Browsing by Subject "Pyridines"

Now showing 1 - 16 of 16

Open Access
Appropriate dose of regorafenib based on body weight of colorectal cancer patients: a retrospective cohort study.
(BMC Cancer, 2023-12-21) Nakashima, Masayuki; Li, Kan; Chen, Qichen; de Silva, Sajith; Li, Hal; Kawakami, Koji; Wei, Qingyi; Luo, Sheng; Zhao, Hong
PURPOSE: Previous randomized studies have shown a survival benefit of using regorafenib but a high rate of adverse events in unresectable colorectal cancer patients. To reduce these adverse events and improve the tolerability, we examined the appropriate dose of regorafenib based on body weight. METHODS: We used a nationwide claims database in Japan and examined the efficacy and safety of regorafenib for patients with metastatic colorectal cancer between groups divided by body weight (60 kg) and median average dose (120 mg) between 2013 and 2018. We also assessed overall survival (OS) and adverse events between these groups. RESULTS: We identified 2530 Japanese patients (heavy weight/high dose: 513, light weight/low dose: 921, heavy weight/low dose: 452, and light weight/high dose: 644). There was no significant difference in the adverse events and OS after inverse probability treatment weighting (IPTW) adjustment between heavy weight/high dose group and light weight/low dose group (hazard ratio, HR=0.97). Among the light-weight patients, higher average dose was associated with shorter OS (IPTW adjusted HR=1.21, 95% CI 1.05 - 1.39, Table 3) while among the heavy-weight patients, there was no significant difference in OS between high and low dose groups (IPTW adjusted HR=1.14, 95% CI 0.95 - 1.37). CONCLUSION: The findings suggest that a low dose of regorafenib for light-weight patients may be as safe and effective as high doses for heavy-weight patients. Further studies should be conducted to identify an appropriate dose based on each patient's physique and condition.
Open Access
Defining and managing COVID-19-associated pulmonary aspergillosis: the 2020 ECMM/ISHAM consensus criteria for research and clinical guidance.
(The Lancet. Infectious diseases, 2021-06) Koehler, Philipp; Bassetti, Matteo; Chakrabarti, Arunaloke; Chen, Sharon CA; Colombo, Arnaldo Lopes; Hoenigl, Martin; Klimko, Nikolay; Lass-Flörl, Cornelia; Oladele, Rita O; Vinh, Donald C; Zhu, Li-Ping; Böll, Boris; Brüggemann, Roger; Gangneux, Jean-Pierre; Perfect, John R; Patterson, Thomas F; Persigehl, Thorsten; Meis, Jacques F; Ostrosky-Zeichner, Luis; White, P Lewis; Verweij, Paul E; Cornely, Oliver A; European Confederation of Medical Mycology; International Society for Human Animal Mycology; Asia Fungal Working Group; INFOCUS LATAM/ISHAM Working Group; ISHAM Pan Africa Mycology Working Group; European Society for Clinical Microbiology; Infectious Diseases Fungal Infection Study Group; ESCMID Study Group for Infections in Critically Ill Patients; Interregional Association of Clinical Microbiology and Antimicrobial Chemotherapy; Medical Mycology Society of Nigeria; Medical Mycology Society of China Medicine Education Association; Infectious Diseases Working Party of the German Society for Haematology and Medical Oncology; Association of Medical Microbiology; Infectious Disease Canada
Severe acute respiratory syndrome coronavirus 2 causes direct damage to the airway epithelium, enabling aspergillus invasion. Reports of COVID-19-associated pulmonary aspergillosis have raised concerns about it worsening the disease course of COVID-19 and increasing mortality. Additionally, the first cases of COVID-19-associated pulmonary aspergillosis caused by azole-resistant aspergillus have been reported. This article constitutes a consensus statement on defining and managing COVID-19-associated pulmonary aspergillosis, prepared by experts and endorsed by medical mycology societies. COVID-19-associated pulmonary aspergillosis is proposed to be defined as possible, probable, or proven on the basis of sample validity and thus diagnostic certainty. Recommended first-line therapy is either voriconazole or isavuconazole. If azole resistance is a concern, then liposomal amphotericin B is the drug of choice. Our aim is to provide definitions for clinical research and up-to-date recommendations for clinical management of the diagnosis and treatment of COVID-19-associated pulmonary aspergillosis.
