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.

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).

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.

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.

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.

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.

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.

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.

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.

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 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.

High-resolution Temporal Representations of Alcohol and Tobacco Behaviors from Social Media Data.

Understanding tobacco- and alcohol-related behavioral patterns is critical for uncovering risk factors and potentially designing targeted social computing intervention systems. Given that we make choices multiple times per day, hourly and daily patterns are critical for better understanding behaviors. Here, we combine natural language processing, machine learning and time series analyses to assess Twitter activity specifically related to alcohol and tobacco consumption and their sub-daily, daily and weekly cycles. Twitter self-reports of alcohol and tobacco use are compared to other data streams available at similar temporal resolution. We assess if discussion of drinking by inferred underage versus legal age people or discussion of use of different types of tobacco products can be differentiated using these temporal patterns. We find that time and frequency domain representations of behaviors on social media can provide meaningful and unique insights, and we discuss the types of behaviors for which the approach may be most useful.

New-to-nature sophorose analog: a potent inducer for gene expression in Trichoderma reesei.

Controlled hydrolysis of lactonic sophorolipids from Starmerella bombicola yields a previously undescribed sophorose analog that potently induces cellulase in Trichoderma reesei Rut-C30. Acid treatment of natural sophorolipids results in a mixture of monoacetylated, deacetylated, and diacetylated sophorolipids in acidic and lactonic forms. Isolation of the active components of the mixture, followed by structure determination by MS and NMR, reveals a new chemical entity, in which the lactone ring has been opened at the C-1' rather than at the C-4″ position of the sophorose moiety. This sophorose ester is resistant to degradation by the host and is at least 28 times more powerful an inducer than sophorose in shake-flask culture. Even at low concentrations (0.05 mM), the chemically modified sophorolipid effectively induces cellulase. With further improvements, this highly enabling technology can potentially reduce the cost of enzymes produced in T. reesei and can facilitate the rapid deployment of enzyme plants to support the nascent cellulosic biofuels and biochemicals industries.

Management of cardiorenal metabolic syndrome in diabetes mellitus: a phytotherapeutic perspective.

Cardiorenal syndrome (CRS) is a complex disease in which the heart and kidney are simultaneously affected and their deleterious declining functions are reinforced in a feedback cycle, with an accelerated progression. Although the coexistence of kidney and heart failure in the same individual carries an extremely bad prognosis, the exact cause of deterioration and the pathophysiological mechanisms underlying the initiation and maintenance of the interaction are complex, multifactorial in nature, and poorly understood. Current therapy includes diuretics, natriuretic hormones, aquaretics (arginine vasopressin antagonists), vasodilators, and inotropes. However, large numbers of patients still develop intractable disease. Moreover, the development of resistance to many standard therapies, such as diuretics and inotropes, has led to an increasing movement toward utilization and development of novel therapies. Herbal and traditional natural medicines may complement or provide an alternative to prevent or delay the progression of CRS. This review provides an analysis of the possible mechanisms and the therapeutic potential of phytotherapeutic medicines for the amelioration of the progression of CRS.

Application of DBS sampling in combination with LC-MS/MS for pharmacokinetic evaluation of a compound with species-specific blood-to-plasma partitioning.

BACKGROUND: Dried blood spot (DBS) sampling in combination with LC-MS/MS has been used increasingly in drug discovery for quantitative analysis to support pharmacokinetic (PK) studies. In this study, we assessed the effect of blood-to-plasma (B:P) partitioning on the bioanalytical performance and PK data acquired by DBS for a compound AMG-1 with species and concentration-dependent B:P ratio. RESULTS: B:P partitioning did not adversely affect bioanalytical performance of DBS for AMG-1. For rat, (B:P ratio of 0.63), PK profiles from DBS and plasma methods were comparable. For dog, concentration-dependence of B:P ratio was observed both in vivo and in vitro. Additional studies demonstrated concentration-dependence of the compound's unbound fraction in plasma, which may contribute to the concentration-dependence of the B:P ratio. CONCLUSION: DBS is a promising sampling technique for preclinical pharmacokinetic studies. For compounds with high B:P ratio, caution needs to be applied for data comparison and interpretation between matrices.

