A dose-escalation study of HP501, a highly selective URAT1 inhibitor, in male Chinese patients with hyperuricemia.

HP501 is a highly selective renal urate transporter 1 (URAT1) inhibitor used for treating hyperuricemia. This study aimed to evaluate the tolerability, pharmacokinetics, and pharmacodynamics of HP501 in male Chinese patients. Patients with hyperuricemia were sequentially assigned to receive oral doses of HP501 (30, 50, 60, 90, and 120 mg) as a single dose on Day 1 and as once-daily doses from Days 4 to 13. Safety, pharmacokinetic, and pharmacodynamic data were collected. Multiple oral doses of HP501 were well-tolerated in all the cohorts. The most common adverse events (≥ 10% of patients) of any grade regardless of drug relationship were gout flare (14 patients, 25.93%), diarrhea (12 patients, 22.22%), elevated ALT (8 patients, 14.81%), hypertriglyceridemia (7 patients, 12.96%), dry mouth (7 patients, 12.96%) and oral ulcer (7 patients, 12.96%). All adverse events were mild or moderate. The Cmax and exposure (AUC) of HP501 was approximately dose-proportional between 30 and 120 mg. A dose-dependent serum uric acid (UA)-lowering effect was observed in the dose range of 30 to 60 mg and the serum UA lowering effect was similar between 90 and 120 mg on day 13, indicating that the maximal serum UA lowering effect of HP501 was achieved at 90 mg in the patients with hyperuricemia. In conclusion, the tolerability, pharmacokinetics, and pharmacodynamics supported 90 mg HP501 for subsequent clinical studies of this highly selective URAT1 inhibitor.Clinical Trial registration: No. CTR20212259 ( http://www.chinadrugtrials.org.cn/ ) was registered in September 2021, and No. CTR20222257 was registered in September 2022.

Prognostic models for predicting overall and cancer-specific survival of patients with initially diagnosed metastatic cervical squamous cell carcinoma: A study based on SEER database.

Cervical squamous cell carcinoma (CSCC) is the most common histological type of cervical cancer (CC). And mCSCC is the end stage of CSCC. The aim of this study was to develop prognostic nomograms that provide better predictions for overall survival (OS) and cancer-specific survival (CSS) in mCSCC patients. Data from patients with initially diagnosed mCSCC were extracted from the Surveillance, Epidemiology, and End Results (SEER) database between 2004 and 2015. The nomograms for OS and CSS were constructed based on Cox regression analysis. The validation of the newly established nomograms was evaluated by concordance index (C-index), calibration curves, and decision curve analyses (DCAs). A total of 2198 patients with mCSCC were included and randomly split into training (n = 1539) and validation (n = 659) cohorts in a 7:3 ratio. Multivariate analyses revealed that the prognostic variables significantly related to the OS and CSS were marital status, T stage, brain metastasis, lung metastasis, tumor size, number of positive lymph nodes, chemotherapy, and radiotherapy. The nomograms were constructed based on these factors. The C-index value of the nomograms for predicting OS and CSS was 0.714 and 0.683, respectively. The calibration curves of the nomograms showed good consistency between nomogram prediction and actual survival for both OS and CSS, and the DCAs showed great clinical usefulness of the nomograms. The mCSCC patients were classified into low- and high-risk groups based on the scores from the nomograms. In the validation cohort, mCSCC patients with low-risk had much higher OS and CSS than those with high-risk. We constructed nomograms for predicting the OS and CSS of patients with initially diagnosed mCSCC. Our models had satisfactory predictive performance and could be useful in survival prediction for mCSCC.

A Phase I Study to Evaluate the Pharmacokinetic Drug‒Drug Interaction of HP501, Febuxostat, and Colchicine in Male Chinese Patients with Hyperuricemia.

BACKGROUND AND OBJECTIVE: HP501 is a highly selective renal urate transporter 1 (URAT1) inhibitor that is being developed for the treatment of hyperuricemia and gout. The primary aim of the present study was to study the pharmacokinetic drug‒drug interactions (DDIs) of HP501, febuxostat, and colchicine in hyperuricemic patients. METHODS: Hyperuricemic patients were randomly divided into group A, receiving HP501 40 mg once daily on days 1 and 4-10, and group B, receiving febuxostat 40 mg once daily on day 1 and HP501 40 mg plus febuxostat 40 mg on days 4-10. All patients received 0.5 mg colchicine once daily from day 4 to 12. Blood samples were collected for measurement of drug concentrations and serum uric acid (sUA) levels. RESULTS: Coadministration of colchicine with HP501 or HP501 plus febuxostat did not affect steady-state exposure to colchicine. Coadministration of HP501 and febuxostat did not significantly change the pharmacokinetic profiles of either drug. Following multiple administrations of HP501 40 mg once daily for 7 days, the maximal percent sUA change from baseline in group A was - 24.77%. The coadministration of HP501 40 mg and febuxostat 40 mg in group B for 7 days resulted in a - 55.82% maximal sUA reduction from baseline, and all patients achieved the goal of sUA < 360 µmol/L. All adverse events (AEs) were either mild or moderate, and the most frequently reported AEs were diarrhea and elevated alanine aminotransferase (ALT) levels. CONCLUSIONS: The concomitant use of HP501, febuxostat, and colchicine did not produce clinically meaningful DDIs in terms of their pharmacokinetic properties. CLINICAL TRIAL REGISTRATION: No. CTR20212261 ( http://www.chinadrugtrials.org.cn/ ) registered September 2021.

