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OBJECTIVES: Allergic diseases and Meniere's disease found to have a possible link in observational study. However, the potential causal relationship between the two is unclear. Therefore, we aimed to explore the causal relationship between allergic diseases and Meniere's disease using a new data analysis technique called bidirectional Mendelian randomization study. METHOD: Summary-level statistics for Meniere's disease and three allergic diseases (asthma, allergic rhinitis, eczema/dermatitis) were obtained from large-scale genome-wide association studies. The inverse variance weighted method was used as the primary measure, supplemented by MR-Egger regression and the weighted median method. To ensure the reliability of the conclusions, Cochran's Q, MR-Egger intercept, MR-PRESSO test, leave-one-out test, and MR Steiger test were used. RESULTS: Inverse-variance weighted method showed asthma (pâ¯=â¯0.008, OR = 3.908, 95% CI 1.424-10.724, adjust_pâ¯=â¯0.024), allergic rhinitis (pâ¯=â¯0.026, OR = 24.714, 95% CI 1.479-412.827, adjust_pâ¯=â¯0.026) and eczema/dermatitis (pâ¯=â¯0.019, OR = 3725.954, 95% CI 3.795 to 3,658,399.580, adjust_pâ¯=â¯0.029) all had a significant effect on Meniere's disease. Reverse Mendelian randomization studies have shown that Meniere's disease does not increase the risk of three allergic diseases. Sensitivity analysis showed no horizontal pleiotropy and heterogeneity for each trait. CONCLUSION: Our Mendelian randomization analysis supports a positive causal relationship between three allergic diseases (asthma, allergic rhinitis, eczema/dermatitis) and Meniere's disease. This suggests that physicians should pay more attention to the Meniere's patient's allergy history and consider allergy avoidance as part of their treatment plan. LEVEL OF EVIDENCE: Mendelian Randomized (MR) studies are second only to randomized controlled trials in terms of the level of evidence.
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BACKGROUND: The prescription of Chinese herbal medicine (CHM) consists of multiple herbs that exhibit synergistic effects due to the presence of multiple components targeting various pathways. In clinical practice, the combination of Erchen decoction and Huiyanzhuyu decoction (EHD) has shown promising outcomes in treating patients with laryngeal squamous cell carcinoma (LSCC). However, the underlying mechanism by which EHD exerts its therapeutic effects in LSCC remains unknown. METHODS: Online databases were utilized for the analysis and prediction of the active constituents, targets, and key pathways associated with EHD in the treatment of LSCC. The protein-protein interaction (PPI) network of common targets was constructed and visualized using Cytoscape 3.8.1 software. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were performed to investigate the functional roles of core targets within the PPI network. Protein clustering was conducted utilizing the MCODE plug-in. The obtained results highlight the principal targets and pathways involved. Subsequently, clinical samples were collected to validate alterations in the levels of these main targets through Western blotting (WB) and immunohistochemistry (IHC). Furthermore, both in vivo and in vitro experiments were conducted to investigate the therapeutic effects of EHD on healing LSCC and elucidate its underlying mechanism. Additionally, to ensure experimental reliability and reproducibility, quality control measures utilizing HPLC were implemented for EHD herbal medicine. RESULTS: The retrieval and analysis of databases in EHD medicine and LSCC disease yielded a total of 116 overlapping targets. The MCODE plug-in methods were utilized to acquire 8 distinct protein clusters through protein clustering. The findings indicated that both the first and second clusters exhibited a size greater than 6 scores, with key genes PI3K and ErbB occupying central positions, while the third and fourth clusters were associated with proteins in the PI3K, STAT3, and Foxo pathways. GO functional analysis reported that these targets had associations mainly with the pathway of p53 mediated DNA damage and negative regulation of cell cycle in terms of biological function; the death-induced signaling complex in terms of cell function; transcription factor binding and protein kinase activity in terms of molecular function. The KEGG enrichment analysis demonstrated that these targets were correlated with several signaling pathways, including PI3K-Akt, FoxO, and ErbB2 signaling pathway. On one hand, we observed higher levels of key genes such as P-STAT3, P-PDK1, P-Akt, PI3K, and ErbB2 in LSCC tumor tissues compared to adjacent tissues. Conversely, FOXO3a expression was lower in LSCC tumor tissues. On the other hand, the key genes mentioned above were also highly expressed in both LSCC xenograft nude mice tumors and LSCC cell lines, while FOXO3a was underexpressed. In LSCC xenograft nude mice models, EHD treatment resulted in downregulation of P-STAT3, P-PDK1, PI3K, P-AKT, and ErbB2 protein levels but upregulated FOXO3a protein level. EHD also affected the levels of P-STAT3, P-PDK1, PI3K, P-AKT, FOXO3a, and ErbB2 proteins in vitro: it inhibited P-STAT3, P-AKT, and ErbB2, while promoting FOXO3a; however, it had no effect on PDK1 protein. In addition, HPLC identified twelve compounds accounting for more than 30% within EHD. The findings from this study can serve as valuable guidance for future experimental investigations. CONCLUSION: The possible mechanism of EHD medicine action on LSCC disease is speculated to be closely associated with the ErbB2/PI3K/AKT/FOXO3a signaling pathway.