Open Access
Drug-drug interaction studies of cardiovascular drugs involving P-glycoprotein, an efflux transporter, on the pharmacokinetics of edoxaban, an oral factor Xa inhibitor.
(Am J Cardiovasc Drugs, 2013-10) Mendell, Jeanne; Zahir, Hamim; Matsushima, Nobuko; Noveck, Robert; Lee, Frank; Chen, Shuquan; Zhang, George; Shi, Minggao
BACKGROUND: Edoxaban, an oral direct factor Xa inhibitor, is in development for thromboprophylaxis, including prevention of stroke and systemic embolism in patients with atrial fibrillation (AF). P-glycoprotein (P-gp), an efflux transporter, modulates absorption and excretion of xenobiotics. Edoxaban is a P-gp substrate, and several cardiovascular (CV) drugs have the potential to inhibit P-gp and increase drug exposure. OBJECTIVE: To assess the potential pharmacokinetic interactions of edoxaban and 6 cardiovascular drugs used in the management of AF and known P-gp substrates/inhibitors. METHODS: Drug-drug interaction studies with edoxaban and CV drugs with known P-gp substrate/inhibitor potential were conducted in healthy subjects. In 4 crossover, 2-period, 2-treatment studies, subjects received edoxaban 60 mg alone and coadministered with quinidine 300 mg (n = 42), verapamil 240 mg (n = 34), atorvastatin 80 mg (n = 32), or dronedarone 400 mg (n = 34). Additionally, edoxaban 60 mg alone and coadministered with amiodarone 400 mg (n = 30) or digoxin 0.25 mg (n = 48) was evaluated in a single-sequence study and 2-cohort study, respectively. RESULTS: Edoxaban exposure measured as area under the curve increased for concomitant administration of edoxaban with quinidine (76.7 %), verapamil (52.7 %), amiodarone (39.8 %), and dronedarone (84.5 %), and exposure measured as 24-h concentrations for quinidine (11.8 %), verapamil (29.1 %), and dronedarone (157.6 %) also increased. Administration of edoxaban with amiodarone decreased the 24-h concentration for edoxaban by 25.7 %. Concomitant administration with digoxin or atorvastatin had minimal effects on edoxaban exposure. CONCLUSION: Coadministration of the P-gp inhibitors quinidine, verapamil, and dronedarone increased edoxaban exposure. Modest/minimal effects were observed for amiodarone, atorvastatin, and digoxin.
Open Access
E2112: Randomized Phase III Trial of Endocrine Therapy Plus Entinostat or Placebo in Hormone Receptor-Positive Advanced Breast Cancer. A Trial of the ECOG-ACRIN Cancer Research Group.
(Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 2021-10) Connolly, Roisin M; Zhao, Fengmin; Miller, Kathy D; Lee, Min-Jung; Piekarz, Richard L; Smith, Karen L; Brown-Glaberman, Ursa A; Winn, Jennifer S; Faller, Bryan A; Onitilo, Adedayo A; Burkard, Mark E; Budd, George T; Levine, Ellis G; Royce, Melanie E; Kaufman, Peter A; Thomas, Alexandra; Trepel, Jane B; Wolff, Antonio C; Sparano, Joseph A
Purpose
Endocrine therapy resistance in advanced breast cancer remains a significant clinical problem that may be overcome with the use of histone deacetylase inhibitors such as entinostat. The ENCORE301 phase II study reported improvement in progression-free survival (PFS) and overall survival (OS) with the addition of entinostat to the steroidal aromatase inhibitor (AI) exemestane in advanced hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer.
Patients and methods
E2112 is a multicenter, randomized, double-blind, placebo-controlled phase III study that enrolled men or women with advanced HR-positive, HER2-negative breast cancer whose disease progressed after nonsteroidal AI. Participants were randomly assigned to exemestane 25 mg by mouth once daily and entinostat (EE) or placebo (EP) 5 mg by mouth once weekly. Primary end points were PFS by central review and OS. Secondary end points included safety, objective response rate, and lysine acetylation change in peripheral blood mononuclear cells between baseline and cycle 1 day 15.
