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PubMed1995

Pharmacologically distinct, pertussis toxin-resistant inward currents evoked by metabotropic glutamate receptor (mGluR) agonists in dorsolateral septal nucleus (DLSN) neurons.

We have reported previously that a selective metabotropic glutamate receptor (mGluR) agonist, (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid (1S,3R-ACPD), caused a slow membrane depolarization in rat dorsolateral septal nucleus (DLSN) neurons. Using single electrode voltage-clamp recording methods, we now investigate the pharmacological properties of the receptor that mediates ACPD-induced membrane currents in DLSN neurons recorded from pertussis toxin (PTX)-treated rats. Two pharmacologically distinct inward currents, that is, the ACPD current and Qm current, have been identified based on their agonist preference and sensitivity to various antagonists. The ACPD current is blocked by L-2-amino-4-phosphonobutyric acid (L-AP4), but is insensitive to L-aspartic acid-beta-hydroxamate (L-AA beta H), (+)-alpha-methyl-4-carboxyphenylglycine (+)-MCPG), or L-2-amino-3-phosphonopropionic acid (L-AP3). The Qm current is blocked by L-AA beta H and (+)-MCPG, but is insensitive to L-AP3 or L-AP4. These two inward currents distribute differentially within subpopulations of DLSN neurons. The ACPD current is the only current observed in most DLSN "burster" neurons, while the Qm current is observed more frequently in DLSN "nonburster" neurons. The pharmacological profiles of these currents suggest that the Qm current is likely mediated by mGluR1 or mGluR5, while the ACPD current is mediated by receptors that are pharmacologically distinct from any of the currently cloned mGluRs.

Animals↗
PubMed1994

[Clinical pharmacology in development of new anticancer agents].

The role of clinical pharmacology in the development of new anticancer agents is discussed. In phase I studies, analysis of pharmacokinetic (PK) and pharmacodynamic (PD) relationship, in other words, the relationship among dose administered, pharmacological parameters and pharmacodynamic effects, is essential in the dose escalating process. In addition, we must pay careful attention to whether linearity between the dose administered and the pharmacological parameters is observed or not so as to assure a safe dose escalation strategy. Comparative analysis of the pharmacokinetics and pharmacodynamics between animal models and patients are also an important factor in safe dose escalation. A simple dose escalation strategy will be possible in such agents as the results of phase I are available in other countries. The concept of pharmacokinetic and/or pharmacodynamic drug interactions is essential in a combination phase I study, although this is not covered in the Good Clinical Practice (GCP) guideline. Pharmacological analysis should continue phase II studies to obtain a more accurate PK/PD relationship not only as to the side effects but also the clinical response, in order to analyze intra- or inter-patient variability in pharmacokinetics as well as pharmacodynamics. This would also be useful to establish population pharmacokinetic model or limited sampling strategy for phase III evaluation.

Antineoplastic Agents↗
PubMed1993

Pharmacological control of portal hypertension.

The initiation and maintenance of portal hypertension, development of portosystemic shunts, including esophagogastric varices, and precipitation of variceal hemorrhage result from a number of different although related hemodynamic variables. Knowledge of these pathophysiological mechanisms is essential for an understanding of the pharmacological therapy of portal hypertension. Conversely, pharmacological studies continue to provide new insights and expand our understanding of these pathophysiological mechanisms. Future pharmacological studies should contribute to our understanding of the role of endothelial-dependent and -independent mechanisms in the regulation of vascular tone in chronic liver disease, the regulation of intrahepatic resistance, and the development and modulation of the portocollateral vascular bed. Ideally, this will yield increasingly effective pharmacological therapies for the management of portal hypertension.

Animals↗
PubMed1994

Pharmacological heterogeneity of the cloned and native human dopamine transporter: disassociation of [3H]WIN 35,428 and [3H]GBR 12,935 binding.

