Ling Meng

H+/K+-ATPase inhibitors: a patent review.

Introduction: H+/K+-ATPase is a P-type ATP-driven cation transporter which exchanges ions (protons, chloride ions, and potassium ions) across the cell membrane. Modulators of H+/K+-ATPase affect H+/K+ exchange. Areas covered: This article describes various H+/K+-ATPase inhibitors of biological importance in clinical studies and drug development for gastric acid-related diseases and gastrointestinal disorders. Expert opinion: H+/K+-ATPase modulators have attracted much interest for their clinical implication in gastric acid-related diseases. Future studies of gastric H+/K+-ATPase inhibitors may focus on the correlation of pharmacogenetics and pharmacogenomics with the gastric acid secretion and development of more effective H+/K+-ATPase inhibitors to increase their residence time such as tenatoprazole and novel chemical-mediated absorption chemicals. The K+-competitive acid pump antagonists (APAs) are invented and independent of an acidic environment with better inhibition of the pump rapidly control acid secretion with a larger extent. The most innovative and promising compounds of APAs is AZD-0865, which is a modification of SCH28080. H+/K+-ATPase inhibitors can be tried to treat other diseases, especially viral infection after numerous clinical trials, and respiratory disease.

FK506-binding protein 12 ligands: a patent review

Introduction: FK506-binding protein 12 (FKBP12) is an endogenous protein with peptidyl-prolyl isomerase (PPIase) activity. Natural compounds FK506, rapamycin and ascomycin, are FKBP12 ligands used for treating organ transplant rejection and other diseases. Small ligands that also interact with FKBP12 are designed and synthetized based on the natural ligands. This suggests that targeting FKBP12 has potential in the treatment of multiple diseases. Areas covered: This article describes the features of FKBP12 and the therapeutic actions of agents targeting FKBP12 reported in the published articles and patents. Expert opinion: The multiple functions of FKBP12 cause side effects during therapy with FKBP12 ligands. The interaction between FKBP12 and other receptors should be explored to guide their use as drugs in the clinical setting. In addition, the neuroprotective mechanism of small-molecule FKBP12 ligands needs further study in order to develop them as novel drugs for treating neurological disorders.

Efficacy and toxicity of capecitabine-based chemotherapy in patients with metastatic or advanced breast cancer: results from ten randomized trials

Abstract Objective: The efficacy and adverse effects of capecitabine-based chemotherapy versus other regimens reported in previous trials were discordant. The aim of the present study was to determine the efficacy and toxicity profiles of capecitabine-based chemotherapy versus capecitabine-free regimens in patients with metastatic and/or advanced breast cancer. Methods: Randomized trials in which capecitabine-based chemotherapy was compared with capecitabine-free chemotherapy were included by searching the PubMed database. Differences in efficacy and grade 3–4 toxicities between capecitabine-based chemotherapy and other chemotherapy were compared. Results: Ten randomized controlled trials were included in our meta-analysis. Compared to patients treated with capecitabine-free chemotherapy, patients treated with capecitabine-based chemotherapy did not have a significantly different complete response (odds ratio (OR): 1.25, 95% confidence interval (CI): 0.87–1.79, p = 0.231), partial response (OR: 1.16, 95% CI: 0.95–1.41, p = 0.147), and overall response (OR: 1.21, 95% CI: 1.00–1.47, p = 0.053). Compared to the capecitabine-free group, less hematological toxicity and more gastrointestinal toxicity occurred in patients treated with capecitabine-based chemotherapy, including neutropenia (OR: 0.34, 95% CI: 0.19–0.59, p < 0.001), anemia (OR: 0.41, 95% CI: 0.20–0.85, p = 0.016), leukocytopenia (OR: 0.50, 95% CI: 0.32–0.78, p = 0.002), and diarrhea (OR: 2.35, 95% CI: 1.62–3.42, p < 0.001). Furthermore, patients in the capecitabine group exhibited a significantly higher rate of grade 3 hand-foot syndrome than the capecitabine-free group (OR: 25.16, 95% CI: 12.27–51.58, p < 0.001). Conclusions: The present study suggests that capecitabine-based chemotherapy is as effective as capecitabine-free chemotherapy in patients with metastatic and/or advanced breast cancer with different toxicity profiles. Capecitabine-based chemotherapy may be better tolerated than capecitabine-free chemotherapy. Due to several limitations in our study, future large randomized trials are needed.