Results
Six hundred eight patients were randomly assigned during March 2014-October 2018. Median age was 63 years (range 29-91), 60% had visceral disease, and 84% had progressed after nonsteroidal AI in metastatic setting. Previous treatments included chemotherapy (60%), fulvestrant (30%), and cyclin-dependent kinase inhibitor (35%). Most common grade 3 and 4 adverse events in the EE arm included neutropenia (20%), hypophosphatemia (14%), anemia (8%), leukopenia (6%), fatigue (4%), diarrhea (4%), and thrombocytopenia (3%). Median PFS was 3.3 months (EE) versus 3.1 months (EP; hazard ratio = 0.87; 95% CI, 0.67 to 1.13; P = .30). Median OS was 23.4 months (EE) versus 21.7 months (EP; hazard ratio = 0.99; 95% CI, 0.82 to 1.21; P = .94). Objective response rate was 5.8% (EE) and 5.6% (EP). Pharmacodynamic analysis confirmed target inhibition in entinostat-treated patients.
Conclusion
The combination of exemestane and entinostat did not improve survival in AI-resistant advanced HR-positive, HER2-negative breast cancer.
Open Access
Emerging treatment options to improve cardiovascular outcomes in patients with acute coronary syndrome: focus on losmapimod.
(Drug Des Devel Ther, 2015) Kragholm, Kristian; Newby, Laura Kristin; Melloni, Chiara
Each year, despite optimal use of recommended acute and secondary prevention therapies, 4%-5% of patients with acute coronary syndrome (ACS) experience relapse of ACS or other cardiovascular events including stroke, heart failure, or sudden cardiac death after the index ACS. The sudden atherosclerotic plaque rupture leading to an ACS event is often accompanied by inflammation, which is thought to be a key pathogenic pathway to these excess cardiovascular events. Losmapimod is a novel, oral p38 mitogen-activated protein kinase (MAPK) inhibitor that targets MAPKs activated in macrophages, myocardium, and endothelial cells that occur as a part of global coronary vascular inflammation following plaque rupture. This review aims to 1) discuss the pathophysiological pathways through which p38 MAPKs may play key roles in initiation and progression of inflammatory disease and how losmapimod is thought to counteract these p38 MAPKs, and 2) to describe the efficacy and safety data for losmapimod obtained from preclinical studies and randomized controlled trials that support the hypothesis that it has promise as a treatment for patients with ACS.
Open Access
Experimental inhibition of porcupine-mediated Wnt O-acylation attenuates kidney fibrosis.
(Kidney Int, 2016-05) Madan, Babita; Patel, Mehul B; Zhang, Jiandong; Bunte, Ralph M; Rudemiller, Nathan P; Griffiths, Robert; Virshup, David M; Crowley, Steven D
Activated Wnt signaling is critical in the pathogenesis of renal fibrosis, a final common pathway for most forms of chronic kidney disease. Therapeutic intervention by inhibition of individual Wnts or downstream Wnt/β-catenin signaling has been proposed, but these approaches do not interrupt the functions of all Wnts nor block non-canonical Wnt signaling pathways. Alternatively, an orally bioavailable small molecule, Wnt-C59, blocks the catalytic activity of the Wnt-acyl transferase porcupine, and thereby prevents secretion of all Wnt isoforms. We found that inhibiting porcupine dramatically attenuates kidney fibrosis in the murine unilateral ureteral obstruction model. Wnt-C59 treatment similarly blunts collagen mRNA expression in the obstructed kidney. Consistent with its actions to broadly arrest Wnt signaling, porcupine inhibition reduces expression of Wnt target genes and bolsters nuclear exclusion of β-catenin in the kidney following ureteral obstruction. Importantly, prevention of Wnt secretion by Wnt-C59 blunts expression of inflammatory cytokines in the obstructed kidney that otherwise provoke a positive feedback loop of Wnt expression in collagen-producing fibroblasts and epithelial cells. Thus, therapeutic targeting of porcupine abrogates kidney fibrosis not only by overcoming the redundancy of individual Wnt isoforms but also by preventing upstream cytokine-induced Wnt generation. These findings reveal a novel therapeutic maneuver to protect the kidney from fibrosis by interrupting a pathogenic crosstalk loop between locally generated inflammatory cytokines and the Wnt/β-catenin signaling pathway.
Open Access
Hedgehog signaling antagonist promotes regression of both liver fibrosis and hepatocellular carcinoma in a murine model of primary liver cancer.
