Material basis and pharmacodynamic mechanism of YangshenDingzhi granules in the intervention of viral pneumonia:Based on serum pharmacochemistry and network pharmacology

Background:YangshenDingzhi granules(YSDZ)are clinically effective in preventing and treating COVID-19.The present study elucidates the underlying mechanism of YSDZ intervention in viral pneumonia by employing serum pharmacochemistry and network pharmacology.Methods:The chemical constituents of YSDZ in the blood were examined using ultraperformance liquid chromatography-quadrupole/orbitrap high-resolution mass spectrometry(UPLC-Q-Exactive Orbitrap MS).Potential protein targets were obtained from the SwissTargetPrediction database,and the target genes associated with viral pneumonia were identified using GeneCards,DisGeNET,and Online Mendelian Inheritance in Man(OMIM)databases.The intersection of blood component-related targets and disease-related targets was determined using Venny 2.1.Protein-protein interaction networks were constructed using the STRING database.The Metascape database was employed to perform enrichment analyses of Gene Ontology(GO)functions and Kyoto Encyclopedia of Genes and Genomes(KEGG)signaling pathways for the targets,while the Cytoscape 3.9.1 software was utilized to construct drug-component-disease-target-pathway networks.Further,in vitro and in vivo experiments were performed to establish the therapeutic effectiveness of YSDZ against viral pneumonia.Results:Fifteen compounds and 124 targets linked to viral pneumonia were detected in serum.Among these,MAPK1,MAPK3,AKT1,EGFR,and TNF play significant roles.In vitro tests revealed that the medicated serum suppressed the replication of H1N1,RSV,and SARS-CoV-2 replicon.Further,in vivo testing analysis shows that YSDZ decreases the viral load in the lungs of mice infected with RSV and H1N1.Conclusion:The chemical constituents of YSDZ in the blood may elicit therapeutic effects against viral pneumonia by targeting multiple proteins and pathways.

Artificial Bear Bile:A Novel Approach to Balancing Medical Requirements and Animal Welfare

Bear bile has been a valuable and effective medicinal material in traditional Chinese medicine(TCM)for over 13 centuries.However,the current practice of obtaining it through bear farming is under scrutiny for its adverse impact on bear welfare.Here,we present a new approach for creating artificial bear bile(ABB)as a high-quality and sustainable alternative to natural bear bile.This study addresses the scientific challenges of creating bear bile alternatives through interdisciplinary collaborations across various fields,including resources,chemistry,biology,medicine,pharmacology,and TCM.A comprehensive efficacy assessment system that bridges the gap between TCM and modern medical terminology has been established,allowing for the systematic screening of therapeutic constituents.Through the utilization of chemical synthesis and enzyme engineering technologies,our research has achieved the environmentally friendly,large-scale production of bear bile therapeutic compounds,as well as the optimization and recomposition of ABB formulations.The resulting ABB not only closely resembles natural bear bile in its composition but also offers advantages such as consistent product quality,availability of raw materials,and independence from threatened or wild resources.Comprehensive preclinical efficacy evaluations have demonstrated the equivalence of the therapeutic effects from ABB and those from commercially available drained bear bile(DBB).Furthermore,preclinical toxicological assessment and phase I clinical trials show that the safety of ABB is on par with that of the currently used DBB.This innovative strategy can serve as a new research paradigm for developing alternatives for other endangered TCMs,thereby strengthening the integrity and sustainability of TCM.

Insulin therapy in type 2 diabetes: Insights into clinical efficacy, patient-reported outcomes, and adherence challenges

Insulin therapy plays a crucial role in the management of type 2 diabetes as the disease progresses.Over the past century,insulin formulations have undergone significant modifications and bioengineering,resulting in a diverse range of available insulin products.These products show distinct pharmacokinetic and pharmacodynamic profiles.Consequently,various insulin regimens have em-erged for the management of type 2 diabetes,including premixed formulations and combinations of basal and bolus insulins.The utilization of different insulin regimens yields disparate clinical outcomes,adverse events,and,notably,patient-reported outcomes(PROs).PROs provide valuable insights from the patient’s perspective,serving as a valuable mine of information for enhancing healthcare and informing clinical decisions.Adherence to insulin therapy,a critical patient-reported outcome,significantly affects clinical outcomes and is influenced by multiple factors.This review provides insights into the clinical effectiveness of various insulin preparations,PROs,and factors impacting insulin therapy adherence,with the aim of enhancing healthcare practices and informing clinical decisions for individuals with type 2 diabetes.

