Efficacy and Safety of Sacubitril/Valsartan Compared With ACEI/ARB on Health-Related Quality of Life in Heart Failure Patients: A Meta-Analysis.

BACKGROUND: Data on the effects of sacubitril/valsartan compared with angiotensin-converting enzyme inhibitors/angiotensin receptor blockers (ACEI/ARB) on health-related quality of life (HRQoL) are limited. OBJECTIVE: To evaluate the comparative effects between sacubitril/valsartan and ACEI/ARB on HRQoL, a systematic review and meta-analysis were performed. METHODS: PubMed, EMBASE, Web of Science, and ClinicalTrials.gov were searched from inception to March 2, 2022 for randomized controlled trials that compared the HRQoL scores, including Kansas City Cardiomyopathy Questionnaire (KCCQ), Minnesota Living with Heart Failure Questionnaire (MLHFQ), or Medical Outcomes Study Short-Form Health Survey 12 or 36 (SF-12/36), between sacubitril/valsartan and ACEI/ARB. After screening, studies that met the inclusion criteria were eventually included and analyzed. RESULTS: A total of 8 studies with 17 390 patients (8693 patients used sacubitril/valsartan, and 8697 patients used ACEI/ARB) were included in this study. Five of these studies used KCCQ, 1 used SF-12/36, 1 used MLHFQ, and 1 used both KCCQ and SF-12/36. The KCCQ overall summary score and its subscales were significantly higher in sacubitril/valsartan compared with ACEI/ARB in heart failure patients with reduced ejection fraction, but were similar in heart failure patients with preserved ejection fraction. Sacubitril/valsartan conferred similar HRQoL scores in MLHFQ and SF-12/36 to ACEI/ARB. The most frequently reported adverse event for sacubitril/valsartan is hypotension and the risk is higher than for ACEI/ARB. CONCLUSIONS: Sacubitril/valsartan may have the potential to improve HRQoL in heart failure patients with reduced ejection fraction compared with ACEI/ARB. Hypotension is the most common adverse event with sacubitril/valsartan compared with ACEI/ARB. The results of this study may contribute to the rational use of sacubitril/valsartan.

A Review of Bioactive Peptides: Chemical Modification, Structural Characterization and Therapeutic Applications.

In recent years, the development and applications of protein drugs have attracted extensive attention from researchers. However, the shortcomings of protein drugs also limit their further development. Therefore, bioactive peptides isolated or simulated from protein polymers have broad application prospects in food, medicine, biotechnology, and other industries. Such peptides have a molecular weight distribution between 180 and 1000 Da. As a small molecule substance, bioactive peptide is usually degraded by various enzymes in the organism and have a short half-life. At the same time, such substances have poor stability and are difficult to produce and store. Therefore, these active peptides may be modified through phosphorylation, glycosylation, and acylation. Compared with other protein drugs, the modified active peptides are more easily absorbed by the body, have longer half-life, stronger targeting, and fewer side effects in addition to higher bioavailability. In the light of their functions, bioactive peptide can be divided into antimicrobial, anti-tumour, anti-angiogenic, antioxidant, anti-fatigue, and anti-hypertensive peptides. This article mainly focuses on the introduction of several promising biologically active peptides functioning as antimicrobial, anti-tumour, antiangiogenic, and antioxidant peptides from the three aspects modification, structural characteristics and mechanism of action.

Pharmacokinetics and vasodilating effect study of beraprost sodium in healthy volunteers.

Currently beraprost sodium (BPS) is widely proposed to ameliorate the symptoms caused by chronic arterial occlusive disease. The objective of this study is to investigate the BPS pharmacokinetic characteristics, its vasodilating effect and the relationship between plasma concentration vs response effect. 12 healthy Chinese volunteers (6 male, 6 female) were chosen to participate in a single center, random, and open design study. After overnight fasting, BPS (dose = 40µg) was administrated orally to each volunteer. The blood samples were collected at different time points (from 0 to 5 h after administration) and BPS concentration was analyzed by LC-MS/MS method. The vasodilating effect was evaluated by detecting the skin microcirculation blood flow of volunteers' fingers with laser Doppler fluxmetry. The Cmax of BPS was (601.14 ± 214.81) pg/mL, the Tmax was (0.58 ± 0.48) h, and AUC0-t was (1020.41±214.63) pg/mL•h. BPS exhibited significant vasodilating effect since the skin microcirculation blood flow increased definitely at 0.25, 0.5, and 0.75 h (all p<0.05) after drug administration, and a positive correlation was presented between the pharmacokinetics and the vasodilating effect, which would be beneficial for guiding BPS dosage in clinical.