(PLoS One, 2011) Philips, GM; Chan, IS; Swiderska, M; Schroder, VT; Guy, C; Karaca, GF; Moylan, C; Venkatraman, T; Feuerlein, S; Syn, WK; Jung, Y; Witek, RP; Choi, S; Michelotti, GA; Rangwala, F; Merkle, E; Lascola, C; Diehl, AM
OBJECTIVE: Chronic fibrosing liver injury is a major risk factor for hepatocarcinogenesis in humans. Mice with targeted deletion of Mdr2 (the murine ortholog of MDR3) develop chronic fibrosing liver injury. Hepatocellular carcinoma (HCC) emerges spontaneously in such mice by 50-60 weeks of age, providing a model of fibrosis-associated hepatocarcinogenesis. We used Mdr2(-/-) mice to investigate the hypothesis that activation of the hedgehog (Hh) signaling pathway promotes development of both liver fibrosis and HCC. METHODS: Hepatic injury and fibrosis, Hh pathway activation, and liver progenitor populations were compared in Mdr2(-/-) mice and age-matched wild type controls. A dose finding experiment with the Hh signaling antagonist GDC-0449 was performed to optimize Hh pathway inhibition. Mice were then treated with GDC-0449 or vehicle for 9 days, and effects on liver fibrosis and tumor burden were assessed by immunohistochemistry, qRT-PCR, Western blot, and magnetic resonance imaging. RESULTS: Unlike controls, Mdr2(-/-) mice consistently expressed Hh ligands and progressively accumulated Hh-responsive liver myofibroblasts and progenitors with age. Treatment of aged Mdr2-deficient mice with GDC-0449 significantly inhibited hepatic Hh activity, decreased liver myofibroblasts and progenitors, reduced liver fibrosis, promoted regression of intra-hepatic HCCs, and decreased the number of metastatic HCC without increasing mortality. CONCLUSIONS: Hh pathway activation promotes liver fibrosis and hepatocarcinogenesis, and inhibiting Hh signaling safely reverses both processes even when fibrosis and HCC are advanced.
Open Access
Melanoma-Derived Wnt5a Promotes Local Dendritic-Cell Expression of IDO and Immunotolerance: Opportunities for Pharmacologic Enhancement of Immunotherapy.
(Cancer Immunol Res, 2015-09) Holtzhausen, Alisha; Zhao, Fei; Evans, Kathy S; Tsutsui, Masahito; Orabona, Ciriana; Tyler, Douglas S; Hanks, Brent A
The β-catenin signaling pathway has been demonstrated to promote the development of a tolerogenic dendritic cell (DC) population capable of driving regulatory T-cell (Treg) differentiation. Further studies have implicated tolerogenic DCs in promoting carcinogenesis in preclinical models. The molecular mechanisms underlying the establishment of immune tolerance by this DC population are poorly understood, and the methods by which developing cancers can co-opt this pathway to subvert immune surveillance are currently unknown. This work demonstrates that melanoma-derived Wnt5a ligand upregulates the durable expression and activity of the indoleamine 2,3-dioxygenase-1 (IDO) enzyme by local DCs in a manner that depends upon the β-catenin signaling pathway. These data indicate that Wnt5a-conditioned DCs promote the differentiation of Tregs in an IDO-dependent manner, and that this process serves to suppress melanoma immune surveillance. We further show that the genetic silencing of the PORCN membrane-bound O-acyl transferase, which is necessary for melanoma Wnt ligand secretion, enhances antitumor T-cell immunity, and that the pharmacologic inhibition of this enzyme synergistically suppresses melanoma progression when combined with anti-CTLA-4 antibody therapy. Finally, our data suggest that β-catenin signaling activity, based on a target gene expression profile that includes IDO in human sentinel lymph node-derived DCs, is associated with melanoma disease burden and diminished progression-free survival. This work implicates the Wnt-β-catenin signaling pathway as a novel therapeutic target in the melanoma immune microenvironment and demonstrates the potential impact of manipulating DC function as a strategy for optimizing tumor immunotherapy.
Open Access
Oral sazetidine-A, a selective α4β2* nicotinic receptor desensitizing agent, reduces nicotine self-administration in rats.