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Medicamentos de Ervas Chinesas , Neoplasias Laríngeas , Farmacologia em Rede , Mapas de Interação de Proteínas , Medicamentos de Ervas Chinesas/farmacologia , Medicamentos de Ervas Chinesas/uso terapêutico , Humanos , Farmacologia em Rede/métodos , Animais , Neoplasias Laríngeas/tratamento farmacológico , Camundongos , Carcinoma de Células Escamosas/tratamento farmacológico , Transdução de Sinais/efeitos dos fármacos , Masculino , Linhagem Celular Tumoral , Camundongos Nus , Feminino , Proliferação de Células/efeitos dos fármacos , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
According to the World Health Organization's world report on hearing, nearly 2.5 billion people worldwide will suffer from hearing loss by 2050, which may contribute to a severe impact on individual life quality and national economies. Sensorineural hearing loss (SNHL) occurs commonly as a result of noise exposure, aging, and ototoxic drugs, and is pathologically characterized by the impairment of mechanosensory hair cells of the inner ear, which is mainly triggered by reactive oxygen species accumulation, inflammation, and mitochondrial dysfunction. Though recent advances have been made in understanding the ability of cochlear repair and regeneration, there are still no effective therapeutic drugs for SNHL. Chinese herbal medicine which is widely distributed and easily accessible in China has demonstrated a unique curative effect against SNHL with higher safety and lower cost compared with Western medicine. Herein we present trends in research for Chinese herbal medicine for the treatment of SNHL, and elucidate their molecular mechanisms of action, to pave the way for further research and development of novel effective drugs in this field.
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The electrochemical behaviors of battery chemistry, especially the operating voltage, are greatly affected by the complex electrode/electrolyte interface, but the corresponding basis understanding is still largely unclear. Herein, the concept of regulating electrode potential by interface thermodynamics is proposed, which guides the improvement of the energy density of Zn-MnO2 battery. A cationic electrolyte strategy is adopted to adjust the charge density of electrical double layer, as well as entropy change caused by desolvation, thus, achieving an output voltage of 1.6 V (vs. Zn2+/Zn) and a capacity of 400 mAh g-1. The detailed energy storage behaviors are also analyzed in terms of crystal field and energy level splitting. Furthermore, the electrolyte optimization benefits the efficient operation of Zn-MnO2 battery by enabling a high energy density of 532 Wh kg-1 based on the mass of cathode and a long cyclic life of more than 500 cycles. This work provides a path for designing high-energy-density aqueous battery via electrolyte strategy, which is expected to be extended to other battery systems.
