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Aims: To compare the efficacy of two power levels in the 577 nm sub-threshold micro pulse laser (SML) treatment of acute central serous chorioretinopathy (aCSC). Methods: A retrospective comparative study was conducted. A total of 65 patients (65 eyes) with aCSC were enrolled. Of which, 32 patients received low power treatment and 33 patients received high power treatment of 577 nm SML. Best-corrected visual acuity (BCVA), central macular thickness (CMT), fundus-monitored microperimetry and height of subfoveal choroidal thickness (SFCT) as well as subretinal fluid (SRF) were evaluated at baseline and 3 months. Results: The height of SFCT and retinal sensitivity in the low power treatment group was significantly better than that in the high power treatment group at 4 weeks (all p < 0.001). Mean BCVA improved from baseline to 3 months after treatments but with no significant difference between the two groups after 3 months (p > 0.05). In the low power group, the CMT decreased from 379.76 ± 139.23 μm at baseline to 176.56 ± 37.78 μm at 3 months, and in the high power group, the CMT decreased from 364.97 ± 143.08 at baseline to 191.77 ± 38.26 μm at 3 months. There was no significant difference at 3 months between the two groups (p > 0.05). Similar results were also found in term of SRF. Conclusions: Timely intervention with 577 nm SML with low power treatment can improve visual acuity, and included anatomic success without adverse events.

Dopamine D3 receptor (D3R) is implicated in multiple psychotic symptoms. Increasing the D3R selectivity over dopamine D2 receptor (D2R) would facilitate the antipsychotic treatments. Herein, novel carbazole and tetrahydro-carboline derivatives were reported as D3R selective ligands. Through a structure-based virtual screen, ZLG-25 (D3R Ki = 685 nmol/L; D2R Ki > 10,000 nmol/L) was identified as a novel D3R selective bitopic ligand with a carbazole scaffold. Scaffolds hopping led to the discovery of novel D3R-selective analogs with tetrahydro-β-carboline or tetrahydro-γ-carboline core. Further functional studies showed that most derivatives acted as hD3R-selective antagonists. Several lead compounds could dose-dependently inhibit the MK-801-induced hyperactivity. Additional investigation revealed that 23j and 36b could decrease the apomorphine-induced climbing without cataleptic reaction. Furthermore, 36b demonstrated unusual antidepressant-like activity in the forced swimming tests and the tail suspension tests, and alleviated the MK-801-induced disruption of novel object recognition in mice. Additionally, preliminary studies confirmed the favorable PK/PD profiles, no weight gain and limited serum prolactin levels in mice. These results revealed that 36b provided potential opportunities to new antipsychotic drugs with the multiple antipsychotic-like properties.

The prevalence of visual impairment (VI) and age-related eye diseases has increased dramatically with the growing aging population in mainland China. However, there is limited comprehensive evidence on the progress of ophthalmic epidemiological research in mainland China to enhance our awareness of the prevention of eye diseases to inform public health policy. Here, we conducted a literature review of the population-based epidemiology of VI and age-related eye diseases in mainland China from the 1st of January 1946 to the 20th of October 2021. No language restrictions were applied. There was significant demographic and geographic variation in the epidemic of VI and age-related eye diseases. There are several factors known to be correlated to VI and age-related eye diseases, including age, gender, family history, lifestyle, biological factors, and environmental exposures; however, evidence relating to genetic predisposition remains unclear. In addition, posterior segment eye diseases, including age-related macular degeneration and diabetic retinopathy, are amongst the major causes of irreversible visual impairments in the senile Chinese population. There remains a significant prevention gap, with only a few individuals showing awareness and achieving optimal medical care with regards to age-related eye diseases. Multiple challenges and obstacles need to be overcome, including the accelerated aging of the Chinese population, the lack of structured care delivery in many underdeveloped regions, and unequal access to care. Despite the progress to date, there are few well-conducted multi-center population-based studies following a single protocol in mainland China, which findings can hopefully provide valuable cues for governmental decision-making and assist in addressing and halting the incidence of VI and age-related eye diseases in China.

