bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Evolving Drug Development Landscape: From Blockbusters to Niche Busters in the Orphan Drug Space
Authors: Kumar Kakkar Ashish , Dahiya Neha 
Published: May 2014

Abstract

Strategy, Management and Health Policy

Large pharmaceutical companies have traditionally focused on the development of blockbuster drugs that target disease states with large patient populations. However, with large‐scale patent expirations and competition from generics and biosimilars, anemic pipelines, escalating clinical trial costs, and global health‐care reform, the blockbuster model has become less viable. Orphan drug initiatives and the incentives accompanied by these have fostered renewed research efforts in the area of rare diseases and have led to the approval of more than 400 orphan products. Despite targeting much smaller patient populations, the revenue‐generating potential of orphan drugs has been shown to be huge, with a greater return on investment than non‐orphan drugs. The success of these “niche buster” therapeutics has led to a renewed interest from “Big Pharma” in the rare disease landscape. This article reviews the key drivers for orphan drug research and development, their profitability, and issues surrounding the emergence of large pharmaceutical firms into the orphan drug space.
The effects of thyroid hormones on brown adipose tissue in humans: a PET‐CT study
Authors: Zhang Qiongyue , Miao Qing , Ye Hongying , Zhang Zhaoyun , Zuo Chuantao , Hua Fengchun , Guan Yihui , Li Yiming 
Published: May 2014

AbstractBackgroundBrown adipose tissue (BAT) is important for energy expenditure through thermogenesis, although its regulatory factors are not well known in humans. There is evidence suggesting that thyroid hormones affect BAT functions in some mammals, but the effects of thyroid hormones on BAT activity in humans are still unclear. The aim of this study was to investigate the effects of thyroid hormones on glucose metabolism of BAT and other organs in humans.MethodsNine Graves' disease‐caused hyperthyroid patients who were newly diagnosed and untreated were studied. Putative brown adipose tissue activity was determined by the integrated 18F‐fluorodeoxyglucose (18F‐FDG) positron‐emission tomography and computed tomography (PET‐CT). All hyperthyroid patients were treated with methimazole and had been monitored until their symptoms disappeared and thyroid hormone levels returned to normal. At the end, a second PET‐CT scan was performed. The average follow‐up period was 77 days. Meanwhile, compared with a group of seventy‐five brown adipose tissue‐negative controls, thyroid hormones of seventy‐five BAT‐positive healthy subjects were measured.ResultsActive brown adipose tissue was not present in any of the hyperthyroid patients. However, one patient with normalized thyroid function showed active BAT after therapy. The free T3 levels and free T4 levels were significantly lower in the 75 BAT‐positive subjects than in the BAT‐negative subjects. All hyperthyroid patients showed symmetrically increased uptake of fluorodeoxyglucose in skeletal muscles before treatment, whereas, the standardized uptake value was substantially decreased after treatment.ConclusionsAbnormally high circulating thyroid hormone levels may not increase brown adipose tissue activity, which may be limited by the increased obligatory thermogenesis of muscle in adult humans. Copyright © 2014 John Wiley & Sons, Ltd.
Benefits of exenatide on obesity and non‐alcoholic fatty liver disease with elevated liver enzymes in patients with type 2 diabetes
Authors: Shao Ning , Kuang Hong Yu , Hao Ming , Gao Xin Yuan , Lin Wen Jian , Zou Wei 
Published: May 2014