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Objective: This study aimed to investigate the clinical effect of ultrasound-guided transradial catheterization (TRC) for ICU patients with shock. Methods: 120 shock patients registered in the ICU of our hospital from January 2019 to June 2022 were selected for prospective study. The control group (60 patients) were treated with palpation-guided TRC. The observation group was treated with ultrasound-guided TRC and was divided into the internal puncture group (internal TRC) and external puncture group (external TRC), with 30 cases in each. The first attempt success rate, total success rate, operation duration, complication, measurement of radial artery, and VAS scores were compared in these groups. Results: The success rate was higher in the observation group than in the control group (P < 0.05), and higher in the internal puncture group than in the external puncture group (P < 0.05). The first attempt success rate was significantly higher in the observation group than in the control group (P < 0.05), with no significant difference in between (P > 0.05). The number of attempts and operation duration were lower in the observation group than in the control group (P < 0.05), with significantly more operation duration in the internal puncture group than in the external puncture group (P < 0.05) and no significant difference in the number of attempts (both P > 0.05). The complication rate was significantly lower in the observation group than in the control group (P < 0.05) and there was no significant difference in between (P > 0.05). The radial artery diameter, cross-sectional area, and depth from the skin in the observation group were larger than those in the control group (P < 0.05) and there was no significant difference in between (P > 0.05). At 1, 6, 24, and 48 h after the surgery, the observation group showed lower VAS scores than the control group (P < 0.05). Conclusion: The ultrasound-guided TRC reduced the number of attempts, the complication rates, and the operation duration. For patients with shock, if Doppler ultrasound cannot detect blood flow, the success rate in the observation group was higher than that in the control group, and its advantage is worthy of promotion in severe patients.
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Aging of hematopoietic stem cells (HSCs) is linked to various blood disorders and malignancies. SIRT1 has been implicated in healthy aging, but its role in HSC aging is poorly understood. Surprisingly, we found that Sirt1 knockout improved the maintenance of quiescence of aging HSCs and their functionality as well as mouse survival in serial bone marrow transplantation (BMT) recipients. The majority of secondary and tertiary BMT recipients of aging wild type donor cells developed B/myeloid mixed phenotype acute leukemia (MPAL), which was markedly inhibited by Sirt1 knockout. SIRT1 inhibition also reduced the growth and survival of human B/myeloid MPAL cells. Sirt1 knockout suppressed global gene activation in old HSCs, prominently the genes regulating protein synthesis and oxidative metabolism, which may involve multiple downstream transcriptional factors. Our results demonstrate an unexpected role of SIRT1 in promoting HSC aging and age-dependent MPAL and suggest SIRT1 may be a new therapeutic target for modulating functions of aging HSCs and treatment of MPAL.
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Leucemia , Sirtuína 1 , Envelhecimento/genética , Animais , Células-Tronco Hematopoéticas/metabolismo , Leucemia/genética , Leucemia/metabolismo , Camundongos , Fenótipo , Sirtuína 1/genética , Sirtuína 1/metabolismoRESUMO
MCL-1 is an attractive target for cancer therapy. We recently discovered highly potent and selective MCL-1 inhibitors containing a fluoroalkene fragment for which an efficient route to the main chiral gem-fluoro-BPin fragment was needed. The key step of this synthesis is a highly stereoselective defluoroborylation of a gem-difluorovinyl intermediate. The latter is reached via a copper-catalyzed diastereoselective opening of dimethyloxirane. These two features allowed a 30-fold improvement in yield, a shorter synthesis, and a decrease in the cost of this crucial building block.
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Antineoplásicos , Antineoplásicos/farmacologia , Cobre , Proteína de Sequência 1 de Leucemia de Células Mieloides , EstereoisomerismoRESUMO
The neural crest is a multipotent cell population that migrates extensively to play important roles during embryonic development. After acquiring motility, trunk neural crest cells delaminate from the spinal cord and migrate to various regions of the body. Several cellular adhesion molecules, such as vinculin, are involved in the regulation of neural crest delamination and migration. In the present study, we found that draxin could inhibit delamination and migration of neural crest cells from the chick spinal cord and abnormal aggregation of the migrating neural crest cells. In the presence of draxin, the resuspended neural crest regained its adhesive ability such that it was significantly increased. Overexpression of draxin caused increased vinculin expression in vivo. Our data indicate that draxin might control delamination and migration of chick trunk neural crest by increasing cell adhesion.
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Galinhas , Crista Neural , Animais , Adesão Celular , Movimento Celular , Medula EspinalRESUMO
An efficient route to the HCV antiviral agent uprifosbuvir was developed in 5 steps from readily available uridine in 50% overall yield. This concise synthesis was achieved by development of several synthetic methods: (1) complexation-driven selective acyl migration/oxidation; (2) BSA-mediated cyclization to anhydrouridine; (3) hydrochlorination using FeCl3/TMDSO; (4) dynamic stereoselective phosphoramidation using a chiral nucleophilic catalyst. The new route improves the yield of uprifosbuvir 50-fold over the previous manufacturing process and expands the tool set available for synthesis of antiviral nucleotides.
