Surgical peri-implantitis treatment with and without guided bone regeneration. A randomized controlled trial.

OBJECTIVE: To evaluate the efficacy of reconstructive peri-implantitis treatment. MATERIALS AND METHODS: Forty participants, with peri-implantitis and a contained intraosseous defect, were randomized to access flap (control) or access flap with xenograft and collagen membrane (test). All received systemic antimicrobials. Blinded examiners recorded probing depths (PD), bleeding and suppuration on probing (BOP & SOP), soft tissue levels, and marginal bone levels (MBL) at baseline and 12 months. Patient reported outcomes were recorded. The primary outcome was PD change. RESULTS: All 40 participants (40 implants) completed the 12-month study. The mean (standard deviation) PD reduction (deepest site) was 4.2 (1.8) mm in the control and 3.7 (1.9) mm in the test group. MBL gain (deepest site) was 1.7 (1.6) mm in the control and 2.4 (1.4) mm in the test group. Absence of BOP & SOP was observed at 60% of both control and test implants. Buccal recession was 0.9 (1.6) mm in the control and 0.4 (1.1) mm in the test group. A successful outcome (absence of PD ≥ 5 mm with BOP, absence of SOP and absence of progressive bone loss) was achieved for 90% of the control and 85% of test group implants. No statistically significant differences in clinical or radiographic parameters were found between treatment groups. 30% of participants experienced mild gastro-intestinal disturbances. Reporting followed CONSORT guidelines. CONCLUSION: Similar clinical and radiographic improvements at 12 months were observed with high levels of patient satisfaction for both the access flap and xenograft covered by collagen membrane groups. Registered clinical trials.gov. ID:NCT03163602 (23/05/2017).

Persistence and adherence to second-generation antipsychotic long-acting injectable medications for schizophrenia: A comparative study in the Australian context.

OBJECTIVE: To examine patient characteristics, persistence and adherence to treatment associated with use of second-generation antipsychotic long-acting injectable (SGA LAI) medications in the Australian real-world setting. METHOD: Five SGA LAIs were compared using a retrospective 10% sample of prescriptions in Australian Pharmaceutical Benefits Scheme (PBS) data: paliperidone palmitate 1-monthly (PP1M), paliperidone palmitate 3-monthly (PP3M), aripiprazole monohydrate (ARI), risperidone (RLAI) and olanzapine pamoate (OLAI). RESULTS: Patients in the PP3M cohort were more persistent with treatment (p < 0.001). Median months of persistence: PP3M (36 months); ARI (18 months); PP1M (11 months); OLAI (8 months); RLAI (4 months). Patients in the PP3M cohort were more adherent to treatment (p < 0.001): PP3M (78%); ARI (51%); PP1M (46%); OLAI (35%); RLAI (33%). CONCLUSIONS: Patients on PP3M treatment showed comparatively longer persistence and better adherence. Treatments for schizophrenia with longer dosing intervals may provide patients with symptomatic stability that could allow for reduced hospitalisations/relapse and increased focus on functional recovery.

Discovery and Characterization of ZL-2201, a Potent, Highly Selective, and Orally Bioavailable Small-molecule DNA-PK Inhibitor.

DNA-dependent protein kinase (DNA-PK), a driver of the non-homologous end-joining (NHEJ) DNA damage response pathway, plays an instrumental role in repairing double-strand breaks (DSB) induced by DNA-damaging poisons. We evaluate ZL-2201, an orally bioavailable, highly potent, and selective pharmacologic inhibitor of DNA-PK activity, for the treatment of human cancerous malignancies. ZL-2201 demonstrated greater selectivity for DNA-PK and effectively inhibited DNA-PK autophosphorylation in a concentration- and time-dependent manner. Initial data suggested a potential correlation between ataxia-telangiectasia mutated (ATM) deficiency and ZL-2201 sensitivity. More so, ZL-2201 showed strong synergy with topoisomerase II inhibitors independent of ATM status in vitro. In vivo oral administration of ZL-2201 demonstrated dose-dependent antitumor activity in the NCI-H1703 xenograft model and significantly enhanced the activity of approved DNA-damaging agents in A549 and FaDu models. From a phosphoproteomic mass spectrometry screen, we identified and validated that ZL-2201 and PRKDC siRNA decreased Ser108 phosphorylation of MCM2, a key DNA replication factor. Collectively, we have characterized a potent and selective DNA-PK inhibitor with promising monotherapy and combinatory therapeutic potential with approved DNA-damaging agents. More importantly, we identified phospho-MCM2 (Ser108) as a potential proximal biomarker of DNA-PK inhibition that warrants further preclinical and clinical evaluation. Significance: ZL-2201, a potent and selective DNA-PK inhibitor, can target tumor models in combination with DNA DSB-inducing agents such as radiation or doxorubicin, with potential to improve recurrent therapies in the clinic.