AbstractBackgroundThe purpose of this study was to evaluate the advantages of exenatide treatment on obesity and non‐alcoholic fatty liver disease (NAFLD) with elevated liver enzymes in patients with type 2 diabetes (T2D).MethodsA total of 60 newly diagnosed patients with obesity, NAFLD with elevated liver enzymes and T2D were included in the study. The patients were randomly divided into two groups. The exenatide treatment group (n = 30) were treated with exenatide and insulin glargine, and the intensive insulin therapy group (n = 30) were treated with insulin aspart and insulin glargine for 12 weeks. Selected clinical characteristics were determined, and ultrasonography was performed at both baseline and 12 weeks following treatment.ResultsAt baseline, the clinical characteristics were matched between the two groups. After 12 weeks, fasting blood glucose (FBG), postprandial blood glucose (PBG), glycosylated haemoglobin (HbA1c), total cholesterol (TC), triglyceride (TG) and total bilirubin levels were significantly decreased in the two groups (p < 0.001). Body weight and waist circumference were significantly decreased in the exenatide group but increased in the intensive insulin group (p < 0.001). The levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST) and γ‐glutamyl transpeptidase (γGGT) in the exenatide group were significantly lower than in the intensive insulin group (p < 0.001). The mean body weight change correlated with the levels of ALT, AST and γGGT change (ALT, r = 0.761; AST, r = 0.733; γGGT, r = 0.752; p < 0.001). Moreover, the reversal rate of fatty liver was significantly higher in the exenatide group (93.3%) than the intensive insulin group (66.7%) (p < 0.01).ConclusionsExenatide has a better hepatic–protective effect than intensive insulin therapy and perhaps represents a unique option for adjunctive therapy for patients with obesity, non‐alcoholic fatty liver disease with elevated liver enzymes and T2D. Copyright © 2014 John Wiley & Sons, Ltd.
Big catch, little sharks: Insight into Peruvian small‐scale longline fisheries
Authors: Doherty Philip D. , Alfaro‐Shigueto Joanna , Hodgson David J. , Mangel Jeffrey C. , Witt Matthew J. , Godley Brendan J. 
Published: May 2014

AbstractShark take, driven by vast demand for meat and fins, is increasing. We set out to gain insights into the impact of small‐scale longline fisheries in Peru. Onboard observers were used to document catch from 145 longline fishing trips (1668 fishing days) originating from Ilo, southern Peru. Fishing effort is divided into two seasons: targeting dolphinfish (Coryphaena hippurus; December to February) and sharks (March to November). A total of 16,610 sharks were observed caught, with 11,166 identified to species level. Of these, 70.6% were blue sharks (Prionace glauca), 28.4% short‐fin mako sharks (Isurus oxyrinchus), and 1% were other species (including thresher (Alopias vulpinus), hammerhead (Sphyrna zygaena), porbeagle (Lamnus nasus), and other Carcharhinidae species (Carcharhinus brachyurus, Carcharhinus falciformis, Galeorhinus galeus). Mean ± SD catch per unit effort of 33.6 ± 10.9 sharks per 1000 hooks was calculated for the shark season and 1.9 ± 3.1 sharks per 1000 hooks were caught in the dolphinfish season. An average of 83.7% of sharks caught (74.7% blue sharks; 93.3% mako sharks) were deemed sexually immature and under the legal minimum landing size, which for species exhibiting k‐selected life history traits can result in susceptibility to over exploitation. As these growing fisheries operate along the entire Peruvian coast and may catch millions of sharks per annum, we conclude that their continued expansion, along with ineffective legislative approaches resulting in removal of immature individuals, has the potential to threaten the sustainability of the fishery, its target species, and ecosystem. There is a need for additional monitoring and research to inform novel management strategies for sharks while maintaining fisher livelihoods.
Baseline characteristics and treatment of patients in Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortality and morbidity in Heart Failure trial (PARADIGM‐HF)
Authors: McMurray John J. V. , Packer Milton , Desai Akshay S , Gong Jianjian , Lefkowitz Martin , Rizkala Adel R. , Rouleau Jean L. , Shi Victor C. , Solomon Scott D. , Swedberg Karl , Zile Michael R. ,   on behalf of the PARADIGM‐HF Committees Investigators
Published: May 2014