Novel therapies for malignant pleural effusion: Anti­angiogenic therapy and immunotherapy (Review).

Patients with a variety of malignancies can develop malignant pleural effusion (MPE). MPE can cause significant symptoms and result in a marked decrease in quality of life and a poor prognosis. MPE is primarily considered as an immune and vascular manifestation of pleural metastases. In the present review, the existing evidence supporting the applicability of anti­angiogenic therapy and immunotherapy for the treatment of MPE was summarized. Patients with MPE have benefited from anti­angiogenic agents, including bevacizumab and endostar; however, no relevant prospective phase III trial has, thus far, specifically analyzed the benefit of anti­angiogenic therapy in MPE. Immunotherapy for MPE may be sufficient to turn a dire clinical situation into a therapeutic advantage. Similar to anti­angiogenic therapy, more clinical data on the efficiency and safety of immunotherapy for controlling MPE are urgently required. The combined use of anti­angiogenic therapy and immunotherapy may be a promising strategy for MPE, which requires to be further understood.

Development of immunotherapy for brain metastasis (Review).

Brain metastasis (BM) is associated with a poor prognosis, with the typical overall survival rate ranging from weeks to months in the absence of treatment. Although the concept of immune privilege in the central nervous system has eroded over time, the advent of immunotherapy has opened a new set of potential therapeutic options for patients with BM. Recently, immunotherapy has been demonstrated to confer survival advantages to patients with multiple malignancies commonly associated with BMs. Data from a number of clinical trials have demonstrated that immune checkpoint inhibitors are effective for patients with BM. In addition, cellular therapies, including the application of chimeric antigen receptors T­cell therapy and dendritic cell vaccine, have also been utilized in the treatment of BM. In the present review, preclinical and clinical evidence supporting the applicability of immunotherapy for the treatment of BMs from melanoma, non­small cell lung cancer (NSCLC) and renal cell carcinoma (RCC) were examined, where the challenges and safety of this treatment modality were also discussed.

Glycyrrhetinic Acid-Modified Norcantharidin Nanoparticles for Active Targeted Therapy of Hepatocellular Carcinoma.

Norcantharidin (NCTD), the demethylated analogue of cantharidin, has been confirmed to have a good anti-tumor effect against hepatocellular carcinoma (HCC). However, its use is limited by its poor water solubility and low tumortargeting efficacy. In the present study, an active-targeted drug delivery nanoplatform was designed to deliver NCTD using a glycyrrhetinic acid (GA)-decorated copolymer (mPEG-PCL-PEI-GA, MPG). The NCTD-loaded polymeric nanoparticles (MPG/NCTD) formed by self-assembly in water exhibited a mean hydrodynamic diameter of roughly 89 nm. In vitro studies revealed that GA-conjugated nanoparticles (AT NPs) had superior cytotoxicity and higher targeting efficacy on HepG2 cells compared to non-conjugated nanoparticles (Non-AT NPs, NAT NPs). Determination of cell apoptosis and cell cycle phase showed that AT NPs resulted in increased cell apoptosis and a distinct increase in the G2 phase (65.30 ± 3.52%, P < 0.01) and S phase (46.39 ± 1.39%, P < 0.01). Evaluation of in vivo anti-tumor activity showed that the AT NPs significantly inhibited tumor growth and prolonged survival of tumor-bearing mice. The expression of Ki-67 and CD31 revealed that AT NPs inhibited cell proliferation and resulted in a decreased microvessel density (MVD). The results indicated that NCTD-loaded GA-modified nanoparticles may have great potential in HCC-targeted therapy.

Honokiol-loaded polymeric nanoparticles: an active targeting drug delivery system for the treatment of nasopharyngeal carcinoma.

