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Yeohong Yoon, Jee Woong Lim, Jiyoung Kim, Younggi Kim, Keun Ho Chun
The aim of our study was to develop ursolic acid (UA) prodrugs in order to overcome UA's weakness, which has an extremely low bioavailability. UA-medoxomil (NX-201), one of our UA prodrugs, showed an improved bioavailability about 200times better than UA in rodent model. According to in vivo test performed with PANC-1 xenograft SCID mouse model, tumor growth rate decreased dose-dependently and 100mg/kg dose of NX-201 had an anticancer effect comparable to gemcitabine. Most of all the combination of NX-201 (50mg/kg, po, daily) and gemcitabine (40mg/kg, iv, 2timesperweek) even reduced tumor size after three weeks...
October 6, 2016: Bioorganic & Medicinal Chemistry Letters
Ronny Peri-Naor, Leila Motiei, David Margulies
Signal transduction pathways, which control the response of cells to various environmental signals, are mediated by the function of signaling proteins that interact with each other and activate one other with high specificity. Synthetic agents that mimic the function of these proteins might therefore be used to generate unnatural signal transduction steps and consequently, alter the cell's function. We present guidelines for designing 'chemical transducers' that can induce artificial communication between native proteins...
September 29, 2016: Journal of Visualized Experiments: JoVE
Lesley J Scott
Intravenous ceftaroline fosamil (Zinforo™), a prodrug that is rapidly converted to its active metabolite ceftaroline, is approved for use in adults and children (from 2 months of age) with complicated skin and soft tissue infections (cSSTIs) or community-acquired pneumonia (CAP). In several multinational trials, ceftaroline fosamil was an effective and generally well tolerated treatment in adult and paediatric patients with cSSTIs or CAP. In the phase 3 CANVAS trials, ceftaroline fosamil treatment was noninferior to vancomycin plus aztreonam in adults with cSSTIs...
October 20, 2016: Drugs
Matt Shirley, Lesley J Scott
Isavuconazole is a second-generation triazole with activity against a broad spectrum of clinically important fungi. Its water-soluble prodrug, isavuconazonium sulfate (Cresemba(®)), available in interchangeable intravenous and oral formulations, is approved in the USA and EU for the treatment of adults with invasive aspergillosis and mucormycosis. In international phase III clinical trials, isavuconazole was efficacious and generally well tolerated in the treatment of these life-threatening diseases. In the phase III SECURE trial, isavuconazole was non-inferior to voriconazole for the primary treatment of invasive mould disease (primarily aspergillosis) and was associated with fewer drug-related treatment-emergent adverse events (TEAEs) than voriconazole...
October 20, 2016: Drugs
Aditya H Gaur, Hilda Kizito, Wasana Prasitsueubsai, Natella Rakhmanina, Mohammed Rassool, Rana Chakraborty, Jagmohan Batra, Pope Kosalaraksa, Wicharn Luesomboon, Danielle Porter, Yongwu Shao, Michael Myers, Lillian Ting, Devi SenGupta, Erin Quirk, Martin S Rhee
BACKGROUND: The prodrug tenofovir alafenamide is associated with improved renal and bone safety compared with tenofovir disoproxil fumarate. We aimed to assess safety, pharmacokinetics, and efficacy of this single-tablet, fixed-dose combination of elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide in HIV-infected, treatment-naive adolescents. METHODS: We did a 48 week, single-arm, open-label trial in treatment-naive adolescents with HIV from ten hospital clinics in South Africa, Thailand, Uganda, and the USA...
October 17, 2016: Lancet HIV
Pooja Gopal, Michelle Yee, Jickky Sarathy, Jian Liang Low, Jansy P Sarathy, Firat Kaya, Véronique Dartois, Martin Gengenbacher, Thomas Dick
Pyrazinamide (PZA) is a critical component of first- and second-line treatments of tuberculosis (TB), yet its mechanism of action largely remains an enigma. We carried out a genetic screen to isolate Mycobacterium bovis BCG mutants resistant to pyrazinoic acid (POA), the bioactive derivative of PZA, followed by whole genome sequencing of 26 POA resistant strains. Rather than finding mutations in the proposed candidate targets fatty acid synthase I and ribosomal protein S1, we found resistance conferring mutations in two pathways: missense mutations in aspartate decarboxylase panD, involved in the synthesis of the essential acyl carrier coenzyme A (CoA), and frameshift mutations in the vitro nonessential polyketide synthase genes mas and ppsA-E, involved in the synthesis of the virulence factor phthiocerol dimycocerosate (PDIM)...
September 9, 2016: ACS Infectious Diseases
Prabodh Chander Sharma, Mona Piplani, Harish Rajak
In the present study, a novel strategy was developed to construct lipid prodrug of norfloxacin. N-Mannich base of norfloxacin was synthesized. The prodrug was obtained by covalently coupling this N-Mannich base with fatty acid hydrazide. The synthesized prodrug was characterized by spectral as well as other physical analysis. The hydrolytic studies of prodrug in buffers (pH 1.2 and 7.4), simulated gastric and intestinal fluid by HPLC analysis were undertaken. The studies revealed that prodrug liberates only about 2% of norfloxacin in HCl buffer (pH 1...