AimTo describe the baseline characteristics and treatment of the patients randomized in the PARADIGM‐HF (Prospective comparison of ARNi with ACEi to Determine Impact on Global Mortality and morbidity in Heart Failure) trial, testing the hypothesis that the strategy of simultaneously blocking the renin–angiotensin–aldosterone system and augmenting natriuretic peptides with LCZ696 200 mg b.i.d. is superior to enalapril 10 mg b.i.d. in reducing mortality and morbidity in patients with heart failure and reduced ejection fraction.MethodsKey demographic, clinical and laboratory findings, along with baseline treatment, are reported and compared with those of patients in the treatment arm of the Studies Of Left Ventricular Dysfunction (SOLVD‐T) and more contemporary drug and device trials in heart failure and reduced ejection fraction.ResultsThe mean age of the 8442 patients in PARADIGM‐HF is 64 (SD 11) years and 78% are male, which is similar to SOLVD‐T and more recent trials. Despite extensive background therapy with beta‐blockers (93% patients) and mineralocorticoid receptor antagonists (60%), patients in PARADIGM‐HF have persisting symptoms and signs, reduced health related quality of life, a low LVEF (mean 29 ± SD 6%) and elevated N‐terminal‐proB type‐natriuretic peptide levels (median 1608 inter‐quartile range 886–3221 pg/mL).ConclusionPARADIGM‐HF will determine whether LCZ696 is more beneficial than enalapril when added to other disease‐modifying therapies and if further augmentation of endogenous natriuretic peptides will reduce morbidity and mortality in heart failure and reduced ejection fraction.
Slow Magnetic Relaxation in a Redox‐Active Tetrathiafulvalene‐Based Ferromagnetic Dysprosium Complex
Authors: Pointillart Fabrice , Golhen Stéphane , Cador Olivier , Ouahab Lahcène 
Published: May 2014

AbstractThe association of the two 4,5‐bis(thiomethyl)‐4′‐carboxytetrathiafulvalene (HL1) and 4,5‐bis(thiomethyl)‐4′‐(2‐pyridyl‐N‐oxide)carbamoyltetrathiafulvalene (L2) with the metalloprecursor [Dy(tta)3]·2H2O (tta = 2‐thenoyltrifluoroacetonate) leads to the formation of the dinuclear complex of formula [Dy(tta)2(L1)(L2)]2·2CH2Cl2. Static magnetic measurements highlight significant ferromagnetic interactions between the DyIII ions, and dynamic magnetic measurements demonstrate single‐molecule‐magnet behaviour with an energy barrier of 20 cm–1 and a relaxation time of 8.6(9) × 10–6 s. The thermal dependence of the magnetic susceptibility was evaluated by using a crystal field approach (Stevens operators), which confirmed the Ising character of the system. Finally, electrochemistry shows a complex multiredox system with the successive oxidations of the two tetrathiafulvalene (TTF) ligands.
Application of the Palladium‐Catalysed Norbornene‐Assisted Catellani Reaction Towards the Total Synthesis of (+)‐Linoxepin and Isolinoxepin
Authors: Qureshi Zafar , Weinstabl Harald , Suhartono Marcel , Liu Hongqiang , Thesmar Pierre , Lautens Mark 
Published: May 2014

AbstractOur ongoing effort towards the development of highly selective transition‐metal‐catalysed C–H activation processes has led to the expansion of the Catellani reaction. In a Pd0/PdII/PdIV‐catalysed domino reaction, an aryl iodide, alkyl iodide and tert‐butyl acrylate were combined to synthesize the carbon framework of the novel lignan (+)‐linoxepin. The enantioselective synthesis highlights the work accomplished in our group and provides an excellent procedure for the reliable and scalable synthesis of architecturally complex scaffolds. This report outlines the synthetic approaches towards this interesting class of biologically active molecules. After the key Catellani/Heck reaction, our synthesis features a Leimeux–Johnson oxidation and a titanium tetrachloride mediated aldol condensation. Finally, a tuneable Mizoroki–Heck reaction was performed to furnish not only the natural product (+)‐linoxepin but also its isoform, which we have named isolinoxepin.
Oral 2‐hydroxyoleic acid inhibits reflex hypersensitivity and open–field‐induced anxiety after spared nerve injury
Authors: Avila‐Martin G. , Galan‐Arriero I. , Ferrer‐Donato A. , Busquets X. , Gomez‐Soriano J. , Escribá P.V. , Taylor J. 
Published: May 2014