Dezhou donkey (Equus asinus) milk a potential treatment strategy for type 2 diabetes.

ETHNOPHARMACOLOGICAL RELEVANCE: Donkey (Equus asinus) milk has become a medical and nutrient product since ancient times. In addition, donkey milk was regarded as a medicinal food and substitute product for infant formula in some ancient western countries. Chinese ancient medical books documented the medicinal value of donkey milk, using donkey milk to treat diabetes, cough and jaundice. AIM OF THE STUDY: To investigate the donkey milk's components and anti-diabetic effect of donkey milk in vitro and in vivo and to study the molecular mechanism of donkey milk was an anti-diabetic medication. MATERIALS AND METHODS: In this study, the gastrointestinal digested donkey milk was simulated in vitro and its products of protein digestion were analyzed by SDS-PAGE. We then performed cell viability assay, insulin secretion assay, animal experiments and ELISA assays to study the anti-diabetic effect of donkey milk in vitro and in vivo. Donkey milk's anti-diabetic molecular mechanism and specific targets were detected by using quantitative real time PCR. RESULTS: Lysozyme (LZ) and α-lactalbumin (α-La) exhibited significantly lower digestibility and higher retention than the other components of donkey milk. In vitro, 500 µg/mL of donkey milk could improve damaged ß-cells viability significantly (P < 0.0001). In vivo, the blood glucose and HOMA-IR of diabetic rats treated with donkey milk were 14.23 ±â€¯5.18 mM and 74.94 ±â€¯23.62, respectively, whereas the diabetic group were 22.18 ±â€¯2.23 mM and 112.16 ±â€¯18.44, respectively (P < 0.01). The SOD value of donkey milk group was 265.87 ±â€¯21.29 U/L, while the SOD value of diabetic group was 193.20 ±â€¯52.07 U/L (P < 0.05). These results indicated that the blood glucose was reduced, the ability of the body to eliminate free radicals was enhanced, antioxidant levels in the body was increased, insulin resistance was improved in type 2 diabetic rats after donkey milk powder fed for 4 weeks. Furthermore, donkey milk could treat diabetes through down-regulating phosphoenolpyruvate carboxykinase 1 (Pck1) and glucose-6-phosphatase (G6PC). CONCLUSIONS: Donkey milk has played an important role in the treatment of type 2 diabetes, and contributed to the development of the donkey milk products.

Vitamin D and depression: mechanisms, determination and application.

Depression is the most common debilitating psychiatric disease, the pathological mechanisms of which are associated with multiple aspects of neural function. While recent evidence has consistently suggested that a suboptimal vitamin D status is frequently observed in patients with depression, the results concerning whether vitamin D insufficiency is a causal factor of depression or is secondary to depressive behavior are conflicting; additionally, the lack of consistency of the method of vitamin D determination between labs has further worsened this confusion. Herein, we reviewed the neuroactivities of vitamin D that may be associated with depression and the current studies and clinical investigations to provide a full overview on the use of vitamin D in the treatment and prevention of depression.

Analysis of phenytoin drug concentration for evaluation of clinical response, uncontrolled seizures and toxicity.