(Pharmacology, biochemistry, and behavior, 2019-04) Rezvani, Amir H; Wells, Corinne; Slade, Susan; Xiao, Yingxian; Kellar, Kenneth J; Levin, Edward D
Sazetidine-A selectively desensitizes α4β2 nicotinic receptors and also has partial agonist effects. We have shown that subcutaneous acute and repeated injections as well as chronic infusions of sazetidine-A significantly reduce intravenous (IV) nicotine self-administration in rats. To further investigate the promise of sazetidine-A as a smoking cessation aid, it is important to determine sazetidine-A effects with oral administration and the time-effect function for its action on nicotine self-administration. Young adult female Sprague-Dawley rats were trained to self-administer IV nicotine at the benchmark dose of 0.03 mg/kg/infusion dose in an operant FR1 schedule in 45-min sessions. After five sessions of training, they were tested for the effects of acute oral doses of sazetidine-A (0, 0.3, 1 and 3 mg/kg) given 30 min before testing. To determine the time-effect function, these rats were administered 0 or 3 mg/kg of sazetidine-A 1, 2, 4 or 23 h before the onset of testing. Our previous study showed that with subcutaneous injections, only 3 mg/kg of sazetidine-A significantly reduced nicotine self-administration, however, with oral administration of sazetidine-A lower dose of 1 mg/kg was also effective in reducing nicotine intake. A similar effect was seen in the time-effect study with 3 mg/kg of oral sazetidine-A causing a significant reduction in nicotine self-administration across all the time points of 1, 2, 4 or 23 h after oral administration. These results advance the development of sazetidine-A as a possible aid for smoking cessation by showing effectiveness with oral administration and persistence of the effect over the course of a day.
Open Access
Sequential psychological and pharmacological therapies for comorbid and primary insomnia: study protocol for a randomized controlled trial.
(Trials, 2016-03-03) Morin, Charles M; Edinger, Jack D; Krystal, Andrew D; Buysse, Daniel J; Beaulieu-Bonneau, Simon; Ivers, Hans
BACKGROUND: Chronic insomnia is a prevalent disorder associated with significant psychosocial, health, and economic impacts. Cognitive behavioral therapies (CBTs) and benzodiazepine receptor agonist (BzRA) medications are the most widely supported therapeutic approaches for insomnia management. However, few investigations have directly compared their relative and combined benefits, and even fewer have tested the benefits of sequential treatment for those who do not respond to initial insomnia therapy. Moreover, insomnia treatment studies have been limited by small, highly screened study samples, fixed-dose, and fixed-agent pharmacotherapy strategies that do not represent usual clinical practices. This study will address these limitations. METHODS/DESIGN: This is a two-site randomized controlled trial, which will enroll 224 adults who meet the criteria for a chronic insomnia disorder with or without comorbid psychiatric disorders. Prospective participants will complete clinical assessments and polysomnography and then will be randomly assigned to first-stage therapy involving either behavioral therapy (BT) or zolpidem. Treatment outcomes will be assessed after 6 weeks, and treatment remitters will be followed for the next 12 months on maintenance therapy. Those not achieving remission will be offered randomization to a second, 6-week treatment, again involving either pharmacotherapy (zolpidem or trazodone) or psychological therapy (BT or cognitive therapy (CT)). All participants will be re-evaluated 12 weeks after the protocol initiation and at 3-, 6-, 9-, and 12-month follow-ups. Insomnia remission, defined categorically as a score < 8 on the Insomnia Severity Index, a patient-reported outcome, will serve as the primary endpoint for treatment comparisons. Secondary outcomes will include sleep parameters derived from daily sleep diaries and from polysomnography, subjective measures of fatigue, mood, quality of life, and functional impairments; and measures of adverse events; dropout rates; and treatment acceptability. Centrally trained therapists will administer therapies according to manualized, albeit flexible, treatment algorithms. DISCUSSION: This clinical trial will provide new information about optimal treatment sequencing and will have direct implication for the development of clinical guidelines for managing chronic insomnia with and without comorbid psychiatric conditions. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01651442 , Protocol version 4, 20 April 2011, registered 26 June 2012.
Open Access
Spotlight on isavuconazole in the treatment of invasive aspergillosis and mucormycosis: design, development, and place in therapy.
