Selexipag for the Treatment of Pediatric Pulmonary Hypertension: A Systematic Review.

PURPOSE: To systematically evaluate the safety, dosing regimen, and efficacy of selexipag for pediatric patients with pulmonary hypertension (PH). METHODS: A literature search of the electronic databases of PubMed, Embase, Web of Science, Cochrane Library, and Google Scholar was performed from inception through February 28, 2023. Two reviewers independently searched and evaluated the quality of the studies and pooled data when appropriate. Full-text articles of studies of children diagnosed with PH and treated with selexipag were eligible. Pediatric patients with PH were classified into 2 groups: the add-on therapy group, in which selexipag was used as a third therapy in addition to the baseline treatment, and the transition therapy group, in which patients were switched from parenteral prostacyclin analogs to selexipag. FINDINGS: Fourteen studies involving 58 pediatric patients with PH were included. All studies were either case reports or case series. Overall, 30 and 28 patients were in the add-on and transition therapy groups, respectively. In both groups, selexipag was initially administered as 50-200 µg twice daily and titrated to a tolerated dosage of 200-1,600 µg twice daily. Prostacyclin analogs were simultaneously weaned for patients in the transition group. In the add-on therapy group, 16 patients (80.0%) were at low risk of the World Health Organization functional class (WHO FC I/II), 12 (76.9%) were at low risk of the 6-minute walk distance (6MWD; >350 m), and 21 (95.5%) were at low risk of the pulmonary vascular resistance index (PVRi; <20 WU/m2). Furthermore, N-terminal pro-brain natriuretic peptide and mean pulmonary arterial pressure were significantly improved. More than 70% of patients experienced common tolerable side effects, such as headache, nausea, and diarrhea. In the transition therapy group, 5 patients (55.6%) were at low risk according to WHO FC I/II, 6 (66.7%) were at low risk according to 6MWD, and 14 (87.5) were at low risk according to PVRi; however, selexipag had no significant effect on their hemodynamic parameters. Additionally, more than 80% of patients experienced no side effects. IMPLICATIONS: Selexipag as add-on therapy or for transition from prostacyclin analogs may have a favorable safety profile and potential efficacy for pediatric patients with PH. Further high-quality evidence of the efficacy and safety of selexipag for the treatment of pediatric PH is warranted.

[Effects of moxibustion at Yongquan (KI 1) on cognition function and lower limb motor function in patients with post-stroke cognitive impairment of kidney essence deficiency].

OBJECTIVE: To observe the effects of moxibustion at Yongquan（KI 1） on the cognitive function and lower limb motor function in patients with post-stroke cognitive impairment of kidney essence deficiency. METHODS: Eighty-four patients with post-stroke cognitive impairment of kidney essence deficiency were randomly divided into an observation group（42 cases，1 case dropped off）and a control group（42 cases，1 case dropped off）.The control group was treated with medication，electroacupuncture，rehabilitation training and repetitive transcranial magnetic stimulation（rTMS）；on the basis of the treatment as the control group，moxibustion at bilateral Yongquan（KI 1）was adopted in the observation group.Both groups were treated once a day，5 days a week with 2-day interval，4 weeks were required. The Montreal cognitive assessment (MoCA) score, mini-mental state examination (MMSE) score, Fugl-Meyer assessment-lower extremity (FMA-LE) score, Berg balance scale (BBS) score, functional independence measure (FIM) score, modified fall efficacy scale (MFES) score and scale for the differentiation of syndromes of vascular dementia (SDSVD) score before and after treatment were observed in the two groups. RESULTS: After treatment，the MoCA, MMSE, FMA-LE, BBS, FIM and MFES scores were higher than those before treatment in both groups (P<0.05), and the scores in the observation group were higher than those in the control group (P<0.05). After treatment，the SDSVD scores were lower than those before treatment in both groups (P< 0.05), and the SDSVD score in the observation group was lower than that in the control group (P< 0.05). CONCLUSION: Moxibustion at Yongquan（KI 1） can improve the cognitive function and motor and balance function of lower limbs in patients with post-stroke cognitive impairment of kidney essence deficiency，reduce the risk of fall and improve the quality of life.