ObjectiveGender differences in ocular biometric measurements of opposite-sex and same-sex twin pairs are still unclear. We aimed to investigate the difference between ocular biometric measurements in adolescent twin pairs.Materials and methodsThis retrospective study included a total of 64 eyes of 64 adolescents from 32 twins. The ocular biometric measurements and refractive prediction error (RE) were acquired from four groups of dizygotic (DZ) twins: boys from same-sex twin-pairs (SSM, n = 20), boys from opposite-sex twin-pairs (OSM, n = 8), girls from opposite-sex twin-pairs (OSF, n = 8), and girls from same-sex twin-pairs (SSF, n = 29).ResultsThe mean age of the patient was 9.92 ± 2.84 (range: 6–18) years. Overall, boys had higher height, AL, WTW, but lower Ks, and Kf than girls (p < 0.05). Specifically, SSF was found to have the lowest lens thickness (LT), anterior chamber depth (ACD), central corneal thickness (CCT), white to white (WTW), and axial length (AL) levels, while the highest keratometry readings in the flat (Kf) and steep (Ks) levels compared with OSM, OSF, and SSM adolescents (p < 0.05). Compared with the OSF adolescents, ACD levels of the SSF adolescents were significantly lower [(2.99 ± 0.35) and (3.26 ± 0.15) mm, p = 0.033)], but Kf indicator was significantly larger [(43.93 ± 1.64) and (42.91 ± 1.75), p = 0.016)].ConclusionOur study indicates that there was a significant difference in ocular biometric measurements between twin pairs, and sharing the uterus with a DZ twin SSF has smaller ocular indicator measurements. Our findings provide information on the eyeball and refractive development in adolescents.

Anoctamin 1 (ANO1) is a kind of calcium-activated chloride channel involved in nerve depolarization. ANO1 inhibitors display significant analgesic activity by the local peripheral and intrathecal administration. In this study, several thiophenecarboxylic acid and benzoic acid derivatives were identified as novel ANO1 inhibitors through the shape-based virtual screening, among which the 4-arylthiophene-3-carboxylic acid analogues with the best ANO1 inhibitory activity were designed, synthesized and compound 42 (IC50 = 0.79 μmol/L) was finally obtained. Compound 42 selectively inhibited ANO1 without affecting ANO2 and intracellular Ca2+ concentration. Subsequently, the analgesic effect was investigated by intragastric administration in pain models. Compound 42 significantly attenuated allodynia which was induced by formalin and chronic constriction injury. Through homology modeling and molecular dynamics, the binding site was predicted to be located near the calcium-binding region between α6 and α8. Our study validates ANO1 inhibitors having a significant analgesic effect by intragastric administration and also provides selective molecular tools for ANO1-related research.

Environmentally friendly microcapsules are becoming more and more widely used due to the increasing demand for environmental safety in pesticides. To compare the impact of differences in wheat herbicide phytotoxicity of different gibberellic acid microcapsule suspensions, two microcapsule suspensions were separately formulated using the phase transfer method and the in situ polymerization method, and the key performance indicators are the size of microcapsules and the degree of encapsulation. Meanwhile, through field trials, the pharmacological and detoxification effects of different types of microcapsule suspensions on the herbicide methyldisulfuron in wheat fields were compared. The microcapsule suspension was prepared by the phase transfer method and the particle sizes D10, D50, and D90 are 0.990, 2.136, and 5.201 μm, respectively; the microcapsule suspension was prepared by the in situ polymerization, the particle sizes D10, D50, and D90 are 4.365, 8.547, and 16.782 μm, respectively. The encapsulation rate of the microcapsules prepared by the phase transfer method and the in situ polymerization method was 86.9% and 91.2%, being higher than 80%, the national standard for capsules. Meanwhile, the release rate conforms to first-order release kinetics in 0–4 days and zero-order release kinetics in 5–28 days. The plot trials' result showed that the detoxification effect of the microcapsules prepared by the in situ polymerization method was significantly better than the detoxification effect of the microcapsules prepared by the phase transfer method and the control agent. The growth index of wheat was higher than that of the untreated check after using the agent.

