Objective:To establish a progressive research strategy for“colonic components analysis-efficacy verification and mechanism exploration-gut microbiota”,screen pharmacodynamic substances,and investigate their mechanis...Objective:To establish a progressive research strategy for“colonic components analysis-efficacy verification and mechanism exploration-gut microbiota”,screen pharmacodynamic substances,and investigate their mechanism via gut microbiota.Methods:The pharmacodynamics of Gegen Qinlian decoction(GQD)were assessed using a mouse model of dextran sulfate sodium-induced ulcerative colitis(UC).Ultra-performance liquid chromatographyquadrupole-orbitrap mass spectrometer was used to identify the prototype and metabolic components of GQD in the colon during UC.To analyze the structure and function of characteristic genera of GQD and its active components,16S rRNA sequencing was performed.Results:We identified 67 prototypic and 14 metabolic components of GQD in the UC colon.The primary prototype components are flavonoids and alkaloids,including puerarin(PUE),baicalin(BAI),and berberine(BER).The metabolism was predominantly sulfonation.Efficacy verification showed that the main active components,puerarin,baicalin,and berberine,had good therapeutic effects on UC.The results of 16S rRNA gene sequencing showed that GQD improved UC by regulating the structure and function of the gut microbiota.The abundance of gut microbiota involved in the metabolism of the prototype componentswas influenced by the corresponding components.The function prediction results showed that PUE was the most comparable to GQD,with 24 consistent pathways.BAI and BER showed comparable gut microbiota regulation pathways.Characteristic pathways of BER include glucometabolic processes.Conclusion:This study focused on the key issues in the gut microbiota pathway and developed a progressive research strategy to understand the transformation mechanisms of colonic components.This research systematically analyzed the active components and metabolic transformation of GQD in the colon during the pathological state of UC,as well as changes in the structure and function of the gut microbiota,clarified the mechanism of GQD and its active components in improving UC via the gut microbiota pathway.展开更多
BACKGROUND Insulin therapy plays a crucial role in managing diabetes.Regulatory guidelines mandate assessing the pharmacokinetics(PK)and pharmacodynamics(PD)of new insulin formulations with euglycemic clamp techniques...BACKGROUND Insulin therapy plays a crucial role in managing diabetes.Regulatory guidelines mandate assessing the pharmacokinetics(PK)and pharmacodynamics(PD)of new insulin formulations with euglycemic clamp techniques before entry into the market.Typically,blood glucose(BG)levels are maintained at 5%below baseline to suppress endogenous insulin secretion in healthy volunteers.However,in scenarios where BG baseline is relatively low,maintaining it at 5%below baseline can increase hypoglycemic risk.Consequently,we adjusted to maintain it at 2.5%below a baseline of<4.00 mmol/L.It remains uncertain whether this adjustment impacts endogenous insulin inhibition or the PD of study insulin.AIM To evaluate and compare the PD and C-peptide status using two different target BG setting methods.METHODS Data came from euglycemic clamp trials assessing the PK/PD of insulin aspart(IAsp)in healthy participants.Target BG was set at 2.5%below baseline for those with a basal BG of<4.00 mmol/L(group A),and at 5%below baseline for others(group B).The area under the curve(AUC)of IAsp(AUC_(IAsp,0-8 h))and GIR from 0 to 8 hours(AUCGIR,0-8 h)was used to characterize the PK and PD of IAsp,respectively.The C-peptide reduction and PK/PD of IAsp were compared between the two groups.RESULTS Out of 135 subjects,15 were assigned to group A and 120 to group B;however,group B exhibited higher basal Cpeptide(1.59±0.36 vs 1.32±0.42 ng/mL,P=0.006).Following propensity score matching to adjust for basal Cpeptide differences,71 subjects(15 in group A and 56 in group B)were analyzed.No significant differences were observed in demographics,IAsp dosage,or clamp quality.Group B showed significantly higher baseline(4.35±0.21 vs 3.91±0.09 mmol/L,P<0.001),target(4.13±0.20 vs 3.81±0.08 mmol/L,P<0.001),and clamped(4.10±0.17 vs 3.80±0.06 mmol/L,P<0.001)BG levels.Both groups exhibited comparable C-peptide suppression(32.5%±10.0%vs 35.6%±12.1%,P=0.370)and similar IAsp activity(AUCGIR,0-8 h:1433±400 vs 1440±397 mg/kg,P=0.952)under nearly equivalent IAsp exposure(AUC_(IAsp,0-8 h):566±51 vs 571±85 ng/mL×h,P=0.840).CONCLUSION Maintaining BG at 2.5%below a baseline of<4.00 mmol/L did not compromise the endogenous insulin suppression nor alter the observed pharmacodynamic effects of the study insulin.展开更多
The epidermal growth factor receptor（EGFR）—tyrosine kinase inhibitors（TKIs） monotherapies have limited efficacy in the treatment of EGFR mutation-negative non-small cell lung cancers（NSCLCs）. In the present stu...The epidermal growth factor receptor（EGFR）—tyrosine kinase inhibitors（TKIs） monotherapies have limited efficacy in the treatment of EGFR mutation-negative non-small cell lung cancers（NSCLCs）. In the present study, we aimed to investigate the combined effect of erlotinib（ER） and cabozantinib（CAB） on NSCLC cell lines harboring wild-type EGFR and to optimize the dosage regimens using pharmacodynamic（PD） modeling and simulation. Therefore, we examined the combined effect of ER and CAB on cell viability, cloning, apoptosis induction, migration and growth dynamics in H1299 and A549 cells. PD modeling and simulation were also performed to quantitatively describe the H1299 cells growth dynamics and to optimize the dosage regimens as well. Our results showed that CAB effectively enhanced the sensitivity of both cell lines to ER. The PD models fitted the data well, and some important parameters were obtained. The exponential（λ_0） and linear（λ_1） growth rates of H1299 cells were 0.0241 h^（–1） and 360 cells？h^（–1）, respectively. The Emax of ER and CAB was 0.0091 h^（–1） and 0.0085 h^（–1）, and the EC50 was 0.812 μM and 1.16 μM, respectively. The synergistic effect observed in the experiments was further confirmed by the estimated combination index φ（1.37）,（95% confidence interval： 1.24–1.50）, obtained from PD modeling. Furthermore, the dosage regimens were optimized using simulations. In summary, both the experimental and modeling results demonstrated the synergistic interaction between ER and CAB in NSCLCs without EGFR mutations. Sequential combinations of ER and CAB provided an option for the therapy of the NSCLCs with wild-type EGFR, which would provide some references for preclinical study and translational research as well.展开更多
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 Heal...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.展开更多
Dahuang-Gancao decoction(DGD)is a classical formula,which is commonly used for reliving constipation in Chinese clinic.The aim of this study was to investigate the pharmacodynamic,pharmacokinetic and tissue distributi...Dahuang-Gancao decoction(DGD)is a classical formula,which is commonly used for reliving constipation in Chinese clinic.The aim of this study was to investigate the pharmacodynamic,pharmacokinetic and tissue distribution alternations of DGD in normal and constipation mice.DGD exhibited stronger purgative effect in constipation mice by the increased fecal excretion and reduced first defection time compared with normal mice.The Cmax,AUC0-t and MRT0-t of rhein,aloe-emodin,rhein-8-O-β-D-glucoside,sennoside A,and glycyrrhizic acid as main bio-active components in DGD were markedly increased in constipation mice.The tissue distribution of the analytes in constipation mice were higher than those in normal mice with rhein>rhein-8-O-β-D-glucoside>aloe-emodin>glycyrrhizic acid>emodin in liver,and glycyrrhizic acid>rhein-8-O-β-D-glucoside>liquitin>sennoside A>rhein>aloe-emodin>emodin in colon.The kidney concentrations of the analytes showed a descending order of rhein>rhein-8-O-β-D-glucoside>sennoside A>glycyrrhizic acid>aloe-emodin>emodin,most of them were higher while rhein was lower in constipation mice than normal mice.The higher exposure of the anthraquinones in plasma,liver and colon may result in the stronger purgative effect in the constipation mice than normal mice.Rhein is mainly excreted through the kidney,the decreased level of rhein in constipation mice may explain the alleviated side effects.Accumulation of glycyrrhizic acid in colon may related with the moderate property of licorice.These results provided the experimental basis for understanding the therapeutic effects and metabolite profile of DGD.展开更多