Gut microbiota-mediated metabolism of Panax notoginseng saponins and its role in pharmacokinetics and pharmacodynamics

Panax notoginseng saponins(PNS)are a class of effective ingredients in Notoginseng Radix et Rhizoma,a well-known herbal medicine called San-Qi in Chinese.After oral administration,PNS inevitably interacts with gut microbiota,and thus affect the pharmacokinetic profiles and pharmacological effects.To date,studies concering gut microbiota-mediated metabolism of PNS have not been reviewed systematically.Herein,we outline the metabolic profiles of Panax notoginseng saponins mediated by gut microbiota,as well as its role in the pharmacokinetics and pharmacodynamics on the basis of reported data.The metabolic pathways of primary saponins are proposed,and step-by-step deglycosylation is found to be the primary degradation pathways of PNS mediated by gut microbiota.Specific microorganisms and enzymes involved in the metabolic processes were summarized.Gut microbiota is deeply involved in the metabolism of PNS,affects the pharmacokinetic profiles,and produces a series of active metabolites.These metabolites were documented to play an essential role in the efficacy of the parent compounds.Future studies should focus on strengthening the real-world evidence,defining the interaction between gut microbiota and PNS,and developing the strategy for modulating gut microbiota to enhance the bioavailability and efficacy of PNS.These information would be useful for further research and clinical application of PNS.

To explore the mechanism of Fuyang Jiebiao granules against viral pneumonia based on network pharmacology and pharmacodynamics

Objective:To investigate the mechanism of Fuyang Jiebiao granule(FYJBKL)in the treatment of viral pneumonia.Methods:Firstly,a network model was constructed using network pharmacology to study the target expression sites of FYJBKL viral pneumonia,so as to determine the main targets and important signal transduction pathways for the treatment of viral pneumonia.Secondly,the main components of the drug and the main target are docked.Then,the fever,sweating and inflammation rat models were established to explore the antipyretic,sweating and anti-inflammatory mechanisms of FYJBKL.Finally,the contents of IL-17,IL-1β,TNF-αand IL-6 in blood samples of rats were analyzed by ELISA method,and the morphological changes of lung tissue were observed by HE staining.Results:Quercetin,luteolin,kaempferol,etc.,and the main mechanism targets are IL-17,IL-1β,TNF-α,IL-6 and so on.Thirty signal pathways were identified by KEGG enrichment analysis,including interleukin-17 signaling pathway(IL-17 signaling pathway),human cytomegalovirus infection pathway(human cytomegalovirus infection),Kaposi's sarcoma associated herpesvirus infection pathway(Kaposi's sarcoma-as-sociated herpesvirus infection)and so on.After the study of molecular docking,we found that the contact efficiency between active substances and possible key targets is good.The high and middle concentration groups of FYJBKL significantly decreased the expression of IL-17,IL-1β,TNF-αand IL-6 in the blood of rats with inflammation(P<0.05).FYJBKL significantly reduced the foot swelling induced by egg white and inhibited the increase of body temperature induced by yeast in rats(P<0.05).HE staining showed that FYJBKL improved pulmonary fibrosis and inflammatory exudation to varying degrees.Conclusion:The effects of FuyangJiebiao granules on the related signal pathways of anti-virus,anti-immune and anti-inflammation as well as biological and cellular processes may be caused by the binding of quercetin,luteolin,kaempferol and other active ingredients to their shared targets.Fuyang Jiebiao granules can improve the related symptoms caused by viral pneumonia,and its mechanism may be related to the activities of TNF,IL-17,IL-6 and other related channels,which are multiple targets of inflammation regulation.

Pharmacodynamic Study of Parallel Groups Comparing the Effect of Rivaroxaban 20 Mg (Laboratorios Leti, S.A.V.) vs Rivaroxaban 20 Mg (Bayer Laboratories) on Prothrombin Time

