Novel drug-drug salt crystals of metformin with ibuprofen or naproxen: Improved solubility, dissolution rate, and synergistic antinociceptive effects.

As the monotherapy of available analgesics is usually accompanied by serious side effects or limited efficacy in the management of chronic pain, multimodal analgesia is widely used to achieve improved benefit-to-risk ratios in clinic. Drug-drug salts are extensively researched to optimize the physicochemical properties of active pharmaceutical ingredients (APIs) and achieve clinical benefits compared with individual APIs or their combination. New drug-drug salt crystals metformin-ibuprofen (MET-IBU) and metformin-naproxen (MET-NAP) were prepared from metformin (MET) and two poorly water-soluble anti-inflammatory drugs (IBU and NAP) by the solvent evaporation method. The structures of these crystals were confirmed by single crystal and powder X-ray diffraction, Hirshfeld surface, Fourier transform infrared spectroscopy and thermal analysis. Both MET-IBU and MET-NAP showed significantly improved solubility and intrinsic dissolution rate than the pure IBU or NAP. The stability test indicated that MET-IBU and MET-NAP have excellent physical stability under stressing test (10 days) and accelerated conditions (3 months). Moreover, isobolographic analysis suggested that MET-IBU and MET-NAP exerted potent and synergistic antinociceptive effects in λ-Carrageenan-induced inflammatory pain in mice, and both of them had an advantage in rapid pain relief. These results demonstrated the potential of MET-IBU and MET-NAP to achieve synergistic antinociceptive effects by developing drug-drug salt crystals.

Removal of Cd from solution and in-situ remediation of Cd-contaminated soil by a mercapto-modified cellulose/bentonite intercalated nanocomposite.

A novel intercalated nanocomposite of mercapto-modified cellulose/bentonite (LCS-BE-SH) was synthesized by high-speed shearing method in one step at room temperature, and was applied to remove Cd from solution and remediate Cd-contaminated soil. Results revealed that cellulose long-chain molecules have intercalated into bentonite nanolayers and interlayer spacing was increased to 1.411 nm, and grafting -SH groups improved adsorption selectivity, which enabled LCS-BE-SH to have distinct capability of Cd adsorption (qmax = 147.21 mg/g). Kinetic and thermodynamics showed that Cd adsorption onto LCS-BE-SH was well fitted by pseudo-second-order and Langmuir adsorption isotherm. Characterizations of the adsorbents revealed that synergistic effect of complexation (e.g., CdS, CdO) and precipitation (e.g., Cd(OH)2, CdCO3) mechanism played a major role in Cd removal. In soil remediation, application of LCS-BE-SH was most effective (67.31 %) in Cd immobilization compared to the control (8.85 %), which reduced exchangeable Cd from 37.03 % to 11.44 %. Meanwhile, soil pH, soil organic matter, available phosphorus, and enzyme activities (catalase, urease, and dehydrogenase) were improved LCS-BE-SH treatment. The main immobilization mechanism in soil included complexation (e.g., CdS, CdO) and precipitation (e.g., Cd(OH)2, Cd-Fe-hydroxide). Overall, this work applied a promising approach for Cd removal in aqueous and Cd remediation in soil by using an effective eco-friendly LCS-BE-SH nanocomposites.

Thiophenpiperazine amide derivatives as new dual MOR and σ1R ligands for the treatment of pain.

A new series of thiophenpiperazine amide derivatives as potent dual ligands for the µ-opioid (MOR) and sigma-1 (σ1R) receptors are reported. Compound 23 exhibited good affinity to σ1R (Ki = 44.7 ± 7.05 nM) and high selectivity to σ2R. Furthermore, Compound 23 exerted MOR agonism and σ1R antagonism and potent analgesic activity in animal moldes (the abdominal constriction test (ED50 = 3.83 mg/kg) and carrageenan-induced inflammatory hyperalgesia model (ED50 = 5.23 mg/kg)). We obtained new dual ligands that might serve as starting points for preparing targeted tools. Furthermore, 23 may be a useful chemical probe for understanding more fully analgesic effects associated with MOR agonism and σ1R antagonism.

Carbazole and tetrahydro-carboline derivatives as dopamine D3 receptor antagonists with the multiple antipsychotic-like properties.

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-ß-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.

