OBJECTIVES: Recently, comparison of drug responses on gene expression has been a major approach to identifying the functional similarity of drugs. Previous studies have mostly focused on a single feature, the expression differences of individual genes. We provide a more robust and accurate method to compare the functional similarity of drugs by diversifying the features of comparison in gene expression and considering the sample dependent variations. METHODS: For differentially expressed gene measurement, we modified the conventional t-test to normalize variations in diverse experimental conditions of individual samples. To extract significant differentially co-expressed gene modules, we searched maximal cliques among the co-expressed gene network. Finally, we calculated a combined similarity score by averaging the two scaled scores from the above two measurements. RESULTS: This method shows significant performance improvement in comparison to other approaches in the test with Connectivity Map data. In the test to find the drugs based on their own expression profiles with leave-one-out cross validation, the proposed method showed an area under the curve (AUC) score of 0.99, which is much higher than scores obtained with previous methods, ranging from 0.71 to 0.93. In the drug networks, we could find well clustered drugs having the same target proteins and novel relations among drugs implying the possibility of drug repurposing. CONCLUSIONS: Inclusion of the features of a co-expressed module provides more implications to infer drug action. We propose that this method be used to find collaborative cellular mechanisms associated with drug action and to simply identify drugs having similar responses.
Biomarkers, Pharmacological ; Drug Repositioning ; Gene Expression Regulation ; Gene Expression* ; Gene Regulatory Networks ; Methods ; Transcriptome*

In order to prove safety and efficacy, herbal medicines must undergo the rigorous scientific researches such as pharmacokinetic and bioavailability, before they are put on the market in the foreign countries. Botanical Drug Products promulgated by the US FDA could guide industry sponsors to develop herbal drugs, which was also an important reference for investigating Chinese herbal medicines. This paper reviews and discusses novel approaches for how to assess systemic exposure and pharmacokinetic of Chinese herbal medicines, which were in line with FDA guidance. This mainly focus on identifying pharmacokinetic markers of botanical products, integral pharmacokinetic study of multiple components, Biopharmaceutics drug disposition classification system, and population pharmacokinetic-pharmacodynamic study in herb-drug interaction.
Animals ; Biomarkers, Pharmacological ; Drugs, Chinese Herbal ; chemistry ; pharmacokinetics ; Herb-Drug Interactions ; Herbal Medicine ; legislation & jurisprudence ; Humans

Metabonomics is a new "-omics" science in post-gene time. Metabonomics can directly understand the physiological and biochemical situation by its "metabolome profile" as a whole, and therefore can provide various information that differs from other "-omics". Metabonomics has been applied in disease diagnosis, assessment of animal models, screening of new drugs, evaluation of drug safety, discovery of new bio-markers of toxicity, as well as research of traditional Chinese medicine.
Animals ; Biomarkers, Pharmacological ; metabolism ; Biomedical Research ; Diagnosis ; Drug Evaluation, Preclinical ; Humans ; Medicine, Chinese Traditional ; Metabolome ; Metabolomics ; Models, Animal ; Toxicity Tests

Recently traditional Chinese medicine (TCM)-induced liver injury has been an unresolved critical issue which impacts TCM clinical safety. The premise and key step to reduce or avoid drug-induced liver injury (DILI) is to identify the drug source of liver injury in early stage. Then the timely withdrawal of drug and treatment can be done. However, the current diagnosis of DILI is primarily governed by exclusive method relying on administering history supplied by patients and experience judgment from doctors, which lacks objective and reliable diagnostic indices. It is obvious that diagnosis of TCM-induced liver injury is especially difficult due to the complicated composition of TCM medication, as well the frequent combination of Chinese and Western drugs in clinic. In this paper, we proposed construction of research pattern and method for objective identification of TCM-related DILI based on translational toxicology, which utilizes clinical specimen to find specific biomarkers and characteristic blood-entering constituents, as well the clinical biochemistry and liver biopsy. With integration of diagnosis marker database, bibliographic database, medical record database and clinical specimen database, an integrative diagnosis database for TCM-related DILI can be established, which would make a transformation of clinical identification pattern for TCM-induced liver injury from subjective and exclusive to objective and index-supporting mode. This would be helpful to improve rational uses of TCM and promote sustainable development of TCM industry.
Animals ; Biomarkers, Pharmacological ; metabolism ; Biopsy ; methods ; Chemical and Drug Induced Liver Injury ; diagnosis ; metabolism ; pathology ; Early Diagnosis ; Humans ; Liver ; drug effects ; pathology ; Medicine, Chinese Traditional ; adverse effects ; Rats