Analysis of Anaphylactic Shock Caused by 17 Types of Traditional Chinese Medicine Injections Used to Treat Cardiovascular and Cerebrovascular Diseases

Several reports describing anaphylactic shock following treatment of cardiovascular and cerebrovascular diseases with Chinese herbal injections were described. Our analysis of these reports showed that anaphylactic shock caused by traditional Chinese medicine (TCM) injections for the treatment of cardiovascular and cerebrovascular diseases is common but also sometimes fatal. Therefore, we proposed the following four suggestions for improving the clinical safety of delivering Chinese herbal injections and reducing the occurrence of allergic shock. First, patients with cardiovascular and cerebrovascular diseases are at high risk, so they should only be given TCM injections after a doctors diagnosis and approval. Second, people in allergic groups can suffer anaphylactic shock, so vigilance is important in the treatment of all age groups, although even more caution should be exercised when treating children or elderly people. In fact, TCM injections may not be appropriate for those age groups, so that they should be carefully considered before treatment. Third, no significant gender differences have been noted in patients with anaphylactic shock, so all patients should be carefully monitored, irrespective of gender. Fourth, the timeframe in which different drugs cause anaphylactic shock varies; thus, patients should be observed as long as possible.

Direct thrombin inhibitors: Patents 2002-2012 (Review)

Acute vascular diseases and other thromboses of the blood system constitute major health risks in developing countries. Thrombin plays a central role in blood coagulation, which is a crucial process involved in thrombosis. Direct thrombin inhibitors (DTIs) such as argatroban, dabigatran, dabigatran etexilate, lepirudin, desirudin and bivalirudin, which bind to thrombin and block its enzymatic activity, are widely and effectively used in the treatment of thromboembolic diseases. DTIs appear to overcome the disadvantages of indirect thrombin inhibitors such as unfractionated heparins (UFH). Although these DTIs show specific advantages over indirect inhibitors, they still present limitations, such as a narrow therapeutic window, and bleeding and anaphylaxis as side-effects. Novel anticoagulant drugs need thus to be developed to overcome these limitations. In the search for additional candidate agents with improved efficacy, safety and high bioavailability in oral administration, a high number of compounds has been identified, such as those derived from the tripeptide template D-Phe-Pro-Arg, aptamers and peptides isolated from blood-sucking animals. These candidates may prove the new agents of choice for the treatment of cardiovascular diseases.

Effect of Toona microcarpa Harms Leaf Extract on the Coagulation System

Toona microcarpa Harms is a tonic, antiperiodic, antirheumatic, and antithrombotic agent in China and India and an astringent and tonic for treating diarrhea, dysentery, and other intestinal infections in Indonesia. In this study, we prepared ethyl-acetate extract from the air-dried leaves of Toona microcarpa Harms and investigated the anticoagulant activities in vitro by performing activated partial thromboplastin time (APTT), prothrombin time (PT), and thrombin time (TT) assays. Antiplatelet aggregation activity of the extract was examined using adenosine diphosphate (ADP), collagen, and thrombin as agonists, and the inhibitions of factor Xa and thrombin were also investigated. Bleeding and clotting times in mice were used to determine its anticoagulant activities in vivo. It is found that Toona microcarpa Harms leaf extract (TMHE) prolonged APTT, PT, and TT clotting times in a dose-dependent manner and significantly inhibited platelet aggregation induced by thrombin, but not ADP or collagen. Clotting time and bleeding time assays showed that TMHE significantly prolonged clotting and bleeding times in vivo. In addition, at the concentration of 1 mg/mL, TMHE inhibited human thrombin activity by 73.98 ± 2.78%. This is the first report to demonstrate that THME exhibits potent anticoagulant effects, possibly via inhibition of thrombin activity.

The expression of RNA-binding protein RBM38 decreased in renal cell carcinoma and represses renal cancer cell proliferation, migration, and invasion

RBM38, a member of RNA recognition motif family of RNA-binding proteins, can regulate the expression of diverse targets by influencing their messenger RNA stability and play a vital role in cancer development. RBM38 may act as an oncogene or suppressor gene in several human tumors. However, its role in human renal cell carcinoma remains unclear. In this study, we found that the expression of RBM38 was lower in renal cell carcinoma tissues and cell lines. Moreover, overexpression of RBM38 could reduce, whereas knockdown of RBM38 could accelerate renal cell carcinoma cell lines growth rate and number of colonies formation of renal cell carcinoma cell lines. Furthermore, RBM38 inhibited renal cell carcinoma cell lines migration and invasion through epithelial–mesenchymal transition suppression by up-regulating E-cadherin and down-regulating β-catenin and vimentin. For in vivo assays, we found that the RBM38-positive group CAKI-1-RBM38 formed smaller tumors in nude mice compared with the control group. Kaplan–Meier analysis showed that renal cell carcinoma patients with lower expression of RBM38 had a significantly shorter survival time than those with higher expression of RBM38 (p = 0.028). All these suggested that RBM38 acts as a tumor suppressor in renal cell carcinoma, which has the potential value for the prediction of renal cell carcinoma prognosis.