Controversy exists as to whether the functional state of the dopamine (DA) transporter is identical to sites mediating the specific binding of selective DA transporter radioligands. Therefore, we compared the pharmacological profile of numerous dopamine transport substrates and inhibitors on [3H]DA uptake with the binding of [3H]WIN 35,428 and [3H]GBR 12,935 to COS-7 cells transiently expressing the cloned human DA transporter. [3H]DA uptake and [3H]WIN 35,428 binding was specific, saturable, and to a single class of binding sites with an estimated Km/Vmax of approximately 2 microM and 6 pmol/min/10(5) cells for DA uptake and Kd/Bmax values of approximately 10 nM and 113 fmol/10(5) cells for [3H]WIN 35,428. [3H]DA uptake was inhibited in a concentration-dependent and uniphasic manner by dopaminergic agents with an appropriate rank order of potency for the DA transporter. Although most uptake blockers inhibited [3H]WIN 35,428 binding in a uniphasic manner, WIN 35,428, Lu 19,005, D-amphetamine, and DA clearly displayed the presence of both high and low affinity components. Comparison of the Ki values for the inhibition of [3H]DA uptake with [3H]WIN 35,428 binding reveals that, for uptake blockers and D-amphetamine, it is the high affinity component that shares pharmacological identity with effects on DA uptake (r = 0.9985), whereas for DA it is the low affinity site. In striking contrast, however, [3H]GBR 12,935 binding to COS-7 cells could not be made to exhibit a pharmacological profile indicative of the DA transporter and suggests that the site regulating functional [3H]DA uptake may not be identical with sites labeled by [3H]GBR 12,935 in these cells. Moreover, these sites appear unrelated to those previously described in native membranes as "piperazine acceptor" or P450 proteins. Comparison of Ki values and rank order of potency for the inhibition of [3H]WIN 35,428 or [3H]GBR 12,935 binding to human caudate membranes reveals pharmacological homology, but not identity, with that of the cloned DA uptake process. Taken together, these data suggest that 1) [3H]WIN 35,428 recognizes two sites of the DA transporter, of which only one appears to represent the functional state of the protein, and 2) [3H]WIN 35,428 and [3H]GBR 12,935 do not appear to bind the same functional form/state of the DA transporter. Whether the nonidentity of binding sites is a manifestation of some post-translational regulatory event (e.g., phosphorylation/accessory binding protein) or caused by the existence of multiple molecular forms of the DA transporter is currently unknown.

Amino Acid Sequence↗
PubMed1996

Pharmacologic characterization of the human 5-hydroxytryptamine2B receptor: evidence for species differences.

The 5-Hydroxytryptamine2B (5-HT2B) receptor was cloned originally from rat stomach fundus and its pharmacology was determined to be consistent with that of the receptor responsible for contraction of rat fundal tissue in response to 5-HT. Recently, the cloning of the human homolog of the 5-HT2B receptor has been reported and, in this study, we report a detailed pharmacological characterization of this human receptor. The cloned human 5-HT2B receptor has high affinity for [3H]5-HT (Kd = 10.6 +/- 1.5 nM), and the pharmacology of this receptor matches closely the rat 5-HT2B receptor, consistent with the structural relatedness of these two proteins. Most compounds tested show no difference in affinity for the human or rat receptors. There were, however, groups of compounds that discriminated between the human and rat 5-HT2B receptors. Examples include certain ergolines such as methysergide and mesulergine, which have higher affinity for the human than for the rat receptor. Similarly, certain benzoylpiperidines, e.g., ketanserin, pirenperone and pipamperone, and the antipsychotics clozapine and olanzapine have higher affinity for the human 5-HT2B receptor. These pharmacological findings reinforce the desirability of having the human forms of receptors when considering drug actions.

Animals↗
PubMed1996

General pharmacology of insulin lispro in animals.

[Lys(B28),Pro(B29)]-human insulin (insulin lispro, CAS 133107-64-9, LY275585, Humalog) is a quick acting insulin analog which is currently undergoing clinical evaluation for the treatment of diabetes. The potential secondary pharmacological activity of insulin lispro was profiled in studies for the evaluation of effects on the central and autonomic nervous system, the cardiovascular system, urine and electrolyte excretion, and gastrointestinal function. In vivo doses ranged from 0.03 to 10 U/kg, administered by the subcutaneous route, while pharmacologic activity in vitro was examined in smooth and cardiac muscle at concentrations of 1 x 10(-9) to 1 x 10(-5) mol/l. Insulin lispro exhibited secondary pharmacological activity in central nervous system tests only at higher doses with the most prominent observations being sedation and decreased responsiveness. Insulin lispro was essentially inactive in tests of autonomic (smooth and cardiac muscle), cardiovascular (mean arterial pressure, heart rate, systolic pressure, diastolic pressure, and pulse pressure), renal (urine and electrolyte excretion) and gastrointestinal (motility) function. In summary, insulin lispro had minimal effect in these pharmacodynamic studies indicating that insulin lispro has minimal potential to produce adverse pharmacological side effects at clinically relevant doses.