The narrow therapeutic index, non-linear pharmacokinetics and unpredictable absorption require regular therapeutic monitoring of phenytoin. The influence of genetic differences, sex, age and race on the phenytoin plasma levels and its metabolites is well recognized. This study is aimed at evaluating phenytoin plasma drug concentration and its relationship with clinical response, persistent seizures and toxicity in different gender and various age groups of Chinese epileptic patients. This knowledge will help the clinicians in adjusting the drug dosages of phenytoin in various sub-groups of epileptic patients for enhancing the safety, efficacy and minimizing the toxicity of phenytoin. A total of 48 plasma samples of epileptic patients for measuring the plasma phenytoin concentration were received. Only patients displaying persistent seizures or suspected of adverse effects were requested for drug monitoring. All these samples were analyzed for therapeutic drug monitoring with Enzyme-multiplied immunoassay technique. Surprisingly, it was found that majorities (85.5%) of samples were out of the reference range, of which 69% of samples were in sub-therapeutic levels and 16.5% of samples were above therapeutic levels. Only 14.5% of all samples had phenytoin levels in the therapeutic range. The difference in plasma concentration of phenytoin was notably altered in gender and various age groups. Careful attention must be applied to specific gender and particular age group on an individual basis in the interpretation of plasma concentration results, in order to facilitate the modification of doses and develop the best approach in treatment and to obtain the desired clinical response because multiple factors can affect the phenytoin plasma concentration. Through these results, it can be concluded that a good correlation exists between phenytoin plasma concentration and clinical response. Therefore, regular therapeutic monitoring of phenytoin and screening of HLA-A, B, C and DRB1 genotypes before prescribing phenytoin in epileptic patients is essentially required to achieve maximum clinical response and prevent the serious toxicity.

Therapeutic drug monitoring of valproic acid.

The unpredictable and unfavorable connection of dose and plasma concentration of valproic acid supports the necessity to regularly measure its plasma concentration. The present study is drug monitoring of valproic acid and comparative evaluation of therapeutic monitoring results of valproic acid for assessment of clinical response, safety and toxicity in different age and gender groups of Chinese epileptic patients. This knowledge will help the clinicians in adjusting the drug dosages of valproic acid in various sub-groups of epileptic patients for enhancing the safety and minimizing the toxicity of valproic acid. A total of 206 plasma samples (126 males and 80 females) of epileptic patients using valproic acid were requested for therapeutic drug monitoring by neurology department of Qilu Hospital. It was found that 29 % of the total samples were found in sub-therapeutic levels, 13% of the samples had toxic levels and 58% of all the samples had valproic acid levels in therapeutic range. The difference in plasma concentration of valproic acid is notably altered in gender and various age groups. However, this requires further investigation. Despite the majority of samples in the therapeutic range, there was an unfavorable clinical response. The outcomes of the current research work exposed that there was a poor correlation between the plasma concentration and clinical response. Careful attention must be applied to specific gender and particular age group on an individual basis in the interpretation of plasma concentration results, in order to facilitate the modification of doses and develop the best approach in treatment and to obtain the desired clinical response because multiple factors can affect the valproic acid plasma concentration. Through these results, it can be concluded that poor correlation exists between valproic acid plasma concentration and clinical response.

Histone Acetyltransferase Mof Affects the Progression of DSS-Induced Colitis.

BACKGROUND/AIMS: Histone acetylation has been demonstrated to be associated with inflammation response. Histone acetyltransferase (HAT) Mof, specifically acetylating lysine 16 of histone H4 (H4K16), has been reported to regulate T cell differentiation. In addition, it has been suggested that acetylation of H4K16 is associated with the inflammatory response. We evaluated the role and potential mechanism of Mof in the development of experimental colitis. METHODS: We used Mof conditional knockout mice to study the role of Mof in dextran sulfate sodium (DSS)-induced colitis and detected the differential expression of genes due to Mof deficiency involved in the inflammatory response, particularly the Th17 signaling pathway, by western blotting, quantitative PCR and RNA sequencing (RNA-seq). RESULTS: A significant elevation of Mof was observed in colonic tissues of mice with DSS-induced colitis. Mof deficiency alleviated the severity of DSS- induced colitis in mice. We found that Th17 signaling pathway associated genes, including Il17a, Il22, RORγt, RORα, Stat3, TGF-ß 1, and Il6, were downregulated in colon tissues with Mof deficiency. RNA-seq data analysis suggested that 68 genes were related to inflammatory response processing and 47 genes were downregulated in Mof defective colon tissues. CONCLUSION: Our study demonstrated that HAT Mof is involved in the development of colitis, and the lack of Mof ameliorates DSS-induced colitis in mice.