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 ...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.展开更多
The present study aimed to establish a pharmacodynamic method using the py Solo software to explore the influence of freeze-dried powders of Shuangxia Decoction(SXD) on the sleep of normal Drosophila melanogaster and ...The present study aimed to establish a pharmacodynamic method using the py Solo software to explore the influence of freeze-dried powders of Shuangxia Decoction(SXD) on the sleep of normal Drosophila melanogaster and the Drosophila melanogaster whose sleep was divested by light. The dose-effect and the time-effect relationships of SXD on sleep were examined. The effect-onset concentration of SXD was 0.25%, the plateau appeared at the concentration of 2.5% and the total sleep time showed a downtrend when the concentration was greater than 2.5%. The sleep time was the longest on the fourth day after SXD was given. The fruit fly sleep deprivation model was repeated by light stimulation at night. The middle dosage group(2.5%) had the best insomnia-curing effect. In conclusion, using the py Solo software, an approach for the pharmacodynamics study was established with Drosophila melanogaster as a model organism to determine the insomnia-curing effects of the traditional Chinese medicine(TCM). Our results demonstrated the reliability of this method. The freeze-dried powders of SXD could effectively improve the sleep quality of Drosophila melanogaster.展开更多
AIM To identify the optimal oral dosing time of Da-Cheng-Qi decoction(DCQD) in rats with acute pancreatitis(AP) based on the pharmacokinetic and pharmacodynamic parameters.METHODS First, 24 male Sprague-Dawley rats we...AIM To identify the optimal oral dosing time of Da-Cheng-Qi decoction(DCQD) in rats with acute pancreatitis(AP) based on the pharmacokinetic and pharmacodynamic parameters.METHODS First, 24 male Sprague-Dawley rats were divided into a sham-operated group [NG(a)] and three model groups [4 h G(a), 12 h G(a) and 24 h G(a)]. The NG(a) and model groups were administered DCQD(10 g/kg.BW) intragastrically at 4 h, 4 h, 12 h and 24 h, respectively, after AP models induced by 3% sodium taurocholate. Plasma samples were collected from the tails at 10 min, 20 min, 40 min, 1 h, 2 h, 4 h, 8 h, 12 h and 24 h after a single dosing with DCQD. Plasma and pancreatic tissue concentrations of the major components of DCQD were determined by high-performance liquid chromatography tandem mass spectroscopy. The pharmacokinetic parameters and serum amylase were detected and compared. Second, rats were divided into a sham-operated group [NG(b)] and three treatment groups [4 h G(b), 12 h G(b) and 24 h G(b)] with three corresponding control groups [MG(b)s]. Blood and pancreatic tissues were collected 24 h after a single dosing with DCQD. Serum amylase, inflammatory cytokines and pathological scores of pancreatic tissues were detected and compared.RESULTS The concentrations of emodin, naringin, honokiol, naringenin, aloe-emodin, chrysophanol and rheochrysidin in the 12 h G(a) group were higher than those in the 4 h G(a) group in the pancreatic tissues(P < 0.05). The area under the plasma concentration-time curve from time 0 to the time of the last measurable concentration values(AUC0→t) for rhein, chrysophanol, magnolol and naringin in the 12 h G(a) group were larger than those in the 4 h G(a) or 24 h G(a) groups. The 12 h G(a) group had a higher Cmax than the other two model groups. The IL-10 levels in the 12 h G(b) and 24 h G(b) groups were higher than in the MG(b)s(96.55 ± 7.84 vs 77.46 ± 7.42, 251.22 ± 16.15 vs 99.72 ± 4.7 respectively, P < 0.05), while in the 24 h G(b) group, the IL-10 level was higher than in the other two treatment groups(251.22 ± 16.15 vs 154.41 ± 12.09/96.55 ± 7.84, P < 0.05). The IL-6 levels displayed a decrease in the 4 h G(b) and 12 h G(b) groups compared to theMG(b)s(89.99 ± 4.61 vs 147.91 ± 4.36, 90.82 ± 5.34 vs 171.44 ± 13.43, P < 0.05). CONCLUSION Late-time dosing may have higher concentrations of the most major components of DCQD, with better pharmacokinetics and pharmacodynamics of antiinflammation than early-time dosing, which showed the late time to be the optimal dosing time of DCQD for AP.展开更多
Eurycoma longifolia Jack(E.longifolia) is a well-recognized traditional herbal medicine that offers a wide dynamic range of biomedical applications including anti-osteoporotic, anticancer, anti-proliferative, anti-mal...Eurycoma longifolia Jack(E.longifolia) is a well-recognized traditional herbal medicine that offers a wide dynamic range of biomedical applications including anti-osteoporotic, anticancer, anti-proliferative, anti-malarial, antimicrobial, antioxidant, aphrodisiac, antiinflammatory, anxiolytic, anti-diabetic, anti-rheumatism and anti-ulcer properties.This review aims to overview the pharmacokinetic and a pharmacodynamic algorithm of E.longifolia and its bioactive components.Analysis of pharmacokinetic profile revealed that E.longifolia exhibit higher bioavailability, high volume of distribution, slow elimination rate, and does not show inhibitory effects on cytochrome P450 isoenzymes.E.longifolia has been used, alone or in combination with other pharmacological agents, in the form of crude extracts, standard extracts, or decoctions of different plant parts(i.e., herbs, shrubs, stem, leaves, and roots) for the treatment of various ailments in animals and humans.Among various bioactive constituents, eurycomanone has been found to be the most remarkable, super-stable, versatile, and most potent phytochemical(isolated or extracted from root extracts) against various types of animals and human diseases.Based on its well-established pharmacokinetic and pharmacodynamic profiles, we suggested that E.longifolia can be a well-accepted complementary and alternative medicine for the treatment of different types of human ailments.展开更多
A comparison of the pharmacodynamic effects of two source plants of Murrayae Folium et Cacumen(MFC),Murraya exotica L.and Murraya paniculata(L.)Jack,was performed in order to supply reference for its multi-source rati...A comparison of the pharmacodynamic effects of two source plants of Murrayae Folium et Cacumen(MFC),Murraya exotica L.and Murraya paniculata(L.)Jack,was performed in order to supply reference for its multi-source rationality and interchangeability in clinical practice.According to the traditional efficacy of MFC,the effects of promoting Qi,relieving pain,promoting blood circulation and removing blood stasis were systematically evaluated by the models of writhing response in mice,foot swelling in rats,gastric emptying and small intestine propulsion in mice,and acute blood stasis in rats,respectively.The results showed that both M.exotica and M.paniculata could significantly inhibit the writhing reaction induced by acetic acid in mice and the paw swelling induced by carrageenan in rats,reduce IL-6,TNF-αand PGE2 levels in plasma of paw-swelling rats and increase gastric empty rate and intestinal propulsive rate.The above-mentioned effects were dose-dependent,and there was no significant difference between M.exotica and M.paniculata at the same doses.Therefore,M.exotica and M.paniculata had the similar anti-inflammatory,analgesic and gastrointestinal motility promotion effects,which provided a support for the pharmacodynamic equivalence of the multi-source plants of MFC.展开更多