Animals↗
PubMedDate not supplied

Metabolism of psychotropic drugs: pharmacological and clinical relevance.

Cytochrome P-450 (CYP) catalyzes phase I metabolic reactions of psychotropic drugs. The main isoenzymes responsible for their biotransformation are CYP1A2, CYP2D6, CYP3A4 and these of the subfamily CYP2C. The majority of metabolites of psychotropic drugs are biologically active. Some of them retain pharmacological properties of parent compounds (eg. selective serotonin reuptake inhibitors, risperidone, carbamazepine, benzodiazepines), but others display quite different (eg. amitriptyline, buspirone) or even opposite (trazodone) profiles. They are present in vivo in concentrations high enough to contribute to pharmacological and clinical effects of the administrated drugs. Active metabolites of psychotropics are also characterized by pharmacokinetic properties different from their parent compounds, e.g. half-life time, plasma protein binding, blood-brain-barrier penetration, the cerebrospinal fluid (CSF) protein binding and tissue binding. These properties lead, in turn, to differences in the brain/plasma and the CSF/plasma concentration ratios between a drug and its metabolites. Therefore studies relating a pharmacological or therapeutic response of psychotropic drug to its plasma concentrations should not disregard the presence of its active metabolites, considering their distinct pharmacological and pharmacokinetic properties. With regard to a low therapeutic index of psychotropics, interindividual differences in the rate of their metabolism, genetic polymorphism of their main metabolic pathways and metabolic interactions in clinical drug combinations, the phenotyping of patients at the beginning of therapy and a control of drug concentrations (and its active metabolites) at a steady state and during coadministration of another drug, may increase the efficiency and safety of the pharmacotherapy of psychiatric disorders.

Animals↗
PubMed1996

Pharmacology of the human gamma-aminobutyric acidA receptor alpha 4 subunit expressed in Xenopus laevis oocytes.

The human gamma-aminobutyric acidA (GABAA) receptor alpha 4 subunit was recently cloned and characterized pharmacologically using radioligand binding techniques. These studies suggested that alpha 4 subunits confer a novel diazepam-insensitive binding site. To further investigate the pharmacology of the alpha 4 subunit, we expressed human alpha 4 beta 2 gamma 2L subunit combinations in oocytes and compared the expression and pharmacology of these receptors with alpha 1 beta 2 gamma 2L, beta 2 gamma 2L, and other possible binary subunit combinations. Apparent GABA affinity was 2-3-fold higher for alpha 4 beta 2 gamma 2L than for alpha 1 beta 2 gamma 2L receptors. Functional modulation of receptors by benzodiazepine-site ligands and other classes of allosteric modulator were assayed over a broad concentration range (0.01-100 microM) on currents that were 10% of the maximum GABA response. Diazepam (0.01-1 microM) did not modulate GABA responses at alpha 4 beta 2 gamma 2L receptors, whereas it increased alpha 1 beta 2 gamma 2L responses by approximately 110%. Bretazenil (0.01-1 microM), a benzodiazepine partial agonist, induced higher efficacy modulation of alpha 4 beta 2 gamma 2L receptors (approximately 83%) than of alpha 1 beta 2 gamma 2L (approximately 25%). The benzodiazepine antagonist flumazenil (0.1-10 microM) unexpectedly potentiated alpha 4 beta 2 gamma 2L responses up to approximately 41%, and the benzodiazepine partial inverse agonist Ro15-4513 (1 microM) potentiated alpha 4 beta 2 gamma 2L responses by approximately 63%. Two other benzodiazepine-site ligands, CGS-9895 and methyl-6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate, had qualitatively similar effects at alpha 1 beta 2 gamma 2L and alpha 4 beta 2 gamma 2L. Modulators such as pentobarbital, 3 alpha-hydroxy-5 alpha-pregnan-20-one, mefenamic acid, and loreclezole also induced similar potentiation at both subtypes of receptor. The pharmacology conferred by the alpha 4 subunit was similar to that conferred by the alpha 6 subunit, to which it shows highest levels of homology, but the two subunits differ in sensitivity to the beta-carboline methyl-6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate. Properties of the alpha 4-containing receptors are consistent with diazepam-insensitive binding sites found in cerebral cortex and other forebrain structures. Characterization of these receptors should further our understanding of mechanisms underlying the behavioral effects of GABA modulators and help in the design of drugs with improved, or novel, therapeutic profiles.