Targeted Literature Review of the Burden of Respiratory Syncytial Infection among High-Risk and Elderly Patients in Asia Pacific Region.

INTRODUCTION: The burden of respiratory syncytial virus (RSV), which causes acute respiratory illness, is well recognized among the pediatric population but also imposes a significant risk to the elderly (age ≥ 60) and those with underlying comorbidities. The study aimed to review the most recent data on epidemiology and burden (clinical and economic) of RSV in the elderly/high-risk populations in China, Japan, South Korea, Taiwan, and Australia. METHODS: A targeted review was conducted of English, Japanese, Korean, and Chinese language articles published from 1 January 2010 to 7 October 2020 relevant for the purpose. RESULTS: A total of 881 studies were identified, and 41 were included. The median proportion of elderly patients with RSV in all adult patients with acute respiratory infection (ARI) or community acquired pneumonia was 79.78% (71.43-88.12%) in Japan, 48.00% (3.64-80.00%) in China, 41.67% (33.33-50.00%) in Taiwan, 38.61% in Australia, and 28.57% (22.76-33.33%) in South Korea. RSV was associated with a high clinical burden on those patients with comorbidities such as asthma and chronic obstructive pulmonary disease. In China, inpatients with ARI showed a significantly higher rate of RSV-related hospitalization than outpatients (13.22% versus 4.08%, p < 0.01). The median length of hospital stay among elderly patients with RSV was longest in Japan (30 days) and shortest in China (7 days). Mortality data varied by region with some studies reporting rates as high as 12.00% (9/75) in hospitalized elderly patients. Finally, data on the economic burden was only available for South Korea, with the median cost of a medical admission for an elderly patient with RSV being US dollar (USD) 2933. CONCLUSION: RSV infection is a major source of disease burden among elderly patients, especially in regions with aging populations. It also complicates the management of those with underlying diseases. Appropriate prevention strategies are required to reduce the burden among the adult, especially the elderly, population. Data gaps regarding economic burden of RSV infection in the Asia Pacific region indicates the need for further research to increase our understanding on the burden of this disease in this region.

CD47-blocking Antibody ZL-1201 Promotes Tumor-associated Macrophage Phagocytic Activity and Enhances the Efficacy of the Therapeutic Antibodies and Chemotherapy.

Tumor-associated macrophages (TAM) are the most abundant immune cells in the tumor microenvironment. They consist of various subsets but primarily resemble the M2 macrophage phenotype. TAMs are known to promote tumor progression and are associated with poor clinical outcomes. CD47 on tumor cells and SIRPα on TAMs facilitate a "don't-eat-me" signal which prevents cancer cells from immune clearance. Therefore, blockade of the CD47-SIRPα interaction represents a promising strategy for tumor immunotherapy. Here, we present the results on ZL-1201, a differentiated and potent anti-CD47 antibody with improved hematologic safety profile compared with 5F9 benchmark. ZL-1201 enhanced phagocytosis in combination with standards of care (SoC) therapeutic antibodies in in vitro coculture systems using a panel of tumor models and differentiated macrophages, and these combinational effects are Fc dependent while potently enhancing M2 phagocytosis. In vivo xenograft studies showed that enhanced antitumor activities were seen in a variety of tumor models treated with ZL-1201 in combination with other therapeutic mAbs, and maximal antitumor activities were achieved in the presence of chemotherapy in addition to the combination of ZL-1201 with other mAbs. Moreover, tumor-infiltrating immune cells and cytokine analysis showed that ZL-1201 and chemotherapies remodel the tumor microenvironment, which increases antitumor immunity, leading to augmented antitumor efficacy when combined with mAbs. Significance: ZL-1201 is a novel anti-CD47 antibody that has improved hematologic safety profiles and combines with SoC, including mAbs and chemotherapies, to potently facilitate phagocytosis and antitumor efficacy.