AbstractBackgroundRecently, fatty acids have been shown to modulate sensory function in animal models of neuropathic pain. In this study, the antinociceptive effect of 2‐hydroxyoleic acid (2‐OHOA) was assessed following spared nerve injury (SNI) with reflex and cerebrally mediated behavioural responses.MethodsInitial antinociceptive behavioural screening of daily administration of 2‐OHOA (400 mg/kg, p.o.) was assessed in Wistar rats by measuring hindlimb reflex hypersensitivity to von Frey and thermal plate stimulation up to 7 days after SNI, while its modulatory effect on lumbar spinal dorsal horn microglia reactivity was assessed with OX‐42 immunohistochemistry. In vitro the effect of 2‐OHOA (120 μM) on cyclooxygenase protein expression (COX‐2/COX‐1 ratio) in lipopolysaccharide‐activated macrophage cells was tested with Western blot analysis. Finally, the effects of 2‐OHOA treatment on the place escape aversion paradigm (PEAP) and the open–field‐induced anxiety test were tested at 21 days following nerve injury compared with vehicle‐treated sham and pregabalin‐SNI (30 mg/kg, p.o.) control groups.ResultsOral 2‐OHOA significantly reduced ipsilateral mechanical and thermal hypersensitivity up to 7 days after SNI. Additionally 2‐OHOA decreased the COX‐2/COX‐1 ratio in lipopolysaccharide‐activated macrophage cells and OX‐42 expression within the ipsilateral lumbar spinal dorsal horn 7 days after SNI. 2‐OHOA significantly restored inner‐zone exploration in the open‐field test compared with the vehicle‐treated sham group at 21 days after SNI.ConclusionsOral administration of the modified omega 9 fatty acid, 2‐OHOA, mediates antinociception and prevents open–field‐induced anxiety in the SNI model in Wistar rats, which is mediated by an inhibition of spinal dorsal horn microglia activation.
Very delayed cervical lymph node metastases from hyalinizing clear cell carcinoma: Report of 2 cases
Authors: Su Henry K. , Wang Beverly Y. , Mannan Abul Ala Syed Rifat , Dewey Eliza H. , Alpert Erin H. , Reis Laura L. Dos , Urken Mark L. 
Published: May 2014

AbstractBackgroundHyalinizing clear cell carcinoma (HCCC) is a rare salivary gland neoplasm most often found in the oral cavity. Although it is generally a low‐grade malignancy that is treated with wide local excision, there is a growing body of evidence pointing toward the potential for more aggressive behavior.MethodsWe reviewed available records of patients with delayed cervical lymph node metastases from HCCC.ResultsTwo patients who were treated with wide local resection for HCCC and remained disease‐free at the primary site were diagnosed with cervical lymph node metastases 10 and 14 years later. We treated both with neck dissection, and 1 patient received adjuvant radiation therapy.ConclusionThese cases illustrate the risk for occult nodal metastases from HCCC with delayed presentation. Clinician awareness of the presence of subclinical metastases in the neck requires thorough long‐term surveillance and potential intervention should nodal disease become manifest. © 2014 Wiley Periodicals, Inc. Head Neck 37: E19‐E21, 2015
Head and neck squamous cell carcinoma lymphatic spread and survival: Relevance of vascular endothelial growth factor family for tumor evaluation
Authors: de Sousa Elen Alves , Lourenço Silvia Vanessa , Moraes Flávia Paiva Prudente de , Vartanian José Guilherme , Gonçalves–Filho João , Kowalski Luiz Paulo , Soares Fernando Augusto , Coutinho–Camillo Cláudia Malheiros 
Published: May 2014

ABSTRACTBackgroundHead and neck squamous cell carcinoma (HNSCC) is primarily a locoregional disease in which the cervical lymph nodes are the chief site of metastasis. The purpose of this study was to examine the relationship between lymphangiogenesis and clinicopathological aspects of HNSCC and its metastasis.MethodsFifty‐two patients with HNSCC and metastatic lymph nodes from 21 of these subjects were analyzed by immunohistochemistry.ResultsThe HNSCC samples were predominantly negative for vascular endothelial growth factor (VEGF)‐C, VEGF‐D, and vascular endothelial growth factor receptor (VEGFR)3. There was an association between the density of lymph vessels (measured by D2‐40 staining) in the lymph nodes and advanced‐stage tumors. There was no link between the expression of these proteins and survival rates.ConclusionAlthough lymphatic spread is a significant event in the progression of HNSCC, the expression of VEGF‐C, VEGF‐D, and VEGFR3 does not correlate with clinicopathological characteristics, suggesting that other signaling pathways mediate lymphangiogenesis in HNSCC. © 2014 Wiley Periodicals, Inc. Head Neck 37: 1410–1416, 2015
Laryngeal osteosarcoma: Case report and literature review
Authors: Kuba Kiyomi , Inoue Hitoshi , Hayashi Takahiro , Matsumura Satoko , Minami Kazuhiko , Takajo Humihiko , Morita Kei , Nakahira Mitsuhiko , Sugasawa Masashi 
Published: May 2014