(Drug design, development and therapy, 2018-01) Jenks, Jeffrey D; Salzer, Helmut Jf; Prattes, Juergen; Krause, Robert; Buchheidt, Dieter; Hoenigl, Martin
In recent decades, important advances have been made in the diagnosis and treatment of invasive aspergillosis (IA) and mucormycosis. One of these advances has been the introduction of isavuconazole, a second-generation broad spectrum triazole with a favorable pharmacokinetic and safety profile and few drug-drug interactions. Phase III trials in patients with IA and mucormycosis demonstrated that isavuconazole has similar efficacy to voriconazole for the treatment of IA (SECURE trial) and liposomal amphotericin B for the treatment of mucormycosis (VITAL trial with subsequent case-control analysis) and a favorable safety profile with significantly fewer ocular, hepatobiliary, and skin and soft tissue adverse events compared to voriconazole. As a result, recent IA guidelines recommend isavuconazole (together with voriconazole) as gold standard treatment for IA in patients with underlying hematological malignancies. In contrast to liposomal amphotericin B, isavuconazole can be safely administered in patients with reduced renal function and is frequently used for the treatment of mucormycosis in patients with reduced renal function. Updated guidelines on mucormycosis are needed to reflect the current evidence and give guidance on the use of isavuconazole for mucormycosis. Studies are needed to evaluate the role of isavuconazole for 1) anti-mold prophylaxis in high-risk patients, 2) salvage treatment for IA and mucormycosis, and 3) treatment for other mold infections such as Scedosporium apiospermum.
Open Access
Subchronic effects of plant alkaloids on anxiety-like behavior in zebrafish.
(Pharmacology, biochemistry, and behavior, 2021-08) Hawkey, Andrew B; Hoeng, Julia; Peitsch, Manuel C; Levin, Edward D; Koshibu, Kyoko
Zebrafish provide a valuable emerging complementary model for neurobehavioral research. They offer a powerful way to screen for the potential therapeutic effects of neuroactive drugs. A variety of behavioral tests for zebrafish have been developed and validated for assessing neurobehavioral function. The novel tank diving test is a straightforward, reproducible way of measuring anxiety-like behavior in zebrafish. When introduced into a novel tank, zebrafish normally dive to the bottom of the tank and then gradually explore the higher levels of the water column as time progresses. Buspirone is an effective anxiolytic drug in humans, which has been found, with acute administration, to reduce this anxiety-like response in zebrafish. The current study used the zebrafish model to evaluate the potential anxiolytic effects of alkaloids, commonly found in Solanaceae plants, with known neuropharmacology relevant to mood regulation. In line with previous findings, acute treatment with anxiolytic positive controls buspirone and the plant alkaloid nicotine reduced the anxiety-like diving response in the zebrafish novel tank diving test. Further, both buspirone and nicotine continued to produce anxiolytic-like effects in zebrafish after 5 days of exposure. In the same treatment paradigm, the effects of five other alkaloids-cotinine, anatabine, anabasine, harmane, and norharmane-were investigated. Cotinine, the major metabolite of nicotine, also caused anxiolytic-like effects, albeit at a dose higher than the effective dose of nicotine. Nicotine's anxiolytic-like effect was not shared by the other nicotinic alkaloids, anabasine and anatabine, or by the naturally present monoamine oxidase inhibitors harmane and norharmane. We conclude that nicotine uniquely induces anxiolytic-like effects after acute and subchronic treatment in zebrafish. The zebrafish model with the novel tank diving test could be a useful complement to rodent models for screening candidate compounds for anxiolytic effects in nonclinical studies.
Open Access
Survivin as a therapeutic target in Sonic hedgehog-driven medulloblastoma.
(Oncogene, 2015-07) Brun, SN; Markant, SL; Esparza, LA; Garcia, G; Terry, D; Huang, J-M; Pavlyukov, MS; Li, X-N; Grant, GA; Crawford, JR; Levy, ML; Conway, EM; Smith, LH; Nakano, I; Berezov, A; Greene, MI; Wang, Q; Wechsler-Reya, RJ
Medulloblastoma (MB) is a highly malignant brain tumor that occurs primarily in children. Although surgery, radiation and high-dose chemotherapy have led to increased survival, many MB patients still die from their disease, and patients who survive suffer severe long-term side effects as a consequence of treatment. Thus, more effective and less toxic therapies for MB are critically important. Development of such therapies depends in part on identification of genes that are necessary for growth and survival of tumor cells. Survivin is an inhibitor of apoptosis protein that regulates cell cycle progression and resistance to apoptosis, is frequently expressed in human MB and when expressed at high levels predicts poor clinical outcome. Therefore, we hypothesized that Survivin may have a critical role in growth and survival of MB cells and that targeting it may enhance MB therapy. Here we show that Survivin is overexpressed in tumors from patched (Ptch) mutant mice, a model of Sonic hedgehog (SHH)-driven MB. Genetic deletion of survivin in Ptch mutant tumor cells significantly inhibits proliferation and causes cell cycle arrest. Treatment with small-molecule antagonists of Survivin impairs proliferation and survival of both murine and human MB cells. Finally, Survivin antagonists impede growth of MB cells in vivo. These studies highlight the importance of Survivin in SHH-driven MB, and suggest that it may represent a novel therapeutic target in patients with this disease.