Background: The prevalence of both atrial fibrillation (FA) and diabetes mellitus (DM) is increasing and they often occur together and constitute a high risk of thrombosis. Rivaroxaban is a Factor Xa inhibitor with a rapid onset and disappearance of action after oral administration;it acts by inhibiting the active form of the coagulation factor. In order to reflect the effect of the action of Rivaroxaban, we used the prothrombin time (PT);however, it′s not the most accurate, but it is the one available in our community. Methods: This was a prospective, randomized, analyst-blinded, parallel group clinical study to verify the efficacy of Rivaroxaban Leti 20 mg (RL) (12 volunteers vs Rivaroxaban Bayer 20 mg (RB) (13 volunteers). The variables were determination of PT and Partial Thromboplastin Time (aPTT) at baseline and at 24, 48 and 72 hours after administering a daily dose of 20 mg for three days. The determination was carried out with the IDG method (Integrated Diagnostics Group Sanzay Corporation) with an International Sensitivity Index (ISI) of 1.17 PT and aPTT were taken before the first dose, and then, every day during the next 3 days, three hours after the ingestion of their daily dose at 7 am. Results: The 25 healthy volunteers were similar in age, BMI, and SBP/DBP level with a greater number of men in the Bayer group. The efficacy of rivaroxaban was similar in both groups with prolongation of PTT to the 2nd day of treatment with PT, and percentage changes from baseline (14.46 ± 0.97 for RB vs 14.17 ± 0.94 RL p: 0.45), PTT results and percentage changes from the base (RB: 34 ± 4.53 RL: 33.46 ± 2.82). The safety of rivaroxaban was good in both groups with no serious adverse events. The equivalence in the logarithmically transformed PT result (ln) on day two, Mean and CI (90%) 99.2 (94.4-104) and 100 (99.5-100.8);neither the means nor the 90% confidence intervals of the PT variable transformed logarithmically to ensure its normality, were far from the 80%-125% allowed for declaration of similarity. Conclusion: The test formulation Rivaroxaban Asarap? 20 mg, manufactured by Leti Laboratories, is interchangeable or bioequivalent in clinical and laboratory response to the reference formulation Xarelto? manufactured by Bayer Laboratories.

Advances in Research Methods of Pharmacodynamic Substances in Traditional Chinese Medicines and Their Application in the Teaching of Traditional Chinese Medicine Analysi

With the continuous progress of science and technology,the research methods of pharmacodynamic substances in traditional Chinese medicine are developing,and the application of these methods in teaching is becoming more and more extensive.By introducing these research methods into the classroom,teachers can help students to deeply understand the nature and mechanism of action of pharmacodynamic substances in traditional Chinese medicine,and improve their interest in and knowledge of traditional Chinese medicine.This paper introduces the definition of pharmacodynamic substances in traditional Chinese medicine,research methods,and their application in the teaching of traditional Chinese medicine analysis.

In vivo recognition of bioactive substances of Polygonum multiflorum for protecting mitochondria against metabolic dysfunction-associated fatty liver disease

BACKGROUND Metabolic dysfunction-associated fatty liver disease(MAFLD)is a severe threat to human health.Polygonum multiflorum(PM)has been proven to remedy mitochondria and relieve MAFLD,but the main pharmacodynamic ingredients for mitigating MAFLD remain unclear.AIM To research the active ingredients of PM adjusting mitochondria to relieve highfat diet(HFD)-induced MAFLD in rats.METHODS Fat emulsion-induced L02 adipocyte model and HFD-induced MAFLD rat model were used to investigate the anti-MAFLD ability of PM and explore their action mechanisms.The adipocyte model was also applied to evaluate the activities of PM-derived constituents in liver mitochondria from HFD-fed rats(mitochondrial pharmacology).PM-derived constituents in liver mitochondria were confirmed by ultra-high-performance liquid chromatography/mass spectrometry(mitochondrial pharmacochemistry).The abilities of PM-derived monomer and monomer groups were evaluated by the adipocyte model and MAFLD mouse model,respectively.RESULTS PM repaired mitochondrial ultrastructure and prevented oxidative stress and energy production disorder of liver mitochondria to mitigate fat emulsion-induced cellular steatosis and HFD-induced MAFLD.PM-derived constituents that entered the liver mitochondria inhibited oxidative stress damage and improved energy production against cellular steatosis.Eight chemicals were found in the liver mitochondria of PM-administrated rats.The anti-steatosis ability of one monomer and the anti-MAFLD activity of the monomer group were validated.CONCLUSION PM restored mitochondrial structure and function and alleviated MAFLD,which may be associated with the remedy of oxidative stress and energy production.The identified eight chemicals may be the main bioactive ingredients in PM that adjusted mitochondria to prevent MAFLD.Thus,PM provides a new approach to prevent MAFLD-related mitochondrial dysfunction.Mitochondrial pharmacology and pharmacochemistry further showed efficient strategies for determining the bioactive ingredients of Chinese medicines that adjust mitochondria to prevent diseases.