ABSTRACTBackgroundSarcomas of the larynx are uncommon tumors, and osteosarcoma is the rarest. Only 24 cases of osteosarcoma of the larynx have been reported. The only case reported in Asia was from Thailand in 1981.MethodsA 55‐year‐old male patient was referred to our hospital because of an 8‐month history of odynophagia and a gradually enlarging left neck mass. A neck CT scan was performed. A literature review was also performed for this report.ResultsThe CT scan revealed extensive calcification with enlargement of the thyroid cartilage. The patient was diagnosed with osteosarcoma and was successfully treated by surgery alone.ConclusionAdequate surgical resection is required for successful treatment of laryngeal sarcomas. Adjuvant therapy is not contraindicated, but chemotherapy may improve the prognosis in patients with high‐grade tumors or metastatic disease. © 2014 Wiley Periodicals, Inc. Head Neck 37: E26‐E29, 2015
One‐Pot Synthesis of Novel Pyrrolo[1,2‐a]quinoxaline‐4(5H)‐ones Using Benzene‐1,2‐diamine, Acetylenedicarboxylates, and β‐Nitrostyrene Derivatives
Authors: Moradi Loghman , Piltan Mohammad , Abasi Golaleh 
Published: May 2014

AbstractThe reaction between a variety of o‐phenylenediamines (=benzene‐1,2‐diamines), dialkyl acetylenedicarboxylates, and derivatives of nitrostyrene (=(E)‐(2‐nitroethenyl)benzene) in the presence of sulfamic acid (SA; H3NSO3) as catalyst led to the corresponding pyrrolo[1,2‐a]quinoxaline‐4(5H)‐one derivatives in high yields.
Stereoselective Total Synthesis of Phenolic Nonadecanediol
Authors: Chinnababu Baggu , Purushotham Reddy Sudina , Venkatesham Kunuru , Chandra Rao Dasireddi , Venkateswarlu Yenamandra 
Published: May 2014

AbstractA simple and highly efficient synthetic route has been developed for synthesis of 1‐(4‐hydroxyphenyl)nonadecane‐3,5‐diol (1). The two stereogenic centers were generated by employing proline asymmetric α‐hydroxylation (MacMillan α‐hydroxylation), Jacobsen's hydrolytic kinetic resolution (HKR), and, finally, Yamaguchi oxirane opening as key steps (Scheme 2).
A New Polyketide from the Mangrove Endophytic Fungus Penicillium sp. sk14JW2P
Authors: Huang Xi‐Shan , Yang Bin , Sun Xue‐Feng , Xia Guo‐Ping , Liu Ya‐Yue , Ma Lin , She Zhi‐Gang 
Published: May 2014

AbstractTwo polyketides were isolated from the mangrove endophytic fungus, Penicillium sp. sk14JW2P, and one derivative with a modified structure. The structures were elucidated by spectroscopic analyses, the structure of the compound 1 was further confirmed by single‐crystal X‐ray diffraction, and its absolute configuration was determined. Compound 1 and 2 showed acetylcholinesterase (AchE) inhibitory activities with IC50 values of 12±0.3 and 79±2 nM, respectively.
Spectroscopic, Thermal, and Structural Studies of Two New Co‐Crystals of [4,4′‐Bithiazole]‐2,2′‐diamine
Authors: Rashidi Ranjbar Zohreh , Morsali Ali , Ghoreishi Amiri Maryam 
Published: May 2014

AbstractTwo new 2 : 1 co‐crystals based on [4,4′‐bithiazole]‐2,2′‐diamine (=2,2′‐diamino‐4,4′‐bithiazole (DABTZ)) with 2,2′‐bipyridine (bipy) and benzo‐18‐crown‐6 (bk) were synthesized by slow‐evaporation method in MeOH. These co‐crystals were characterized by means of elemental analysis, and IR, and 1H‐ and 13C‐NMR spectroscopy. Also, thermal analyses under air atmosphere and X‐ray crystallography have been performed on these structures. X‐Ray single‐crystal analyses revealed that these networks contain large vacant voids. These structures, [(DABTZ)2(bipy)] and [(DABTZ)2(bk)(MeOH)], crystallized in monoclinic and triclinic forms with space groups of P21/c and P$\bar 1$, respectively. The self‐assembly of these compounds in the solid state is likely caused by both H‐bonding and ππ stacking.
Pintoxolanes A–C, Highly Functionalized 3,14‐Oxa‐bridged Cembranoids from the Caribbean Gorgonian Coral Eunicea pinta
Authors: Figueroa Janet , Vera Brunilda , Rodríguez Abimael D. 
Published: May 2014