Open Access
Use of PER977 to reverse the anticoagulant effect of edoxaban.
(N Engl J Med, 2014-11-27) Ansell, Jack E; Bakhru, Sasha H; Laulicht, Bryan E; Steiner, Solomon S; Grosso, Michael; Brown, Karen; Dishy, Victor; Noveck, Robert J; Costin, James C
Open Access
Wnt signaling suppresses MAPK-driven proliferation of intestinal stem cells.
(The Journal of clinical investigation, 2018-08) Kabiri, Zahra; Greicius, Gediminas; Zaribafzadeh, Hamed; Hemmerich, Amanda; Counter, Christopher M; Virshup, David M
Intestinal homeostasis depends on a slowly proliferating stem cell compartment in crypt cells, followed by rapid proliferation of committed progenitor cells in the transit amplifying (TA) compartment. The balance between proliferation and differentiation in intestinal stem cells (ISCs) is regulated by Wnt/β-catenin signaling, although the mechanism remains unclear. We previously targeted PORCN, an enzyme essential for all Wnt secretion, and demonstrated that stromal production of Wnts was required for intestinal homeostasis. Here, a PORCN inhibitor was used to acutely suppress Wnt signaling. Unexpectedly, the treatment induced an initial burst of proliferation in the stem cell compartment of the small intestine, due to conversion of ISCs into TA cells with a loss of intrinsic ISC self-renewal. This process involved MAPK pathway activation, as the proliferating cells in the base of the intestinal crypt contained phosphorylated ERK1/2, and a MEK inhibitor attenuated the proliferation of ISCs and their differentiation into TA cells. These findings suggest a role for Wnt signaling in suppressing the MAPK pathway at the crypt base to maintain a pool of ISCs. The interaction between Wnt and MAPK pathways in vivo has potential therapeutic applications in cancer and regenerative medicine.
Open Access
α4β2 Nicotinic receptor desensitizing compounds can decrease self-administration of cocaine and methamphetamine in rats.
(European journal of pharmacology, 2019-02) Levin, Edward D; Rezvani, Amir H; Wells, Corinne; Slade, Susan; Yenugonda, Venkata M; Liu, Yong; Brown, Milton L; Xiao, Yingxian; Kellar, Kenneth J
Sazetidine-A [6-(5(((S)-azetidine-2-yl)methoxy)pyridine-3-yl)hex-5-yn-1-ol] is a selective α4β2 nicotinic receptor desensitizing agent and partial agonist. Sazetidine-A has been shown in our previous studies to significantly reduce nicotine and alcohol self-administration in rats. The question arises whether sazetidine-A would reduce self-administration of other addictive drugs as well. Nicotinic receptors on the dopaminergic neurons in the ventral tegmental area play an important role in controlling the activity of these neurons and release of dopamine in the nucleus accumbens, which is critical mechanism for reinforcing value of drugs of abuse. Previously, we showed that the nonspecific nicotinic antagonist mecamylamine significantly reduces cocaine self-administration in rats. In this study, we acutely administered systemically sazetidine-A and two other selective α4β2 nicotinic receptor-desensitizing agents, VMY-2-95 and YL-2-203, to young adult female Sprague-Dawley rats and determined their effects on IV self-administration of cocaine and methamphetamine. Cocaine self-administration was significantly reduced by 0.3 mg/kg of sazetidine-A. In another set of rats, sazetidine-A (3 mg/kg) significantly reduced methamphetamine self-administration. VMY-2-95 significantly reduced both cocaine and methamphetamine self-administration with threshold effective doses of 3 and 0.3 mg/kg, respectively. In contrast, YL-2-203 did not significantly reduce cocaine self-administration at the same dose range and actually significantly increased cocaine self-administration at the 1 mg/kg dose. YL-2-203 (3 mg/kg) did significantly decrease methamphetamine self-administration. Sazetidine-A and VMY-2-95 are promising candidates to develop as new treatments to help addicts successfully overcome a variety of addictions including tobacco, alcohol as well as the stimulant drugs cocaine and methamphetamine.

Browsing by Subject "Pyridines"

Purpose

Patients and methods

Results

Conclusion