Two different initial treatment regimens of Conbercept in diabetic macular edema: 12-month results from a multicenter randomized controlled study.

BACKGROUND: The optimal treatment regimen for diabetic macular edema (DME) and predictors for its treatment`s outcome need emerging evidence but currently poorly studied. METHODS: A prospective, multicenter, open label randomized controlled study among adult patients with DME was conducted. Eyes were randomized to three or six doses initial Conbercept treatments. Additional injections were suggested pro re nata (PRN) over 12 months. Optical coherence tomography angiography (OCTA) was adopted to quantify the macular vessel density. Visual acuity gain and anatomical improvement and their associated factors were evaluated by multivariable linear regression. RESULTS: 41 patients with 59 eyes participated in current study. Patients in both 3 + PRN (n = 32 eyes) or 6 + PRN (n = 27 eyes) treatments experienced similar best-corrected visual acuity (BCVA) gain and anatomical improvement, including the central macular thickness, foveal avascular aone (FAZ) and the retinal vessel density. Over 12 months, eyes in the 6 + PRN group received better changes of the deep capillary plexus (2.53 ± 5.45%). In multivariate linear regression, the age significantly affected visual outcome in 3 + PRN group (ß = -0.014, P = 0.028), while the initial CMT (ß = -0.001, P = 0.022) and FAZ area (ß = -0.946, P = 0.007) associated with visual outcome in 6 + PRN group. Furthermore, the duration of diabetes exhibited significant results on CMT among 3 + PRN group (ß= -7.516, P = 0.04). CONCLUSIONS: Both 3 + and 6 + initial treatment regimens of Conbercept loading dose achieved parallel anatomical and functional visual improvement, while 6 + group had a trend of better treatment outcome. Older age, higher initial CMT and longer duration of diabetes might influence the clinical outcomes over 12 months from baseline.

Pregabalin can interact synergistically with Kv7 channel openers to exert antinociception in mice.

Chronic pain is a common public health problem and remains an unmet medical need. Currently available analgesics usually have limited efficacy for the treatment of chronic pain, including neuropathic pain and persistent inflammatory pain, or they are accompanied by many adverse side effects. The voltage-gated calcium channel blocker (pregabalin) and potassium channel openers (flupirtine and retigabine) have been widely used for the management of chronic pain, but their effectiveness in combination is unclear. In this research, we evaluated the antinociceptive effects of pregabalin in combination with flupirtine or retigabine in carrageenan-induced inflammatory pain and paclitaxel-induced peripheral neuropathy in mice using the von Frey test. Isobolographic analysis indicated that pregabalin exerted synergistic antinociceptive effects when combined with flupirtine or retigabine in neuropathic and inflammatory pain models. Furthermore, the antinociceptive effects of pregabalin, flupirtine/retigabine, and their combinations were significantly attenuated by the Kv7 channel blocker XE991. The favored dose ratio between pregabalin and flupirtine/retigabine in combinations was also investigated. Finally, we evaluated the motor coordination of their combinations using the rotarod test, and the outcomes underpinned their safety. Collectively, our results support the potential use of pregabalin in combination with flupirtine or retigabine to alleviate chronic pain.

Evaluating the One-Year Efficacy of Combined Anti-VEGF and Dexamethasone Implant Treatment for Macular Edema in Retinal Vein Occlusions.

BACKGROUND Retinal vein occlusion-induced macular edema (RVO-ME) is a significant global cause of vision loss, with the effectiveness of combined anti-vascular endothelial growth factor (anti-VEGF) drugs and dexamethasone implantation (DEX I) being a relevant, yet not thoroughly explored, area of interest.The aim of this study was to evaluate the 1-year clinical efficacy of combination therapy using anti-vascular endothelial growth factor (VEGF) drugs and dexamethasone implantation (DEX I) in the treatment of macular edema secondary to retinal vein occlusion (RVO-ME). MATERIAL AND METHODS This retrospective study analyzed data from 34 RVO-ME patients treated at the Inner Mongolia Chaoju Eye Hospital between January 2020 and December 2021. All patients underwent initial DEX I treatment, followed by the introduction of anti-VEGF drugs, and were observed for one year. Retinal structural and vascular changes were measured using spectral domain optical coherence tomography (SD-OCT) and OCT angiography (OCTA). The study also evaluated shifts in best corrected visual acuity (BCVA) throughout the observation period. RESULTS Following the combined therapy, patients showed significant improvements in BCVA, intraocular pressure (IOP), central retinal thickness (CRT), and retinal vessel density (VD) (all P<0.05). Upon stratifying the results by RVO type, patients with branch retinal vein occlusion (BRVO)-ME displayed more significant BCVA improvement and CRT reduction at various post-treatment intervals compared to those with central retinal vein occlusion (CRVO)-ME (all P<0.05). CONCLUSIONS The combined use of anti-VEGF drugs and DEX I showed promising one-year efficacy in treating RVO-ME, with greater improvements noted in patients with BRVO-ME compared to those with CRVO-ME. Despite the positive results, close monitoring of IOP elevation, a notable side effect, remains crucial.