AIM： To develop a pharmacodynamic model of porta hypertension from chronic hepatitis. METHODS： Pathological changes and collagen depositions were analyzed using morphometry to confirm CCI4-induced chronic hepatitis....AIM： To develop a pharmacodynamic model of porta hypertension from chronic hepatitis. METHODS： Pathological changes and collagen depositions were analyzed using morphometry to confirm CCI4-induced chronic hepatitis. At do, d28, ds6 and d84 of the process, the portal perfused velocities （μL/min） in isolated rat livers were exactly controlled with a quanti-fied pump. The pressure （mmHg） was monitored with a Physiological System. The geometric concentrations of phenylephrine or acetylcholine were added to a fixed volume （300 mL） of the circulating perfusate. The equation, the median effective concentration and its 95% confidence intervals of phenylephrine or acetyl- choline were regressed with Prism-4 software in non-linear fit and various slopes. In the isolated perfused rat livers with chronic hepatitis, both median effective concentrations were defined as the pharmacodynamic model of portal hypertension.CONCLUSION： A pharmacodynamic model of portal hypertension in isolated perfused rat livers with chronic hepatitis was defined as the median effective concen- trations of phenylephrine and acetylcholine.展开更多
The property theory of Chinese materia medica is one of the foundations of traditional Chinese medicine.The property of Chinese materia medica(PCMM)is a multi-dimensional expression of the effect of Chinese materia me...The property theory of Chinese materia medica is one of the foundations of traditional Chinese medicine.The property of Chinese materia medica(PCMM)is a multi-dimensional expression of the effect of Chinese materia medica(CMM),and it is related to the clinical prescription that fully reflects the clinical effect evaluation of CMM in a holistic,systematic,and scientific way.This paper discusses the source,development,and application of the PCMM by considering not only the five dimensions that constitute the PCMM but also the recognition of the human body and disease as given in traditional Chinese medicine.This paper aims to provide theoretical guidance for the rational use and development of CMM.展开更多
Batifiban, a synthetic cyclic peptide, is a potent platelet glycoprotein GPⅡb/Ⅲa antagonist which may be useful in the treatment and prevention of acute coronary syndromes. The pharmacokinetics and pharmacodymanic ...Batifiban, a synthetic cyclic peptide, is a potent platelet glycoprotein GPⅡb/Ⅲa antagonist which may be useful in the treatment and prevention of acute coronary syndromes. The pharmacokinetics and pharmacodymanic （inhibition of platelet aggregation） effects, and tolerability of batifiban were investigated in healthy subjects following single bolus injection with doses of 55, 110, or 220 μg/kg, or multiple doses of an bolus followed intravenous infusion for 24 h （180 μg/kg plus 2.0 μg/minokg, and 220 μg/kg plus 2.5μg/minokg） in this phase I clinical trial. Plasma levels of batifiban and areas under the curve were found to be proportional to doses. Batifiban was rapidly eliminated with a half-life of approximately 2.5 h. Significant differences were noted for plasma levels of batifiban and areas under the curve between males and females. No significant differences in the terminal half-life were found between males and females. Batifiban reversibly inhibited ex vivo platelet aggregation in a dose- and concentration-dependent manner, consistent with its mechanism as a GPⅡ b/Ⅲa antagonist. Single and multiple intravenous doses of batifiban were found to be safe and well tolerated in healthy subjects. These results support a bolus injection plus intravenous infusion regimen of batifiban for the treatment and prevention of acute coronary syndromes.展开更多
Previous study has shown that dopamine D1 receptor(D1DR)agonists,fenoldopam(FEN)and l-stepholidine(l-SPD),have inhibitory effects on breast cancer lung metastasis.To quantitatively describe and predict the pharmacodyn...Previous study has shown that dopamine D1 receptor(D1DR)agonists,fenoldopam(FEN)and l-stepholidine(l-SPD),have inhibitory effects on breast cancer lung metastasis.To quantitatively describe and predict the pharmacodynamic(PD)properties of FEN and l-SPD and to explore the PD model structure of cancer metastasis treating drugs,we used the data of lung metastasis in 4T1 breast cancer mice under the treatment of either FEN or l-SPD,and established a PD model.The PD model assumed an exponential growth for both primary tumor and metastasis.The primary tumor emitted cells to form metastases,and the cell emitting rate was proportional to power form of the primary tumor weight.The total number of lung metastasis was set as the target value.D1DR agonists inhibited metastasis by inhibiting cell emitting rate instead of the growth rate of primary tumor or metastasis.The model results showed that the decrease in the number of lung metastases was roughly proportional to the square of the drug dose.The values of PD coefficient reflected the inhibitory ability of the drugs,and that of l-SPD(0.274 kg/mg)was greater than that of FEN(0.0393 kg/mg).This PD model can quantitatively describe the effects of FEN and l-SPD on the progression of lung metastasis in 4T1 primary breast cancer mice and can predict the time course of drug efficacy at multiple doses,providing a reference for PD model structure of other drugs for cancer metastasis indication.展开更多
The ultimate goal of transplantation is the donor-specific immune tolerance, but at least in the first 15 to 20 years of this century, immunosuppressive agents are still the determinant of clinical outcome of transpla...The ultimate goal of transplantation is the donor-specific immune tolerance, but at least in the first 15 to 20 years of this century, immunosuppressive agents are still the determinant of clinical outcome of transplant recipients. Individualizing patient's immunosuppression to optimize the balance between therapeutic efficacy and the occurrence of adverse events poses a great challenge to physicians. DATA SOURCES:The data in this article were taken mostly from MEDLINE (2000-2004), part of which were from the research of the authors. RESULTS:Individualized immunosuppression remains a problem because of the narrow therapeutic index and wide inter- and intra-patient variation of commonly-used im- munosuppressants. Recent progress in study of pharmaco-kinetics and pharmacodynamics improved the clinical outcome of transplant recipients. More importantly, the emergence of pharmacogenomics might provide a promising and complementary tool for traditional therapeutic drug monitoring (TDM). CONCLUSIONS:Individualizing organ recipient's immunosuppression to balance the therapeutic efficacy and the adverse events represents a great challenge to transplant clinicians. Pharmacogenomics shows great promise for an interesting and hopefully better future.展开更多
The work aims to investigate the in vitro release,pharmacokinetics(PK),pharmacodynamics(PD)and PK-PD relationships of Salvianolic Acid B micro-porous osmotic pump pellets(SalB-MPOPs)in angina pectoris New Zealand Whit...The work aims to investigate the in vitro release,pharmacokinetics(PK),pharmacodynamics(PD)and PK-PD relationships of Salvianolic Acid B micro-porous osmotic pump pellets(SalB-MPOPs)in angina pectoris New Zealand White(NZW)rabbits,compared with those of SalB immediate-release pellets(SalB-IRPs).The SalB plasma concentrations and Superoxide dismutase levels(PD index)were recorded continuously at predetermined time interval after administration,and the related parameters were calculated by using Win-Nonlin software.The release profile of MPOPs was more sustained than that of IRPs.PK results indicated that the mean C_(max)was significantly lower,the SalB plasma concentrations were steadier,both area under concentration-time curve from 0 to 24 h(AUC_(0-24 h))and from 0 to infinity(AUC_(0-∞))were presented larger,and both the peak concentration time(T_(max))and mean residence time(MRT)were prolonged for MPOPs,as compared with those of IRPs.PD results suggested that peak drug effect(E_(max))was lower and the equilibration rate constant(k_(e0))between the central compartment and the effect compartment was higher of MPOPs vs.those of IRPs.PKePD relationships demonstrated that the effectconcentration-time(ECT)course of MPOPs was clockwise hysteresis loop,and that of IRPs was counter-clockwise hysteresis loop.Collectively,those results demonstrated that MPOPs were potential formulations in treating angina pectoris induced by atherosclerosis.展开更多