PURPOSE: Cinacalcet is effective for treating refractory secondary hyperparathyroidism (SHPT), but little is known about the response rates and clinical factors influencing the response. MATERIALS AND METHODS: A prospective, single-arm, multi-center study was performed for 24 weeks. Cinacalcet was administered to patients with intact parathyroid hormone (iPTH) level greater than 300 pg/mL. Cinacalcet was started at a dose of 25 mg daily and titrated until 100 mg to achieve a serum iPTH level <300 pg/mL (primary end point). Early response to cinacalcet was defined as a decrease of iPTH more than 50% within one month. RESULTS: Fifty-seven patients were examined. Based on the magnitude of iPTH decrease, patients were divided into responder (n=47, 82.5%) and non-responder (n=10, 17.5%) groups. Among the responders, 38 achieved the primary end point, whereas 9 patients showed a reduction in serum iPTH of 30% or more, but did not reach the primary end point. Compared to non-responders, responders were significantly older (p=0.026), female (p=0.041), and diabetics (p<0.001). Additionally, early response was observed more frequently in the responders (30/47, 63.8%), of whom the majority (27/30, 90.0%) achieved the primary end point. Multivariate analysis showed that lower baseline iPTH levels [odds ratio (OR) 0.96, 95% confidence interval (CI) 0.93-0.99], the presence of diabetes (OR 46.45, CI 1.92-1125.6) and early response (OR 21.54, CI 2.94-157.7) were significant clinical factors affecting achievement of iPTH target. CONCLUSION: Cinacalcet was effective in most hemodialysis patients with refractory SHPT. The presence of an early response was closely associated with the achievement of target levels of iPTH.
Adult ; Aged ; Biomarkers, Pharmacological/blood ; Calcium/blood ; Female ; Humans ; Hyperparathyroidism, Secondary/*drug therapy ; Male ; Middle Aged ; Naphthalenes/adverse effects/*therapeutic use ; Parathyroid Hormone/*blood ; *Renal Dialysis ; Treatment Outcome

Naodesheng (NDS) formula, which consists of Rhizoma Chuanxiong, Lobed Kudzuvine, Carthamus tinctorius, Radix Notoginseng, and Crataegus pinnatifida, is widely applied for the treatment of cardio/cerebrovascular ischemic diseases, ischemic stroke, and sequelae of cerebral hemorrhage, etc. At present, the studies on NDS formula for Alzheimer's disease (AD) only focus on single component of this prescription, and there is no report about the synergistic mechanism of the constituents in NDS formula for the potential treatment of dementia. Therefore, the present study aimed to predict the potential targets and uncover the mechanisms of NDS formula for the treatment of AD. Firstly, we collected the constituents in NDS formula and key targets toward AD. Then, drug-likeness, oral bioavailability, and blood-brain barrier permeability were evaluated to find drug-like and lead-like constituents for treatment of central nervous system diseases. By combining the advantages of machine learning, molecular docking, and pharmacophore mapping, we attempted to predict the targets of constituents and find potential multi-target compounds from NDS formula. Finally, we built constituent-target network, constituent-target-target network and target-biological pathway network to study the network pharmacology of the constituents in NDS formula. To the best of our knowledge, this represented the first to study the mechanism of NDS formula for potential efficacy for AD treatment by means of the virtual screening and network pharmacology methods.
Alzheimer Disease ; drug therapy ; pathology ; physiopathology ; Autoanalysis ; Biological Availability ; Biomarkers ; Biomarkers, Pharmacological ; Databases, Chemical ; Drug Combinations ; Drug Discovery ; methods ; Drugs, Chinese Herbal ; chemistry ; pharmacology ; therapeutic use ; Humans ; Machine Learning ; Molecular Docking Simulation ; Neural Networks, Computer ; Peptide Fragments ; chemistry ; Permeability