Changes in choroidal thickness in myopic children with 0.01% atropine: Evidence from a 12-month follow-up.

PURPOSE: To investigate the changes of low-dose atropine (0.01%) on the choroidal thickness (ChT) of young children with low myopia. METHODS: A total of 25 eyes of 25 low myopic children were included. All subjects were prescribed 0.01% atropine eye drops to be applied once per night before bedtime in involving eyes. The ChT and ocular biometry parameters were measured before and after 1 month, 3 months, 6 months and 12 months. The children were followed up for 12 months. RESULTS: At 3 months, the ChT under the fovea significantly increased (309.96±70.82 µm) in comparison with the baseline (297.92±66.31 µm, P<0.0001) and was continuous thickening till 12 months after treatments with 0.01% atropine. Similarly, the changes of ChT under the fovea significantly increased from baseline to 3 months in comparison with the baseline to 1 month after treatments (P<0.0001). There was a significant relationship between changes in subfoveal ChT and central cornea thickness (CCT, beta=-1.76, 95% confidence intervals: -3.49 to -0.04, P = 0.045). CONCLUSIONS: Using low dose atropine eye drops significantly increased subfoveal ChT after 3 months in eyes of myopic children. In addition, the changes in subfoveal ChT may be associated with the changes of CCT.

Flupirtine and antihistamines exert synergistic anti-nociceptive effects in mice.

RATIONALE: Drug combinations are commonly used in pain management, which can produce potent analgesic effects with reduced dosage and adverse effects. OBJECTIVE: This study was designed to evaluate the anti-nociceptive effects and adverse effects of new combinations of flupirtine (a Kv7 potassium channel opener) and antihistamines (promethazine, fexofenadine) on acute and chronic pain in mice, and the possible mechanisms behind the synergistic analgesic effects were preliminarily investigated. METHODS: In acetic acid writhing test, carrageenan-induced inflammatory pain model, and paclitaxel-induced neuropathic pain model, the interaction indexes (γ) between flupirtine and antihistamines were determined by isobolographic analysis. Furthermore, the Kv7 channel blocker XE991 was used to determine whether the effects of single agents and drug combinations on paclitaxel- and carrageenan-induced mechanical allodynia were mediated by Kv7 channels. Finally, hepatotoxicity markers, liver histopathology, and the rotarod test were used to investigate the adverse effects of drugs in combination doses. RESULTS: The interaction indexes of flupirtine-promethazine and flupirtine-fexofenadine in all the above three pain models were lower than 1. The analgesic effects of flupirtine (13 mg/kg), promethazine (5 mg/kg), fexofenadine (20 mg/kg), and their combinations were antagonized significantly by XE991 (3 mg/kg). And the adverse effects of flupirtine and antihistamines in combination doses were not significantly different from the vehicle group. CONCLUSIONS: Flupirtine and antihistamines produced synergistic analgesic effects in all the above pain models. The analgesic effects of antihistamines were partially mediated by Kv7/M channels, and the activation of Kv7/M channels may be partly responsible for the synergistic analgesic effects between flupirtine and antihistamines.

Design, synthesis and evaluation of heterocyclic 2-phenylacetate derivatives as water-soluble rapid recovery hypnotics.