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BACKGROUND: Rosai-Dorfman disease (RDD) is a rare benign proliferative disease whose etiology is not clear and may be related to infection or unexplained immune dysfunction. The authors present a case of RDD with lung involvement in a 10-year-old patient. CASE SUMMARY: A 10-year-old girl found that her left cervical lymph nodes were enlarged for more than 7 mo, and the largest range was about 6.5 cm × 5.9 cm × 8.1 cm. Cervical magnetic resonance imaging showed multiple masses in the left neck, with low signal intensity on T1-weighted images and high signal intensity on T2-weighted images. A malignant tumor, with a high possibility of lymph node metastasis, was initially considered. At the same time, lung computed tomography showed multiple nodules of different sizes scattered on both sides of the lung, with uniform internal density. Thus, a possible metastatic tumor was considered. Finally, RDD was diagnosed by pathology and immunohistochemistry. According to the antibiogram, clindamycin was administered for 2 wk, and prednisone acetate was administered for 7 wk. Nine months later, the ulcer in the left neck was better than before, but the imaging showed that the lesion was not controlled. CONCLUSION: The diagnosis of RDD cannot be made by a single tool and its treatment is a long-term exploratory process. Follow-up is necessary.
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Chronic myeloid leukemia (CML) is an age-dependent blood malignancy. Like many other age-dependent human diseases, laboratory animal research of CML uses young mice that do not factor in the influence of aging. To understand how aging may impact animal modeling of human age-dependent diseases, we established the first aging mouse model of human CML in BALB/c mice in the advanced age defined by 75% survival. This model was developed by noncytotoxic depletion of bone marrow lineage-positive cells followed by BCR-ABL retroviral transduction and transplantation. CML developed in aging mice shared many similarities to that in young mice, but had increased incidence of anemia that is often seen in human CML. Importantly, we showed that aging of both donor hematopoietic stem cells and recipient bone marrow niche impacted BCR-ABL mediated leukemogenesis and leukemia spectrum. Optimal CML induction relied on age-matching for donors and recipients, and cross-transplantation between young and old mice produced a mixture of different leukemia. Therefore, our model provides initial evidence of the feasibility and merit of CML modeling in aging mice and offers a new tool for future studies of CML stem cell drug resistance and therapeutic intervention in which aging would be taken into consideration as an influencing factor.
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Leucemia Mielogênica Crônica BCR-ABL Positiva , Animais , Células da Medula Óssea , Proteínas de Fusão bcr-abl , Células-Tronco Hematopoéticas , Camundongos , Camundongos Endogâmicos BALB C , RetroviridaeRESUMO
BACKGROUND: Laryngeal contact granuloma (LCG) is difficult to treat and frequently associated with high persistence and recurrence, despite the availability of both surgical and pharmacological treatment options. An appropriate strategy is therefore needed to help patients with multiple recurrences of LCG to potentially avoid unnecess-ary surgery. CASE SUMMARY: We describe the case of a 34-year-old male patient with recurrent LCG in which a good response was achieved through successful management of laryngophar-yngeal reflux disease using a combination pharmacotherapeutic regimen consisting of anti-reflux therapy, pepsin secretion inhibition, bile acid neutralization, and lifestyle modifications. This patient underwent surgery to excise the granuloma, then relapsed, underwent a second surgery, which was followed by a second recurrence. The granuloma then disappeared after 9 mo of combined treatment with ilaprazole enteric-coated capsules (10 mg qd), mosapride tablets (5 mg tid) and compound digestive enzyme capsules (2 tablets). The drug regimen was discontinued after one year, and no recurrence of the lesion has been reported during the one-year follow-up period. CONCLUSION: We report a combination of pharmacotherapeutics and lifestyle modifications for the management of laryngopharyngeal reflux disease to address recurring LCG.