Novel 'Stereoscopic Response' Strategy Can Be Used in Combination Therapy.

Future cancer therapy will depend on combination therapy with multiple drugs to achieve maximum effects and minimum toxicity. Due to the complexity and significance of the tumor microenvironment (TME), it is vital to elucidate this complicated environment when designing a co-delivery system. There are numerous potent target sites in the TME to facilitate simultaneous and selective delivery. Currently, nanocarriers are used frequently in co-delivery systems for multiple antitumor treatments. Nanocarriers can efficiently deliver drugs and achieve synergistic effects, but the potent barriers in the TME and their inherent limitations have restricted their use. It is crucial to design an effected co-delivery system associated with the TME to achieve better anti-tumor activity, which we define as a "stereoscopic response." Although there are many obstacles in this field, the combination of simultaneous response in the TME with drug activity may present a promising strategy to achieve innovative, safe, and effective treatment.

Higher Anti-angiogenesis Activity, Better Cellular Uptake and Longer Half-life of a Novel Glyco-modified Endostatin by Polysulfated Heparin.

BACKGROUND: Endostatin (ES) is a promising anti-angiogenesis protein and has been approved for the treatment of non-small cell lung cancer, but short half-life, poor stability and nonspecific delivery caused great pain to patients and produced unsatisfactory treatment effectiveness. OBJECTIVE: In this work, in order to overcome these disadvantages, ES was covalently modified by polysulfated heparin (PSH) with the expectancy of longer half-life, higher anti-angiogenesis activity and better cellular uptake. METHODS: To characterize the cellular uptake, flow cytometry and confocal laser scanning microscopy were used to study the intracellular localization of fluorescein isothiocyanate-labeled ES and PSH-ES in EAhy926 endothelial cells. Zebrafish model was used to study the anti-angiogenesis activities of ES and its derivatives in vivo. The 125I-radiolabeled ES and PSH-ES were administered to healthy BALC/c mice for the pharmacokinetics study. RESULTS: Compared with ES, better cellular uptake effects were detected in PSH-ES group. Both ES and PSH-ES showed inhibition on the intersegmental vessels formation, while PSH-ES displayed a higher one. The half-life of PSH-ES was lengthened and area under the curve (AUC) was increased. At the same time, ES and PSH-ES were both widely and rapidly distributed in the lungs, livers, kidneys and hearts with little difference. CONCLUSION: The results indicated that PSH displayed good properties as a novel glyco-modifier for protein and peptide. The results also showed that PSH-ES displayed better cellular uptake, higher antiangiogenesis activity and prolonged half-life, which would lead to better anti-tumour effects.

Bioequivalence Study of Warfarin in Healthy Chinese Volunteers With a Validated High-Performance Liquid Chromatography-Mass Spectrometry Method.

This study was designed to investigate the pharmacokinetics of an innovative film-coated warfarin sodium tablet and to compare it with the marketed sugar-coated warfarin sodium tablet in humans. A single-dose, open-label, randomized, two-way crossover study was performed in 24 healthy Chinese male volunteers. They were administered 2.5 mg of innovative film-coated warfarin sodium tablets or the marketed sugar-coated warfarin sodium tablets. Blood samples were collected at different time points after dosing for investigation of the pharmacokinetics of warfarin in human plasma. A sensitive liquid chromatography mass spectrometry method was established to determine warfarin in plasma. Drug and Statistics 2.1.1 was applied to calculate the pharmacokinetics parameters. The main pharmacokinetic parameters for film-coated and sugar-coated warfarin were the following: t½ , 103.5 ± 18.8 and 105.8 ± 21.3 hours; Tmax , 0.7 ± 0.5 and 1.3 ± 0.8 hours; Cmax , 347.8 ± 74.8 and 322.9 ± 75.7 ng/mL; AUC0∼360 , 16,024.2 ± 3713.9 and 15,586.6 ± 3477.0 ng·mL-1 ·h; AUC0∼∞ , 17,335.7 ± 4089.1 and 16,912.0 ± 3911.2 ng·mL-1 ·h, respectively. The human pharmacokinetics of film-coated and sugar-coated warfarin were slightly different. The oral absorption and bioavailability of innovative film-coated warfarin were slightly higher than those of the sugar-coated warfarin. This study is vital to clinical usage of warfarin not only because of the pharmacokinetic parameters of the 2 pharmaceutical dosage forms of warfarin but also to obtain data on the prevalence of CYP2C9 and VKORC1 genes and their influence on the concentration of warfarin.