In this work, a series of novel heterocyclic 2-phenylacetate derivatives were designed and synthesized as water-soluble and rapid recovery hypnotic agents. After introducing heterocyclic ring to the amide group of propanidid, the obtained propanidid derivatives showed greatly improved hydrophilicity and good anesthetic activity. In three animal experiments (mice, rats, and rabbits), compounds 13-15 showed potent hypnotic potency (HD50 = 7.6, 6.5, 7.4 mg/kg in rabbits, respectively) and higher therapeutic indexes (TI = 17.3, 16.6, 15.2 in rabbits, respectively) than propanidid (TI = 14.7 in rabbits) or propofol (TI = 5.4 in rabbits). Moreover, the recovery time of compounds 13-15 (time to walk, 96.6, 79.6, 81.4 s in rabbits, respectively) were shorter than that of propanidid (124.5 s in rabbits) or propofol (425.3 s in rabbits). The experimental results suggested the potential of compounds 13-15 as water-soluble anesthetics with rapid recovery profile.

Foveal avascular zone in normal human eyes by optical coherence tomography angiography.

OBJECTIVE: To analyze the influence factors of the area of superficial plexus foveal avascular zone (FAZ) and related indexes of fovea measured with optical coherence tomography angiography (OCT-A) in normal subjects. METHODS: This was a cross-sectional study from November 2020 to May 2021 in the Inner Mongolia Autonomous Region, China. Each subject received related eye examination. The correlation between all the factors and superficial plexus FAZ were analyzed under univariable and multivariable linear regression analysis. RESULTS: Finally, 239 subjects with sufficient data were recruited in the study, including 108 males and 131 females, aged 27.41±4.63 years. The area of superficial plexus FAZ was 0.33±0.16 mm2. In the univariate regression, gender (ß = 41.702, 95%CI: 9.152 to 74.253, P = 0.012), drinking (ß = -66.074, 95%CI: -99.197 to -32.951, P = 0.001) and axial length (ß = -15.874, 95%CI: -29.562 to -2.185, P = 0.023) were associated with superficial plexus FAZ area. In multivariate regression analysis results, drinking (ß = -42.410, 95%CI = -79.388 to -5.432, P = 0.025) was significantly correlated with superficial plexus FAZ area. CONCLUSION: The area of superficial plexus FAZ was not affected by age, gender, systematical and biochemical indicators, but related to the status of drinking.

Local auxin biosynthesis regulates brace root angle and lodging resistance in maize.

Root lodging poses a major threat to maize production, resulting in reduced grain yield and quality, and increased harvest costs. Here, we combined expressional, genetic, and cytological studies to demonstrate a role of ZmYUC2 and ZmYUC4 in regulating gravitropic response of the brace root and lodging resistance in maize. We show that both ZmYUC2 and ZmYUC4 are preferentially expressed in root tips with partially overlapping expression patterns, and the protein products of ZmYUC2 and ZmYUC4 are localized in the cytoplasm and endoplasmic reticulum, respectively. The Zmyuc4 single mutant and Zmyuc2/4 double mutant exhibit enlarged brace root angle compared with the wild-type plants, with larger brace root angle being observed in the Zmyuc2/4 double mutant. Consistently, the brace root tips of the Zmyuc4 single mutant and Zmyuc2/4 double mutant accumulate less auxin and are defective in proper reallocation of auxin in response to gravi-stimuli. Furthermore, we show that the Zmyuc4 single mutant and the Zmyuc2/4 double mutant display obviously enhanced root lodging resistance. Our combined results demonstrate that ZmYUC2- and ZmYUC4-mediated local auxin biosynthesis is required for normal gravity response of the brace roots and provide effective targets for breeding root lodging resistant maize cultivars.

Agreement of anterior segment measurements between LenStar LS 900 optical biometer and OPD Scan III wavefront aberrometer devices in eyes with cataract.