In the present study,we aimed to investigate the protective effect of Yuebi Jiazhu Decoction(YBJZD)on the kidney of adriamycin nephropathy(AN)rats.Rats were injected with adriamycin for modeling,except for the control...In the present study,we aimed to investigate the protective effect of Yuebi Jiazhu Decoction(YBJZD)on the kidney of adriamycin nephropathy(AN)rats.Rats were injected with adriamycin for modeling,except for the control group.After the successful establishment of the animal model,rats were randomly divided into the model group,YBJZD low-,medium-,and high-dose groups,and the positive group.The 24-h urine samples were collected.Biochemical indicators were monitored,and kidney tissues were collected for pathological analysis using light microscopy.The results showed that through 4 weeks of drug intervention,the urinary protein level was lower in the YBJZD and positive groups compared with the model group(P<0.05).Serum levels of BUN,SCr,and TG were significantly lower(P<0.01),and ALB was significantly higher(P<0.01)in the YBJZD and positive groups compared with the model group.Compared with the model group,the pathological injury of kidney tissue in the YBJZD and positive groups was significantly alleviated.These outcomes proved that YBJZD had a renal protective effect on AN rats.展开更多
Lignocaine is an essential drug on World Health Organisation essential drug list, considered efficacious, safe and cost-effective for any health-care system. Despite its ubiquitous use in medicine and surgery, there a...Lignocaine is an essential drug on World Health Organisation essential drug list, considered efficacious, safe and cost-effective for any health-care system. Despite its ubiquitous use in medicine and surgery, there are few detailed reviews of its pharmacokinetics and pharmacodynamics. Being an amide-type local anesthetic and Class 1b antiarrhythmic, lignocaine is most frequently used clinically for its anesthetic and antiarrhythmic benefits. However, lignocaine has important antinociceptive, immuno-modulating, and antiinflammatory properties. Information pertaining to the pharmacokinetics and pharmacodynamics of lignocaine was examined by performing a literature search of Pub Med, Embase and MEDLINE(via Ovid), pharmacology textbooks and online sources. We present a focused synopsis of lignocaine's pharmacological composition, indications for use and mechanisms of action, focusing on its anti-inflammatory, immuno-modulating and analgesia effects. In addition we review the dosing regimes and infusion kinetics of lignocaine in the clinical setting. Finally, we review the evidence for ligocaine's modulation of the inflammatory response during major surgery and its specific effects on cancer recurrence. These indirect effects of local anesthetics in tumor development may stem from the reduction of neuroendocrine responses to the stress response elicited by major surgery and tissue damage, enhanced preservation of immune-competence, in addition to opioid-sparing effects of modulating tumor growth.展开更多
OBJECTIVE To compare the pharmacokinetics and pharmacodynamics of PEG30-rhG-CSF administered to beagle dogs at three different dosages with PEG20-rhG-CSF administered at one dosage, and to provide an experimental basi...OBJECTIVE To compare the pharmacokinetics and pharmacodynamics of PEG30-rhG-CSF administered to beagle dogs at three different dosages with PEG20-rhG-CSF administered at one dosage, and to provide an experimental basis for clinical trials.METHODS Beagle dogs received single, subcutaneous doses of PEG30-rhG-CSF at 100, 200 and 400 μg/kg or PEG20-rhG-CSF at 200 μg/kg. PEG30-rhG-CSF and PEG20-rhG-CSF concentrations in serum were analyzed using an enzymeqinked immunosorbent assay （ELISA）. WBC, ANC and PLT counts of whole blood samples were measured using fully automated analytic instrumentation. Pharmacokinetic and pharmacodynamic parameters were calculated using DAS 2.0 statistical analysis software.METHODS Beagle dogs received single, subcutaneous doses of PEG30-rhG-CSF at 100, 200 and 400 μg/kg or PEG20-rhG-CSF at 200μg/kg. PEG30-rhG-CSF and PEG20-rhG-CSF concentrations in serum were analyzed using an enzyme-linked immunosorbent assay （ELISA）. WBC, ANC and PLT counts of whole blood samples were measured using fully automated analytic instrumentation. Pharmacokinetic and pharmacodynamic parameters were calculated using DAS 2.0 statistical analysis software. RESULTS The pharmacokinetic parameters of PEG30-rhG-CSF calculated from the serum concentration data determined by ELISA were as follows： the mean elimination half-life （t1/2ke） was 40.6 h （33.5-45.4 h）; the mean time to reach peak concentration （Tmax） was 19.2 h （11.7-24.0 h）; the drug clearance from the serum （CL） was decreased with increasing doses; the peak concentration （Cmax） and the area under the serum concentration-time curve （AUC） were increased with increasing doses. For PEG20-rhG- CSF, the half-life was shorter （12 h） and Tmax was achieved much earlier （10 h） relative to PEG30-rhG-CSF. The AUC of PEG30- rhG-CSF was much greater than that of PEG20-rhG-CSF, and the relative bioavailability with a subcutaneous injection was 158.7%. Administration of single doses of PEG30-rhG-CSF resulted in substantial increases in the absolute The time to reach ANC （ANCTmax） neutrophil count （ANC）. was 72 h. The maximum observed absolute neutrophil counts （ANCmax） and the area over the baseline effect curve （AOBEC） was increased with increasing doses. The effect-elimination half-life （t1/2E） ranged from 60 h to 80 h after subcutaneous administration. The PLT count was slightly elevated 8-12 h after s.c. injection, and declined after 24 h. CONCLUSION The mean elimination half-life of PEG30-rhG- CSF was longer than that of PEG20-rhG-CSF at the same dose, and the other main pharmacokinetic and pharmacodynamic parameters of PEG30-rhG-CSF, including C ANCmax, AUC and AOBEC were much greater than those following PEG20-rhG-CSF injection.展开更多
Objective:This study was designed to characterize the pharmacokinetics and pharmacodynamicsof high dose epirubicin in cancer patients.Methods:Eleven patients with malignant tumors were administered with adose of 100 m...Objective:This study was designed to characterize the pharmacokinetics and pharmacodynamicsof high dose epirubicin in cancer patients.Methods:Eleven patients with malignant tumors were administered with adose of 100 mg·m2 epirubicin.The concentration of epirubicin was determined by high-performance liquidchromatographic(HPLC)assay.The modelling data were performed with a compartment pharmacokinetic modellingprogram(PCNONLIN).Hematological toxicity was used as the pharmacodynamic index.The relationships amongthe pharmacokinetics and pharmacodynamics and other factors affecting dose modulation were assessed.Results:The pharmacokinetics of high dose epirubicin was best described by a typical three-compartment model.It showedwide interindividual variation.There was no correlation between its pharmacokinetics and pharmacodynamics.Agewas closely correlated with epirubicin clearance.Conclusions:There was no difference in the pharmacokineticparameters between high dose and low dose.Total clearance appeared to decrease with age,which indicatesthe necessity of reducing dose for the elderly patients.The tolerance was good for patients receiving a dose of100 mg·m2 epirubicin.展开更多
基金supported by Fundamental Research Funds for the Central Universities(2022-ZXFZJJ-028).