October 18, 2016: Current Drug Delivery
ByungSu Yoo
Heart failure (HF) represents a significant healthcare issue because of its ever-increasing prevalence, poor prognosis and complex pathophysiology. The cornerstone of modern drug therapy in chronic HF is the inhibition of neurohormonal activation that plays a crucial role in the pathophysiology of HF development and progression and, more specifically, of the renin-angiotensin-aldosterone system (RAAS) and the sympathetic nervous system. LCZ696 is a first-in-class, angiotensin receptor NEP inhibitor (ARNI) that consists of a supramolecular complex of a molecule of the ARB valsartan in combination with a molecule of the NEP inhibitor prodrug AHU377 (also known as sacubitril)...
September 2016: Journal of Hypertension
Ashley M Stokes, Charles P Hart, C Chad Quarles
High-grade gliomas are often characterized by hypoxia, which is associated with both poor long-term prognosis and therapy resistance. The adverse role hypoxia plays in treatment resistance and disease progression has led to the development of hypoxia imaging methods and hypoxia-targeted treatments. Here, we determined the tumor hypoxia and vascular perfusion characteristics of 2 rat orthotopic glioma models using 18-fluoromisonidozole positron emission tomography. In addition, we determined tumor response to the hypoxia-activated prodrug evofosfamide (TH-302) in these rat glioma models...
September 2016: Tomography: a Journal for Imaging Research
Keren Turjeman, Yechezkel Barenholz
BACKGROUND: Steroids are the most efficacious anti-inflammatory agents. However, their toxicities and side-effects compromise their clinical application. Various strategies and major efforts were dedicated for formulating viable liposomal glucocorticosteroids (GCs), so far none of these were approved. OBJECTIVES: To evaluate these approaches for formulating GC-delivery systems, especially liposomes, and with focus on the Barenholz Lab experience. METHODS: We developed PEGylated nano-liposomes (NSSL) remotely loaded with water-soluble amphipathic weak acid GC-prodrugs...
October 18, 2016: Journal of Drug Targeting
S Binita Chanu, Samya Banerjee, Mithun Roy
Cancer-specific anticancer drugs are still an elusive goal. Using light as the temporal control to generate cytotoxic species from photo-activated prodrug in the presence or absence of molecular oxygen has shown potential application targeted chemotherapy as in photodynamic therapy (PDT). In the present work we explored the chemistry of several photo-active (μ-oxo)diiron(III) complexes of the following formulation [{Fe(μ-O) (L-his)(B)}2](ClO4)2 (1a-1c), [Fe2(μ-O)(H2O)2B4](ClO4)4 (2b, 2c) and [Fe2(μ-O)(μ-O2CMe)B4](ClO4)3 (3b, 3c), L-his = l-histidine, B is 2,2'-bipyridine, 1,10-phenanthroline (phen) and dipyrido[3,2-d:2',3'-f]quinoxaline (dpq) complexes for tumor-specific anticancer activity...
September 28, 2016: European Journal of Medicinal Chemistry
Andrew V Stachulski, Karl Swift, Mark Cooper, Stephen Reynolds, Daniel Norton, Steven D Slonecker, Jean-François Rossignol
Thiazolides are polypharmacology agents with at least three mechanisms of action against a broad spectrum of parasites, bacteria and viruses. In respiratory viruses they inhibit the replication of orthomyxoviridae and paramyxoviridae at a post-translational level. Nitazoxanide 1a, the prototype thiazolide, was originally developed as an antiparasitic agent and later repurposed for the treatment of viral respiratory infections. The second generation thiazolides following nitazoxanide, such as the 5-chloro analogue RM-5038 2a, are also broad-spectrum antiviral agents as we have reported...
September 26, 2016: European Journal of Medicinal Chemistry
Guangming Gong, Wenya Liu, Shudong Wang
This study aimed to reduce the cytotoxicity and improve the targeting of aclacinomycin (ACM) by covalently coupling it with amino-oxyacetic acid (AOA) to generate an active intermediate, AOA-ACM. AOA-ACM was conjugated with self-assembled human serum albumin (HSA) nanoparticles constructed using tris(2-carboxyethyl)phosphine (TCEP) as disulfide bond breaking molecules in an 'opening stage-intermediate-closing stage' route, in which the hydrophobic interaction, interchange of sulfhydryl and hydrogen bond may be the key factors in the assembling process...
October 17, 2016: Nanotechnology
Qin Wang, Katherine J Franz
Metal ions are essential for a wide range of physiological processes, but they can also be toxic if not appropriately regulated by a complex network of metal trafficking proteins. Intervention in cellular metal distribution with small-molecule or peptide chelating agents has promising therapeutic potential to harness metals to fight disease. Molecular outcomes associated with forming metal-chelate interactions in situ include altering the concentration and subcellular metal distribution, inhibiting metalloenzymes, enhancing the reactivity of a metal species to elicit a favorable biological response, or passivating the reactivity of a metal species to prevent deleterious reactivity...