JAK/STAT Signal Transduction: Promising Attractive Targets for Immune, Inflammatory and Hematopoietic Diseases.

BACKGROUND: JAK/STAT signal pathway, a requisite part in the signaling process of growth factors and cytokines, has become attractive targets for numerous immune, inflammatory and hematopoietic diseases. OBJECTIVE: Herein, we present a review of the JAK/STAT signal pathway, the structure, biological function, mechanism of the JAKs and STATs along with a summary of the up-to-date clinical or approved JAK inhibitors which are involved in the treatment of various kinds of tumors and other immunity indications. Moreover, kinds of recently discovered JAKs inhibitors with potent activity or promising selectivity are also briefly discussed. CONCLUSION: Research and development of isoform selective JAK inhibitors has become a hot topic in this field. With the assistance of high throughput screening and rational drug design, more and more JAK inhibitors with improved selective profiles will be discovered as biological probes and even therapeutic agents.

Hyperosmolarity evokes histamine release from ileum mucosa by stimulating a cholinergic pathway.

Changes in extracellular osmolarity lead to alteration in cellular volume. In the study, we examined the effects of hyperosmolarity on short-circuit currents (Isc) in the rat ileum using the Ussing chamber technique. Mucosal exposure to 20 mM glucose evoked a decrease of ISC in the rat ileum, which was antagonized by the stretch-activated channel blocker GdCl3, TTX and atropine, respectively. In contrast, it was not blocked by phlorizin, a Na+-glucose cotransporter SGLT1 inhibitor. Furthermore, the unabsorbed substances, such as sucrose, lactulose or urea, also induced a decrease of ISC in rat ileum. ELISA results revealed that 20 mM glucose stimulated the release of histamine from rat ileum mucosa, which was attenuated by TTX. In addition, the glucose-induced ISC was depressed by pyrilamine, a histamine H1 receptor blocker (H1 antagonist) whereas it was not affected by ranitidine (H2 antagonist), clobenpropit (H3 antagonists) or JNJ7777120 (H4 antagonist), respectively. The ion substitution experiments suggest that the changes of Na+ and HCO3- ion flux underlie the glucose-induced ISC. In conclusion, osmotic stimulus decreased the basal ISC of rat ileum by evoking histamine release from ileum mucosa. The changes of Na+ and HCO3- ion transport are involved in the glucose-evoked decrease of basal ISC.

A comparison of liquid chromatography-tandem mass spectrometry (LC-MS/MS) and enzyme-multiplied immunoassay technique (EMIT) for the determination of the cyclosporin A concentration in whole blood from Chinese patients.

Cyclosporin A (CyA) is an immunosuppressive agent widely used in clinical therapy. In the therapeutic process, the blood concentration of CyA should be monitored to avoid or prevent rejection and toxicity. The objectives of this study were to compare the correlation of liquid chromatography-tandem mass spectrometry (LC-MS/MS) and enzyme-multiplied immunoassay technique (EMIT) for the determination of the CyA concentration in human blood and to provide evidence for the rational usage of EMIT in clinical practice. Blood samples collected from 132 patients undergoing a liver or kidney transplant or patients with aplastic anemia at Qilu Hospital of Shandong University were tested using the two methods. The calibration curve was linear from 25-500 ng·mL-1 for LC-MS/MS and from 50-450 ng·mL-1 for EMIT. The inter- and intra-day RSDs were less than 15%. The CyA blood concentration according to EMIT was 3.5 ng·mL-1 more than that according to LC-MS/MS. The 95% confidence interval was -10.0~16.9 ng·mL-1. The CyA blood concentration according to the two methods did not differ significantly (p > 0.05). LC-MS/MS and EMIT were suitable methods for determining the CyA blood concentration. The two methods were closely correlated (r2 = 0.969), but the CyA blood concentration according to EMIT was slightly higher than that according to LC-MS/MS. The clinical significance of this finding needs to be further evaluated.