文摘Objective:To establish a progressive research strategy for“colonic components analysis-efficacy verification and mechanism exploration-gut microbiota”,screen pharmacodynamic substances,and investigate their mechanism via gut microbiota.Methods:The pharmacodynamics of Gegen Qinlian decoction(GQD)were assessed using a mouse model of dextran sulfate sodium-induced ulcerative colitis(UC).Ultra-performance liquid chromatographyquadrupole-orbitrap mass spectrometer was used to identify the prototype and metabolic components of GQD in the colon during UC.To analyze the structure and function of characteristic genera of GQD and its active components,16S rRNA sequencing was performed.Results:We identified 67 prototypic and 14 metabolic components of GQD in the UC colon.The primary prototype components are flavonoids and alkaloids,including puerarin(PUE),baicalin(BAI),and berberine(BER).The metabolism was predominantly sulfonation.Efficacy verification showed that the main active components,puerarin,baicalin,and berberine,had good therapeutic effects on UC.The results of 16S rRNA gene sequencing showed that GQD improved UC by regulating the structure and function of the gut microbiota.The abundance of gut microbiota involved in the metabolism of the prototype componentswas influenced by the corresponding components.The function prediction results showed that PUE was the most comparable to GQD,with 24 consistent pathways.BAI and BER showed comparable gut microbiota regulation pathways.Characteristic pathways of BER include glucometabolic processes.Conclusion:This study focused on the key issues in the gut microbiota pathway and developed a progressive research strategy to understand the transformation mechanisms of colonic components.This research systematically analyzed the active components and metabolic transformation of GQD in the colon during the pathological state of UC,as well as changes in the structure and function of the gut microbiota,clarified the mechanism of GQD and its active components in improving UC via the gut microbiota pathway.
基金This retrospective analysis incorporated data from two clinical trials(CTR20220854 and CTR20222843)sponsored by Chongqing Chenan Biopharmaceutical Co.,Ltd.and Jiangsu Hengrui Pharmaceuticals Co.,Ltd.However,these sponsors did not partake in the study design,data interpretation,or manuscript preparation.
文摘BACKGROUND Insulin therapy plays a crucial role in managing diabetes.Regulatory guidelines mandate assessing the pharmacokinetics(PK)and pharmacodynamics(PD)of new insulin formulations with euglycemic clamp techniques before entry into the market.Typically,blood glucose(BG)levels are maintained at 5%below baseline to suppress endogenous insulin secretion in healthy volunteers.However,in scenarios where BG baseline is relatively low,maintaining it at 5%below baseline can increase hypoglycemic risk.Consequently,we adjusted to maintain it at 2.5%below a baseline of<4.00 mmol/L.It remains uncertain whether this adjustment impacts endogenous insulin inhibition or the PD of study insulin.AIM To evaluate and compare the PD and C-peptide status using two different target BG setting methods.METHODS Data came from euglycemic clamp trials assessing the PK/PD of insulin aspart(IAsp)in healthy participants.Target BG was set at 2.5%below baseline for those with a basal BG of<4.00 mmol/L(group A),and at 5%below baseline for others(group B).The area under the curve(AUC)of IAsp(AUC_(IAsp,0-8 h))and GIR from 0 to 8 hours(AUCGIR,0-8 h)was used to characterize the PK and PD of IAsp,respectively.The C-peptide reduction and PK/PD of IAsp were compared between the two groups.RESULTS Out of 135 subjects,15 were assigned to group A and 120 to group B;however,group B exhibited higher basal Cpeptide(1.59±0.36 vs 1.32±0.42 ng/mL,P=0.006).Following propensity score matching to adjust for basal Cpeptide differences,71 subjects(15 in group A and 56 in group B)were analyzed.No significant differences were observed in demographics,IAsp dosage,or clamp quality.Group B showed significantly higher baseline(4.35±0.21 vs 3.91±0.09 mmol/L,P<0.001),target(4.13±0.20 vs 3.81±0.08 mmol/L,P<0.001),and clamped(4.10±0.17 vs 3.80±0.06 mmol/L,P<0.001)BG levels.Both groups exhibited comparable C-peptide suppression(32.5%±10.0%vs 35.6%±12.1%,P=0.370)and similar IAsp activity(AUCGIR,0-8 h:1433±400 vs 1440±397 mg/kg,P=0.952)under nearly equivalent IAsp exposure(AUC_(IAsp,0-8 h):566±51 vs 571±85 ng/mL×h,P=0.840).CONCLUSION Maintaining BG at 2.5%below a baseline of<4.00 mmol/L did not compromise the endogenous insulin suppression nor alter the observed pharmacodynamic effects of the study insulin.
基金National Natural Science Foundation of China(NSFC,Grant No.81273583)
文摘The epidermal growth factor receptor（EGFR）—tyrosine kinase inhibitors（TKIs） monotherapies have limited efficacy in the treatment of EGFR mutation-negative non-small cell lung cancers（NSCLCs）. In the present study, we aimed to investigate the combined effect of erlotinib（ER） and cabozantinib（CAB） on NSCLC cell lines harboring wild-type EGFR and to optimize the dosage regimens using pharmacodynamic（PD） modeling and simulation. Therefore, we examined the combined effect of ER and CAB on cell viability, cloning, apoptosis induction, migration and growth dynamics in H1299 and A549 cells. PD modeling and simulation were also performed to quantitatively describe the H1299 cells growth dynamics and to optimize the dosage regimens as well. Our results showed that CAB effectively enhanced the sensitivity of both cell lines to ER. The PD models fitted the data well, and some important parameters were obtained. The exponential（λ_0） and linear（λ_1） growth rates of H1299 cells were 0.0241 h^（–1） and 360 cells？h^（–1）, respectively. The Emax of ER and CAB was 0.0091 h^（–1） and 0.0085 h^（–1）, and the EC50 was 0.812 μM and 1.16 μM, respectively. The synergistic effect observed in the experiments was further confirmed by the estimated combination index φ（1.37）,（95% confidence interval： 1.24–1.50）, obtained from PD modeling. Furthermore, the dosage regimens were optimized using simulations. In summary, both the experimental and modeling results demonstrated the synergistic interaction between ER and CAB in NSCLCs without EGFR mutations. Sequential combinations of ER and CAB provided an option for the therapy of the NSCLCs with wild-type EGFR, which would provide some references for preclinical study and translational research as well.
基金Supported by National Natural Science Foundation of China,No.81374042,No.81370091 and No.81573857
文摘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.
