding of myopia can be difficult to ascertain for clinicians. Although small-scale studies provide valuable snapshots of data, findings tend to be population-specific and thus difficult to extrapolate to global audiences. In this study, big data were used to provide a more comprehensive depiction of global market interest in myopia.
METHODS
Google Trends data were used to analyze searches relating to myopia between January 2004 and August 2023. Data extracted were related to use of the terms myopia control and myopia management, with further searches executed for common myopia control interventions: orthokeratology, contact lenses, atropine, and glasses. Analysis into the search interest of other refractive error states, hyperopia and astigmatism, was also undertaken along with alternative terms that may be used to describe myopia. Where relevant, search trends were considered worldwide, by country, and over time.
RESULTS
Myopia was a more popular search term than common layman alternatives such as nearsighted or shortsighted. Myopia control was found to be more popular than myopia management, and of the specific myopia interventions, atropine was most popular. Compared with astigmatism and hyperopia, relative search volumes were greatest for myopia, on average accounting for approximately 50% of the relative search volume at the country level.
CONCLUSIONS
The differences identified in both popularity of myopia-related search terms and specific interventions may provide the basis for improvements in public messaging and facilitate patient-practitioner communication.
Topics: Humans; Astigmatism; Hyperopia; Big Data; Myopia; Atropine
PubMed: 38350056
DOI: 10.1097/OPX.0000000000002094 -
Eye & Contact Lens Oct 2023Repeated low-level red light (RLRL) therapy has been suggested to be effective in children with myopia. However, evidence from randomized controlled trials (RCTs) is... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Repeated low-level red light (RLRL) therapy has been suggested to be effective in children with myopia. However, evidence from randomized controlled trials (RCTs) is still limited. We performed a meta-analysis of RCTs to systematically evaluate the efficacy of RLRL on changes of axial length (AL) and cycloplegic spherical equivalent refraction (SER) in children with myopia.
METHODS
Relevant RCTs were obtained through a search of electronic databases including PubMed, Embase, Cochrane Library, Wanfang, and China National Knowledge Infrastructure from inception to September 15, 2022. A random-effects model was used to pool the results after incorporating the influence of potential heterogeneity. Subgroup analyses were performed according to the control treatment and follow-up duration.
RESULTS
A total of seven RCTs involving 1,031 children with myopia, aged 6 to 16 years, were included in the meta-analysis. Compared with control treatment without RLRL, treatment with RLRL was associated with a significantly reduced AL (mean difference [MD]: -0.25 mm, 95% confidence interval [CI]: -0.32 to -0.17, P <0.001; I 2 =13%) and a significantly increased cycloplegic SER (MD: 0.60 D, 95% CI: 0.44-0.76, P <0.001; I 2 =20%). Further subgroup analyses showed consistent results in studies comparing children wearing single vision lenses and those receiving active treatment including orthokeratology or low-dose atropine eye drops, as well as studies of treatment duration of 6 and 12 months.
CONCLUSIONS
Results of the meta-analysis suggested that RLRL treatment is effective for slowing down the progression of myopia in children aged 6 to 16 years.
Topics: Child; Humans; Atropine; Axial Length, Eye; Disease Progression; Mydriatics; Myopia; Phototherapy; Randomized Controlled Trials as Topic; Refraction, Ocular
PubMed: 37565498
DOI: 10.1097/ICL.0000000000001020 -
Clinical and Translational Science Mar 2024Sialorrhea or drooling is a common problem in children and adults with neurodevelopmental disorders. It can negatively impact the quality of life due to its physical and...
Sialorrhea or drooling is a common problem in children and adults with neurodevelopmental disorders. It can negatively impact the quality of life due to its physical and psychological manifestations. Providers commonly prescribe atropine eye drops for topical administration to the oral mucosa, as an off-label treatment to manage sialorrhea. However, the off-label use of atropine eye drops can be associated with medication and dosing errors and systemic side effects. To address these limitations of treatment, we developed a mucoadhesive topical oral gel formulation of atropine as an alternative route to off-label administration of atropine eye drops. In this clinical pharmacokinetic (PK) study, we evaluated the safety and PK of atropine gel (0.01% w/w) formulation after single-dose administration to the oral mucosa in 10 healthy volunteers. The PK data showed that after topical administration to the oral mucosa, atropine followed a two-compartment PK profile. The maximum plasma concentration and area under the curve extrapolated to infinite time were 0.14 ng/mL and 0.74 h·ng·mL , respectively. The absorption rate constant calculated by the compartmental analysis was 0.4 h . Safety parameters, such as heart rate, blood pressure, and oxygen saturation, did not significantly change before and after administration of the gel formulation, and no adverse events were observed in all participants who received atropine gel. These data indicate that atropine gel formulation has a satisfactory PK profile, is well-tolerated at the dose studied, and can be further considered for clinical development as a drug product to treat sialorrhea.
Topics: Adult; Child; Humans; Healthy Volunteers; Quality of Life; Sialorrhea; Area Under Curve; Ophthalmic Solutions; Atropine Derivatives; Administration, Oral
PubMed: 38465519
DOI: 10.1111/cts.13753 -
JCI Insight Nov 2023The penetration of allergens through the epithelial layer is the initial step in the development of allergic conjunctivitis. Although pollinosis patients manifest...
The penetration of allergens through the epithelial layer is the initial step in the development of allergic conjunctivitis. Although pollinosis patients manifest symptoms within minutes after pollen exposure, the mechanisms of the rapid transport of the allergens remain unclear. In the present study, we found that the instillation of pollen shells rapidly induces a large number of goblet cell-associated antigen passages (GAPs) in the conjunctiva. Antigen acquisition by stromal cells, including macrophages and CD11b+ dendritic cells, correlated with surface GAP formation. Furthermore, a substantial amount of antigen was transported to the stroma during the first 10 minutes of pollen exposure, which was sufficient for the full induction of an allergic conjunctivitis mouse model. This inducible, rapid GAP formation and antigen acquisition were suppressed by topical lidocaine or trigeminal nerve ablation, indicating that the sensory nervous system plays an essential role. Interestingly, pollen shell-stimulated GAP formation was not suppressed by topical atropine, suggesting that the conjunctival GAPs and intestinal GAPs are differentially regulated. These results identify pollen shell-induced GAP as a therapeutic target for allergic conjunctivitis.
Topics: Animals; Mice; Humans; Conjunctivitis, Allergic; Goblet Cells; Allergens; Pollen; Conjunctiva
PubMed: 37819721
DOI: 10.1172/jci.insight.168596