The purpose of this study was to develop a novel drug delivery system for a sustained and targeted delivery of honokiol (HK) to the nasopharyngeal carcinoma (NPC) HNE-1 cell lines, since the folate receptor (FR) is over-expressed on their surface. Emulsion solvent evaporation was used to develop the active targeting nanoparticles-loaded HK (ATNH) using copolymerpoly (ɛ-caprolactone)-poly (ethyleneglycol)-poly (ɛ-caprolactone) (PCEC), which was modified with folate (FA) by introducing Polythylenimine (PEI). ATNH characterization, including particle size distribution, morphology, drug loading, encapsulation efficiency and drug release, was performed. Transmission electron microscopy (TEM) and Fourier transform infrared spectroscopy (FTIR) were employed to evaluate the shape and construction, respectively. MTT assay, cell uptake study and apoptosis test were assayed to detect the antitumor properties and targeting uptake by HNE-1 cells in vitro. Cell-cycle redistribution, 18 F-FDG PET/CT and immunohistochemistry were performed in vivo. The ATNH we developed were successfully synthesized and showed a suitable size distribution, high encapsulation efficiency, gradual release, and targeting uptake by the cells in vitro. Moreover, ATNH significantly inhibited tumor growth, metabolism, proliferation, micro-vessel generation, and caused cell-cycle arrest at G1 phase. Thus, these nanoparticles we developed might represent a novel formulation for HK delivery and a promising potential therapy in the treatment of cancer.

Periostin Promotes Neural Stem Cell Proliferation and Differentiation following Hypoxic-Ischemic Injury.

Neural stem cell (NSC) proliferation and differentiation are required to replace neurons damaged or lost after hypoxic-ischemic events and recover brain function. Periostin (POSTN), a novel matricellular protein, plays pivotal roles in the survival, migration, and regeneration of various cell types, but its function in NSCs of neonatal rodent brain is still unknown. The purpose of this study was to investigate the role of POSTN in NSCs following hypoxia-ischemia (HI). We found that POSTN mRNA levels significantly increased in differentiating NSCs. The proliferation and differentiation of NSCs in the hippocampus is compromised in POSTN knockout mice. Moreover, NSC proliferation and differentiation into neurons and astrocytes significantly increased in cultured NSCs treated with recombinant POSTN. Consistently, injection of POSTN into neonatal hypoxic-ischemic rat brains stimulated NSC proliferation and differentiation in the subventricular and subgranular zones after 7 and 14 days of brain injury. Lastly, POSTN treatment significantly improved the spatial learning deficits of rats subjected to HI. These results suggest that POSTN significantly enhances NSC proliferation and differentiation after HI, and provides new insights into therapeutic strategies for the treatment of hypoxic-ischemic encephalopathy.

Neuroprotective effects of oligodendrocyte progenitor cell transplantation in premature rat brain following hypoxic-ischemic injury.

Periventricular leukomalacia (PVL) is a common ischemic brain injury in premature infants for which there is no effective treatment. The objective of this study was to determine whether transplanted mouse oligodendrocyte progenitor cells (OPCs) have neuroprotective effects in a rat model of PVL. Hypoxia-ischemia (HI) was induced in 3-day-old rat pups by left carotid artery ligation, followed by exposure to 6% oxygen for 2.5 h. Animals were assigned to OPC transplantation or sham control groups and injected with OPCs or PBS, respectively, and sacrificed up to 6 weeks later for immunohistochemical analysis to investigate the survival and differentiation of transplanted OPCs. Apoptosis was evaluated by double immunolabeling of brain sections for caspase-3 and neuronal nuclei (NeuN), while proliferation was assessed using a combination of anti-Nestin and -bromodeoxyuridine antibodies. The expression of brain-derived neurotrophic factor (BDNF) and Bcl-2 was examined 7 days after OPC transplantation. The Morris water maze was used to test spatial learning and memory. The results showed that transplanted OPCs survived and formed a myelin sheath, and stimulated BDNF and Bcl-2 expression and the proliferation of neural stem cells (NSC), while inhibiting HI-induced neuronal apoptosis relative to control animals. Moreover, deficits in spatial learning and memory resulting from HI were improved by OPC transplantation. These results demonstrate an important neuroprotective role for OPCs that can potentially be exploited in cell-based therapeutic approaches to minimize HI-induced brain injury.

Clinical value of spectral CT in diagnosis of negative gallstones and common bile duct stones.