基金supported by the National Natural Science Foundation of China(No.81603258)Youth Talent Project Funded by Shaanxi Higher Education Association for Science and Technology(No.20180307)+1 种基金Subject Innovation Team of Shaanxi University of Chinese Medicine(No.2019-YL10)Key Research and Development Program of Shaanxi(No.2019-SF-300)
文摘Dahuang-Gancao decoction(DGD)is a classical formula,which is commonly used for reliving constipation in Chinese clinic.The aim of this study was to investigate the pharmacodynamic,pharmacokinetic and tissue distribution alternations of DGD in normal and constipation mice.DGD exhibited stronger purgative effect in constipation mice by the increased fecal excretion and reduced first defection time compared with normal mice.The Cmax,AUC0-t and MRT0-t of rhein,aloe-emodin,rhein-8-O-β-D-glucoside,sennoside A,and glycyrrhizic acid as main bio-active components in DGD were markedly increased in constipation mice.The tissue distribution of the analytes in constipation mice were higher than those in normal mice with rhein>rhein-8-O-β-D-glucoside>aloe-emodin>glycyrrhizic acid>emodin in liver,and glycyrrhizic acid>rhein-8-O-β-D-glucoside>liquitin>sennoside A>rhein>aloe-emodin>emodin in colon.The kidney concentrations of the analytes showed a descending order of rhein>rhein-8-O-β-D-glucoside>sennoside A>glycyrrhizic acid>aloe-emodin>emodin,most of them were higher while rhein was lower in constipation mice than normal mice.The higher exposure of the anthraquinones in plasma,liver and colon may result in the stronger purgative effect in the constipation mice than normal mice.Rhein is mainly excreted through the kidney,the decreased level of rhein in constipation mice may explain the alleviated side effects.Accumulation of glycyrrhizic acid in colon may related with the moderate property of licorice.These results provided the experimental basis for understanding the therapeutic effects and metabolite profile of DGD.
基金Supported by the National Natural Science Foundation of China,No.81603519,No.81573857,and No.81374042
文摘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.
基金supported by National Natural Science Foundation of China(No.81173521)the Central University Basic Scientific Research Project of Ministry of Education,China(No.2015-JYB-XS068)
文摘The present study aimed to establish a pharmacodynamic method using the py Solo software to explore the influence of freeze-dried powders of Shuangxia Decoction(SXD) on the sleep of normal Drosophila melanogaster and the Drosophila melanogaster whose sleep was divested by light. The dose-effect and the time-effect relationships of SXD on sleep were examined. The effect-onset concentration of SXD was 0.25%, the plateau appeared at the concentration of 2.5% and the total sleep time showed a downtrend when the concentration was greater than 2.5%. The sleep time was the longest on the fourth day after SXD was given. The fruit fly sleep deprivation model was repeated by light stimulation at night. The middle dosage group(2.5%) had the best insomnia-curing effect. In conclusion, using the py Solo software, an approach for the pharmacodynamics study was established with Drosophila melanogaster as a model organism to determine the insomnia-curing effects of the traditional Chinese medicine(TCM). Our results demonstrated the reliability of this method. The freeze-dried powders of SXD could effectively improve the sleep quality of Drosophila melanogaster.
基金Supported by the National Natural Science Foundation of China,No.81374042,No.81370091 and No.81603480
文摘AIM To identify the optimal oral dosing time of Da-Cheng-Qi decoction(DCQD) in rats with acute pancreatitis(AP) based on the pharmacokinetic and pharmacodynamic parameters.METHODS First, 24 male Sprague-Dawley rats were divided into a sham-operated group [NG(a)] and three model groups [4 h G(a), 12 h G(a) and 24 h G(a)]. The NG(a) and model groups were administered DCQD(10 g/kg.BW) intragastrically at 4 h, 4 h, 12 h and 24 h, respectively, after AP models induced by 3% sodium taurocholate. Plasma samples were collected from the tails at 10 min, 20 min, 40 min, 1 h, 2 h, 4 h, 8 h, 12 h and 24 h after a single dosing with DCQD. Plasma and pancreatic tissue concentrations of the major components of DCQD were determined by high-performance liquid chromatography tandem mass spectroscopy. The pharmacokinetic parameters and serum amylase were detected and compared. Second, rats were divided into a sham-operated group [NG(b)] and three treatment groups [4 h G(b), 12 h G(b) and 24 h G(b)] with three corresponding control groups [MG(b)s]. Blood and pancreatic tissues were collected 24 h after a single dosing with DCQD. Serum amylase, inflammatory cytokines and pathological scores of pancreatic tissues were detected and compared.RESULTS The concentrations of emodin, naringin, honokiol, naringenin, aloe-emodin, chrysophanol and rheochrysidin in the 12 h G(a) group were higher than those in the 4 h G(a) group in the pancreatic tissues(P < 0.05). The area under the plasma concentration-time curve from time 0 to the time of the last measurable concentration values(AUC0→t) for rhein, chrysophanol, magnolol and naringin in the 12 h G(a) group were larger than those in the 4 h G(a) or 24 h G(a) groups. The 12 h G(a) group had a higher Cmax than the other two model groups. The IL-10 levels in the 12 h G(b) and 24 h G(b) groups were higher than in the MG(b)s(96.55 ± 7.84 vs 77.46 ± 7.42, 251.22 ± 16.15 vs 99.72 ± 4.7 respectively, P < 0.05), while in the 24 h G(b) group, the IL-10 level was higher than in the other two treatment groups(251.22 ± 16.15 vs 154.41 ± 12.09/96.55 ± 7.84, P < 0.05). The IL-6 levels displayed a decrease in the 4 h G(b) and 12 h G(b) groups compared to theMG(b)s(89.99 ± 4.61 vs 147.91 ± 4.36, 90.82 ± 5.34 vs 171.44 ± 13.43, P < 0.05). CONCLUSION Late-time dosing may have higher concentrations of the most major components of DCQD, with better pharmacokinetics and pharmacodynamics of antiinflammation than early-time dosing, which showed the late time to be the optimal dosing time of DCQD for AP.
基金Ministry of Agriculture for providing New Application for Herbal Research Grant Scheme(NRGS)(NH1014D040) and supports
文摘Eurycoma longifolia Jack(E.longifolia) is a well-recognized traditional herbal medicine that offers a wide dynamic range of biomedical applications including anti-osteoporotic, anticancer, anti-proliferative, anti-malarial, antimicrobial, antioxidant, aphrodisiac, antiinflammatory, anxiolytic, anti-diabetic, anti-rheumatism and anti-ulcer properties.This review aims to overview the pharmacokinetic and a pharmacodynamic algorithm of E.longifolia and its bioactive components.Analysis of pharmacokinetic profile revealed that E.longifolia exhibit higher bioavailability, high volume of distribution, slow elimination rate, and does not show inhibitory effects on cytochrome P450 isoenzymes.E.longifolia has been used, alone or in combination with other pharmacological agents, in the form of crude extracts, standard extracts, or decoctions of different plant parts(i.e., herbs, shrubs, stem, leaves, and roots) for the treatment of various ailments in animals and humans.Among various bioactive constituents, eurycomanone has been found to be the most remarkable, super-stable, versatile, and most potent phytochemical(isolated or extracted from root extracts) against various types of animals and human diseases.Based on its well-established pharmacokinetic and pharmacodynamic profiles, we suggested that E.longifolia can be a well-accepted complementary and alternative medicine for the treatment of different types of human ailments.