ZL-1211 Exhibits Robust Antitumor Activity by Enhancing ADCC and Activating NK Cell-mediated Inflammation in CLDN18.2-High and -Low Expressing Gastric Cancer Models.

CLDN18.2 (Claudin18.2)-targeting therapeutic antibodies have shown promising clinical efficacy in approximately 30% of gastric cancers expressing high levels of CLDN18.2 and less pronounced activity in low expressing malignancies. Here, we report that ZL-1211 is a mAb targeting CLDN18.2 engineered to promote enhanced antibody-dependent cellular cytotoxicity (ADCC) with the goal of achieving more potent activity in a wider spectrum of high- and low-CLDN18.2 expressing tumors. ZL-1211 demonstrated more robust in vitro ADCC activity than clinical benchmark not only in CLDN18.2-high but also CLDN18.2-low expressing gastric tumor cell lines. Greater antitumor efficacy was also observed in mouse xenograft models. Natural killer (NK) cell played critical roles in ZL-1211 efficacy and NK-cell depletion abrogated ZL-1211-mediated ADCC activity in vitro. ZL-1211 efficacy in vivo was also dependent on the presence of an NK compartment. Strikingly, NK cells strongly induced an inflammatory response in response to ZL-1211 treatment, including increased IFNγ, TNFα, and IL6 production, and were recruited into tumor microenvironment in patient-derived gastric tumors expressing CLDN18.2 upon ZL-1211 treatment to lyse the tumor cells. Taken together, our data suggest that ZL-1211 more effectively targets CLDN18.2-high gastric cancers as well as -low expressing malignancies that may not be eligible for treatment with the leading clinical benchmark by inducing enhanced ADCC response and activating NK cells with robust inflammation to enhance antitumor efficacy. Clinical activity of ZL-1211 is currently under evaluation in a phase I clinical trial (NCT05065710). Significance: ZL-1211, anti-CLDN18.2 therapeutic antibody can target CLDN18.2-high as well as -low gastric cancers that may not be eligible for treatment with clinical benchmark. ZL-1211 treatment induces NK-cell activation with robust inflammation to further activate antitumor immunity in tumor microenvironment.

Discovery of amide replacements that improve activity and metabolic stability of a bis-amide smoothened antagonist hit.

A bis-amide antagonist of Smoothened, a seven-transmembrane receptor in the Hedgehog signaling pathway, was discovered via high throughput screening. In vitro and in vivo experiments demonstrated that the bis-amide was susceptible to N-acyl transferase mediated amide scission. Several bioisosteric replacements of the labile amide that maintained in vitro potency were identified and shown to be metabolically stable in vitro and in vivo.

An Australian Real-World Study of Treatment Persistence of Ustekinumab in Crohn's Disease.