Therapeutic Characterization of ^(131)I-Labeled Humanized Anti-B7-H3 Antibodies for Radioimmunotherapy for Glioblastoma

B7 homolog 3(B7-H3)has attracted much attention in glioblastoma(GBM)radioimmunotherapy(RIT)due to its abnormally high expression on tumor cells.In this study,we report that two specific humanized anti-human B7-H3 antibodies(hu4G4 and hu4H12)derived from mouse anti-human B7-H3 antibodies that were generated by computer-aided design and exclusively recognize membrane expression of B7-H3 by human glioma cells,Hu4G4 and hu4H12 were radiolabeled with^(89)Zr for RIT antibody screening.Micro-positron emission tomography(PET)imaging,biodistribution and pharmacokinetic(PK)analyses of^(89)Zr-labeled antibodies were performed in U87-xenografted models.^(125)I labelling of the antibodies for single-photon emission computed tomography(SPECT)imaging was also used to investigate the biological behavior of the antibodies in vivo.Fu rthermore,the pharmacodynamic(PD)of the^(131)Ilabeled antibodies were evaluated in U87-xenografted mice and GL261 Red-FLuc-B7-H3 in situ glioma tumor models.Micro-PET imaging and biodistribution analysis with a gamma counter showed that^(89)Zr-deferoxamine(DFO)-hu4G4 had higher tumor targeting performance with lower liver uptake than^(89)Zr-DFO-(hu4H12,immunoglobulin G(IgG)).The biodistribution results of^(125)I-SPECT imaging were similar to those of^(89)Zr-PET imaging,though the biodistribution in long bone joints and the thyroid varied.The PD analysis results indicated that^(131)I-hu4G4 had an excellent therapeutic effect and high safety with no apparent toxicity.Interestingly,^(131)I-hu4G4 improved the tumor vasculature in tissues with higher expression of collagen typeⅣand platelet-derived growth factor receptorβ(PDGFR-β)compared with control treatment,as determined by immunofluorescence(IF),which contributed to inhibiting tumor growth.Taken together,our data indicate that hu4G4 exhibits good tumor targeting and specificity,achieves low nonspecific concentrations in normal tissues,and has acceptable PK characteristics.^(131)I-hu4G4 also exerts effective antitumor effects with an ideal safety profile.Therefore,we expect hu4G4 to be an excellent antibody for the development of GBM RIT.

New therapy for oral ulcer:Evodia rutaecarpa patch combined with acupoint application

Background:Oral ulcer is the most common and easily recurrent disease in stomatology,which influence the patients’communication,normal dietary,and sleep.Evodia rutaecarpa(ER)is a traditional Chinese herbal medicine recorded in ancient Chinese medical books,which has a medicinal history of more than 2,000 years.Clinically,the application of ER at plantar Yongquan point(KI1)is effective in the treatment of oral ulcer.The purpose of this study was to combine the modern transdermal drug delivery system with traditional Chinese medicine to develop the transdermal absorption patch of ER and apply it to the treatment of oral ulcer at Yongquan point of plantar.Methods:Firstly,the medicinal materials of ER were extracted and the extracted materials were prepared into dispersed ER patch.The formulation and preparation process were screened by orthogonal design method and single factor investigation method.The adhesive and transdermal properties of the patch were used as the evaluation index of the preparation.Secondly,Wistar rats were used as experimental animals to establish a rat model of mouth ulcers.Wistar rats were randomly divided into normal group,model group(A),model group(B),low dose group,medium dose group and high dose group.the efficacy of ER on rat’s oral ulcer model was evaluated through three aspect such as apparent index,pathological index and biochemical index.Results:The patch had suitable adhesion and good skin penetration,which was an effective treatment for oral ulcer.In vivo pharmacodynamic studies,compared with the normal group,the body mass and food intake of rats in each group after modeling decreased,the amount of drinking water increased,the tissue structure of oral mucosa was damaged,and the levels of inflammatory factors(TNF-α,IL-6)and malondialdehyde increased,the levels of anti-inflammatory factors(IL-10),cell growth factor(epidermal growth factor,TGF-β_(1))and superoxide dismutase decreased.Compared with the model group,the body weight and food intake of each dosing group increased,water consumption decreased,the oral mucosal tissue structure was more complete,the levels of TNF-α,IL-6 and malondialdehyde decreased,the levels of IL-10,epidermal growth factor,TGF-β1 and superoxide dismutase increased,and the changes of various indexes were dose-related.Conclusion:ER patch can inhibit inflammatory reaction,enhance the antioxidant defense ability of the body,and promote the repair of damaged oral mucosa,so as to play an effective role in the treatment of oral ulcer.