Animals↗
PubMed1997

The neurobiology and pharmacology of depression. A comparative overview of serotonin selective antidepressants.

BACKGROUND: Over the past decade, targeted drug design has led to significant advances in the pharmacological management of depression. A serendipitous approach to drug discovery has therefore been replaced by the development of drugs acting on predetermined neurobiological targets recognised to be involved in the pathology of depressive illness. The first of these 'designer drugs', were the selective serotonin (5-HT) re-uptake inhibitors (SSRIs), followed more recently by venlafaxine and nefazodone which, in addition to 5-HT uptake, also target noradrenaline (NA) uptake and 5-HT2 receptors, respectively. METHODS: This paper reviews the biochemistry and pharmacology of depression. From this foundation, the relevance of 5-HT selectivity is discussed followed by a comparison of the clinical pharmacology and pharmacokinetics of 5-HT-selective antidepressants. RESULTS: Despite their common action on synaptic 5-HT uptake, structural heterogeneity among the group allows differences to be observed in kinetic and pharmacological parameters, viz. plasma half-life (T1/2), liver metabolism, protein binding, receptor affinities and selectivity ratios. This not only leeds to different attributes which assist in the successful management of a particular patient, but will also predict subtle difference in drug interaction risks and in side-effect profiles of clinical relevance. CONCLUSION: 5-HT-selective antidepressants may be more dissimilar than similar, and these differences can allow the clinician to identify clinically reliable determinates predicting side-effects and, possibly, to identify suitable patients for a particular drug.

Antidepressive Agents↗
PubMed1997

Pharmacology of lobeline, a nicotinic receptor ligand.

In this study we investigated the pharmacology of lobeline, a high affinity nicotinic ligand with a unique pharmacological profile, in different in vitro and in vivo tests. Although lobeline displaced [3H]-nicotine binding sites in the rat brain with a Ki of 4.4 nM, it did not activate alpha4beta2 expressed receptors in frog oocytes. The in vivo pharmacological effects of lobeline were highly complex. Lobeline, at the time of maximal effect, dose-dependently produced motor impairment and decreased locomotor activity and body temperature in mice after s.c. treatment. However, antinociception was present after intrathecal but not after s.c. administration of lobeline in the tail-flick tests. The behavioral effects of lobeline were not blocked by pretreatment with either mecamylamine or dihydro-beta-erythroidine. In addition, lobeline given s.c. enhanced nicotine-induced antinociception in a dose-related manner. No acute tolerance developed to either lobeline's behavioral or antinociceptive effect after s.c. or intrathecal administration, respectively. However, tolerance developed to lobeline's pharmacological effects after chronic treatment with the drug for 10 days (15 mg/kg, s.c. twice a day). Furthermore, cross-tolerance between lobeline and nicotine developed after chronic treatment with either drug. Although the alpha4beta2 receptor is unlikely to mediate the agonist effects of lobeline, our results indicate that lobeline does interact with the nicotinic receptor in a novel fashion.

Animals↗
PubMedDate not supplied

[The pharmacological correction of factors limiting human work capacity].

The problem of pharmacological correction of working capacity and rehabilitation after exhausting physical exertion is discussed from the standpoint of current advances and detection of factors limiting man's working capacity. The removal of factors interfering with the development of optimal possibilities of man through the effect of medicinal drugs is considered. The article discusses the energy sources providing for the performance of physical work differing in power and duration in accordance with the specificity of a type of sports as a most convenient model for studying adaptation to physical exertion. Factors limiting the working capacity of athletes are classified on the basis of current advances in biochemistry and physiology. All pharmacological agents influencing human working capacity are classified according to the potency zones determining the supply of energy. Pharmacological monitoring of man's capacity for work is in fact disclosure of factors limiting it and their pharmacological correction. This allows planning of the means for excluding the use of dope drugs in sports medicine and scientifically substantiated use of drugs in heavy branches of industry, for promoting climato-zone adaptation, and in extreme conditions. It is shown that the use of strongly active drugs is not necessary because a large reserve is available of drugs of plant and animal origin possessing much lesser side effects.

Adaptation, Physiological↗
PubMed1998

The pharmacological effects of ginkgo biloba, a plant extract, on the brain of dementia patients in comparison with tacrine.