Purpose: The purpose of the study is to evaluate the effects of 0.01% atropine eye drops on accommodative system parameters among teenagers with low myopia.Methods: Ninety-five myopic teenagers [39 boys (8.69 ± 2.473) and 56 girls (8.54 ± 2.054) aged 5–17 years] with no history of eye disease were enrolled. Biometric and accommodative system parameters were evaluated before and at 1 week, 1 month, 3 months, and 6 months of 0.01% atropine eye drop instillation.Results: Participants without accommodative demand at 6 months demonstrated insignificant changes after the atropine instillation (all p > 0.05). Nevertheless, there were significant differences in accommodative sensitivity, accommodative amplitude, accommodative responsiveness, and negative relative accommodation (NRA) at 3 months compared with baseline after atropine instillation (all p < 0.05). Except spherical equivalent refraction, cornea thickness, intraocular pressure, and axial length were stable after the 0.01% atropine instillation (all p > 0.05).Conclusion: Morphologically, current measurements suggested that 0.01% atropine had favorable reduction of accommodation for childhood low myopia over a half-year period.

Purpose: Dry eye disease (DED) is projected to have increasing public health burden in China with the aging population. No published studies on the epidemiology of DED have been found in grasslands. We estimated DED prevalence among older adults living in grasslands of northern China and investigated its associated factors and impact on vision-related quality of life (VR-QoL).Methods: A multistage cluster random sampling technique was used to select Mongolian and Han participants aged over 40 from November 2020 to May 2021 in this area. An assessment of DED was performed with Ocular Surface Disease Index (OSDI) questionnaire, Schirmer's I test (ST), and Tear film break up time (TBUT). All the participants completed the Chinese version of National Eye Institute Visual Function Questionnaire (NEI-VFQ-25) assessing VR-QoL.Results: Of the 1,400 enumerated residents, 1,287 were examined. The overall age and gender standardized prevalence of DED was 34.5%, of which, 32.6% of Mongolian and 35.4% of Han had DED. In a multivariate model, statistically significant associations were found with advancing age [odds ratio (OR) 1.03, 95% confidence interval (CI) 1.02–1.04], female gender (OR 1.32, 95% CI 1.04–1.68), smoking (OR 0.7, 95% CI 0.5–0.98), anti-fatigue eye-drop use (OR 0.56, 95% CI 0.41–0.77), milk product intake (OR 0.55, 95% CI 0.39–0.77), number of household members (OR 0.8, 95% CI 0.72–0.88). DED was associated with lower scores on VR-QoL (β= −0.14, P < 0.01). Similar results were observed when analyses were stratified by ethnicity.Conclusions: The novelty-associated factors for DED in the grasslands area were anti-fatigue eye drop use, milk product intake, and number of household members. DED and its components were associated with VR-QoL. Further prospective studies are needed to confirm these findings.

Neuropathic pain is often closely associated with nerve injury or inflammation, and the role of traditional nonsteroidal anti-inflammatory drugs as adjuvants for treating chemotherapy-induced peripheral neuropathic pain remains unclear. In this study, the potential synergistic antinociceptive effects of indomethacin–pregabalin and meloxicam–pregabalin were evaluated in paclitaxel-induced neuropathic pain and carrageenan-induced inflammatory pain in rodents. Although indomethacin and meloxicam alone only slightly relieved mechanical allodynia in the above two models, isobolographic analysis showed that the combination of indomethacin or meloxicam with pregabalin produced significant synergistic antinociceptive effects for paclitaxel-induced neuropathic pain (IN-PGB, experimental ED25 = [4.41 (3.13–5.82)] mg/kg, theoretical ED25 = [8.50 (6.62–10.32)] mg/kg; MEL-PGB, experimental ED25 = [3.96 (2.62–5.46)] mg/kg, theoretical ED25 = [7.52 (5.73–9.39)] mg/kg). In addition, MEL-PGB dosed via intraplantar injection into the left paw, intragastric injection, or intraperitoneal injection reversed paclitaxel-induced allodynia, indicating that they may act at multiple sites in the neuroaxis and periphery. However, indomethacin–pregabalin and meloxicam–pregabalin exerted antagonistic antiallodynic interactions in carrageenan-induced inflammatory pain in rats. Taken together, coadministration of indomethacin or meloxicam with pregabalin may possess potential therapeutic advantages for treating chemotherapy-induced neuropathic pain.