INTRODUCTION: Real-world treatment persistence to ustekinumab for Crohn's disease (CD) was studied using Australian Pharmaceutical Benefits Scheme (PBS) data. Demographic and treatment pattern characteristics were also investigated. METHODS: Our retrospective cohort analysis included PBS 10% sample data for ustekinumab from September 2017 to March 2020, and for other biologics from October 2007 to capture earlier line(s) of therapy. Included patients received ustekinumab for CD prescribed by a gastroenterologist. Treatment persistence overall and by prior biologic experience, mono- or combination therapy, sex and age were estimated using Kaplan-Meier methods. A Cox proportional hazards regression analysis was performed to assess the effect of age, sex and line of therapy on persistence. RESULTS: Data were available for 301 patients. Of these, 58.8% were female and 76.7% were aged 26-65 years. Median follow-up from first ustekinumab dispense was 16 months. Median persistence to ustekinumab had not been reached. Twelve-month persistence to ustekinumab was 82.6% (95% CI 78.1-87.5%). Patients receiving ustekinumab as their first biologic therapy had 12-month persistence of 88.0% (80.8-95.9%) compared to 80.6% (75.0-86.6%) for patients who had previously received other biologic therapies (p=0.059). The adjusted analysis showed a trend to longer persistence for patients receiving ustekinumab as their first biologic therapy compared to biologic experienced patients (HR 1.86 (95% CI 0.95-3.63), p=0.070). Males had higher persistence to ustekinumab than females (HR 0.36 (0.20-0.66), p<0.001). Receiving ustekinumab as a monotherapy or in combination with azathioprine, mercaptopurine, 5ASAs, methotrexate, or corticosteroids had no effect on persistence (p=0.22). CONCLUSION: In an Australian real-world setting, persistence to ustekinumab was demonstrated to be over 80% at 12 months. Use as monotherapy or in combination with other therapy for CD did not affect persistence. Differences in treatment persistence by gender and previous biologic use warrant further investigation as further long-term data becomes available.

Investigation of collision-induced dissociations involving odd-electron ion formation under positive electrospray ionization conditions using accurate mass.

Collision induced dissociation (CID) has been extensively used for structure elucidation. CID in the electrospray ionization (ESI) and atmospheric pressure chemical ionization (APCI) modes has been found to generate mostly even-electron fragment ions while it has been occasionally reported to form odd-electron free radical ions. However, the structural requirements and the fragmentation mechanisms for free-radical CIDs have not been well characterized in the literature. For this purpose, we studied a series of aromatic and non-aromatic compounds such as sulfonamides, N-aryl amides, tert-butyl-substituted aromatic compounds, aryl alkyl ethers, and O-alkyl aryl oximes using the LTQ and LTQ Orbitrap linear ion trap mass spectrometers. The accurate measurement of the fragment ion masses established the unambiguous assignment of the fragment structures resulting from the test compounds. Our results showed that free radical fragmentation is structure dependent and is to a large extent correlated with the neighboring groups in the structures that stabilize the newly formed free radical ions.

Design of 1-piperazinyl-4-arylphthalazines as potent Smoothened antagonists.

The Hedgehog (Hh) signaling pathway regulates cell proliferation and differentiation in developing tissues, and abnormal activation of the Hh pathway has been linked to several tumor subsets. As a transducer of Hh signaling, the GPCR-like protein Smoothened (Smo) is a promising target for disruption of unregulated Hh signaling. A series of 1-amino-4-arylphthalazines was developed as potent and orally bioavailable inhibitors of Smo. A representative compound from this class demonstrated significant tumor volume reduction in a mouse medulloblastoma model.

Addressing PXR liabilities of phthalazine-based hedgehog/smoothened antagonists using novel pyridopyridazines.

Pyridopyridazine antagonists of the hedgehog signaling pathway are described. Designed to optimize our previously described phthalazine smoothened antagonists, a representative compound eliminates a PXR liability while retaining potency and in vitro metabolic stability. Moreover, the compound has improved efficacy in a hedgehog/smoothened signaling mouse pharmacodynamic model.

Acne - best practice management.

BACKGROUND: Acne vulgaris can have a substantial impact on a patient's quality of life; there can be significant psychosocial consequences and it can leave permanent physical scarring. Early and effective acne treatment is important. OBJECTIVE: To describe the outcome of an accredited clinical audit investigating general practitioner management of acne vulgaris and to provide an outline of current 'best practice' acne management. DISCUSSION: The audit was conducted over two cycles with GPs receiving educational material between cycles. Eighty-five GPs contributed data on 1638 patients. General practitioner management of acne was assessed against a set of preset standards and some acne treatment was found to be inconsistent with best practice, particularly for patients with moderate and moderate to severe acne, where many patients were either being undertreated or treatment with antibiotic therapy was suboptimal. It is likely that this treatment gap is overestimated due to practical limitations of the audit process; however, the audit revealed a need to address the main sources of apparent divergence from best practice to improve the quality use of acne therapies.