In 1994, a standardized dry extract of Ginkgo biloba leaves (SeGb), has been approved by German health authorities for the treatment of primary degenerative dementia and vascular dementia. More than 24 different brands of Ginkgo biloba extract are sold in the United States. Tacrine, also known as tetrahydroaminoacrine (THA), and donepezil are currently the only drugs approved in the United States for the treatment of Alzheimer's disease. Previous studies demonstrated that SeGb and tacrine induce significant pharmacological effects on the brains of young, healthy human males, as determined by bioelectrical activity measurements obtained using the quantitative pharmaco-electroencephalogram (QPEEG) method. The type of central nervous system (CNS) effects we have seen on computer-analyzed EEGs (CEEGs) after administration of tacrine or EGb suggests both are "cognitive activators" which are, as a class of products, characterized by a (prepost) relative increase of 7.5 to 13 Hz ("alpha") and decrease of 1.3 to 7.5 Hz ("delta" and "theta") activity. To determine whether EGb or tacrine had noticeable pharmacological effects on elderly subjects diagnosed with possible or probable Alzheimer's, the present open, uncontrolled trial was conducted. Data from 18 subjects (11 males, 7 females) at an average age of 67.4 years with light to moderate dementia (Mini Mental mean score = 23.7, ranges: 15-29 [Geriatric Depression Scale mean scores = 3.7; range: 3.2-5.4]) were analyzed for this presentation. Each subject was randomly administered a single oral "Test-Dose" of either 40 mg of tacrine or 240 mg of EGb2 in two separate sessions within 3- to 7-day intervals. Before drug administration and at 1- and 3-hour intervals after drug administration, CEEGs were recorded for a minimum of 10 minutes. The CEEGs were analyzed using Period Analysis programs we developed for QPEEG. The results indicated that both EGb and, to a lesser degree, tacrine induced pharmacological effects, as established by QPEEG measurements, in the CNS similar to those previously established in healthy, young subjects. The type of CNS effects produced by EGb (as established by HZI's CEEG psychotropic drug database) in elderly dementia patients were similar to those induced by tacrine responders as well as those seen after the administration of other "cognitive activators" (pramiracetam, vinpocetine, BMY-21502, suloctidil, and lisuride) and anti-dementia drugs approved in the United States or Europe (tacrine, donepezil, nimodipine, piracetam, and oxiracetam) from our database. The results also showed that 240 mg of EGb has typical cognitive activator CEEG profiles (responders) in more subjects (8 of 18) than 40 mg tacrine (3 of 18 subjects). Because of the small sample size, we could not test the hypothesis that subjects who showed cognitive activator-type pharmacological response to the first Test-Dose of EGb or tacrine also exhibit more therapeutic effects (compared to nonresponders) when drugs are administered chronically.

Aged↗
PubMedDate not supplied

Adherence to non-pharmacologic therapy for hypertension: problems and solutions.

The efficacy of a number of non-pharmacologic interventions in the therapy of primary hypertension has been firmly established. Most prominently, weight reduction, sodium restriction, and alcohol restriction have significant effects on lowering blood pressure. Increased physical activity contributes to management of hypertensive patients in a variety of ways: apart from having a direct impact on blood pressure level, it is an important supportive factor in a weight-reducing regime. The success in applying these non-pharmacologic measures in standard patient population is rather limited. A salient example is the lack of success in weight reduction. Reduction of sodium in the diet is somewhat more successful, however, the problem is that most of the salt intake is non-discretionary. Adherence to physical activity regimes is in the range of what has been observed in pharmacologic therapy. Research and experience in the past few years are providing a better understanding of the factors determining compliance with prescribed therapeutical regimes. Further research is needed to develop innovative strategies for providing efficacious non-pharmacologic measures to hypertensive patients.

Alcohol Drinking↗
PubMed2002

Towards a core curriculum in clinical pharmacology for undergraduate medical students in Europe.

Undergraduate medical education has been under the spotlight for many years in Europe. In the United Kingdom the General Medical Council, which validates the final medical examination in all UK Medical Schools, has been trying to influence the curriculum for at least the last 50 years. Following their publication of the document "Tomorrow's Doctors" in 1993 many medical schools in the UK have completely changed their curriculum design away from didactic learning and towards an integrated problem-orientated or problem-based approach. There has been concern that, as the process continues, some of the more traditional learning of pharmacology and clinical pharmacology may be lost with nothing to replace it. This manuscript describe two ways of developing a core curriculum for clinical pharmacology. The first uses a drug orientated approach (almost an essential drug list) where drugs are listed according to whether they are essential for students to know about with just over 120 chemical entities; and a shorter list of drugs that students would be expected to know about but not know in any detail. The second approach is a disease-orientated one with three types of disease process: a list of 67 disease states that students must know how to manage (category M), a list of 158 diseases that students must be able to diagnose (category D) and a list of 36 diseases that students should be aware of. The disease orientated approach, though designed in one EU country (the UK) has been field tested in a second (Germany) with little difficulty in transfer.