OBJECTIVE: To investigate the clinical value of spectral CT in diagnosis of negative gallstones and common bile duct stones primarily. METHODS: All patients diagnosed with negative biliary stones were analyzed and examined by spectral CT scanner retrospectively. Based on acquired raw imaging data, image series were reconstructed as described below: the optimal contrast-to-noise ratio monochromatic energy images, calcium- and fat- based material decomposition images and spectral curve images. All these imaging series were analyzed quantitatively and qualitatively. RESULTS: The contrast between negative stones and adjacent bile was 6.87 ± 5.48 HU on hybrid energy CT images and 47.30 ± 24.05 HU on optimal monochromatic energy CT images. The mean concentration of calcium in bile and negative stones was 19.36 ± 5.12 and 3.88 ± 6.60 mg/mL, and the fat in bile and negative stones was 998.48 ± 11.79 and 1035.68 ± 15.36 mg/mL. Effective atomic number Z of negative stones (6.60 ± 0.45) was lower than that of bile (7.65 ± 0.13). The slopes of the spectral curves for negative stones were k 90-40KeV = 1.43 ± 0.63 and k 140-90KeV = 0.19 ± 0.08, and for bile, they were k 90-40KeV = -0.27 ± 0.09 and k 140-90KeV = -0.04 ± 0.01. The same stone showed different densities in different imaging groups. The positive rate of conventional CT images was lower than that of other imaging groups. CONCLUSION: Spectral CT has a high diagnostic value for negative gallstones or bile duct stones, and material decomposition CT images and spectral curves can make an accurate diagnosis.

Cerebral hypoxia-ischemia increases toll-like receptor 2 and 4 expression in the hippocampus of neonatal rats.

AIM OF THE STUDY: Recent reports provide evidence that Toll-like receptors (TLRs) play a crucial role in cerebral ischemic injuries and neuronal cell death. The precise role of TLRs in mediating neuronal damage remains to be fully elucidated. In this study, we investigated the expression of TLR2 and TLR4 in the hippocampus of the neonatal rats. MATERIALS AND METHODS: Postnatal day 7 Sprague-Dawley rats were used. The hypoxia-ischemia brain injury models were made by ligature of the left common carotid artery and then inhalation of 8%O(2)/92%N(2) for 2 h. TLR2 and TLR4 expression was assessed with immunohistochemical staining and Western blot assays at 3d, 7d, and 14d after injury. RESULTS: At the 3d and 7d time points, we found a significant increase in the number of TLR2 and TLR4 positive cells in the hippocampus of the HI group when compared with the sham group (P<0.01). Western blot showed similar results. CONCLUSIONS: The study indicates that TLR2 and TLR4 are involved in the hypoxic-ischemic injury of full-term neonatal brains.

Short-term effects of hypothermia on axonal injury, preoligodendrocyte accumulation and oligodendrocyte myelination after hypoxia-ischemia in the hippocampus of immature rat brain.

Hypothermia is known to improve neurological recovery of animals and humans exposed to hypoxic-ischemic (HI) injury. However, the underlying mechanisms of the neuroprotective effects of hypothermia are only partially understood, including decreased excitotoxicity and apoptosis, and suppressed inflammation. There are few studies about the hypothermic effects on axonal injury and oligodendrocyte (OL) lineage degeneration, which are important components of neonatal brain injuries that cause cognitive disability. We hypothesized that mild hypothermia would reduce axonal injury and increase myelination in the hippocampus after HI. We performed left carotid artery ligation followed by 8% oxygen for 2 h in 7-day-old rats. Animals were divided into a hypothermic group (rectal temperature 32-33°C for 24 h) and a normothermic group (36-37°C for 24 h) immediately after HI. Animals were sacrificed at 1, 3 and 7 days for immunohistochemistry or Western blot analysis. We detected neuron loss by microtubule-associated protein 2 labeling and axonal injury by non-phosphorylated neurofilament (SMI32) with neurofilament 200 (NF200) double staining. We examined early OL progenitors by A2B5 or NG2, preoligodendrocytes (preOLs) by O4, and mature OLs by 2,3-cyclic nucleotide 3-phosphodiesterase (CNPase) and glutathione S-transferase (GST)-pi staining. Apoptosis was studied by active caspase-3. Hypothermia was associated with a significant elevation of neurons and axons in the hippocampal CA1 region after HI. Early OL progenitors (A2B5(+)) were elevated, but preOLs (O4(+)) and active caspase-3 were dramatically reduced in the hypothermic rat brain. Further study showed that the apoptotic rate of preOLs (caspase-3(+)-O4(+)/O4(+)) was markedly attenuated by hypothermic treatment compared to normothermic animals. The immunoreactivity of CNPase and GST-pi and the protein level of the myelin basic protein significantly increased in the hippocampus of hypothermia-treated rat brain. Axonal myelination also increased in hypothermic animals, which were tested by myelin basic protein and NF200 double staining and electron microscopy. These results showed that hypothermia reduced HI damage to axons and OL myelination coincided with increased early OL progenitor proliferation and decreased preOL accumulation and apoptosis. This study suggested new aspects that may contribute to elucidate the mechanism of hypothermic neuroprotection in neonatal rat brain.