Orally Bioavailable Small-Molecule CD73 Inhibitor (OP-5244) Reverses Immunosuppression through Blockade of Adenosine Production.

The adenosinergic pathway represents an attractive new therapeutic approach in cancer immunotherapy. In this pathway, ecto-5-nucleotidase CD73 has the unique function of regulating production of immunosuppressive adenosine (ADO) through the hydrolysis of AMP. CD73 is overexpressed in many cancers, resulting in elevated levels of ADO that correspond to poor patient prognosis. Therefore, reducing the level of ADO via inhibition of CD73 is a potential strategy for treating cancers. Based on the binding mode of adenosine 5'-(α,ß-methylene)diphosphate (AOPCP) with human CD73, we designed a series of novel monophosphonate small-molecule CD73 inhibitors. Among them, OP-5244 (35) proved to be a highly potent and orally bioavailable CD73 inhibitor. In preclinical studies, 35 completely inhibited ADO production in both human cancer cells and CD8+ T cells. Furthermore, 35 lowered the ratio of ADO/AMP significantly and reversed immunosuppression in mouse models, indicating its potential as an in vivo tool compound for further development.

The role of herbal PPAR modulators in the treatment of cardiometabolic syndrome.

For thousands of years, natural medicines have played an important role in treating and preventing human diseases worldwide. Natural products offer large structural diversity, and modern techniques for separation, structure elucidation, screening and combinatorial synthesis have led to revitalization of plant products as sources of new drugs. The number of people with cardiometabolic syndrome is increasing worldwide. This is expected to increase the prevalence of potentially harmful distortions of lipid distribution and thus intensify the need for appropriate intervention. With increasing evidence of the pathophysiological importance of the dyslipidaemia associated with type 2 diabetes mellitus, hypertension and insulin resistance, a more aggressive approach to lipid management is required. Nuclear receptors are an attractive and promising target for drug development. Functioning as transcription factors and thereby controlling cellular processes at the level of gene expression, modulation of nuclear receptor activity produces selective alterations in downstream gene expression. These characteristics, combined with their involvement in significant diseases, make nuclear receptors a key target for the development of disease-specific therapy. This review examines natural product libraries as a rich source of ligands for nuclear receptors and their potential as promising therapeutic agents for clinical practice. Continual evolution in drug discovery from plants remains an important source of new pharmaceuticals. Furthermore, by uncovering the regulatory mechanisms and transcriptional targets of the PPARs and other related receptors, it will be possible to provide a comprehensive insight into the pathogenesis of metabolic disease and, at the same time, offer valuable information for rational drug design, ultimately leading to a reduction in the chronic microvascular complications of cardiometabolic syndrome.

In vivo morphologic comparison of saphenous vein grafts and native coronary arteries following non-ST elevation myocardial infarction.

OBJECTIVE: This study aimed to assess the pathophysiological differences between saphenous vein grafts (SVG) and native coronary arteries (NCA) following presentation with non-ST elevated myocardial infarction (NSTEMI). BACKGROUND: There is accelerated pathogenesis of de novo coronary disease in harvested SVG following coronary artery bypass (CABG) surgery, which contributes to both early and late graft failure, and is also causal in adverse outcomes following vein graft PCI. However in vivo assessment, with OCT imaging, comparing the differences between vein grafts and NCAs has not previously been performed. METHODS: We performed a retrospective, observational, analysis in patients who underwent PCI with adjunctive OCT imaging following presentation with NSTEMI, where the infarct-related artery (IRA) was either in an SVG or NCA. RESULTS: A total of 1550 OCT segments was analysed from thirty patients with a mean age of 66.3 (±9.0) years were included. The mean graft age of 13.9 (±5.6) years in the SVG group. OCT imaging showed that the SVG group had evidence of increased lipid pool burden (lipid pool quadrants, 2.1 vs 2.7; p = 0.021), with a reduced fibro-atheroma cap-thickness in the SVG group (45.0 µm vs 38.5 µm; p = 0.05) and increased burden of calcification (calcified lesion length = 0.4 mm vs 1.8 mm; p = 0.007; calcified quadrants = 0.2 vs 0.9; p = 0.001; arc of superficial calcium deposits = 11.6° vs 50.9°; p = 0.007) when compared to NCA. CONCLUSION: This OCT study has demonstrated that vein grafts have a uniquely atherogenic environment which leads to the development of calcified, lipogenic, thin-capped fibro-atheroma's, which may be pivotal in the increased, acute and chronic graft failure rate, and may underpin the increased adverse outcomes following vein graft PCI.