Pharmacodynamic study of cannabidiol on bleomycin-induced pulmonary fibrosis in rats

Objective:To study the protective effect of cannabidiol(CBD)on rats with pulmonary fibrosis and explore the possible mechanism of the use of CBD in the treatment of pulmonary fibrosis.Methods:Sixty SD rats were randomly divided into the normal control group,model group,prednisone group,CBD low,medium and high dose groups(12,36,108 mg/kg,ig),10 rats in each group.Except for the normal control group,the other 5 groups were all induced by tracheal injection of bleomycin to rat models of pulmonary fibrosis.After modeling,the rats were given intragastric administration once a day for 28 consecutive days and samples were taken.The degree of pulmonary edema was detected;the pathological changes of lung tissue were observed by HE and Masson staining;tumor necrosis factorα(TNF-α),interleukin-1β(IL-1β),interleukin-6(IL-6)and lung tissue superoxide dismutase(SOD),malondialdehyde(MDA),hydroxyproline(HYP)contents were measured by ELISA,transforming growth factor-β1(TGF-β1)andα-smooth muscle protein(α-SMA)concentration were detected by immunocytochemical method,real-time fluorescent quantitative PCR(qRT-PCR)method was used to detect the mRNA expression levels of TGF-β1,α-SMA,Nrf2 and nuclear transcription factor-κB p65(NF-κB p65).Results:The lung organ coefficient and W/D value were significantly decreased in the CBD administration group(P<0.05);medium and high doses of CBD could reduce the number of collagen fibers and fibroblasts;the pulmonary fibrosis in the low,medium,and high dose groups of CBD was significantly lower.The levels of TNF-α,IL-1β,and IL-6 in rat serum,as well as MDA and HYP in lung tissue,were significantly lower compared to the model group.Additionally,the level of SOD was significantly increased(P<0.05);The expression ofα-SMA was decreased compared with the model group(P<0.05);the contents of TGF-β1,α-SMA and NF-κB p65 mRNA in lung tissue decreased,and the expression level of Nrf2 mRNA increased(P<0.05).Especially,the high-dose group had the most significant effect.Conclusion:CBD can significantly reduce the degree of pulmonary fibrosis in rats,and its potential mechanism may be related to inhibiting inflammatory response,enhancing antioxidant capacity and inhibiting the protein expression of TGF-β1 andα-SMA.

Anorectal Pharmacodynamics and In Vitro Drug Release of Clerodendrum bungei Steud.Extract Gel

[Objectives]To determine the optimal preparation technology of Clerodendrum bungei Steud.extract gel by orthogonal test and gel quality test method in General Rule 0114 of Chinese Pharmacopoeia(Volume IV,2020 Edition),and to study its anorectal pharmacodynamics and drug release in vitro.[Methods]Carbomer 940,propylene glycol and absolute ethyl alcohol were selected as the main factors,and the preparation technology of C.bungei Steud.extract gel was optimized by orthogonal test.The mouse model of ulcerative hemorrhoids was established with glacial acetic acid(HAC)and compared with Ma Yinglong musk hemorrhoids ointment.The recovery of trauma was compared between the two groups.At the same time,porcine small intestine was used as semi-permeable membrane to make diffusion cell to simulate anal environment,and the drug release in vitro was studied.[Results]The C.bungei Steud.extract gel was smooth in appearance and good in stability.It could effectively treat anal ulcer in mice and release quickly in vitro.[Conclusions]The formula is reasonable,and the effect of animal experiment is remarkable,which can provide a new treatment plan for ulcerative hemorrhoids.

Pharmacokinetics/Pharmacodynamics study of Fixtral SB as compared to supra bioavailable itraconazole and conventional itraconazole