October 17, 2016: Accounts of Chemical Research
Chao Liu, Shrinivas G Dumbre, Christophe Pannecouque, Chunsheng Huang, Roger G Ptak, Michael G Murray, Steven De Jonghe, Piet Herdewijn
The synthesis of four l-2'-deoxy-threose nucleoside phosphonates with the natural nucleobases adenine, thymine, cytosine, and guanosine has been performed. Especially the adenine containing analogue (PMDTA) was endowed with potent antiviral activity displaying an EC50 of 4.69 μM against HIV-1 and an EC50 value of 0.5 μM against HBV, whereas completely lacking cytotoxicity. The synthesis of a number of phosphonomonoamidate and phosphonobisamidate prodrugs of PMDTA led to a boost in antiviral potency. The most potent congeners were a l-aspartic acid diisoamyl ester phenoxy prodrug and a l-phenylalanine propyl ester phosphonobisamidate prodrug that both display anti-HIV and anti-HBV activities in the low nanomolar range and selectivity indexes of more than 300...
October 17, 2016: Journal of Medicinal Chemistry
Stefano Perni, Polina Prokopovich
The efficient delivery of therapeutic molecules to the cartilage of joints is major obstacle in developing useful therapeutic interventions; hence, a targeted drug delivery system for this tissue is critical. We have overcome the challenge by developing a system that employs electrostatic attraction between the negatively charged constituents of cartilage and a positively charged polymer, Poly-beta amino esters (PBAEs). We have demonstrated cartilage uptake of Dexamethasone (DEX) covalently bound to the PBAE was doubled and retention in tissues prolonged compared to the equivalent dose of the commercial drug formulation...
October 13, 2016: Nanomedicine: Nanotechnology, Biology, and Medicine
Maria Eliza Freitas, Marta Ruiz-Lopez, Susan H Fox
Levodopa remains the most effective treatment for Parkinson's disease and is considered the gold standard therapy. However, disease progression and changes in the gastrointestinal tract result in a declining window of treatment response in a majority of patients. Efforts have been made recently to improve levodopa bioavailability either by developing more effective oral formulations or by innovating routes of administration (intestinal infusion, transcutaneous or inhaled levodopa). IPX066 is a novel levodopa-carbidopa (LD/CD) oral formulation combining immediate-release (IR) and extended-release (ER) LD/CD recently approved in the USA and the EU...
October 14, 2016: CNS Drugs
Melania Olivieri, Emanuele Amata, Shila Vinciguerra, Jole Fiorito, Giovanni Giurdanella, Filippo Drago, Nunzia Caporarello, Orazio Prezzavento, Emanuela Arena, Loredana Salerno, Antonio Rescifina, Gabriella Lupo, Carmelina Daniela Anfuso, Agostino Marrazzo
(±)-MRJF22 [(±)-2], a novel prodrug of haloperidol metabolite II obtained by conjugation to valproic acid via an ester bond, exhibits antiangiogenic activity being able to reduce Human Retinal Endothelial Cells (HREC) viability in a comparable manner to Bevacizumab. Moreover, (±)-2 was able to significantly reduce viable cells count, endothelial cell migration and tube formation in Vascular endothelial growth factor A (VEGF-A) stimulated HREC cultures.
October 14, 2016: Journal of Medicinal Chemistry
Francesco Trotta, Fabrizio Caldera, Roberta Cavalli, Marco Soster, Chiara Riedo, Miriam Biasizzo, Gloria Uccello Barretta, Federica Balzano, Valentina Brunella
BACKGROUND: L-DOPA is an amino acid precursor to the neurotransmitter dopamine that is extensively used as a prodrug for the treatment of Parkinson's disease. However, L-DOPA is an unstable compound: when exposed to light or added to aqueous solutions, it may degrade, compromising its therapeutic properties. RESEARCH DESIGN AND METHODS: In this work, a new type of drug-loaded cyclodextrin-based nanosponge, obtained using molecular imprinting, is described for the prolonged and controlled release of L-DOPA...
October 13, 2016: Expert Opinion on Drug Delivery
Surinder K Sharma, Kenneth D Bagshawe
The generation of cytotoxic drugs, selectively within tumours, from non-toxic prodrugs by targeted enzymes provides a powerful system for cancer therapy. In the form of Antibody directed enzyme prodrug therapy (ADEPT), this approach has shown feasibility in the clinic. Areas covered: Although numerous enzyme prodrug combinations have been reported over the last two decades, only the CPG2 ADEPT system has progressed to clinical trials. Using readily available components such as chemical antibody enzyme conjugate or recombinant multifunctional fusion protein, delivery of a specific enzyme to tumours, its elimination from non-tumour sites and prodrug activation has been achieved with therapeutic benefit in the clinic...
October 13, 2016: Expert Opinion on Biological Therapy
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