Olanzapine is a commonly used drug in the treatment of schizophrenia, but its clinical application has been restricted by metabolic-related side effects. In order to mitigate the weight gain side effects caused by olanzapine, other drugs with different targets were selected for combined use and evaluated in animal models of schizophrenia. SEP-363856 is a novel psychotropic agent which is under phase III clinical trials for schizophrenia treatment. The aim of the research was to evaluate whether co-administration of olanzapine and SEP-363856 exerts synergistic anti-schizophrenic effects in the apomorphine (APO)-induced climbing test, the MK-801-induced hyperactivity test, and the Morris water maze test, and therefore reduces the weight gain side effects induced by olanzapine. Through isobolographic analysis, the results showed a synergistic interaction in the climbing test; the experimental ED30 (3 mg/kg) was significantly smaller (p < 0.05) than the theoretical ED30 (5 mg/kg). Additionally, such potentiating effects appeared additive in the MK-801 challenge experiment. Co-treatment with an effective dose of olanzapine and a low dose of SEP-363856 reversed MK-801-induced cognitive impairment symptoms in mice. Moreover, combination treatment with olanzapine and SEP-363856 controls sustained weight gain in mice with chronic exposure to olanzapine. These results support further clinical trials to test the effectiveness of co-treatment of olanzapine and SEP-363856 for controlling symptoms and weight gain in patients with schizophrenia during antipsychotic treatments.

Here, we explored the possible interaction between duloxetine and SEP-363856 (SEP-856) in depression-related reactions. The results showed that oral administration of duloxetine showed powerful antidepressant-like effects in both the forced swimming test (FST) and the suspension tail test (TST). SEP-856 orally administered alone also exerted an antidepressant-like effect in FST and TST, especially at doses of 0.3, 1, and 10 mg/kg. In addition, duloxetine (15 mg/kg) and SEP-856 (15 mg/kg) both showed antidepressant-like effects in the sucrose preference test (SPT). Most importantly, in the above experiments, compared with duloxetine alone, the simultaneous use of duloxetine and SEP-856 caused a more significant antidepressant-like effect. It is worth noting that doses of drug combination in FST and TST did not change the motor activities of mice in the open-field test (OFT). Thus, duloxetine and SEP-856 seem to play a synergistic role in regulating depression-related behaviors and might be beneficial for refractory depression.

Background: Myelination, degeneration and regeneration are implicated in crucial responses to injury in the peripheral nervous system. Considering the progression of amyotrophic lateral sclerosis (ALS), we used the superoxide dismutase 1 (SOD1)-G93A transgenic mouse model of ALS to investigate the effects of mutant SOD1 on the peripheral nerves. Methods: Changes in peripheral nerve morphology were analyzed in SOD1 mutant mice at various stages of the disease by toluidine blue staining and electron microscopy (EM). Schwann cell proliferation and recruitment of inflammatory factors were detected by immunofluorescence staining and quantitative reverse transcription PCR and were compared between SOD1 mutant mice and control mice. Furthermore, western blotting (WB) and TUNEL staining were used to investigate axonal damage and Schwann cell survival in the sciatic nerves of mice in both groups. Results: An analysis of the peripheral nervous system in SOD1-G93A mice revealed the following novel features: (i) Schwann cells and axons in mutant mice underwent changes that were similar to those seen in the control mice during the early development of peripheral nerves. (ii) The peripheral nerves of SOD1-G93A mice developed progressive neuropathy, which presented as defects in axons and myelin, leading to difficulty in walking and reduced locomotor capacity at a late stage of the disease. (iii) Macrophages were recruited and accumulated, and nerve injury and a deficit in the blood-nerve barrier were observed. (iv) Proliferation and the inflammatory micro-environment were inhibited, which impaired the regeneration and remyelination of axons after crush injury in the SOD1-G93A mice. Conclusions: The mutant human SOD1 protein induced axonal and myelin degeneration during the progression of ALS and participated in axon remyelination and regeneration in response to injury.