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The BCR-ABL1 fusion gene generating an oncogenic tyrosine kinase is a hallmark of chronic myeloid leukemia (CML), which can be successfully targeted by BCR-ABL1 tyrosine kinase inhibitors (TKIs). However, treatment-free remission has been achieved in a minority of patients due to evolving TKI resistance and intolerance. Primary or acquired resistance to the approved TKIs and progression to blast crisis (BC), thus, remain a major clinical challenge that requires alternative therapeutic strategies. Here, we first demonstrate that donor natural killer (NK) cells prepared using a protocol adopted in clinical trials can efficiently eliminate CML-BC blasts, with TKI resistance regardless of BCR-ABL1 mutations, and preferentially target CD34+CD38- leukemic stem cells (LSC), a potential source of disease relapse. Mechanistically, the predominant expression of PVR, a ligand for the NK cell-activating DNAM-1 receptor, in concert with ICAM-1, a ligand for NK cell adhesion, confer this susceptibility to NK cells, despite the lack of ligands for NKG2D, a principal NK cell activating receptor, as an immune evasion mechanism. With these mechanistic insights, our findings provide a proof-of-concept that donor NK cell-based therapy is a viable strategy for overcoming TKI resistance in CML, particularly the advanced, multi-TKI-resistant CML with dismal outcome.
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Erchen plus Huiyanzhuyu decoction (EHD), a Chinese herbal medicine (CHM) formula that consists of Erchen decoction and Huiyanzhuyu decoction, has achieved satisfactory results in the clinic. The main function of EHD is to remove phlegm and blood stasis, and EHD is suitable for phlegm-coagulation-blood-stasis (PCBS) syndrome in laryngeal cancer (LC). In this study, a xenograft mouse model of LC with PCBS syndrome was constructed by feeding a high-fat diet, swimming in ice water, and subcutaneously injecting epinephrine hydrochloride for 2 weeks. Based on the successful Chinese medicine syndrome model, Hep2-luciferase-GFP cells were injected subcutaneously under the armpit of the right upper limb in mice to form tumours. A mouse model of LC with PCBS syndrome was established via heterotopic transplantation. Then, the mice received intragastric administration of different concentrations of EHD daily, and cisplatin (DDP) was intraperitoneally injected every week for 21 days. Tumour fluorescence in mice was measured with a living animal imager on days 7, 14, 21, and 28 during treatment. The results of this experiment confirmed that a mouse model of Chinese medicine syndrome was successfully constructed. Moreover, EHD slowed the growth of xenograft tumours in nude mice; decreased the expression levels of STAT3, p-STAT3, and cyclin D1; and upregulated the expression level of P27. In brief, EHD inhibited laryngeal tumour growth in a xenograft mouse model of PCBS syndrome and regulated the STAT3/cyclin D1 signalling pathway. This study was the first to construct a Chinese medicine xenograft mouse model of LC with PCBS syndrome; in addition, this study clarified that EHD regulated the STAT3/cyclin D1 signalling pathway to inhibit the growth of LC and that EHD may be a promising novel therapeutic compound for the treatment of patients with LC.
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ETHNOPHARMACOLOGICAL RELEVANCE: Laryngeal carcinoma (LC) is one of the most common malignant head and neck cancers with high incidence and mortality rates. Erchen decoction plus Huiyanzhuyu decoction (EHD) is commonly used for treating LC patients and produces beneficial results. However, the mechanisms underlying the effects of EHD remain unclear. AIM OF THE STUDY: The present study aimed to analyse the anticancer effects of EHD on the LC cell cycle, apoptosis, migration and invasion in vitro and to explore the underlying biological mechanisms. MATERIALS AND METHODS: TU212 and Hep-2 cells were used. The antitumour effects of EHD were detected by CCK8, microscopy, flow cytometry, EdU incorporation, Hoechst 33342 staining, wound-healing, and transwell assays to assess viability, morphology, apoptosis, cell cycle, migration and invasion, respectively. Furthermore, STAT3 and related proteins were evaluated in laryngeal squamous cell carcinoma (LSCC) cells by Western blot (WB) analysis. RESULTS: EHD treatment significantly decreased STAT3 and p-STAT3 protein expression levels in LSCC cells. EHD blocked the cell cycle at the G0/G1 phase and induced LSCC apoptosis. Moreover, the viability, migration, and invasion of LSCC cells were markedly inhibited by EHD. In addition, the expression of the cell cycle-related proteins cyclin D1 and cyclin B1 was downregulated in LSCC cells, but P27 expression was increased after EHD treatment. Regarding apoptosis-related proteins, EHD also reduced Bcl-2 expression but upregulated Bax and caspase-3 expression in LSCC cells. In the migration- and invasion-related protein analyses, EHD downregulated MMP-9 expression and upregulated E-cadherin expression. CONCLUSIONS: These results suggest that EHD has an anticancer effect in LSCC. EHD treatment induces apoptosis and inhibits the cell cycle, migration and invasion of LSCC cells, but further work is warranted to address the mechanisms.