基金National Natural Science Foundation of China(Grant Nos.81773864,81473106)National Key R&D Program of China(Grant No.2019YFC1711000)。
文摘A comparison of the pharmacodynamic effects of two source plants of Murrayae Folium et Cacumen(MFC),Murraya exotica L.and Murraya paniculata(L.)Jack,was performed in order to supply reference for its multi-source rationality and interchangeability in clinical practice.According to the traditional efficacy of MFC,the effects of promoting Qi,relieving pain,promoting blood circulation and removing blood stasis were systematically evaluated by the models of writhing response in mice,foot swelling in rats,gastric emptying and small intestine propulsion in mice,and acute blood stasis in rats,respectively.The results showed that both M.exotica and M.paniculata could significantly inhibit the writhing reaction induced by acetic acid in mice and the paw swelling induced by carrageenan in rats,reduce IL-6,TNF-αand PGE2 levels in plasma of paw-swelling rats and increase gastric empty rate and intestinal propulsive rate.The above-mentioned effects were dose-dependent,and there was no significant difference between M.exotica and M.paniculata at the same doses.Therefore,M.exotica and M.paniculata had the similar anti-inflammatory,analgesic and gastrointestinal motility promotion effects,which provided a support for the pharmacodynamic equivalence of the multi-source plants of MFC.
基金Supported by The Major State Creative New Drug Project,No.2009ZX09502-017Education Ministry Science Foundation ofChina,No. 108019
文摘AIM： To develop a pharmacodynamic model of porta hypertension from chronic hepatitis. METHODS： Pathological changes and collagen depositions were analyzed using morphometry to confirm CCI4-induced chronic hepatitis. At do, d28, ds6 and d84 of the process, the portal perfused velocities （μL/min） in isolated rat livers were exactly controlled with a quanti-fied pump. The pressure （mmHg） was monitored with a Physiological System. The geometric concentrations of phenylephrine or acetylcholine were added to a fixed volume （300 mL） of the circulating perfusate. The equation, the median effective concentration and its 95% confidence intervals of phenylephrine or acetyl- choline were regressed with Prism-4 software in non-linear fit and various slopes. In the isolated perfused rat livers with chronic hepatitis, both median effective concentrations were defined as the pharmacodynamic model of portal hypertension.CONCLUSION： A pharmacodynamic model of portal hypertension in isolated perfused rat livers with chronic hepatitis was defined as the median effective concen- trations of phenylephrine and acetylcholine.
基金This study was supported by the National Natural Science Foundation of China(81430094)。
文摘The property theory of Chinese materia medica is one of the foundations of traditional Chinese medicine.The property of Chinese materia medica(PCMM)is a multi-dimensional expression of the effect of Chinese materia medica(CMM),and it is related to the clinical prescription that fully reflects the clinical effect evaluation of CMM in a holistic,systematic,and scientific way.This paper discusses the source,development,and application of the PCMM by considering not only the five dimensions that constitute the PCMM but also the recognition of the human body and disease as given in traditional Chinese medicine.This paper aims to provide theoretical guidance for the rational use and development of CMM.
文摘Batifiban, a synthetic cyclic peptide, is a potent platelet glycoprotein GPⅡb/Ⅲa antagonist which may be useful in the treatment and prevention of acute coronary syndromes. The pharmacokinetics and pharmacodymanic （inhibition of platelet aggregation） effects, and tolerability of batifiban were investigated in healthy subjects following single bolus injection with doses of 55, 110, or 220 μg/kg, or multiple doses of an bolus followed intravenous infusion for 24 h （180 μg/kg plus 2.0 μg/minokg, and 220 μg/kg plus 2.5μg/minokg） in this phase I clinical trial. Plasma levels of batifiban and areas under the curve were found to be proportional to doses. Batifiban was rapidly eliminated with a half-life of approximately 2.5 h. Significant differences were noted for plasma levels of batifiban and areas under the curve between males and females. No significant differences in the terminal half-life were found between males and females. Batifiban reversibly inhibited ex vivo platelet aggregation in a dose- and concentration-dependent manner, consistent with its mechanism as a GPⅡ b/Ⅲa antagonist. Single and multiple intravenous doses of batifiban were found to be safe and well tolerated in healthy subjects. These results support a bolus injection plus intravenous infusion regimen of batifiban for the treatment and prevention of acute coronary syndromes.
基金Natural Science Foundation of Beijing(Grant No.7192100).
文摘Previous study has shown that dopamine D1 receptor(D1DR)agonists,fenoldopam(FEN)and l-stepholidine(l-SPD),have inhibitory effects on breast cancer lung metastasis.To quantitatively describe and predict the pharmacodynamic(PD)properties of FEN and l-SPD and to explore the PD model structure of cancer metastasis treating drugs,we used the data of lung metastasis in 4T1 breast cancer mice under the treatment of either FEN or l-SPD,and established a PD model.The PD model assumed an exponential growth for both primary tumor and metastasis.The primary tumor emitted cells to form metastases,and the cell emitting rate was proportional to power form of the primary tumor weight.The total number of lung metastasis was set as the target value.D1DR agonists inhibited metastasis by inhibiting cell emitting rate instead of the growth rate of primary tumor or metastasis.The model results showed that the decrease in the number of lung metastases was roughly proportional to the square of the drug dose.The values of PD coefficient reflected the inhibitory ability of the drugs,and that of l-SPD(0.274 kg/mg)was greater than that of FEN(0.0393 kg/mg).This PD model can quantitatively describe the effects of FEN and l-SPD on the progression of lung metastasis in 4T1 primary breast cancer mice and can predict the time course of drug efficacy at multiple doses,providing a reference for PD model structure of other drugs for cancer metastasis indication.
文摘The ultimate goal of transplantation is the donor-specific immune tolerance, but at least in the first 15 to 20 years of this century, immunosuppressive agents are still the determinant of clinical outcome of transplant recipients. Individualizing patient's immunosuppression to optimize the balance between therapeutic efficacy and the occurrence of adverse events poses a great challenge to physicians. DATA SOURCES:The data in this article were taken mostly from MEDLINE (2000-2004), part of which were from the research of the authors. RESULTS:Individualized immunosuppression remains a problem because of the narrow therapeutic index and wide inter- and intra-patient variation of commonly-used im- munosuppressants. Recent progress in study of pharmaco-kinetics and pharmacodynamics improved the clinical outcome of transplant recipients. More importantly, the emergence of pharmacogenomics might provide a promising and complementary tool for traditional therapeutic drug monitoring (TDM). CONCLUSIONS:Individualizing organ recipient's immunosuppression to balance the therapeutic efficacy and the adverse events represents a great challenge to transplant clinicians. Pharmacogenomics shows great promise for an interesting and hopefully better future.
基金This study is financially supported by the major project of National Science and Technology of China for new drugs development(No.2009ZX09310-004)Jiangsu Province Ordinary College and University innovative research programs(No.CX10B-374Z).