Palbociclib (PAL) is an effective anti-breast cancer drug, but its use has been partly restricted due to poor bioavailability (resulting from extremely low water solubility) and serious adverse reactions. In this study, two cocrystals of PAL with resorcinol (RES) or orcinol (ORC) were prepared by evaporation crystallization to enhance their solubility. The cocrystals were characterized by single crystal X-ray diffraction, Hirshfeld surface analysis, powder X-ray diffraction, differential scanning calorimetry, thermogravimetric analysis, Fourier transform infrared and scanning electron microscopy. The intrinsic dissolution rates of the PAL cocrystals were determined in three different dissolution media (pH 1.0, pH 4.5 and pH 6.8), and both cocrystals showed improved dissolution rates at pH 1.0 and pH 6.8 in comparison to the parent drug. In addition, the cocrystals increased the solubility of PAL at pH 6.8 by 2–3 times and showed good stabilities in both the accelerated stability testing and stress testing. The PAL-RES cocrystal also exhibited an improved relative bioavailability (1.24 times) than PAL in vivo pharmacokinetics in rats. Moreover, the in vitro cytotoxicity assay of PAL-RES showed an increased IC50 value for normal cells, suggesting a better biosafety profile than PAL. Co-crystallization may represent a promising strategy for improving the physicochemical properties of PAL with better pharmacokinetics.

Cocrystallization is an important route to tuning the solubility in drugs development, including improving and reducing. Five cocrystals of aripiprazole (ARI) with resveratrol (RSV) and kaempferol (KAE), ARI-RSV, ARI2-RSV1·MeOH, ARI-KAE, ARI-KAE·EtOH, ARI-KAE·IPA, were synthesized and characterized. The single crystal of ARI2-RSV1·MeOH, ARI-KAE·EtOH, and ARI-KAE·IPA were analyzed by single crystal X-ray diffraction (SCXRD). The SCXRD showed multiple intermolecular interactions between API and the coformers, including hydrogen bond, halogen bond, and π-π interactions. Dissolution rate of the two nonsolvate ARI-RSV and ARI-KAE cocrystals were investigated through powder dissolution experiment in pH = 4.0 acetate buffer and pH = 6.8 phosphate buffer. The result showed that RSV could reduce the dissolution rate and solubility of ARI in both medium through cocrystallization. However, KAE improved the dissolution rate and solubility of ARI in pH = 4.0 medium, on the contrary, the two solubility indicators of ARI were both reduced for ARI-KAE cocrystal.

The design of a series of novel flavone derivatives was synthesized as potential broad-spectrum antipsychotics by using multi-receptor affinity strategy between dopamine receptors and serotonin receptors. Among them, 7-(4-(4-(6-fluorobenzo[d]isoxazol-3-yl) piperidin- 1-yl) butoxy)-2,2-dimethylchroman-4-one (6j) exhibited a promising preclinical profile. Compound 6j not only showed high affinity for dopamine D2, D3, and serotonin 5-HT1A, 5-HT2A receptors, but was also endowed with low to moderate activities on 5-HT2C, α1, and H1 receptors, indicating a low liability to induce side effects such as weight gain, orthostatic hypotension and QT prolongation. In vivo behavioral studies suggested that 6j has favorable effects in alleviating the schizophrenia-like symptoms without causing catalepsy. Taken together, compound 6j has the potential to be further developed as a novel atypical antipsychotic.

In this work, a series of arylpiperazine derivatives were synthesized and screened by in vivo pharmacological trials. Among the tested compounds, 2-(4-(3-(trifluoromethyl)phenyl)piperazin-1-yl)-1-phenylethanone (18) and 2-(4-(2,3-dimethylphenyl)piperazin-1-yl)-1-phenylethanone (19) exhibited potent analgesic activities in both the mice writhing and mice hot plate tests. They showed more than 70% inhibition relative to controls in the writhing test, and increased latency by 116.0% and 134.4%, respectively, in the hot plate test. Furthermore, compound 18 was also active in the models of formalin pain and neuropathic pain without sedative side effects.