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Antineoplásicos/uso terapêutico , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Medicamentos de Ervas Chinesas/uso terapêutico , Invasividade Neoplásica/prevenção & controle , Carcinoma de Células Escamosas de Cabeça e Pescoço/tratamento farmacológico , Proteínas Reguladoras de Apoptose/metabolismo , Proteínas de Ciclo Celular/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Regulação para Baixo/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Células Hep G2 , Humanos , Neoplasias Laríngeas/metabolismo , Transdução de Sinais/efeitos dos fármacos , Carcinoma de Células Escamosas de Cabeça e Pescoço/metabolismo , Regulação para Cima/efeitos dos fármacosRESUMO
Copper ions play a critical role in human islet amyloid polypeptide (hIAPP) aggregation, which has been found in more than 90% of patients with type-2 diabetes (T2D). The role of Cu(ii) in the cell cytotoxicity with hIAPP has been explored in two aspects: inhibiting the formation of fibrillar structures and stimulating the generation of reactive oxygen species (ROS). In this work, we carried out spectroscopic studies of Cu(ii) interacting with several hIAPP fragments and their variants as well. Electron paramagnetic resonance (EPR) measurements and Amplex Red analysis showed that the amount of H2O2 generated in hIAPP(11-28) solution co-incubated with Cu(ii) was remarkably more than hIAPP(1-11) and hIAPP(28-37). Furthermore, the H2O2 level was seriously reduced when His18 of hIAPP(11-28) was replaced by Arg(R) or Ser(S), indicating that His18 is the key residue of Cu(ii) binding to hIAPP(11-28) to promote H2O2 generation. This is likely because the donation of electrons from the peptide to Cu(ii) ions would result in the formation of the redox-active complexes, which could stimulate the formation of H2O2. Overall, this study provides further insight into the molecular mechanism of Cu(ii) induced ROS generation.
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The "baby boomers" born in 1946-1964 in the United States (U.S.) started to reach the age of 65 in 2011, rapidly accelerating U.S. population aging. There are great public concerns about its impact on health care with anticipation of rising cancer incidences. We examined the incidences and deaths of leukemia and overall cancer in the U.S. from 1998 to 2018. The acute myeloid leukemia (AML) and chronic myeloid leukemia (CML) incidences remained constant prior to 2011 but have climbed up substantially since then, and the chronic lymphocytic leukemia (CLL) incidence has increased continuously since 1998. The significant increase of myeloid leukemia and CLL incidences was strongly correlated with the U.S. population aging. The incidence of all cancers was increased in correlation with a small increase in aging population prior to 2011, but surprisingly has changed marginally since 2011, which was not significantly correlated with the accelerated population aging. We observed the most substantial decline of deaths with CML, whereas AML deaths continued to rise in the past 20 years. In conclusion, the overall cancer incidence was not increased as fast as previously feared with aging Americans; however, the incidences of myeloid leukemia and CLL significantly outpaced that of all cancers.
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Estudos Epidemiológicos , Leucemia Mielogênica Crônica BCR-ABL Positiva/mortalidade , Leucemia Mieloide Aguda/mortalidade , Neoplasias/mortalidade , Idoso , Idoso de 80 Anos ou mais , Envelhecimento/patologia , Feminino , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Leucemia Mieloide Aguda/patologia , Masculino , Pessoa de Meia-Idade , Neoplasias/patologia , Crescimento Demográfico , Estados Unidos/epidemiologiaRESUMO
Modern process research and development can often be hampered by the tedious method development required to chromatographically resolve mixtures of chemical species with very similar physical properties. Herein, we describe a simple approach for the development and implementation of an efficient ultra-high performance liquid chromatography (UHPLC) assay that is extensively applied to the separation and analysis of multicomponent reaction mixtures of closely related pharmaceutical intermediates and impurities. Methods are optimized using multi-column and multi-solvent UHPLC screening in conjunction with chromatography simulation software (ACD Labs/LC Simulator). This approach is implemented to enable the separation, identification, mapping and control of impurities formed within the process chemistry optimization of the dimeric catalyst used in the synthesis of new drug substances. The final method utilized a sub-2 µm C18 stationary phase (2.1 mm I.D. × 50 mm length, 1.7 µm particle size ACQUITY UPLC BEH C18) with a non-conventional chaotropic mobile phase buffer (35 mM potassium hexafluorophosphate in 0.1% phosphoric acid/acetonitrile) in order to achieve baseline separation of all reaction components. The chromatographic simulation and modeling strategy served to generate 3D resolution maps with robust separation conditions that match the outcome of subsequent experimental data (overall ΔtR < 0.35%). Our multi-column UHPLC screening with computer-assisted chromatographic modeling is a great addition to the toolbox of synthetic chemists and can be a powerful tool for streamlining process chemistry optimization in organic chemistry laboratories across both academic and industrial sectors.