BACKGROUND Itraconazole is a broad-spectrum triazole antifungal inhibiting fungal growth by inhibiting ergosterol synthesis and exhibits a nonlinear pharmacokinetic profile.Erratic absorption pattern with wide fluctuations in blood levels causes inconsistent and unpredictable clinical behaviour of this drug despite its low minimum inhibitory concentration(MIC)as compared to other antifungal agents.AIM To compare the oral bioavailability and bioequivalence of Fixtral SB(supra bioavailable itraconazole)with reference product R2(supra bioavailable 2×50 mg itraconazole).METHODS The study population consisted of 54 healthy volunteers,aged between 18-45 years and randomized to receive a single oral dose of either test[T;Fixtral SB(supra bioavailable itraconazole)100 mg]or reference product(R1;Sporanox 100 mg×2 capsules and R2;Lozanoc capsules 50 mg×2 capsules).Blood samples were taken pre-dose and post-dose up to 96 h.The study evaluated bioequivalence by comparing the oral bioavailability of the test product with reference product R2.The pharmacodynamic characteristics of the drug were evaluated by comparing the test product with reference product R1.Pharmacokinetics(PK)-PD comparative analysis[area under the concentration-time curve(AUC)/minimum inhibitory concentration(MIC)>25]was performed for conventional itraconazole 100 mg and supra bioavailable itraconazole 50 mg.Adverse events(AEs)assessments were performed in each study period and post-study evaluation.RESULTS Statistical analysis of primary PK variables revealed bioequivalence,with confidence intervals being completely inside the acceptance criteria of 80%-125%.The peak concentration levels of itraconazole were achieved at 10 h(T)and 8.5 h(R2),respectively.Pharmacodynamic parameter assessment showed that AUC/MIC for R1 are comparable to Fixtral SB 100mg for MIC levels up to 16mcg/mL(P>0.05 and observed P=0.3196).Six AEs were observed that were mild to moderate in severity and resolved.No severe AE was reported.CONCLUSION Test product itraconazole Capsule 100 mg is bioequivalent with the reference product(R2)at 100 mg dose(2 capsules of Lozanoc®50 mg)under fed conditions.Pharmacodynamics activity in terms of AUC/MIC is comparable between the test product at 100 mg dose and marketed itraconazole 200 mg.Fixtral SB is expected to have therapeutically similar efficacy at half the equivalent dose.Tested formulations were found to be safe and well tolerated.

Hypoglycemic Effect of Intravenous Polyethylene Glycol-Coated Liposomal Insulin on Normal Rats

Aim To evaluate liposome as an injectable delivery system of proteins, insulin was chosen as model drug and the hypoglycemic effect of PEG-coated liposomal insulin was tested.Methods The PEG-coated liposomal insulin was prepared by reversal-phase emulsion evaporation.For pharmacodynamic study, insulin (2.5 IU*kg-1) was intravenously administered in phosphated-buffered saline (PBS) solution, conventional liposomes, and PEG-coated liposomes, separately, to normal Wistar rats.Blood glucose levels were determined by the glucose oxidase method.Results The mean diameter of the PEG-coated liposomal insulin was 58.4 nm, while the encapsulation ratio reached 18.33%.After intravenous administration of insulin solution, insulin liposome, and PEG-coated liposomal insulin, the minimum blood glucose concentrations (Cmin %) reached 25.26±5.75%, 33.92±12.42%, and 42.39±10.5% of the initial level, respectively, and the time periods to reach the minimum blood glucose level (Tmin) were 0.7±0.3 h, 1.2±0.4 h, and 2.3±0.7 h, respectively.The relative pharmacological bioavailabilities of insulin liposome and PEG-coated liposomal insulin were 98.03% and 99.70%, respectively, compared with the control of insulin solution.Conclusion PEG-coated liposome can be developed as a relatively sustained injectable delivery system for insulin.Moreover, the liposome coated with PEG may have advantages over normal liposome.

Pharmacokinetics and pharmacodynamics of Da-Cheng-Qi decoction in the liver of rats with severe acute pancreatitis

AIM To explore the pharmacokinetics and pharmacodynamics of Da-Cheng-Qi decoction (DCQD) in the liver of rats with severe acute pancreatitis (SAP) based on an herbal recipe tissue pharmacology hypothesis. METHODS Healthy male Sprague-Dawley rats were randomly divided into a sham operation group (SOG); a model group (MG); and low-, median- and high-dose treatment groups (LDG, MDG, and HDG, respectively). Different dosages (6, 12 and 24 g/kg for the LDG, MDG, and HDG, respectively) of DCQD were administered to the rats with SAP. The tissue concentrations of aloeemodin, rhein, emodin, chrysophanol, honokiol, rheo chrysophanol, magnolol, hesperidin, naringenin and naringin in the liver of the treated rats were detected by high-performance liquid chromatography tandem mass spectrometry. Alanine transaminase (ALT) and aspartate transaminase (AST) in serum, inflammatory mediators in the liver and pathological scores were evaluated. RESULTS The major components of DCQD were detected in the liver, and their concentrations increased dose-dependently. The high dose of DCQD showed a maximal effect in ameliorating the pathological damages, decreasing the pro-inflammatory mediators tumor necrosis factor-a and interleukin (IL)-6 and increasing anti-inflammatory mediators IL-4 and IL-10 in the liver. The pathological scores in the pancreas for the MG were significantly higher than those for the SOG (P < 0.05). DCQD could reduce the pathological scores in the pancreas and liver of the rats with SAP, especially in the HDG. Compared to the SOG, the ALT and AST levels in serum were higher in the MG (P < 0.05), while there was no statistical difference in the MG and HDG. CONCLUSION DCQD could alleviate liver damage by altering the inflammatory response in rats with SAP based on the liver distribution of its components.