GLYX-13, a NMDAR glycine-site partial agonist, was discovered as a promising antidepressant with rapidly acting effects but no ketamine-like side effects. However, the reported synthetic process route had deficiencies of low yield and the use of unfriendly reagents. Here, we report a scaled-up synthesis of GLYX-13 with an overall yield of 30% on the hectogram scale with a column chromatography-free strategy, where the coupling and deprotection reaction conditions were systematically optimized. Meanwhile, the absolute configuration of precursor compound of GLYX-13 was identified by X-ray single crystal diffraction. Finally, the activity of GLYX-13 was verified in the cortical neurons of mice through whole-cell voltage-clamp technique.

BACKGROUND: Soft drugs are molecules that are purposefully designed to be rapidly metabolized (metabolically labile). In anesthesia, the soft drug is useful because it enables precise titration to effect and rapid recovery, which might allow swift and clear-headed recovery of consciousness and early home readiness. Propofol may cause delayed awakening after prolonged infusion. Propanidid and AZD3043 have a different metabolic pathway compared to propofol, resulting in a short-acting clinical profile. Fluorine imparts a variety of properties to certain medicines, including an enhanced absorption rate and improved drug transport across the blood-brain barrier. We hypothesized that the introduction of fluorine to the frame structure of propanidid and AZD3043 would further accelerate the swift and clear-headed recovery of consciousness. To test this hypothesis, we developed a series of fluorine-containing phenyl acetate derivatives. METHODOLOGY/PRINCIPAL FINDINGS: Fluorine-containing phenyl acetate derivatives were synthesized, and their hypnotic potencies and durations of LORR following bolus or infusion administration were determined in mice, rats and rabbits. The metabolic half-lives in the blood of various species were determined chromatographically. In vitro radioligand binding and γ-aminobutyric acidA (GABAA) receptor electrophysiology studies were performed. Among the 12 synthesized fluorine-containing phenyl acetate derivatives, compound 5j induced comparable duration of LORR with AZD3043, but more rapid recovery than AZD3043, propanidid and propofol. The time of compound 5j to return to walk and behavioral recovery are approximately reduced by more than 50% compared to AZD3043 in mice and rats and rabbits. The HD50 of compound 5j decreased with increasing animal size. CONCLUSIONS/SIGNIFICANCE: The rapid recovery might make compound 5j suitable for precise titration and allow swift and clear-headed recovery of consciousness and early home readiness.

BACKGROUND: It is important to develop novel antipsychotics that can effectively treat schizophrenia with minor side-effects. The aim of our work is to develop novel antipsychotics that act on dopamine D(2) and D(3), serotonin 5-HT(1A) and 5-HT(2A) receptors with low affinity for the serotonin 5-HT(2C) and H(1) receptors, which can effectively cure positive symptoms, negative symptoms and cognitive impairment without the weight gain side-effect. METHODOLOGY/PRINCIPAL FINDINGS: A series of 2-substituted-5-thiopropylpiperazine (piperidine) -1,3,4-oxadiazoles derivatives have been synthesized and the target compounds were evaluated for binding affinities to D(2), 5-HT(1A) and 5-HT(2A) receptors. Preliminary results indicated that compounds 14, 16 and 22 exhibited high affinities to D(2), 5-HT(1A) and 5-HT(2A) receptors among these compounds. Further binding tests showed that compound 22 had high affinity for D(3) receptor, and low affinity for serotonin 5-HT(2C) and H(1) receptors. In addition, compound 22 inhibited apomorphine-induced climbing behavior and MK-801-induced hyperactivity with no extrapyramidal symptoms liability in mice. Moreover, compound 22 exhibited acceptable pharmacokinetic properties. CONCLUSIONS/SIGNIFICANCE: Compound 22 showed an atypical antipsychotic activity without liability for extrapyramidal symptoms. We anticipate compound 22 to be useful for developing a novel class of drug for the treatment of schizophrenia.