PURPOSE: To compare the inter-device agreement of anterior eye segment measurements between LenStar LS 900 optical biometer and OPD Scan III wavefront aberrometer. METHODS: This is a retrospective study involving 59 patients (78 eyes) with cataract. Their angle Alpha, angle Kappa, pupil size and white-to-white (WTW) distance were measured by LenStar LS 900 optical biometer and OPD Scan III wavefront aberrometer, respectively, and pairwise agreement comparisons were performed between them. RESULTS: The most agreement of various parameters was occurred, with intraclass correlation coefficient (ICC) of WTW = 0.930; angle Alpha = 0.853; angle Kappa = 0.898; and pupil size = 0,976 in bright environment. Furthermore, in dark environment, the ICC of WTW, angle Alpha, angle Kappa, and pupil size were 0.927, 0.791, 0.915, and 0.990, respectively. Bland-Altman plot showed similar excellent agreement in the outcomes of the two devices for these measurements testing. CONCLUSIONS: There was an excellent agreement between the LenStar LS 900 optical biometer and OPD Scan III wavefront aberrometer for WTW, angle Alpha, angle Kappa, and pupil size measurements. In clinical practice, these measurements obtained by LenStar LS 900 optical biometer and OPD Scan III wavefront aberrometer can be used interchangeably.

UB2/UB3/TSH4-anchored transcriptional networks regulate early maize inflorescence development in response to simulated shade.

Increasing planting density has been adopted as an effective means to increase maize (Zea mays) yield. Competition for light from neighbors can trigger plant shade avoidance syndrome, which includes accelerated flowering. However, the regulatory networks of maize inflorescence development in response to high-density planting remain poorly understood. In this study, we showed that shade-mimicking treatments cause precocious development of the tassels and ears. Comparative transcriptome profiling analyses revealed the enrichment of phytohormone-related genes and transcriptional regulators among the genes co-regulated by developmental progression and simulated shade. Network analysis showed that three homologous Squamosa promoter binding protein (SBP)-like (SPL) transcription factors, Unbranched2 (UB2), Unbranched3 (UB3), and Tasselsheath4 (TSH4), individually exhibited connectivity to over 2,400 genes across the V3-to-V9 stages of tassel development. In addition, we showed that the ub2 ub3 double mutant and tsh4 single mutant were almost insensitive to simulated shade treatments. Moreover, we demonstrated that UB2/UB3/TSH4 could directly regulate the expression of Barren inflorescence2 (BIF2) and Zea mays teosinte branched1/cycloidea/proliferating cell factor30 (ZmTCP30). Furthermore, we functionally verified a role of ZmTCP30 in regulating tassel branching and ear development. Our results reveal a UB2/UB3/TSH4-anchored transcriptional regulatory network of maize inflorescence development and provide valuable targets for breeding shade-tolerant maize cultivars.

Sex differences in ocular biometric measurements: A twin study.

Objective: Gender 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 methods: This 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). Results: The 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)]. Conclusion: Our 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.

Epidemiology, health policy and public health implications of visual impairment and age-related eye diseases in mainland China.

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.

Benzylaminofentanyl derivates: Discovery of bifunctional µ opioid and σ1 receptor ligands as novel analgesics with reduced adverse effects.

To develop safer and potent analgesics, we designed, synthesized, and evaluated a new series of benzylaminofentanyl derivates as bifunctional µ opioid receptor (MOR) and σ1 receptor (σ1R) ligands. Compound 68 (Tao-191) showed desirable MOR agonism (Ki = 6.5 nΜ; EC50 = 48.5 nΜ, Emax = 66.3%) and σ1R antagonism (Ki = 35.7 nM) in vitro, and exerted powerful analgesic effects in the abdominal constriction test (ED50 = 0.32 mg/kg, in mice), formalin-induced pain test (phase II, ED50 = 2.26 mg/kg, in rats), and paclitaxel-induced neuropathic pain model (ED50 = 0.30 mg/kg, in mice). The contributions of MOR and σ1R to its antinociceptive effect were verified by combined administration with the MOR antagonist naloxone and the σ1R agonist PRE-084, respectively. At equianalgesic doses, compound 68 induced fewer MOR-related side effects-including physical and psychological dependence, respiratory depression, constipation, and acute hyperlocomotion-than fentanyl. The results provide a rationale for further exploration of the action and safety of dual MOR/σ1R ligands as a promising avenue for the development of potent and safe analgesics.

Effects of Different Environment-Friendly Gibberellic Acid Microcapsules on Herbicide Injury of Wheat.

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.

Synergistic Antinociceptive Effects of Indomethacin-Pregabalin and Meloxicam-Pregabalin in Paclitaxel-Induced Neuropathic Pain.

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.

The Potential Antidepressant Action of Duloxetine Co-Administered with the TAAR1 Receptor Agonist SEP-363856 in Mice.

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.