Discovery of a Potent Steroidal Glucocorticoid Receptor Antagonist with Enhanced Selectivity against the Progesterone and Androgen Receptors (OP-3633).

Structure-based modification of mifepristone (1) led to the discovery of novel mifepristone derivatives with improved selectivity profile. Addition of a methyl group at the C10 position of the steroid has a significant impact on progesterone receptor (PR) and androgen receptor (AR) activity. Within this series, OP-3633 (15) emerged as a glucocorticoid receptor (GR) antagonist with increased selectivity against PR and AR, improved cytochrome P450 inhibition profile, and significantly improved pharmacokinetic properties compared to 1. Furthermore, 15 demonstrated substantial inhibition of GR transcriptional activity in the GR positive HCC1806 triple negative breast cancer xenograft model. Overall, compound 15 is a promising GR antagonist candidate to clinically evaluate the impact of GR inhibition in reversal or prevention of therapy resistance.

Pomegranate flower: a unique traditional antidiabetic medicine with dual PPAR-alpha/-gamma activator properties.

PPARs are transcription factors belonging to the superfamily of nuclear receptors. PPAR-alpha is involved in the regulation of fatty acid (FA) uptake and oxidation, inflammation and vascular function, while PPAR-gamma participates in FA uptake and storage, glucose homeostasis and inflammation. The PPARs are thus major regulators of lipid and glucose metabolism. Synthetic PPAR-alpha or PPAR-gamma agonists have been widely used in the treatment of dyslipidaemia, hyperglycaemia and their complications. However, they are associated with an incidence of adverse events. Given the favourable metabolic effects of both PPAR-alpha and PPAR-gamma activators, as well as their potential to modulate vascular disease, combined PPAR-alpha/-gamma activation has recently emerged as a promising concept, leading to the development of mixed PPAR-alpha/-gamma activators. However, some major side effects associated with the synthetic dual activators have been reported. It is unclear whether this is a specific effect of the particular synthetic compounds or a class effect. To date, a medication that may combine the beneficial metabolic effects of PPAR-alpha and PPAR-gamma activation with fewer undesirable side effects has not been successfully developed. Pomegranate plant parts are used traditionally for the treatment of various disorders. However, only pomegranate flower has been prescribed in Unani and Ayurvedic medicines for the treatment of diabetes. This review provides a new understanding of the dual PPAR-alpha/-gamma activator properties of pomegranate flower in the potential treatment of diabetes and its associated complications.

Salacia root, a unique Ayurvedic medicine, meets multiple targets in diabetes and obesity.

In many traditional schools of medicine it is claimed that a balanced modulation of several targets can provide a superior therapeutic effect and decrease in side effect profile compared to a single action from a single selective ligand, especially in the treatment of certain chronic and complex diseases, such as diabetes and obesity. Diabetes and obesity have a multi-factorial basis involving both genetic and environmental risk factors. A wide array of medicinal plants and their active constituents play a role in the prevention and treatment of diabetes. Salacia roots have been used in Ayurvedic medicine for diabetes and obesity since antiquity, and have been extensively consumed in Japan, the United States and other countries as a food supplement for the prevention of obesity and diabetes. Recent pharmacological studies have demonstrated that Salacia roots modulate multiple targets: peroxisome proliferator-activated receptor-alpha-mediated lipogenic gene transcription, angiotensin II/angiotensin II type 1 receptor, alpha-glucosidase, aldose reductase and pancreatic lipase. These multi-target actions may mainly contribute to Salacia root-induced improvement of type 2 diabetes and obesity-associated hyperglycemia, dyslipidemia and related cardiovascular complications seen in humans and rodents. The results of bioassay-guided identification indicate that mangiferin, salacinol, kotalanol and kotalagenin 16-acetate are at least in part responsible for these multi-target regulatory activities of Salacia roots. The evidence suggests that this unique traditional medicine fulfills a multiple-target strategy in the prevention and treatment of diabetes and obesity. Although toxicological studies have suggested minimal adverse effects of the herbal medicine in rodents, a clinical trial is crucial to further confirm the safety of Salacia roots. In addition, further mechanistic studies are necessary in order to allow a better understanding of how use of Salacia root may interact with other therapeutic interventions.