Application of injectable hydrogels in cancer immunotherapy.

Immunotherapy is a revolutionary and promising approach to cancer treatment. However, traditional cancer immunotherapy often has the disadvantages of limited immune response rate, poor targeting, and low treatment index due to systemic administration. Hydrogels are drug carriers with many advantages. They can be loaded and transported with immunotherapeutic agents, chemical anticancer drugs, radiopharmaceuticals, photothermal agents, photosensitizers, and other therapeutic agents to achieve controlled release of drugs, extend the retention time of drugs, and thus successfully trigger anti-tumor effects and maintain long-term therapeutic effects after administration. This paper reviews recent advances in injectable hydrogel-based cancer immunotherapy, including immunotherapy alone, immunotherapy with combination chemotherapy, radiotherapy, phototherapy, and DNA hydrogel-based immunotherapy. Finally, we review the potential and limitations of injectable hydrogels in cancer immunotherapy.

Curcumin Relieves Chronic Unpredictable Mild Stress-Induced Depression-Like Behavior through the PGC-1α/FNDC5/BDNF Pathway.

METHODS: All rats were randomly divided into four groups, namely, control, CUMS, CUMS + CUR, and CUMS + CUR + SR18292 (PGC-1α inhibitor). Behavioral tests were conducted to assess the antidepressant-like effects of CUR. The expressions of PGC-1α, estrogen-related receptor alpha (ERRα), FNDC5, and BDNF were determined to investigate the regulatory effects of CUR on the PGC-1α/FNDC5/BDNF pathway. The PGC-1α inhibitor SR18292 was used to explore the role of PGC-1α in the induction of BDNF by CUR. RESULTS: Daily gavage of 100 mg/kg CUR successfully attenuated the abnormal behaviors induced by CUMS and effectively prevented CUMS-induced reduction of PGC-1α, ERRα, FNDC5, and BDNF expressions. CUR also enhanced PGC-1α and ERRα translocation from cytoplasm to nucleus. Furthermore, we found that CUR supplementation effectively promoted neurocyte proliferation and suppressed neuronal apoptosis induced by CUMS. Of note, the PGC-1α inhibitor SR18292 remarkably reversed the beneficial effects of CUR on depressed rats, indicating an important role of PGC-1α in the antidepressant-like effects of CUR. CONCLUSION: Collectively, our data evaluating the neuroprotective action of CUR in the CUMS rats highlights the involvement of the PGC-1α/FNDC5/BDNF pathway in the antidepressant-like effects of CUR.

Remote pharmacy service in primary care: The implementation of a cloud-based pre-prescription review system.

BACKGROUND: To reduce the occurrence of inappropriate prescription in primary care through the introduction of a cloud-based pre-prescription review system. OBJECTIVE: We aimed to describe the implementation of a cloud-based pre-prescription review system in the pharmacy practice of Chinese community health centers (CHCs), which currently have few qualified pharmacists. PRACTICE DESCRIPTION: The cloud-based pre-prescription review system featured reviews by remote clinical pharmacists and targeted the prevention of inappropriate prescription in primary care. PRACTICE INNOVATION: This study describes the implementation of remote pharmacy at 22 CHCs in Futian District, Shenzhen, China. A pre-prescription system was developed and deployed in the cloud, which is linked to CHCs, and a consortium of qualified clinical pharmacists located in tertiary hospital. All prescriptions were mandatorily reviewed before printing and payment. First, prescriptions were reviewed using cloud-based rational drug use software. Then any detected potentially inappropriate prescriptions were reviewed by the remote pharmacist. The pharmacist consortium also modified review rules to improve efficiency and accuracy. EVALUATION METHODS: The frequency and proportions of potentially inappropriate prescriptions identified by the review software and the remote pharmacist consortium were analyzed descriptively. RESULTS: During the 6-month study period (July 1, 2019-December 31, 2019), 340,117 prescription entries from general practitioners in 22 community health care centers were reviewed. Of these, 6479 (3.0%) unique potential entries were suspended for pharmacist review, of which 3230 (49.9%) needed correction from prescribers in the CHCs. The most common corrections were related to improper administration routes or drug-drug interactions or had no justified indications. CONCLUSION: Inappropriate prescription is not uncommon in CHCs. The cloud-based prescription prereview model proposed in this study can serve as an important tool for the prevention of inappropriate prescription in primary care. The pre-prescription review system also provided opportunities for pharmacists to participate in the enhancement of patient care in primary care.