Targeting autophagy augments the activity of DHA-E3 to overcome p-gp mediated multi-drug resistance.

Multidrug resistance (MDR) is a major obstacle for successful chemotherapy treatment. Searching for effective MDR modulators and combining them with anticancer drug therapies has been a promising strategy against clinical MDR. In our previous study, we have found that DHA-E3, a synthetic derivative of DHA, has the ability to modulate the function of P-glycoprotein (P-gp) and reverse MDR in cancer cells. In this study, we further evaluated the reversal effect of DHA-E3 on MDR and explored its mechanism of action in vitro. Our findings showed that DHA-E3 significantly potentiated the cytotoxicity of vincristine(VCR) and adriamycin(ADR) in the P-gp over-expressing KB/VCR and A02 cells. The mechanistic study found that DHA-E3 increased the intracellular accumulation of ADR and rhodamine-123 by directly inhibiting the drug-transport activity of P-gp. In the present study, we found that DHA-E3 not only reversed MDR, but also induced autophagy in MDR cancer cells. To determine whether DHA-E3-induced autophagy is an adaptive survival response or contributes to cell death, we manipulated autophagic activity using autophagy inhibitor 3-MA or siRNA targeting Beclin1. We found that the reversal activity of DHA-E3 was significantly exacerbated in the presence of 3-MA or blocking the expression of Beclin1. These results suggest that DHA-E3 is capable of reversing MDR, induction of autophagy represents a defense mechanism and inhibiting this process may be an effective strategy to augment the reversal activity of reversal agents.

Recent Advance in Tumor-associated Carbohydrate Antigens (TACAs)-based Antitumor Vaccines.

Cancer cells can be distinguished from normal cells by displaying aberrant levels and types of carbohydrate structures on their surfaces. These carbohydrate structures are known as tumor-associated carbohydrate antigens (TACAs). TACAs were considered as promising targets for the design of anticancer vaccines. Unfortunately, carbohydrates alone can only evoke poor immunogenicity because they are unable to induce T-cell-dependent immune responses, which is critical for cancer therapy. Moreover, immunotolerance and immunosuppression are easily induced by using natural occurring TACAs as antigens due to their endogenous property. This review summarizes the recent strategies to overcome these obstacles: (1) covalently coupling TACAs to proper carriers to improve immunogenicity, including clustered or multivalent conjugate vaccines, (2) coupling TACAs to T-cell peptide epitopes or the built-in adjuvant to form multicomponent glycoconjugate vaccines, and (3) developing vaccines based on chemically modified TACAs, which is combined with metabolic engineering of cancer cells.

Simple, rapid and highly sensitive HPLC method for measurement of Lamotrigine in human plasma and its clinical applications.

Spikes in Lamotrigine concentrations levels and associated clinical toxicity may occur unpredictably. This study describes the development and validation of a simple, more rapid, highly sensitive and economical method for measuring Lamotrigine (LTG) concentration levels in human plasma using HPLC-UV and its clinical applications. Analyte from plasma was extracted with methanol (protein precipitation) and separated on the analytical column Diamonsil C18 (150mm×4.6mm, 5µm) Waters-Milford, MA, United States. Mixture of 0.1% Trifluoroacetate and Methanol used as mobile phase in a 59:41 volume/volume mixture with an isocratic flow rate of 1.5 ml/min and wavelength was adjusted to 260nm. Standard curve of lamotrigine showed good linearity over the range of 1.0-50µg/mL (r2=0.9961) and LLOQ was 1.0µg/ml. The Specificity, Recovery, Accuracy, Stability, Robustness and RSDs for both intraday and interday precision were within acceptable limits. The highly sensitive HPLC assay for determination of LTG in human plasma was demonstrated, validated and applied in Therapeutic Drug Monitoring (TDM) of sixty seven epilepsy patients who were using LTG. The proposed method can be easily applied in routine Therapeutic monitoring of LTG, Besides TDM, stated method can be also very useful for Bioequivalence studies, Pharmacovigilance and Pharmacokinetics studies.