Determining between chyle leak and anastomotic leak after esophageal reconstruction: the utility of methylene blue dye.

OBJECTIVES/HYPOTHESIS: Two common complications of esophagectomy and immediate reconstruction comprise thoracic duct injury leading to chyle leak and anastomotic leakage. These can delay optimized nutrition, speech, and swallowing rehabilitation, and thus are important to identify and treat accordingly. When either chyle leak or anastomotic leak are clinically suspected, differentiation between the two can be very difficult clinically. As both complications may result in an increase in drain output once oral intake has occurred, an effective, quick, and accurate tool is required to determine whether this increase in drain output is related to an anastomotic leak or with a increase activity in chyle production. STUDY DESIGN: Retrospective descriptive study. METHODS: Description of the use of oral methylene blue dye as a safe, simple, and quick clinical bedside test. RESULTS: When ingested orally, an anastomotic leak will lead to blue dye staining the neck drain output immediately (within seconds to minutes). A chyle leak may also result in blue staining of the drain output; however, this is not an immediate phenomenon, and rather, based on the bioavailability of methylene blue this would take a minimum of 1 hour, and more likely up to 4 hours, as the dye is absorbed into mesenteric lymphatics and travels via the thoracic duct. CONCLUSIONS: With no documented contraindications or side effects from its oral use (in the absence of hypersensitivity reactions), methylene blue is an inexpensive and freely available test in the postoperative setting of esophageal reconstruction.

Healing the diabetic heart: modulation of cardiometabolic syndrome through peroxisome proliferator activated receptors (PPARs).

Cardiometabolic syndrome is a mixture of interrelated risk factors predisposing individuals to elevated risk of atherosclerotic cardiovascular disease and type 2 diabetes mellitus. Nuclear receptors, specifically peroxisome proliferator-activated receptors (PPARs), were identified to play a pivotal role in the regulation of metabolic homeostasis. However, with rosiglitazone currently under intense scrutiny great concerns have arisen regarding the safety of the thiazolidinedione PPAR-γ agonist family as a whole. This review discusses the current concern with PPAR-γ agonists by exploring if PPARs can still be considered worth pursuing as a viable target for cardiovascular diseases. We examine current research focusing on identifying ligands that are dual and pan-PPAR agonists, selective PPAR-γ modulators, PPAR-ß/δ agonists and that are of natural origin.

Modulation of diabetic retinopathy pathophysiology by natural medicines through PPAR-γ-related pharmacology.

Diabetic retinopathy (DR) is one of the most common microvascular complications of diabetes and remains a major cause of preventable blindness among adults at working age. DR involves an abnormal pathology of major retinal cells, including retinal pigment epithelium, microaneurysms, inter-retinal oedema, haemorrhage, exudates (hard exudates) and intraocular neovascularization. The biochemical mechanisms associated with hyperglycaemic-induced DR are through multifactorial processes. Peroxisome proliferator-activated receptor-γ (PPAR-γ) plays an important role in the pathogenesis of DR by inhibiting diabetes-induced retinal leukostasis and leakage. Despite DR causing eventual blindness, only a few visual or ophthalmic symptoms are observed until visual loss develops. Therefore, early medical interventions and prevention are the current management strategies. Laser photocoagulation therapy is the most common treatment. However, this therapy may cause retinal damage and scarring. Herbal and traditional natural medicines may provide an alternative to prevent or delay the progression of DR. This review provides an analysis of the therapeutic potential of herbal and traditional natural medicines or their active components for the slowdown of progression of DR and their possible mechanism through the PPAR-γ pathway.

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.

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.