Risk of major bleeding among users of direct oral anticoagulants combined with interacting drugs: A population-based nested case-control study.

AIMS: To assess the association between concurrent use of potential pharmacokinetic or pharmacodynamic interacting drugs and major bleeding among direct oral anticoagulant (DOAC) users. METHODS: We performed a case-control study nested in a cohort of new users of DOACs (dabigatran etexilate, apixaban or rivaroxaban). Data were obtained from the UK Clinical Practice Research Datalink linked to Hospital Episode Statistics (2008-2015). Cases were patients hospitalized having a primary diagnosis of major bleeding. Up to 4 controls were matched on age, sex, index date and region. Odds ratios (ORs) for the risk of major bleeding were assessed by conditional logistic regression analysis and adjusted for well-known covariates for the risk of bleeding. RESULTS: We identified 393 patients with a major bleeding from a total of 23 492 new users of DOACs and 1494 matched controls. Most subjects were users of rivaroxaban (58.8%) on the index date. The concurrent use of pharmacodynamic interacting drugs was associated with an increased risk of major bleeding (21.6% of cases vs 13.5% of controls, adjusted odds ratio [aOR] 1.92; 95% confidence interval [CI], 1.40-2.66). For the antiplatelet drugs the aOR was 2.01 (95% CI, 1.29-3.11) and for the selective serotonin reuptake inhibitors the aOR was 1.68 (95% CI, 1.10-2.59). We found no increased risk of major bleeding for concurrent use of pharmacokinetic interacting drugs vs DOACs alone (45.0 vs 51.2%; aOR: 0.77; 95% CI: 0.53-1.10). CONCLUSION: Among patients taking DOACs the concurrent use of antiplatelet drugs or selective serotonin reuptake inhibitors was associated with increased risk of major bleeding, while pharmacokinetic interacting drugs do not increase this risk.

Integrated Network Pharmacology and Metabonomics to Reveal the Myocardial Protection Effect of Huang-Lian-Jie-Du-Tang on Myocardial Ischemia.

Myocardial ischemia (MI) is one of the most common cardiovascular diseases with high incidence and mortality. Huang-Lian-Jie-Du-Tang (HLJDT) is a classic traditional Chinese prescription to clear "heat" and "poison". In this study, we used a deliberate strategy integrating the methods of network pharmacology, pharmacodynamics, and metabonomics to investigate the molecular mechanism and potential targets of HLJDT in the treatment of MI. Firstly, by a network pharmacology approach, a global view of the potential compound-target-pathway network based on network pharmacology was constructed to provide a preliminary understanding of bioactive compounds and related targets of HLJDT for elucidating its molecular mechanisms in MI. Subsequently, in vivo efficacy of HLJDT was validated in a rat model. Meanwhile, the corresponding metabonomic profiles were used to explore differentially induced metabolic markers thus providing the metabolic mechanism of HLJDT in treating MI. The results demonstrated the myocardial protection effect of HLJDT on ischemia by a multicomponent-multitarget mode. This study highlights the reliability and effectiveness of a network pharmacology-based approach that identifies and validates the complex of natural compounds in HLJDT for illustrating the mechanism for the treatment of MI.

Comparison of dosing algorithms for acenocoumarol and phenprocoumon using clinical factors with the standard care in the Netherlands.