Curriculum↗
PubMed2026

Integrated network pharmacology, molecular docking, and experimental validation to reveal the potential mechanism of Ginsenoside Rg1 on chronic obstructive pulmonary disease.

Ginsenoside Rg1 (GS Rg1), a natural flavonoid exhibiting anti-inflammatory and antioxidant properties, holds significant potential for treatment chronic obstructive pulmonary disease (COPD). Nevertheless, the precise mechanisms underlying its therapeutic effects remain to be fully elucidated. This study aimed to explore the role and potential mechanism of GS Rg1 in the treatment of COPD using network pharmacology, molecular docking, and experimental validation.Targets related to GS Rg1 and COPD were screened from public databases, and the potential common targets were then imported into the STRING database to construct a protein-protein interaction (PPI) network. Gene ontology (GO) and Kyoto encyclopedia of genes and genomes (KEGG) enrichment analysis were performed to identify key signaling pathways. Molecular docking was employed to predict the binding interactions between GS Rg1 and core targets. A BEAS-2B cell model induced by lipopolysaccharide(LPS) and cigarette smoke extract(CSE) was used to explore the protective mechanisms of GS Rg1. Western blot analysis was conducted to validate the critical targets and pathways involved in the anti-COPD effects of GS Rg1. Network pharmacology analysis revealed 105 common targets between GS Rg1 and COPD. The EGFR/PI3K/AKT and EGFR/STAT3 signaling pathways were selected for further validation. GS Rg1 was demonstrated to effectively inhibit inflammation and mucus hypersecretion in vitro models of COPD. Western blot results showed that GS Rg1 treatment significantly downregulated the expression of proteins involved in the EGFR/PI3K/AKT and EGFR/STAT3 signaling pathway, consistent with the network pharmacology findings. CSE/LPS exposure induces inflammation and oxidative stress in COPD by disrupting the EGFR/PI3K/AKT and EGFR/STAT3 signaling pathways, and GS Rg1 significantly alleviates these effects, which may be partially through regulating the EGFR/PI3K/AKT and EGFR/STAT3 signaling pathway.

Ginsenosides↗
PubMed2000

Quality use of medicines: where does pharmacology 'end'? Invited ASCEPT Lecture. Australasian Society of Clinic and Experimental Pharmacologists and Toxicologists.

1. Pharmacology can be defined very narrowly (e.g. as solely a laboratory based specialty) or more broadly to include issues surrounding rational drug use in the community. 2. While the hypothetio-deductive approach is more clearly in evidence in laboratory and clinical pharmacological experimentation, it is no less important in the comparatively less-well charted area of drug use in the community. 3. Just as laboratory pharmacology has built new partnerships with molecular biology and genetics, the exploration of community drug use brings pharmacologists into partnership with other disciplines (epidemiology, economics, behavioural science) and other sectors (consumers, government, health professionals and industry). 4. Implementing Australia's Quality Use of Medicines Policy (1992) has led to vigorous exploration of issues and problems in medicinal drug use in the community and much scientific study of causes and potential interventions to improve the situation. 5. The Australian National Prescribing Service (1998) is attempting to bring an evidence-based approach to the many facets of prescribing and drug use, by prescribers and consumers alike. 6. Innovation commonly occurs at the interface between the boundaries of traditional disciplines.

Australia↗
PubMed2026

Elucidating the mechanism of Buyang Huanwu Decoction in the treatment of ischemic stroke: A network pharmacology and molecular docking study.