AbstractThree new cembrane‐based diterpenes possessing the rare 3,14‐oxa‐bridged moiety were isolated from the hexane extract of a southwestern Caribbean gorgonian octocoral, Eunicea pinta, together with seven known cembranoid diterpenes. The structures of pintoxolanes A–C (1–3, resp.), including their relative configurations, were deduced from spectroscopic data and chemical‐correlation experiments. Experimental evidence hinting to a plausible biogenesis of the 3,14‐oxalane moiety is provided. Preliminary cytotoxicity data for compounds 1–3 toward human cancer cell lines are also provided.
Two New Alkaloids from the Roots of Aconitum sinomontanumNakai
Authors: Xu Bin , Xue Jiehua , Tan Junjie , Jiang Shanhao , Guo Fujiang , Li Yiming 
Published: May 2014

AbstractTwo new alkaloids, ranaconidine (=20‐ethyl‐1α,14α,16β‐trimethoxyaconitane‐4,7,8,10‐tetrol; 1) and N‐(chloromethyl)taspine (=1‐[2‐(N‐(chloromethyl)‐N,N‐dimethylaminium)ethyl]‐3,8‐dimethoxybenzopyrano[5,4,3‐cde]benzopyran‐5,10‐dione; 2), together with two known compounds, i.e., benzethonium chloride (3) and ranaconine (4) were isolated from the roots of Aconitum sinomontanum Nakai. The structures of the compounds were elucidated on the basis of spectral evidences and in the comparison with previously published data.
Reduction of 3‐Aminoquinoline‐2,4(1H,3H)‐diones and Deamination of the Reaction Products
Authors: Klásek Antonín , Lyčka Antonín , Rouchal Michal , Rudolf Ondřej , Růžička Aleš 
Published: May 2014

Abstract3‐Aminoquinoline‐2,4‐diones were stereoselectively reduced with NaBH4 to give cis‐3‐amino‐3,4‐dihydro‐4‐hydroxyquinolin‐2(1H)‐ones. Using triphosgene (=bis(trichloromethyl) carbonate), these compounds were converted to 3,3a‐dihydrooxazolo[4,5‐c]quinoline‐2,4(5H,9bH)‐diones. The deamination of the reduction products using HNO2 afforded mixtures of several compounds, from which 3‐alkyl/aryl‐2,3‐dihydro‐1H‐indol‐2‐ones and their 3‐hydroxy and 3‐nitro derivatives were isolated as the products of the molecular rearrangement.
I2‐Catalyzed Divergent Regioselective Addition of Methoxybenzenes with Ethenylbenzenes under Microwave Irradiation
Authors: Nageswara Rao Nalajala , Raghavender Reddy Maddi , Ramakrishna Konakalla , Mitaram Meshram Harshadas 
Published: May 2014

AbstractA highly efficient synthesis of 1,2,2‐triarylethanones has been developed from simple and commercially available electron‐rich arenes and styrenes (ethenylbenzenes).
Synthesis of Z‐Protected Aib‐ and Phe(2Me)‐Containing Pentapeptides and Their Crystal Structures
Authors: Arnhold Franziska S. , Linden Anthony , Heimgartner Heinz 
Published: May 2014

AbstractA series of pentapeptide derivatives containing α,α‐disubstituted α‐amino acids have been prepared by a combination of the ‘azirine/oxazolone method’ and segment condensations. X‐Ray crystal‐structure determinations of the molecular structures confirmed the presence of helical conformations stabilized by β‐turns of type III or III′. Pentapeptides containing (R)‐Phe(2Me) form a right‐handed helix, whereas those containing (S)‐Phe(2Me) adopt a left‐handed helical structure.