BACKGROUND: It has not been investigated how much the use of clinical factors in a dosing algorithm improves the percentage of time in therapeutic range (TTR). The present study aimed to compare the effect of dosing algorithms for acenocoumarol and phenprocoumon including clinical patient characteristics with standard care in the Netherlands. SETTING: The pre-EU-PACT study, an observational study in the Netherlands, was used to obtain standard care data. Data from the Dutch patients in the EU-PACT trial (comparing the use of a clinical algorithm with and without genetic information) was used for the clinical dosing algorithm. METHODS: For both acenocoumarol and phenprocoumon, the percentage of time in, below and above therapeutic International Normalized Ratio (INR) range during 12weeks after treatment initiation were assessed in both studies. RESULTS: During the weeks 2-12, the clinical dosing algorithm of acenocoumarol (80 patients) led to a higher TTR (74.3% versus 68.0% in range 2.0-3.5, 95% Confidence interval [CI] difference: 0.5% to 11.8%), and a reduced percentage of time below INR 2 and above INR 3.5, compared with standard care (272 patients). For phenprocoumon, compared with standard care (484 patients), 80 patients treated by the dosing algorithm did not obtained a significantly higher TTR in range 2.0-3.5 or a lower percentage of time above 3.5, however, they spent more time with INR below 2. CONCLUSION: The use of a clinical dosing algorithm for acenocoumarol seemed to improve the quality of anticoagulation therapy during the treatment of initial 2-12 weeks. For phenprocoumon, there was no statistically difference in anticoagulation control.

Hypoxia/oxidative stress alters the pharmacokinetics of CPU86017-RS through mitochondrial dysfunction and NADPH oxidase activation.

AIM: Hypoxia/oxidative stress can alter the pharmacokinetics (PK) of CPU86017-RS, a novel antiarrhythmic agent. The aim of this study was to investigate the mechanisms underlying the alteration of PK of CPU86017-RS by hypoxia/oxidative stress. METHODS: Male SD rats exposed to normal or intermittent hypoxia (10% O2) were administered CPU86017-RS (20, 40 or 80 mg/kg, ig) for 8 consecutive days. The PK parameters of CPU86017-RS were examined on d 8. In a separate set of experiments, female SD rats were injected with isoproterenol (ISO) for 5 consecutive days to induce a stress-related status, then CPU86017-RS (80 mg/kg, ig) was administered, and the tissue distributions were examined. The levels of Mn-SOD (manganese containing superoxide dismutase), endoplasmic reticulum (ER) stress sensor proteins (ATF-6, activating transcription factor 6 and PERK, PRK-like ER kinase) and activation of NADPH oxidase (NOX) were detected with Western blotting. Rat liver microsomes were incubated under N2 for in vitro study. RESULTS: The Cmax, t1/2, MRT (mean residence time) and AUC (area under the curve) of CPU86017-RS were significantly increased in the hypoxic rats receiving the 3 different doses of CPU86017-RS. The hypoxia-induced alteration of PK was associated with significantly reduced Mn-SOD level, and increased ATF-6, PERK and NOX levels. In ISO-treated rats, the distributions of CPU86017-RS in plasma, heart, kidney, and liver were markedly increased, and NOX levels in heart, kidney, and liver were significantly upregulated. Co-administration of the NOX blocker apocynin eliminated the abnormalities in the PK and tissue distributions of CPU86017-RS induced by hypoxia/oxidative stress. The metabolism of CPU86017-RS in the N2-treated liver microsomes was significantly reduced, addition of N-acetylcysteine (NAC), but not vitamin C, effectively reversed this change. CONCLUSION: The altered PK and metabolism of CPU86017-RS induced by hypoxia/oxidative stress are produced by mitochondrial abnormalities, NOX activation and ER stress; these abnormalities are significantly alleviated by apocynin or NAC.

Hypoxia alters pharmacokinetics of argirein because of mitochondrial dysfunction that is alleviated by apocynin.