Discovery of a Potent and Selective Steroidal Glucocorticoid Receptor Antagonist (ORIC-101).

The glucocorticoid receptor (GR) has been linked to therapy resistance across a wide range of cancer types. Preclinical data suggest that antagonists of this nuclear receptor may enhance the activity of anticancer therapy. The first-generation GR antagonist mifepristone is currently undergoing clinical evaluation in various oncology settings. Structure-based modification of mifepristone led to the discovery of ORIC-101 (28), a highly potent steroidal GR antagonist with reduced androgen receptor (AR) agonistic activity amenable for dosing in androgen receptor positive tumors and with improved CYP2C8 and CYP2C9 inhibition profile to minimize drug-drug interaction potential. Unlike mifepristone, 28 could be codosed with chemotherapeutic agents readily metabolized by CYP2C8 such as paclitaxel. Furthermore, 28 demonstrated in vivo antitumor activity by enhancing response to chemotherapy in the GR+ OVCAR5 ovarian cancer xenograft model. Clinical evaluation of safety and therapeutic potential of 28 is underway.

Gypenoside XLIX, a naturally occurring PPAR-alpha activator, inhibits cytokine-induced vascular cell adhesion molecule-1 expression and activity in human endothelial cells.

Vascular cell adhesion molecule-1 (VCAM-1) is involved in several diseases, including chronic inflammation and atherosclerosis. Inhibition of the expression of this adhesion molecule is one of the key targets of anti-inflammatory, anti-cancer and anti-atherosclerotic drugs. Gynostemma pentaphyllum is a traditional medicine widely used in the treatment of respiratory inflammation, hyperlipidemia and atherosclerosis. However, its molecular mechanisms of action are still largely unknown. Gypenoside XLIX, a dammarane-type glycoside, is a prominent component of G. pentaphyllum. We have recently demonstrated Gypenoside XLIX to be a selective peroxisome proliferator-activated receptor (PPAR)-alpha activator. Here we demonstrate that Gypenoside XLIX concentration-dependently (0-300 microM) inhibited VCAM-1 promoter activity after induction by cytokine tumor necrosis factor (TNF)-alpha in human umbilical vein endothelial cells (HUVECs) transfected with promoter-reporter construct pVCAM-1-LUC. Furthermore, Gypenoside XLIX inhibited TNF-alpha-induced VCAM-1 mRNA and protein overexpression in HUVECs. The result of the enzyme immunoassay demonstrated that Gypenoside XLIX inhibited TNF-alpha-induced increase in cell surface VCAM-1 protein levels in HUVECs. In the present study we show that activities of Gypenoside XLIX are similar to those of Wy-14643, a potent synthetic PPAR-alpha activator. Furthermore, Gypenoside XLIX-induced inhibition on TNF-alpha-stimulated VCAM-1 promoter hyperactivity was completely abolished by a selective blocker of PPAR-alpha, MK-886. Thus, our findings suggest that Gypenoside XLIX inhibits cytokine-induced VCAM-1 overexpression and hyperactivity in human endothelial cells via a PPAR-alpha-dependent pathway. These data provide new insight into the rational basis of the use of the traditional Chinese herbal medicine G. pentaphyllum in the treatment of inflammatory and cardiovascular diseases, including atherosclerosis.