A large number of functional disorders and uncomfortable symptoms often remain following ischemic stroke (IS). Existing drug therapy is not ideal for the direct improvement of symptoms, which often leads to poor patient compliance with physical rehabilitation therapy. Buyang Huanwu Decoction (BYHWD) is a famous prescription that is effective in treating IS, especially during the sequela stage of IS. We analyzed the therapeutic mechanism of BYHWD through network pharmacology. This study aims to investigate the potential active ingredients, targets, and signaling pathways of BYHWD for the treatment of IS, utilizing network pharmacology and molecular docking technology. The active ingredients of 7 Chinese herbs in BYHWD were obtained from the Traditional Chinese Medicine Systems Pharmacology and HERB databases, and IS-related disease targets were searched in the DisGeNET, GeneCards, and OMIM databases. The protein-protein interaction network was constructed using the STRING database and analyzed by Cytoscape 3.10.2 software. Additionally, the target genes were uploaded to the Database for Annotation, Visualization, and Integrated Discovery website for Gene Ontology alongside Kyoto Encyclopedia of Genes and Genomes analyses. With the assistance of AutoDockTools and PyMOL software (Schrödinger, Inc.), a validation of molecular docking results and a visualization of the results were performed. The results showed that there were 190 intersection targets between the active drug components and IS, corresponding to 61 active components, among which the top 5 target genes were tumor suppressor protein 53, Jun proto-oncogene, AKT serine/threonine kinase 1, mitogen-activated protein kinase 1, and estrogen receptor alpha. The PI3K-Akt signaling pathway is one of the top 10 pathways. The molecular docking results indicated that most of the top 5 targets had good affinities for the 8 core compounds. This computational analysis suggests that BYHWD may treat IS through multiple targets and pathways. It may play a neuroprotective role by regulating the inflammatory response, oxidative stress, apoptosis, autophagy, and vascular endothelial homeostasis. The identification of core effective components provides a theoretical foundation and candidate compounds for further investigation into new drugs for the treatment of sequelae after IS.

Drugs, Chinese Herbal↗
PubMed2026

[Study on mechanism of Wendan Decoction in intervening in nonalcoholic fatty liver disease based on proteomics and network pharmacology].

This study systematically explored the molecular mechanism of Wendan Decoction(WDD) in treating nonalcoholic fatty liver disease(NAFLD) by integrating network pharmacology, proteomics, and experimental validation. A mouse NAFLD model was established using a high-fat diet, and the mice were randomly divided into a blank control group, a model group, a positive drug group(simvastatin, 3.03 mg·kg~(-1)), and low-(3.035 g·kg~(-1)), medium-(6.07 g·kg~(-1)), and high-dose(12.14 g·kg~(-1)) WDD groups, with intervention lasting for 6 weeks. After the intervention, the serum levels of alanine aminotransferase(ALT), aspartate aminotransferase(AST), triglycerides(TG), total cholesterol(TC), low-density lipoprotein cholesterol(LDL-C), and high-density lipoprotein cholesterol(HDL-C) were measured using an automatic biochemical analyzer. The serum levels of interleukin-1β(IL-1β), interleukin-6(IL-6), and tumor necrosis factor-α(TNF-α) were detected by ELISA. Liver histopathology was observed via hematoxylin-eosin(HE) staining and oil red O staining. Network pharmacology was used to predict potential targets and pathways, and proteomics was applied to identify differentially expressed proteins and related pathways. RT-qPCR and Western blot were performed to detect mRNA and protein expression of relevant genes. Animal experiments demonstrated that WDD dose-dependently ameliorated hepatic steatosis, inflammation, and lipid deposition, significantly reducing serum levels of ALT, AST, TG, TC, LDL-C, and pro-inflammatory cytokines(IL-1β, IL-6, and TNF-α), while significantly increasing serum HDL-C levels. Network pharmacology screening identified naringenin, baicalein, and other key active components, which were involved in pathways such as the peroxisome proliferator-activated receptor(PPAR), lipid, and atherosclerosis pathways. Proteomics further revealed differentially expressed pathways including the PPAR and advanced glycation end product-receptor(AGE-RAGE) signaling pathways. Integrated analysis highlighted the PPAR signaling pathway as the core mechanism. Molecular biology validation showed that WDD significantly regulated the mRNA expression of sterol regulatory element-binding protein-1c(SREBP-1c), fatty acid synthase(FASN), carnitine palmitoyl transferase 1A(CPT1A), acyl-CoA oxidase 1(ACOX1), and PPARα, as well as protein expression of PPARα, CPT1A, and PPARγ in mouse liver tissue. These results suggested that WDD might exert a multi-component, multi-target, and multi-pathway synergistic effect to improve lipid metabolism disorders and inflammatory responses with the PPAR signaling pathway as the central hub, thereby alleviating NAFLD progression.

Animals↗