OBJECTIVES: Pharmacokinetics (PK) of argirein might be changed in response to mitochondrial (MITO) dysfunction and activated nicotinamide adenine dinucleotide phosphate oxidase (NOX) on hypoxia. We hypothesized that hypoxic changes in MITO and NOX could alter PK and tissue distribution of argirein. We tested if these changes in PK of argirein by hypoxia could be relieved by apocynin (APO), a blocker of NOX, through normalizing MITO and NOX. METHODS: Male Sprague-Dawley rats were exposed to hypoxia (O2 10% ± 5% 8 h per day) for 7 days and treated with APO (80 mg/kg, i.g.) in the last 4 days. The PK and tissue distribution of argirein were monitored by measuring its main metabolite rhein using HPLC analysis. Manganese superoxide dismutase (MnSOD) and NOX were assayed. KEY FINDINGS: The PK parameters and concentrations of rhein in the kidney, liver, heart and testes were significantly altered under hypoxia, accompanied with a reduced MnSOD and upregulated NOX compared with the normal. Altered argirein PK and distribution in these organs were relieved following APO administration. CONCLUSION: Abnormal PK and distribution of argirein by assaying its metabolite rhein are significant, consequent to hypoxic injury that is significantly ameliorated by APO through normalizing MITO and NOX.

Male hypogonadism induced by high fat diet and low dose streptozotocin is mediated by activated endoplasmic reticulum stress and IκBß and attenuated by argirein and valsartan.

Male hypogonadism is frequently accompanied with type 2 diabetes due to testicular dysfunction, but the origin of the pathogenesis is not known. We measured whether pro-inflammatory factors including endoplasmic reticulum (ER) stress chaperones and inhibitory κBß (IκBß) contribute to testis damage in type 2 diabetic rats produced by a high-fat diet (HFD) and low dose streptozotocin (STZ). We determined whether these can be attenuated by the anti-inflammatory activity of argirein a derivative of rhein as compared to valsartan. Reduced testosterone and LH (luteinizing hormone) levels in serum were significant in association with a decrease in the levels of mRNA and steroidogenic acute regulatory protein (StAR), insulin receptor substrate (IRS-1), activated IκBß and ER stress chaperone C/EBP homologous protein (CHOP) in the diabetic testis and sperm count, motility and sexual behaviors were reduced in vivo. Additionally, Leydig cells cultured with high glucose showed upregulated IκBß, ER stress sensor PERK (PKR-like ER kinase) and p-Akt/Akt in vitro. These changes may be due to a component of inflammation linked to activated NADPH oxidase and were significantly alleviated by either argirein or valsartan. In conclusion, diabetic testopathy induced by a HFD and low STZ is characterized by an entity of inflammation and is alleviated by argirein and valsartan through normalizing activated IκBß and ER stress.

Hepatosteatosis and hepatic insulin resistance are blunted by argirein, an anti-inflammatory agent, through normalizing endoplasmic reticulum stress and apoptosis in diabetic liver.

OBJECTIVES: Insulin resistance represents a mechanism underlying defect metabolism of carbohydrate and lipid linked to inflammatory reactions in diabetic liver. We hypothesized that the changes may be secondary to endoplasmic reticulum (ER) stress, which could be alleviated by either argirein or valsartan. METHODS: Hepatosteatosis in diabetic liver was induced in rats fed with a high-fat diet (HFD) for 12 weeks combined with a single low dose of streptozotocin (STZ 35 mg/kg, ip). Interventions (mg/kg/d, po)with either argirein (50, 100 and 200) or valsartan (12) were conducted in the last 4 weeks. KEY FINDINGS: In diabetic liver fat was significantly accumulated in association with elevated hepatic glucose, serum insulin and homeostasis model assessment of insulin resistance value. Downregulated glucose transporter 4, insulin receptor substrate-1 and leptin receptor (P < 0.01) were found relative to normal, where DNA ladder, downregulated B cell lymphoma/leukemia-2, upregulated B cell lymphoma/leukemia-2 Associated X protein and upregulated ER stress chaperones such as Bip/GRP78 (also known as Binding Protein, BiP), PKR-like ER kinase (PERK), p-PERK/PERK and C/EBP homologous protein were significant. These abnormalities were significantly ameliorated by argirein and valsartan. CONCLUSIONS: Hepatosteatosis induced by HFD/low STZ manifests insulin resistance and apoptosis, linked to an entity of low-grade inflammation due to activated ER stress sensors. With anti-inflammatory activity either argirein or valsartan blunts hepatosteatosis through normalizing ER stress and apoptosis in the diabetic liver.