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Carbamatos/isolamento & purificação , Cromatografia Líquida de Alta Pressão/métodos , Compostos Heterocíclicos com 2 Anéis/isolamento & purificação , Cromatografia Líquida de Alta Pressão/instrumentação , Simulação por ComputadorRESUMO
BACKGROUND: People with allergic rhinitis (AR) often seek help from Chinese medicine due to dissatisfaction with conventional treatments. Lung-spleen qi deficiency syndrome (LSQDS) is the most common type of AR, and the Chinese herbal medicine formula bi min fang (BMF) is commonly prescribed for AR patients with LSQDS. However, direct evidence supporting its efficacy and safety is not available, and its potential mechanism of action remains unclear. METHODS/DESIGN: This paper presents a double-blind, double-dummy, randomized controlled trial. After a 2-week run-in period, 80 AR patients with LSQDS will be recruited and randomly allocated to the BMF group or the control group in a 1:1 ratio. The patients in the BMF group will receive BMF and the placebo for levocetirizine hydrochloride orally, while the control group participants will receive levocetirizine hydrochloride and the placebo for BMF orally. All participants will receive 4 weeks of treatment and 12 weeks of follow-up. The primary outcome is a change in the Total Nasal Symptom Score (TNSS). Secondary outcomes include changes in scores for the standard version of the Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ(S)), and visual analog scale (VAS); changes in serum levels of the cytokines interleukin-4, interferon-γ, transforming growth factor ß-1, and interleukin-17; and changes in the gut microbiota composition in the stool. The TNSS, RQLQ(S), and VAS will be recorded at the beginning of, middle of and after the treatment period and at the end of each month in the 3-month follow-up period. Blood and stool samples will be collected at baseline and the end of the treatment. The aforementioned four cytokines will be detected in the serum using enzyme-linked immunosorbent assays, and the stool gut microbiota will be detected using 16S ribosomal ribonucleic acid sequencing. Any side effects of the treatment will be recorded. DISCUSSION: The results of this trial will provide consolidated evidence of the effect of BMF on AR and the potential mechanism by which BMF acts. This study will be the first to explore the mechanism of action of Chinese herbal medicine on the gut microbiota in AR. TRIAL REGISTRATION: Chinese Clinical Trial Registry, ChiCTR-IPR-17010970 . Registered on 23 March 2017.
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Antialérgicos/administração & dosagem , Medicamentos de Ervas Chinesas/administração & dosagem , Rinite Alérgica/tratamento farmacológico , Administração Oral , Adolescente , Adulto , Idoso , Antialérgicos/efeitos adversos , China , Citocinas/sangue , Método Duplo-Cego , Esquema de Medicação , Medicamentos de Ervas Chinesas/efeitos adversos , Feminino , Microbioma Gastrointestinal/efeitos dos fármacos , Humanos , Masculino , Pessoa de Meia-Idade , Qualidade de Vida , Ensaios Clínicos Controlados Aleatórios como Assunto , Rinite Alérgica/sangue , Rinite Alérgica/diagnóstico , Rinite Alérgica/microbiologia , Fatores de Tempo , Resultado do Tratamento , Adulto JovemRESUMO
The development of a commercial manufacturing route to verubecestat (MK-8931) is described, highlights of which include the application of a continuous processing step to outcompete fast proton transfer in a Mannich-type ketimine addition, a copper-catalyzed amidation reaction, and an optimized guanidinylation procedure to form the key iminothiadiazine dioxide core.