文摘The work aims to investigate the in vitro release,pharmacokinetics(PK),pharmacodynamics(PD)and PK-PD relationships of Salvianolic Acid B micro-porous osmotic pump pellets(SalB-MPOPs)in angina pectoris New Zealand White(NZW)rabbits,compared with those of SalB immediate-release pellets(SalB-IRPs).The SalB plasma concentrations and Superoxide dismutase levels(PD index)were recorded continuously at predetermined time interval after administration,and the related parameters were calculated by using Win-Nonlin software.The release profile of MPOPs was more sustained than that of IRPs.PK results indicated that the mean C_(max)was significantly lower,the SalB plasma concentrations were steadier,both area under concentration-time curve from 0 to 24 h(AUC_(0-24 h))and from 0 to infinity(AUC_(0-∞))were presented larger,and both the peak concentration time(T_(max))and mean residence time(MRT)were prolonged for MPOPs,as compared with those of IRPs.PD results suggested that peak drug effect(E_(max))was lower and the equilibration rate constant(k_(e0))between the central compartment and the effect compartment was higher of MPOPs vs.those of IRPs.PKePD relationships demonstrated that the effectconcentration-time(ECT)course of MPOPs was clockwise hysteresis loop,and that of IRPs was counter-clockwise hysteresis loop.Collectively,those results demonstrated that MPOPs were potential formulations in treating angina pectoris induced by atherosclerosis.
基金supported by Applied basic Research Project of Science and Technology Department of Shanxi Province(Grant No.201901D-111343)the Open Project of Key Laboratory of Shanxi Province(Grant No.SXIDL-2018-09)Shanxi University of Traditional Chinese Medicine Science and Technology Innovation Ability Training program“basic Research special project”(Grant No.2020PY-JC-20).
文摘In the present study,we aimed to investigate the protective effect of Yuebi Jiazhu Decoction(YBJZD)on the kidney of adriamycin nephropathy(AN)rats.Rats were injected with adriamycin for modeling,except for the control group.After the successful establishment of the animal model,rats were randomly divided into the model group,YBJZD low-,medium-,and high-dose groups,and the positive group.The 24-h urine samples were collected.Biochemical indicators were monitored,and kidney tissues were collected for pathological analysis using light microscopy.The results showed that through 4 weeks of drug intervention,the urinary protein level was lower in the YBJZD and positive groups compared with the model group(P<0.05).Serum levels of BUN,SCr,and TG were significantly lower(P<0.01),and ALB was significantly higher(P<0.01)in the YBJZD and positive groups compared with the model group.Compared with the model group,the pathological injury of kidney tissue in the YBJZD and positive groups was significantly alleviated.These outcomes proved that YBJZD had a renal protective effect on AN rats.
文摘Lignocaine is an essential drug on World Health Organisation essential drug list, considered efficacious, safe and cost-effective for any health-care system. Despite its ubiquitous use in medicine and surgery, there are few detailed reviews of its pharmacokinetics and pharmacodynamics. Being an amide-type local anesthetic and Class 1b antiarrhythmic, lignocaine is most frequently used clinically for its anesthetic and antiarrhythmic benefits. However, lignocaine has important antinociceptive, immuno-modulating, and antiinflammatory properties. Information pertaining to the pharmacokinetics and pharmacodynamics of lignocaine was examined by performing a literature search of Pub Med, Embase and MEDLINE(via Ovid), pharmacology textbooks and online sources. We present a focused synopsis of lignocaine's pharmacological composition, indications for use and mechanisms of action, focusing on its anti-inflammatory, immuno-modulating and analgesia effects. In addition we review the dosing regimes and infusion kinetics of lignocaine in the clinical setting. Finally, we review the evidence for ligocaine's modulation of the inflammatory response during major surgery and its specific effects on cancer recurrence. These indirect effects of local anesthetics in tumor development may stem from the reduction of neuroendocrine responses to the stress response elicited by major surgery and tissue damage, enhanced preservation of immune-competence, in addition to opioid-sparing effects of modulating tumor growth.
基金National High Technology Research and Development Program of China(No.2007BAI14IB04)Major State Basic Research Development Program(No.2004CB518902)
文摘OBJECTIVE To compare the pharmacokinetics and pharmacodynamics of PEG30-rhG-CSF administered to beagle dogs at three different dosages with PEG20-rhG-CSF administered at one dosage, and to provide an experimental basis for clinical trials.METHODS Beagle dogs received single, subcutaneous doses of PEG30-rhG-CSF at 100, 200 and 400 μg/kg or PEG20-rhG-CSF at 200 μg/kg. PEG30-rhG-CSF and PEG20-rhG-CSF concentrations in serum were analyzed using an enzymeqinked immunosorbent assay （ELISA）. WBC, ANC and PLT counts of whole blood samples were measured using fully automated analytic instrumentation. Pharmacokinetic and pharmacodynamic parameters were calculated using DAS 2.0 statistical analysis software.METHODS Beagle dogs received single, subcutaneous doses of PEG30-rhG-CSF at 100, 200 and 400 μg/kg or PEG20-rhG-CSF at 200μg/kg. PEG30-rhG-CSF and PEG20-rhG-CSF concentrations in serum were analyzed using an enzyme-linked immunosorbent assay （ELISA）. WBC, ANC and PLT counts of whole blood samples were measured using fully automated analytic instrumentation. Pharmacokinetic and pharmacodynamic parameters were calculated using DAS 2.0 statistical analysis software. RESULTS The pharmacokinetic parameters of PEG30-rhG-CSF calculated from the serum concentration data determined by ELISA were as follows： the mean elimination half-life （t1/2ke） was 40.6 h （33.5-45.4 h）; the mean time to reach peak concentration （Tmax） was 19.2 h （11.7-24.0 h）; the drug clearance from the serum （CL） was decreased with increasing doses; the peak concentration （Cmax） and the area under the serum concentration-time curve （AUC） were increased with increasing doses. For PEG20-rhG- CSF, the half-life was shorter （12 h） and Tmax was achieved much earlier （10 h） relative to PEG30-rhG-CSF. The AUC of PEG30- rhG-CSF was much greater than that of PEG20-rhG-CSF, and the relative bioavailability with a subcutaneous injection was 158.7%. Administration of single doses of PEG30-rhG-CSF resulted in substantial increases in the absolute The time to reach ANC （ANCTmax） neutrophil count （ANC）. was 72 h. The maximum observed absolute neutrophil counts （ANCmax） and the area over the baseline effect curve （AOBEC） was increased with increasing doses. The effect-elimination half-life （t1/2E） ranged from 60 h to 80 h after subcutaneous administration. The PLT count was slightly elevated 8-12 h after s.c. injection, and declined after 24 h. CONCLUSION The mean elimination half-life of PEG30-rhG- CSF was longer than that of PEG20-rhG-CSF at the same dose, and the other main pharmacokinetic and pharmacodynamic parameters of PEG30-rhG-CSF, including C ANCmax, AUC and AOBEC were much greater than those following PEG20-rhG-CSF injection.
文摘Objective:This study was designed to characterize the pharmacokinetics and pharmacodynamicsof high dose epirubicin in cancer patients.Methods:Eleven patients with malignant tumors were administered with adose of 100 mg·m2 epirubicin.The concentration of epirubicin was determined by high-performance liquidchromatographic(HPLC)assay.The modelling data were performed with a compartment pharmacokinetic modellingprogram(PCNONLIN).Hematological toxicity was used as the pharmacodynamic index.The relationships amongthe pharmacokinetics and pharmacodynamics and other factors affecting dose modulation were assessed.Results:The pharmacokinetics of high dose epirubicin was best described by a typical three-compartment model.It showedwide interindividual variation.There was no correlation between its pharmacokinetics and pharmacodynamics.Agewas closely correlated with epirubicin clearance.Conclusions:There was no difference in the pharmacokineticparameters between high dose and low dose.Total clearance appeared to decrease with age,which indicatesthe necessity of reducing dose for the elderly patients.The tolerance was good for patients receiving a dose of100 mg·m2 epirubicin.