Mechanistic considerations for the use of monoclonal antibodies for cancer therapy

Since the approval of rituximab in 1997, monoclonal antibodies(mAbs) have become an increasingly important component of therapeutic regimens in oncology. The success of mAbs as a therapeutic class is a result of great strides that have been made in molecular biology and in biotechnology over the past several decades. Currently, there are 14 approved mAb products for oncology indications, and there are ten additional mAbs in late stages of clinical trials. Compared to traditional chemotherapeutic agents, mAbs have several advantages, including a long circulating half-life and high target specificity. Antibodies can serve as cytotoxic agents when administered alone, exerting a pharmacologic effect through several mechanisms involving the antigen binding(Fab) and/or Fc domains of the molecule, and mAbs may also be utilized as drug carriers, targeting a toxic payload to cancer cells. The extremely high affinity of mAbs for their targets, which is desirable with respect to pharmacodynamics(i.e., contributing to the high therapeutic selectivity of mAb), often leads to complex, non-linear, target-mediated pharmacokinetics. In this report, we summarize the pharmacokinetic and pharmacodynamics of mAbs that have been approved and of mAbs that are nearing approval for oncology indications, with particular focus on the molecular and cellular mechanisms responsible for their disposition and efficacy.

Preparation and evaluation of nattokinaseloaded self-double-emulsifying drug delivery system

In the present study,we prepared nattokinase-loaded self-double-emulsifying drug delivery system(SDEDDS)and investigated its preliminary pharmacodynamics.The type and concentration of oil phase,inner aqueous phase and emulsifier were screened to prepare optimum nattokinase-loaded SDEDDS.Next,the optimum formulations were characterized based on microstructure,volume-weighted mean droplet size,self-emulsifying rate,yield,storage stability,in vitro release and in vivo pharmacodynamics studies.The water/oil/watermultiple emulsions exhibited typicalmultiple structure,with relatively small volumeweighted mean droplet size 6.0±0.7μm and high self-emulsifying ability(self-emulsifying time<2 min).Encapsulation of nattokinase was up to 86.8±8.2%.The cumulative release of nattokinase within 8 h was about 30%,exhibiting a sustained release effect.The pharmacodynamics study indicated that nattokinase-loaded SDEDDS could significantly prolong the whole blood clotting time in mouse and effectively improve the carrageenan-induced tail thrombosis compared with nattokinase solution.Moreover,we showed that SDEDDS could successfully self-emulsify into water/oil/water multiple emulsions upon dilution in dispersion medium with gentle stirring and effectively protect nattokinase activity in gastric environment.Our findings suggested that SDEDDS could be a promising strategy for peptide and protein drugs by oral administration.

Pharmacokinetics and pharmacodynamics of Shengjiang decoction in rats with acute pancreatitis for protecting against multiple organ injury

AIM To explore the pharmacokinetics and pharmacodynamics of Shengjiang decoction(SJD) in rats with acute pancreatitis(AP) for protecting against multiple organ injury.METHODS An AP model was established by retrograde perfusion of 3.5% sodium taurocholate into the biliopancreatic duct, and a control group(CG) received 0.9% sodium chloride instead. Twelve male Sprague-Dawley rats were randomly divided into a CG treated with SJD(CG + SJD) and a model group treated with SJD(MG + SJD), both of which were orally administered with SJD(5 g/kg) 2 h after surgery. Blood samples were collected via the tail vein at 10, 20, and 40 min and 1, 2, 3, 4, 6, 8, and 12 h after a single dose of SJD to detect its main components using high-performance liquid chromatography-tandem mass spectrometry. The pharmacokinetic parameters were compared. In the pharmacodynamic experiment, 18 male SpragueDawley rats were randomly divided into a CG, an AP model group(MG), and an SJD treated AP group(SJDG). Serum amylase, lipase, and inflammatory cytokines were measured, and heart, lung, liver, spleen, pancreas, kidney, and intestine tissues were collected for pathological examination.RESULTS The MG + SJD displayed significantly shorter mean residence time(MRT) and higher clearance(CL) for emodin and aloe-emodin; significantly shorter time of maximum concentration and T1/2 and a lower area under curve(AUC) for aloe-emodin; a significantly higher AUC and lower CL for rhein; and longer MRT and lower CL for chrysophanol than the CG + SJD. In the pharmacodynamic experiment, the amylase, interleukin(IL)-6, IL-10, and tumor necrosis factor(TNF)-α levels in the MG were higher than those in the CG(P < 0.05). After the herbal decoction treatment, the SJDG had higher IL-10 and lower TNF-α levels than the MG(P < 0.05). The MG had the highest pathological scores, and the pathological scores of the lung, pancreas, kidney, and intestine in the SJDG were significantly lower than those in the MG(P < 0.05).CONCLUSION AP may have varying effects on the pharmacokinetics of the major SJD components in rats. SJD might alleviate pathological injuries of the lung, pancreas, kidney, and intestine in rats with AP via regulating pro-and antiinflammatory responses, which might guide the clinical application of SJD for AP treatment.