PURPOSE: Identification of subgroups of patients who differ in their response to treatment could help to establish which of the best available chemotherapeutic options are best, based on biological activity. In metastatic colorectal cancer (CRC), novel molecular-targeted agents that act on pathways that regulate cell growth, the cell cycle, apoptosis, angiogenesis, and invasion are being developed. Here, we employed an in vitro chemosensitivity assay to evaluate the biological efficacy of conventional monotherapies and combination chemotherapy with targeted drugs. METHODS: The chemosensitivities of 12 CRC cell lines to the established regimens FOLFOX (5-fluorouracil [5-FU] + leucovorin + oxaliplatin) and FOLFIRI (5-FU + leucovorin + irinotecan) and to therapy with these regimens in combination with the biologically targeted drugs bevacizumab or cetuximab were comparatively evaluated for their effects on apoptotic and autophagic cell death processes, angiogenesis, and invasion. RESULTS: Each of the chemotherapeutic regimens promoted apoptotic cell death and invasion. All drug regimens caused significantly greater apoptotic cell death with activation of caspase-3 in SW480 cells compared to other cells, effects that were associated with a remarkable reduction in matrix metalloproteinase-9 activity. The FOLFOX regimen more effectively promoted apoptotic cell death, angiogenesis, and invasion than the FOLFIRI regimen. Combination therapy with FOLFOX/FOLFIRI regimen and bevacizumab produced a moderate angiogenesis-blocking effect in most cell lines. CONCLUSION: The results validate our in vitro chemosensitivity assay, and suggest that it may be applied to help determine adequate regimens in individual CRC patients based on the biological characteristics of their tumors.
Antibodies, Monoclonal, Humanized ; Antineoplastic Combined Chemotherapy Protocols ; Apoptosis ; Autophagy ; Bevacizumab ; Biomarkers, Pharmacological ; Caspase 3 ; Cell Cycle ; Cell Death ; Cell Line ; Cetuximab ; Colorectal Neoplasms ; Drug Therapy, Combination ; Fluorouracil ; Humans ; Leucovorin ; Matrix Metalloproteinase 9 ; Organoplatinum Compounds ; Population Characteristics

The new generation cyclooxygenase (COX-2) inhibitor could reduce the gastrointestinal side effect of NSAID drugs, but eventually increase the cardiovascular risk, because its selective inhibition of COX-2 induces the imbalance between PGI2 and TXA2 and the reduction of vasodilatory NO. Under pathological conditions, active oxygen species (O2-*2, etc) were used to induce endo- thelial dysfunction, activate NF-κB to induce expressions of pro-inflammatory cytokines IL-1β and TNF-α, increase ET-1, TXA2 with vasoconstrictor effect, reduce PGI2 and NO with vasodilatory effect, generate further oxidative damage together with NO, and reduce the bioavailability of NO. NO-NSAIDs and NO-Coxibs drugs raised the level of NO by introducing NO-donor (ONO2). NSAIDs drugs enhanced the anti-inflammatory activity of COX-2 and reduced gastrointestinal side effects by inhibiting selectively COX-2. If antioxidant structures with active ingredients of traditional Chinese medicines were introduced to improve the antioxidant activity of NSAIDs, they could scavenge the active oxygen species to protect the normal function of vascular endothelia and enhance the bioavailability of NO, which is conducive to enhance the cardiovascular safety of cyclooxygenase (COX-2) inhibitor.
Anti-Inflammatory Agents ; therapeutic use ; Biomarkers, Pharmacological ; Cardiovascular Diseases ; drug therapy ; enzymology ; immunology ; Cyclooxygenase 2 ; immunology ; Cyclooxygenase 2 Inhibitors ; adverse effects ; therapeutic use ; Drugs, Chinese Herbal ; therapeutic use ; Humans ; NF-kappa B ; immunology ; Reactive Oxygen Species ; immunology ; Tumor Necrosis Factor-alpha ; immunology