Tryptase inhibitors: a patent review

ABSTRACT Introduction: Tryptase is one of the main serine-proteinases located in the secretory granules of mast cells, and is released through degranulation, which is involved in the pathogenesis of allergic inflammatory disease, cardiovascular diseases, lung fibrosis and tumor. Therefore, inhibitors targeting tryptase may represent a new direction for the treatment of allergic inflammatory disease and other diseases. Areas covered: In this article, we discussed the history and development of tryptase inhibitors and described a variety of tryptase inhibitors via their structures and biological importance in clinical studies and drug development for tryptase-related diseases. Expert opinion: Initial tryptase inhibitors based on indole structure as the hydrophobic substituent on a benzylamine-piperidine template have low specificity and poor bioavailability. Therefore, designing new and specific inhibitors targeting tryptase should be involved in future clinical studies. Modifications toward indoles with varying N-substitution, introducing an amide bond, and growing the chain length contribute to an increase in the specific selectivity and potency of tryptase inhibitors. Tryptase has become the research hotspot to explore many related diseases. Therefore, there has been growing appreciation for the potential importance of the tryptase inhibitors as a target for treating these diseases.

Analysis of patents on anti-rheumatoid arthritis therapies issued in China

Introduction: The etiology of rheumatoid arthritis (RA) is complex and diverse. Chronic inflammatory processes with joint dysfunction can cause permanent disability. Therefore, the development of new drugs and therapies for RA is very important. Areas covered: This review analyzes the existing patents on anti-RA products in China to help pharmaceutical companies and individuals patent potential candidate drugs for RA treatment. Expert opinion: Three hundred and seventeen patents were analyzed, including 172 patents for Traditional Chinese Medicines (TCMs, 54.2%), 65 for synthetic compounds (20.5%), 55 for biological products (17.4%) and 25 patents for the drug preparation process (7.9%). Among the TCM patents, 73.8% were of various preparations for different Chinese medicines, 23.8% were of herbal extracts and 2.3% were of herbal extract derivatives. Synthetic compounds were involved in more than 30 targets, some small-molecule drugs that target signaling kinases such as p38 MAPK, Janus kinase may become important directions in the management of RA. Biological disease-modifying antirheumatic drugs (bDMARDs) are the most efficacious drugs for RA treatment. As the classic therapeutic target in RA, TNF-α has the largest number of bDMARD patents. In addition, it is expected that new targets such as high-mobility group protein B1, thioredoxin domain-containing protein 5 (TXNDC5) and B lymphocyte stimulator (BlyS) will play a significant role in RA as potential targets for new treatments. The largest number of all the published patent applications are claiming TCMs, which may provide substantial new information for anti-RA drug development. The largest number of all the published patent applications are claiming TCMs, which may provide huge information for anti-RA drug development.

Poly (Adp-Ribosyl) Polymerase 1 Inhibitors: A Patent Review

BACKGROUND Poly (ADP-ribosyl) polymerase 1 (PARP1) is important in maintaining genomic stability, repairing DNA damage, and regulating transcriptional processes. Altered PARP1 activity is associated with a multitude of pathologies especially cancer. The broad application prospects of PARP1 inhibitors attract many well-known pharmaceutical companies, which promotes the development of PARP1 inhibitors. OBJECTIVE Present review aims to introduce PARP1 inhibitors by their structures and try to point out future development direction of PARP1 inhibitors. METHOD Details regarding the PARP1and PARP1 inhibitors are obtained from PubMed literatures and patent databases. CONCLUSION The action mode of PARP1 inhibitors developed so far is competing with NAD+ for the catalytic site of PARP1. Using such inhibitors affects multiple NAD+-dependent enzymatic pathways, which results in secondary toxic effects. Designing inhibitors targeting other binding sites on the PARP1 protein is a strategy to bypass this pitfall. Analyzing the structure-activity relationships of active PARP1 inhibitors described in the patents, we conclude that for the binding activity, amide group, aromatic ring or heterocyclic ring with rich electronics and heteroatom-substituted in the meta position of amide group are essential. Big substituents introduced in the heterocyclic ring can enhance inhibitory activity and improve solubility or other physicochemical properties. Clinical trials of PARP1 inhibitor were focused on cancer therapies and have achieved remarkable results.