Metabolic and hepatic effects of liraglutide,obeticholic acid and elafibranor in diet-induced obese mouse models of biopsy-confirmed nonalcoholic steatohepatitis

AIM To evaluate the pharmacodynamics of compounds in clinical development for nonalcoholic steatohepatitis(NASH) in obese mouse models of biopsy-confirmedNASH.METHODS Male wild-type C57 BL/6 J mice(DIO-NASH) and Lep^(ob/ob)(ob/ob-NASH) mice were fed a diet high in trans-fat(40%), fructose(20%) and cholesterol(2%) for 30 and 21 wk, respectively. Prior to treatment, all mice underwent liver biopsy for confirmation and stratification of liver steatosis and fibrosis, using the nonalcoholic fatty liver disease activity score(NAS) and fibrosis staging system. The mice were kept on the diet and received vehicle, liraglutide(0.2 mg/kg, SC, BID), obeticholic acid(OCA, 30 mg/kg PO, QD), or elafibranor(30 mg/kg PO, QD) for eight weeks. Within-subject comparisons were performed on changes in steatosis, inflammation, ballooning degeneration, and fibrosis scores. In addition, compound effects were evaluated by quantitative liver histology, including percent fractional area of liver fat, galectin-3, and collagen 1 a1.RESULTS Liraglutide and elafibranor, but not OCA, reduced body weight in both models. Liraglutide improved steatosis scores in DIO-NASH mice only. Elafibranor and OCA reduced histopathological scores of hepatic steatosis and inflammation in both models, but only elafibranor reduced fibrosis severity. Liraglutide and OCA reduced total liver fat, collagen 1 a1, and galectin-3 content, driven by significant reductions in liver weight. The individual drug effects on NASH histological endpoints were supported by global gene expression(RNA sequencing) and liver lipid biochemistry.CONCLUSION DIO-NASH and ob/ob-NASH mouse models show distinct treatment effects of liraglutide, OCA, and elafibranor, being in general agreement with corresponding findings in clinical trials for NASH. The present data therefore further supports the clinical translatability and utility of DIO-NASH and ob/ob-NASH mouse models of NASH for probing the therapeutic efficacy of compounds in preclinical drug development for NASH.

Intra-articular delivery of tetramethylpyrazine microspheres with enhanced articular cavity retention for treating osteoarthritis

Tetramethylpyrazine(TMP) is a traditional Chinese herbal medicine with strong antiinflammatory and cartilage protection activities, and thus a promising candidate for treating osteoarthritis. However, TMP is rapidly cleared from the joint cavity after intra-articular injection and requires multiple injections to maintain efficacy. The aim of this study was to encapsulate TMP into poly(lactic-co-glycolic acid)(PLGA) microspheres to enhance the TMP retention in the joint, reducing injection frequencies and decreasing dosage. TMP microspheres were prepared by emulsion/solvent evaporation method. The intra-articular retention of the drug was assessed by detecting the drug concentration distributed in the joint tissue at different time points. The therapeutic effect of TMP microspheres was evaluated by the swelling of knee joints and histologic analysis in papain-induced OA rat model. The prepared freezedried microspheres with a particle size of about 10 μm can effectively prolong the retention time of the drug in the articular cavity to 30 d, which is 4.7 times that of the TMP solution.Intra-articular injection of TMP microspheres efficiently relieved inflammatory symptoms,improved joint lesions and decreased the depletion of proteoglycan. In conclusion, intraarticular injection of TMP loaded microspheres was a promising therapeutic method in the treatment of OA.